* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
As shown in Figure 1-step i, 4-chloro-7H-pyrrolo[2,3-d]pyrimidine(compound 1001) (130 mg, 0.847 mmol) was dissolved in 3 mL of methanol and hydrogenated under 1 atm of hydrogen over Pd-C 10percent for 16 hours. Concentration to dryness provided 100 mg (98percent) of 7H-pyrrolo[2,3-d ]pyrimidine [compound 1002, 1H-NMR(CD3OD): δ 9.4 (s, IH); 9.1 (s, IH); 7.9 (s, IH); 7.1 (s, IH)].
97%
With ammonium formate In methanol for 2 h; Heating / reflux
(R)-6-Pyrrolidin-2-ylmethyl-7H-pyrrolo[2,3-d]pyrimidine.(Compound 95) Commercially available 6-chloro-7-deazapurine (1.58 g, 10.3 mmol), 3.25 g ammonium formate (51.6 mmol) and 20percent Pd(OH)2/C (140 mg) were combined in MeOH (50 ml) and warmed to reflux for 2 hours. The mixture was cooled, filtered, concentrated and re-dissolved in MeOH. Filtration over 25 g SCX-2 (MeOH followed by 1 N NH3/MeOH), followed by flash chromatography (ethyl acetate/MeOH (9/1)) afforded compound 90 (1.2 g, 4.02 mmol, 97percent) amorphous material. 1H-NMR (400 MHz, CDCl3): δ 11.1 (bs, 1H), 9.1 (bs, 1H), 9.0 (bs, 1H), 7.45-7.40 (m, 1H), 6.68-6.62 (m, 1H).
Reference：
[1] Patent: WO2007/41130, 2007, A2, . Location in patent: Page/Page column 40; Sheet 1/9
[2] Patent: US2008/9514, 2008, A1, . Location in patent: Page/Page column 26-27
[3] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 21, p. 5247 - 5250
[4] European Journal of Medicinal Chemistry, 2008, vol. 43, # 6, p. 1248 - 1260
[5] Patent: WO2012/2568, 2012, A1, . Location in patent: Page/Page column 37
4
[ 530-91-6 ]
[ 3680-69-1 ]
[ 271-70-5 ]
Yield
Reaction Conditions
Operation in experiment
65%
With potassium hydroxide In aqueous potassium hydroxide
Example 3 4-(2-tetralyloxy)-7H-pyrrolo[2,3-d]pyrimidine. To a solution of 2-hydroxytetralin (1.482 g, 10 mM) in 80 ml of aqueous potassium hydroxide solution containing 1.683 g (30 mM) of solid potassium hydroxide is added 4-chloro-pyrrolo[2,3-d]pyrimidine (1.536 g, 10 mM). The reaction mixture is stirred for about 0.5 h at room temperature until most of the 6-chloro-pyrido[2,3-d]pyrimidine dissolves and then heated on the steam bath for further 0.5 h. The mixture is cooled, filtered and the residue recrystallized from hot aqueous ethanol to give pure title compound in 65percent yield. MS m/z 265.
With caesium carbonate In DMF (N,N-dimethyl-formamide) at 20℃; for 1 h;
lodomethane (12.2 mL, 195 MMOL) was added to a solution of 4-Chloro-7H- pyrrolo [2,3-d] pyrimidine (15.0 g, 97.7 MMOL) and cesium carbonate (47.7 g, 146.5 MMOL) IN DMF (200 mL). The reaction mixture was stirred at room temperature 1 h, quenched with H20 (500 mL), and extracted with EtOAc (3X200ML). The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash column chromatography (silica, 2: 8X3 : 7 EtOAc: hexanes) provided the title compound as an off-white solid (15.4 g, 94percent). MS: 168.5 (MH+) ; HPLC Rf : 3.45 min. (HPLC method 4); HPLC purity: 96percent.
83%
Stage #1: With potassium <i>tert</i>-butylate In tetrahydrofuran at 0 - 20℃; for 0.333333 h; Stage #2: at 0 - 20℃; for 4 h;
Step 1 : To a stirred solution of 4-chloro-7/-/-pyrrolo[2,3-d]pyrimidine (4 g, 26.143 mmol) in THF (40 mL) was added potassium tertiary butoxide (3.8 g, 33.986 mmol, 1.3 equiv) at 0°C. The reaction mixture was allowed to stir at room temperature for 20 min. Methyl iodide (2.4 mL, 39.215 mol, 1.5 equiv) was added at 0°C to the reaction mixture and stirred for 4h at room temperature. The solvent was evaporated, diluted with ice water (50 mL) and the precipitated solid was filtered & dried in vacuo to give 4-chloro-7-methyl- 7H-pyrrolo[2,3-d]pyrimidine as off white solid (3.6 g, 83 percent). LCMS (ES) m/z = 168.1 [M+H]+. H NMR (400 MHz, DMSO-d6) δ ppm 3.84 (s, 3H), 6.62 (d, J = 3.2 Hz, 1 H), 7.72 (d, J = 3.2 Hz, 1 H), 8.62 (s, 1 H).
81%
With caesium carbonate In 1-methyl-pyrrolidin-2-one at 15 - 23℃; for 4.5 h;
Add Cs2CO3(845 g, 2.60 mol) at 15 °C to a solution of 4-chloro-7H-pyrrolo[2,3- d]pyrimidine (200 g, 1.29 mol) in N-methyl-2-pyrrolidone (1.20 L). Warm to 23 °C, add Mel (202 g, 1.43 mol) dropwise over 30 min, and stir for 4 h. After this time, pour onto ice-water (2.00 L) and stir for 30 min. Filter, then slurry material in H20 (1.00 L). Filter and dry to give the title compound (180 g, 81percent). ES/MS m/z (35C1) 168.0 (M+H).
Reference：
[1] Patent: WO2004/56830, 2004, A1, . Location in patent: Page 93
[2] Bioorganic and medicinal chemistry letters, 2002, vol. 12, # 16, p. 2153 - 2157
[3] Patent: WO2017/46739, 2017, A1, . Location in patent: Page/Page column 89
[4] Patent: WO2018/194885, 2018, A1, . Location in patent: Page/Page column 15
[5] Journal of Medicinal Chemistry, 2012, vol. 55, # 16, p. 7193 - 7207
[6] Chemische Berichte, 1981, vol. 114, # 6, p. 2056 - 2063
[7] Patent: WO2011/119663, 2011, A1, . Location in patent: Page/Page column 81-82
[8] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 18, p. 5473 - 5482
[9] MedChemComm, 2014, vol. 5, # 10, p. 1500 - 1506
[10] Patent: WO2017/212012, 2017, A1, . Location in patent: Page/Page column 33; 34
[11] Patent: TW2018/2094, 2018, A, . Location in patent: Page/Page column 47; 77; 115
8
[ 100-44-7 ]
[ 3680-69-1 ]
[ 16019-34-4 ]
Reference：
[1] Journal of Medicinal Chemistry, 1995, vol. 38, # 19, p. 3884 - 3888
[2] Patent: US2002/19526, 2002, A1,
9
[ 100-39-0 ]
[ 3680-69-1 ]
[ 16019-34-4 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 18, p. 5473 - 5482
Reference：
[1] Organic and Biomolecular Chemistry, 2013, vol. 11, # 31, p. 5189 - 5193
[2] Journal of Medicinal Chemistry, 2009, vol. 52, # 19, p. 5974 - 5989
12
[ 3680-69-1 ]
[ 22276-95-5 ]
Yield
Reaction Conditions
Operation in experiment
95%
With N-Bromosuccinimide In N,N-dimethyl-formamide at 20℃; for 72 h;
General procedure: To a solution of readily available 3a (20mmol) in N, N-dimethylformamide (DMF) (15mL) was added NCS/NBS (21mmol) and the reaction mixture was stirred at room temperature for 72h. Then ice water (150mL) was poured into the mixture, the precipitate was filtered, washed with water (3×100mL), and dried to give 3b and 3c.
95%
With N-Bromosuccinimide In N,N-dimethyl-formamide at 20℃; for 12 h;
Dissolve 4-chloro-pyrrolo[2,3-d]pyrimidine (20 mmol) in DMF (6 mL), add NBS or NCS (21 mmol) in portions on ice bath, react at room temperature for 12 h, and pour the reaction mixture into 80 mL of ice. In the water, a large number of off-white solids precipitated and were filtered. The filter cake was washed with 15 mL of water and dried to give Intermediate 2. 4-Chloro-5-bromo-pyrrolo[2,3-d]pyrimidine (2b) Off-white solid, yield 95percent
95%
With N-Bromosuccinimide In N,N-dimethyl-formamide at 20℃; for 15 h;
A solution of 4-chloro-71-I-pyrroio[2,3-dipyrimidine (56a) (50 g, 0.32 mol) in DMF (300 mL) was charged with N-bromosuccininiide (64.0 g, 0.35 mol) and stirred at RT for 15 h. The reaction mixture was quenched with ice-cold water (1 IL), filtered, rinsed with ice-cold water (200 mL), and dried on high vacuum, The crude compound was redissoived in 20percent MeOH in DCM (2 IL), dried over anhvdrous sodium sulfate and concentrated under reduced pressure to obtain 56b as light brown solid (73 g, 0.31 mol, 95percent yield), ‘H NMR (400 MHz, DMSO-d6): ö 1297 (s, IFI). 862 (s, IH), 7.95 (s, 11:1). LCMS Purity: 98.7percent: ERMS (ESI) m/z calcd for [M±FIj: 231.93/233.93. Found: 23 1.92/233.92.
94.6%
With N-Bromosuccinimide In N,N-dimethyl-formamide at 20℃; for 12 h;
4-chloro-7H-pyrrolo[2,3-d]pyrimidine (20mmol) was dissolved in 20ml DMF, was added NBS (21mmol), stirred at room temperature 12h, After the reaction was completed, the reaction solution was poured into 200 ml of ice water. Filtration, the filter cake was washed with water and dried to give Intermediate 2. Off-white solid with a yield of 94.6percent.
92%
With N-Bromosuccinimide In dichloromethane for 2 h; Heating / reflux
With N-Bromosuccinimide In N,N-dimethyl-formamide at 20℃; Inert atmosphere
4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (2 g, 13.02 mmol) was dissolved in 20 mL dimethylformamide. N-Bromosuccinimide (2.55 g, 14.33 mmol) was added under argon atmosphere. The reaction was stirred at room temperature overnight. The crude was poured into water and the precipitate formed was filtered and washed with water. The yellow solid obtained was dried in the vacuum oven to give 2.77 g (91 .5percent yield) of the title compound. Purity 99percent.LRMS (m/z): 232 (M+1 )+.
89%
With N-Bromosuccinimide In chloroform for 1 h; Heating / reflux
METHOD K 5-Bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine To a stirred solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (30 g/0.02 mol) dissolved in 75 mL of chloroform was added 3.5 grams (0.02 mol) of N-bromosuccinamide and the resulting mixture refluxed for 1 hour. After cooling to room temperature, the precipitate was removed by filtration and dried under reduced pressure affording 4.1 grams (89percent) of the title compound. 1H NMR (400 MHz) (CDCl3)δ: 7.93 (d, 1H, J=2.8 Hz), 8.60 (s, 1H).
84%
With N-Bromosuccinimide In chloroform for 1 h; Reflux
To a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (3.00 g) in chloroform (85 mL)) was added N-bromosuccinimide (3.55 g), and the mixture was heated to reflux for 1 hour. The reaction mixture was cooled to room temperature, and the precipitates were collected by filtration and purified by column chromatography on silica gel (solvent; hexane/ethyl acetate = 70/30 to 20/80) to give 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (3.83 g) as a colorless powder (yield: 84percent). MS(APCI)m/z; 232/234[M+H]+.
83%
With N-Bromosuccinimide In dichloromethane at 20℃; for 2.5 h;
Synthesis 2-1 -A; 5-Bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine; A suspension of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.49 g, 3.2 mmol) and N-bromosuccinimide (0.68 g, 3.8 mmol) in dry dichloromethane (20 mL) was stirred at room temperature for 2.5 hours. The suspension was diluted with methanol and evaporated onto silica. The crude product was purified using flash column chromatography, eluting with 2:1 hexanes-ethyl acetate, to yield the title compound as an off-white solid (0.613 g, 2.64 mmol, 83percent).1H NMR (500 MHz, CD3OD) δ 7.64 (1 H, s), 8.56 (1 H, s); LC-MS (2) R1 3.34 min; m/z (ESI) 236, 234, 232 [MH+].
82%
With N-bromoacetamide In dichloromethane for 0.666667 h; Reflux
A. Preparation of 5-bromo-4-chloro-7H-pyrrolo[23-d]pyrimidine. To a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1.2 g, 7.8 mmol) in CH2Cl2 (25 mL) was added N-bromoacetamide (1.2 g, 8.7 mmol) in CH2Cl2 (25 mL). The reaction mixture was refluxed for 40 minutes, then concentrated and washed with cold water. The crude material was recrystallized from a minimal amount of isopropanol and dried under vacuum to give the title compound (82percent) as light-gray solid. MS (ES+) [M+H]+=232.
81.5%
With N-bromoacetamide In dichloromethane for 0.666667 h; Heating / reflux
6.18. Example 18(S)-4-(5-cyano-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-(3-(isopropylcarbamoyl)phenyl)-2-methylpiperazine-1-carboxamide A. Preparation of 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine. To a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1.2 g, 7.8 mmol) in CH2Cl2 (25 ml) was added N-bromoacetamide (1.186 g, 8.6 mmol) in CH2Cl2 (25 ml). The mixture was heated at reflux temperature for 40 mins, then cooled to room temperature, and concentrated under vacuum to give an off-white solid. Cold water (40 ml) was added to the solid, which was then collected by filtration, washed with cold water (5 ml), and dried under vacuum. The product was recrystallized from a minimum amount of isopropanol to yield pure 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1.475 g, 81.5percent).
79%
With N-Bromosuccinimide In chloroform-d1 for 2.5 h; Heating / reflux
To a suspension of 4-Chloro-7H-pyrrolo [2,3-d] pyrimidine (2.5g, 16 mmol) in CDC13 (65 mL) was added NBS (2.9g, 16 mmol) and the reaction mixture stirred and heated at reflux for 2.5 hours. The mixture was cooled to room temperature, the solids isolated by vacuum filtration, rinsed with cold CHC13 and air dried to give 5-Bromo-4-chloro-7H- pyrrolo [2, 3-d] pyrimidine (3. 0g, 79percent. ) LCMS (APCI+) m/z 232 and 234 [M+H] + ; Rt: 2.32 min. 1H NMR (DMSO-d6,400 MHz) 6 12. 98 (1H, br. s), 8.63 (1H, s), 7.96 (1H, s. )
79%
With N-Bromosuccinimide In N,N-dimethyl-formamide for 16 h;
To a solution of 4-chloro-7H-pyrrolo[2,3-d] pyrimidine Q-1 (870 mg, 5.67 mmol) in DMF (14.2 mE, 0.4M) was added N135 (1.1 g, 6.23 mmol) at room temperature. The reaction was stirred overnight for 16 h. ECMS showed the starting material was consumed and product formed. The reaction mixture was quenched with sat. aq. NaHCO3, then extracted with EtOAc. The EtOAc was washed with brine, dried with Na2504, filtered and concentrated to give a dark brown solid. The solid was suspended in CH2C12, then loaded onto a 12 g ISCO solid load cartridge and purified 0-50percent EtOAc/Heptane to give 204mg as a light tan solid. The insoluble light brown solid was also the product and dried to give 839mg as a light brown solid. The combined material gave 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimi- dine (Q-3)(1.043 g, 79percent). ECMS [M+1] 232/234; ‘H NMR (400 MHz, DMSO-d5) ö ppm 12.96 (bt s., 1H), 8.62 (s, 1H), 7.94 (s, 1H)
74%
With N-Bromosuccinimide In dichloromethane at 20 - 30℃;
4-chloro-7H-pyrrolo[2,3-d]pyrimidine (2-E, 20.0 g, 130.7 mmol) dissolved in DCM (800 mL) was treated portion-wise with N-bromosuccinimide (26.7 g, 149.8 mmol), while maintaining the temperature around 25-30° C. The reaction mixture was stirred at room temperature overnight. Water was added (500 mL) and the phases were separated. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was triturated in Et2O affording after filtration 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine as a white solid (2-F, 22.43 g, 74percent). M.p.: 242-244° C.; NMR (400 MHz, DMSO-d6) δ 12.96 (s, 1H), 8.61 (s, 1H), 7.94 (s, 1H); MS m/z 232 [M(35Cl, 79Br)+H]+, 234 [M(35Cl, 81Br)+H]+, 234 [M(37Cl, 79Br)+H]+, 236 [M(37Cl, 81Br)+H]+.
74%
With N-Bromosuccinimide In dichloromethane at 20 - 30℃;
Step 1 : 5-bromo-4-chloro-7H-pyrrolo[2,3-i ]pyrimidine (Intermediate 2-F) [00140] 4-chloro-7H-pyrrolo[2,3-fiT]pyrimidine (2-E, 20.0 g, 130.7 mmol) dissolved in DCM (800 mL) was treated portion-wise with N-bromosuccinimide (26.7 g, 149.8 mmol), while maintaining the temperature around 25-30 °C. The reaction mixture was stirred at room temperature overnight. Water was added (500 mL) and the phases were separated. The organic phase was dried over Na2S04, filtered and concentrated in vacuo. The crude product was triturated in Et20 affording after filtration 5-bromo-4-chloro-7H-pyrrolo[2,3-if]pyrimidine as a white solid (2-F, 22.43 g, 74percent). M.p.: 242-244 °C; NMR (400 MHz, DMSO-< δ 12.96 (s, 1H), 8.61 (s, 1H), 7.94 (s, 1H); MS m/z 232 [M(35C1, 79Br)+H]+, 234 [M(35C1, 81Br)+H]+, 234 [M(37C1, 79Br)+H]+, 236 [M(37C1, 81Br)+H]+.
74%
With N-Bromosuccinimide In dichloromethane at 20 - 30℃;
4-chloro-7H-pyrrolo2,3-dipyrimidine (2-E, 20.0g, 130.7mmol) dissolved in DCM (800 mL) was treated portion-wise with N-bromosuccinimide (26.7 g. 149.8 mmol), while maintaining the temperature around 25-30°C. The reaction mixture was stirred at room temperature overnight. Water was added (500 mL) and the phases were separated. The organic phase was dried over NaSO4, filtered and concentrated in vacuo. The crude product was triturated in Et2O affording after filtration 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine as a white solid (2-F, 22.43 g, 74percent).
73.7%
With N-Bromosuccinimide In dichloromethane at 25℃; for 0.5 h;
PREPARATION 155-bromo-4-chloro-1 /-/-pyrrolo[2,3-c/]pyriA mixture of 4-chloro-1 H-pyrrolo[2,3-c ]pyrimidine (10 g, 65.1 mmol) in CH2CI2 (400 mL) at 25 °C was treated with NBS (13.91 g, 78 mmol) and stirred for 30 min before being concentrated. The resulting brown solid was triturated with water (-500 mL) and after drying, was triturated with EtOAc to afford the title compound (12.4 g, 73.7percent) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.99 (br. s, 1 H), 8.64 (s, 1 H), 7.97 (d, J = 2.76 Hz, 1 H); MS (m/z) 232.9 (M+H+).
69.1%
With N-Bromosuccinimide In dichloromethane at 20℃; for 1 h;
PREPARATION 6; <n="117"/>5-bromo-4-chloro-7H-pyrrolor2,3-dlpyrimidineN-Bromosuccinimide (6.84 g, 38.42 mmol) was added portionwise to 4-chloro-7H- pyrrolo[2,3-d]pyrimidine (5g, 32.56 mmol) in dichloromethane, dry (125ml) at 2O0C under nitrogen. The resulting suspension was stirred at 20 0C for 1 hour. The reaction mixture was evaporated and the resulting brown solid was triturated with water to give a purple solid which was collected by filtration. The crude solid was triturated with hot MeOH to give a solid which was collected by filtration. The hot trituration was repeated to give 5- bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (5.23 g, 69.1 percent) as a cream solid. IH NMR (400.13 MHz, DMSO-d6) δ 7.94 (IH, s), 8.63 (IH, s), 12.95 (IH, s) MS m/e MH+ 232
69.1%
With N-Bromosuccinimide In dichloromethane at 20℃; for 1 h;
PREPARATION H5-bromo-4-chloro-7H-pyrrolor2,3-dlpyrimidine; <n="109"/>N-Bromosuccinimide (6.84 g, 38.42 mmol) was added portionwise to 4-chloro-7H- pyrrolo[2,3-d]pyrimidine (5g, 32.56 mmol) in dichloromethane, dry (125ml) at 2O0C under nitrogen. The resulting suspension was stirred at 20 0C for 1 hour. The reaction mixture was evaporated and the resulting brown solid was triturated with water to give a purple solid which was collected by filtration. The crude solid was triturated with hot MeOH to give a solid which was collected by filtration. The hot trituration was repeated to give 5- bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (5.23 g, 69.1 percent) as a cream solid. IH NMR (400.13 MHz, DMSO-d6) δ 7.94 (IH, s), 8.63 (IH, s), 12.95 (IH, s) MS m/e MH+ 232
69.1%
With N-Bromosuccinimide In dichloromethane at 20℃; for 1 h;
Intermediate 50: 5-bromo-4-chloro-7H-pyrrolo[2.,3-dlpyrimidineN-Bromosuccinimide (6.84 g, 38.42 mmol) was added portionwise to 4-chloro-7H- pyrrolo[2,3-d]pyrimidine (5 g, 32.56 mmol) in DCM, dry (125 mL) at 2O0C under nitrogen. The resulting suspension was stirred at 20 0C for 1 hour. The reaction mixture was evaporated and the resulting brown solid was triturated with water to give a purple solid which was collected by filtration. The crude solid was triturated with hot MeOH to give a solid which was collected by filtration. The hot trituration was repeated to give 5-bromo-4- chloro-7H-pyrrolo[2,3-d]pyrimidine (5.23 g, 69.1 percent) as a cream solid. 1R NMR (400.13 MHz, DMSO-d6) δ 7.94 (IH, s), 8.63 (IH, s), 12.95 (IH, s) MS m/e MH+ 234.
66%
With N-Bromosuccinimide In dichloromethane at 20℃; for 1 h;
Synthesis of Compound 16.1 To a stirred solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (2 g, 13 mmol) in DCM (80 ml) was added N-Bromosuccinamide (3.2 g, 18 mmol) at RT. After 1 hour, the solvent was removed in vacuo, and then the solid was washed (water) and recrystalized (MeOH) to afford compound 16.1 (2 g, 66percent) as an off-white solid. 1H-NMR (200 MHz, DMSO-d6) δ 12.96 (bs, 1H), 8.62 (s, 1H), 7.95 (s, 1H). MS m/z 234 [M+1]+.
66%
With N-Bromosuccinimide In dichloromethane at 20℃; for 3 h; Inert atmosphere
To a suspension of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (3.99 g, 26.0 mmol, 1.0 eq) in dry DCM(150 mL) under argon, N-bromosuccinimide (6.02 g, 33.8 mmol, 1.3 eq) was added and the resulting mixture was stirred at RT for 3 h. The reaction mixture was diluted with MeOH (30 mL) and then concentrated in vacuo to yield a slight brown solid. The residue was triturated with H20 (150 mL). The solid was collected by filtration and then re-crystallized in MeOH to afford 5-bromo-4-chloro-7H-pyrrolo[2,3-d] pyrimidine (4.0 g, 66percent yield).
With N-chloro-succinimide In N,N-dimethyl-formamide at 20℃; for 72 h;
General procedure: To a solution of readily available 3a (20mmol) in N, N-dimethylformamide (DMF) (15mL) was added NCS/NBS (21mmol) and the reaction mixture was stirred at room temperature for 72h. Then ice water (150mL) was poured into the mixture, the precipitate was filtered, washed with water (3×100mL), and dried to give 3b and 3c.
95%
With N-chloro-succinimide In N,N-dimethyl-formamide at 20℃; for 12 h;
Dissolve 4-chloro-pyrrolo[2,3-d]pyrimidine (20 mmol) in DMF (6 mL), add NBS or NCS (21 mmol) in portions on ice bath, react at room temperature for 12 h, and pour the reaction mixture into 80 mL of ice. In the water, a large number of off-white solids precipitated and were filtered. The filter cake was washed with 15 mL of water and dried to give Intermediate 2. 4,5-dichloro-pyrrolo[2,3-d]pyrimidine (2a) Gray solid, yield 95percent
88%
With N-chloro-succinimide In dichloromethane for 72 h; Heating / reflux
3H, m), 2.4 (3H, s), 1.31 (3H, J=6.8 Hz, d); MS (ES+) [M+H]+=455.6.15. Example 15(S)-N-(3-bromophenyl)-4-(5-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N'-cyano-2-methylpiperazine-1-carboximidamide A. Preparation of 4,5-dichloro-7H-pyrrolo[2,3-d]pyrimidine: 4-Chloro-pyrrolo[2,3-d]pyrimidine (0.5 g, 3.26 mmol) was suspended in anhydrous CH2Cl2 (25 ml), and N-chlorosuccinimide (0.87 g, 6.52 mmol) was added. The reaction mixture was refluxed for 3 days, then cooled to room temperature. The white solid was collected by filtration to give 5-dichloro-7H-pyrrolo[2,3-d]pyrimidine (0.54 g, 2.9 mmol, 88percent).1H NMR (CD3OD): δ 8.57 (1H, s), 7.60 (1H, s); MS (ES+) [M+H]+=188.
80%
With N-chloro-succinimide In dichloromethane at 20℃; for 6 h; Heating / reflux
PREPARATION 7; 4,5-dichloro-7H-pyrrolor2,3-dlpyrimidineN-Chlorosuccinimide (4.78 g, 35.81 mmol) was added portionwise to a stirred suspension of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (5g, 32.56 mmol) in DCM, dry (125ml) at room temperature. The resulting suspension was stirred for 1 hour then heated to reflux for 5 hours, then allowed to cool down and left to stir at room temperature overnight. The reaction mixture was evaporated and suspended in water (50 mL). The suspension was filtered giving crude product as a grey solid. The solid was suspended in hot methnol and filtered. The solid was then suspended in hot ethyl acetate and filtered to give 4,5- dichloro-7H-pyrrolo[2,3-d]pyrimidine (4.87 g, 80 percent) as a grey solid. IH NMR (400.13 MHz, DMSO-d6) δ 7.91 (IH, s), 8.64 (IH, s), 12.87 (IH, s) MS m/e MH+ 188
80%
With N-chloro-succinimide In dichloromethane at 20℃; Heating / reflux
PREPARATION I4,5-dichloro-7H-pyrrolor2,3-dlpyrimidine; N-Chlorosuccinimide (4.78 g, 35.81 mmol) was added portionwise to a stirred suspension of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (5g, 32.56 mmol) in DCM, dry (125ml) at room temperature. The resulting suspension was stirred for 1 hour then heated to reflux for 5 hours, then allowed to cool down and left to stir at room temperature overnight. The reaction mixture was evaporated and suspended in water (50 mL). The suspension was filtered giving crude product as a grey solid. The solid was suspended in hot methnol and filtered. The solid was then suspended in hot ethyl acetate and filtered to give 4,5- dichloro-7H-pyrrolo[2,3-d]pyrimidine (4.87 g, 80 percent) as a grey solid. IH NMR (400.13 MHz, DMSO-d6) δ 7.91 (IH, s), 8.64 (IH, s), 12.87 (IH, s) MS m/e MH+ 188
72%
With N-chloro-succinimide In dichloromethane at 20℃; for 18 h;
METHOD I 4,5-Dichloro-7H-pyrrolo[2,3-d]pyrimidine 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (154 mg, 1.0 mmol) was suspended in 6.0 mL of dry dichloromethane in a flame-dried flask and to this mixture was added N-chlorosuccinimide (147 mg, 1.1 mmol) in one portion. The resulting mixture stirred at room temperature for 18 h, at which time the solvent was removed under reduced pressure. The residue was triturated with water and isolated by filtration to afford 137 mg (72percent) of the title compound as a gray solid, mp 224-227° C.(dec). LRMS: 188 (M+1).
Reference：
[1] Synthesis, 2011, # 9, p. 1442 - 1446
[2] Archiv der Pharmazie, 2016, vol. 349, # 5, p. 356 - 362
[3] European Journal of Medicinal Chemistry, 2017, vol. 138, p. 543 - 551
[4] Patent: CN107556318, 2018, A, . Location in patent: Paragraph 0101-0105
[5] Journal of Medicinal Chemistry, 1988, vol. 31, # 11, p. 2086 - 2092
[6] Patent: US2009/42893, 2009, A1, . Location in patent: Page/Page column 13
[7] Helvetica Chimica Acta, 1994, vol. 77, # 4, p. 897 - 903
[8] Patent: WO2008/75109, 2008, A1, . Location in patent: Page/Page column 115
[9] Patent: WO2008/75110, 2008, A1, . Location in patent: Page/Page column 107
[10] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 5, p. 2052 - 2062
[11] Patent: US6635762, 2003, B1, . Location in patent: Page/Page column 25
[12] Patent: US2009/264450, 2009, A1, . Location in patent: Page/Page column 7
[13] Patent: WO2012/80735, 2012, A1, . Location in patent: Page/Page column 11; 43
[14] Patent: WO2015/143712, 2015, A1, . Location in patent: Page/Page column 50; 51
16
[ 128-09-6 ]
[ 3680-69-1 ]
[ 115093-90-8 ]
Reference：
[1] Journal of Medicinal Chemistry, 2009, vol. 52, # 21, p. 6515 - 6518
17
[ 3680-69-1 ]
[ 123148-78-7 ]
Yield
Reaction Conditions
Operation in experiment
100%
With N-iodo-succinimide; sodium sulfate In ethanol; N,N-dimethyl-formamide
Step 1. 4-Chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (Compound 3) 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine 10.75g (70 mmol) (Toronto Research Chemicals, Inc) and N-iodosuccinimide (16.8g, 75 mmol) were dissolved in 400 mL of dry DMF and left at ambient temperature in the darkness over night. The solvent was evaporated. The yellow residue was suspended in hot 10percent solution of Na2SO3, filtered, washed twice with hot water and crystallized from ethanol to yield 14.6 g (74.6percent) of the title compound as off-white crystals. The mother liquid was evaporated up to 1/3 volume and crystallized again from ethanol to give 2.47 g (12.3percent) of the title product. Total yield is close to 100percent.
100%
With N-iodo-succinimide; sodium sulfate In ethanol; N,N-dimethyl-formamide
Step 1. 4-Chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (Compound 3) 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine 10.75 g (70 mmol) (Toronto Research Chemicals, Inc) and N-iodosuccinimide (16.8 g, 75 mmol) were dissolved in 400 mL of dry DMF and left at ambient temperature in the darkness over night. The solvent was evaporated. The yellow residue was suspended in hot 10percent solution of Na2SO3, filtered, washed twice with hot water and crystallized from ethanol to yield 14.6 g (74.6percent) of the title compound as off-white crystals. The mother liquid was evaporated up to 1/3 volume and crystallized again from ethanol to give 2.47 g (12.3percent) of the title product; Total yield is close to 100percent; M.p. 212-214 (decomposition); UV λmax: 307, 266, 230, 227 nm (methanol); MS: 277.93 (M-H), 313 (M+Cl); 1H-NMR (DMSO-d6): 12.94 (s, 1H, NH), 8.58 (s, 1H, H-2), 7.94 (s, 1H, H-8).
100%
With N-iodo-succinimide; sodium sulfate In ethanol; N,N-dimethyl-formamide
Step 1. 4-Chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine 10.75 g (70 mmol) and N-iodosuccinimide (16.8 g, 75 mmol) were dissolved in 400 mL of dry DMF and left at ambient temperature in the darkness over night. The solvent was evaporated. The yellow residue was suspended in hot 10percent solution of Na2SO3, filtered, washed twice with hot water and crystallized from ethanol to yield 14.6 g (74.6percent) of the title compound as off-white crystals. The mother liquid was evaporated up to 1/3 volume and crystallize again from ethanol to give 2.47 g (12.3percent) of the title product; Total yield is close to 100percent; Tm: 212-214 (decompose); UV λmax: 307, 266, 230, 227 nm (methanol); MS: 277.93 (M-H), 313 (M+Cl); 1H-NMR (DMSO-d6): δ 12.94 (s, 1H), 8.58 (s, 1H), 7.94 (s, 1H).
100%
With N-iodo-succinimide; sodium sulfate In ethanol; N,N-dimethyl-formamide
Step 1. 4-Chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine 10.75g (70 mmol) and N-iodosuccinimide (16.8g, 75 mmol) were dissolved in 400 mL of dry DMF and left at ambient temperature in the darkness over night. The solvent was evaporated. The yiellow residue was suspended in hot 10percent solution of Na2SO3, filtered, washed twice with hot water and crystallized from ethanol to yield 14.6 g (74.6percent) of the title compound as off-white crystals. The mother liquid was evaporated up to 1/3 volume and crystallized again from ethanol to give 2.47 g (12.3percent) of the title product. The total yield is close to 100percent; Tm 212-214° C. (dec); UV λmax: 307, 266, 230, 227 nm (methanol); MS: 277.93 (M-H), 313 (M+Cl); 1H-NMR (DMSO-d6): 12.94 (s, 1H, NH), 8.58 (s, 1H, H-2), 7.94 (s, 1H, H-8).
100%
With N-iodo-succinimide In N,N-dimethyl-formamide at 0 - 20℃;
Step 1To a solution of 4-chloro-7H-pyrro]o[2,3-d]pyrimidine (8.0 g , 52.32 mmol, 1.0 eq) in DMF (40 raL), NiS ( 15.7g , 57.55 mmol, 1.1 eq) was added at 0° C. The reaction mixture was stirred overnight at room temperature. Water (40 rnL) was added to the reaction mixture, extracted with EtOAc. The organic layer was dried over Na2S04 and concentrated under vacuum to give 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (14.6 g, 100 percent in yield).
100%
With N-iodo-succinimide In N,N-dimethyl-formamide at 0 - 20℃;
Step 1To a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (8.0 g , 52.32 mmol, 1.0 eq) in DMF (40 mL), NIS ( 15.7g , 57.55 mmol, 3.1 eq) was added at 0° C. The reaction mixture was stirred overnight at room temperature. Water (40 mL) was added to the reaction mixture, extracted with EtOAc. The organic layer was dried over Na2S(3/4 and concentrated under vacuum to give 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (14.6 g, 100 percent in yield)
100%
With N-iodo-succinimide In N,N-dimethyl-formamide at 0 - 20℃;
Step 1. To a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (8.0 g, 52.32 mmol, 1.0 eq) in DMF (40 mL), NIS (15.7g,57.55 mmol, 1.1 eq) was added at 0° C. The reaction mixture was stirred overnight at room temperature. Water (40 mL) was added to the reaction mixture,extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under vacuum to give 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (14.6 g, 100 percent in yield).
100%
With N-iodo-succinimide In N,N-dimethyl-formamide at 0 - 20℃;
Step 1 To a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (8.0 g, 52.32 mmol, 1.0 eq) in DMF (40 mL), NIS (15.7 g, 57.55 mmol, 1.1 eq) was added at 0° C. The reaction mixture was stirred overnight at room temperature. Water (40 mL) was added to the reaction mixture, extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under vacuum to give 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (14.6 g, 100percent in yield).
100%
With N-iodo-succinimide In N,N-dimethyl-formamide at 0 - 20℃;
4-chloro-7H-pyrrolo[2,3-d]pyrimidine (8.0 g, 52.32 mmol, 1.0 eq) was dissolved in DMF (40 mL), NIS (15.7 g, 57.55 mmol, 1.1 eq) was added at 0°C, stirred overnight at room temperature, 200 mL of saturated Na2S2O3 solution was added, filtered, washed with water three times, and dried in vacuum to obtain 14.6 g (100percent) of products. 1H NMR (400 MHz, d6-DMSO): δ 12.94 (s, 1H), 8.59 (s, 1H), 7.93 (d, J = 2.4 Hz, 1H).
99%
With N-iodo-succinimide In N,N-dimethyl-formamide at 20℃; for 1 h;
A solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (201) (500 mg, 3.25 mmol) and NIS (805 mg, 1.1 eq, 3.6 mmol) in DMF (1 mL) was stirred at room temperature for 1 h. The mixture was concentrated in vacuo, then water (10 mL) was added. The resulting solid was collected by filtration. Then dried in vacuo to afford the desired product, 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (202) (900 mg, 99percent yield) as a off-white solid. ESI-MS m/z: 277.85 [M−H]−. The product obtained was used directly in the next step without purification.
95%
With N-iodo-succinimide In N,N-dimethyl-formamide for 20 h; Inert atmosphere; Darkness
To a dry 250 mL round bottomed flask under argon was added 1.8 g (11.9 mmol) of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine and 3.0 g of N-iodosuccinamide (13.1 mmol). The solids were dried under high vacuum for 5 hours and the flask was refilled with argon. Dry DMF (100 mL) was added and the solution was stirred in the dark for 20 hours. The reaction was quenched with methanol and concentrated. The residue was then diluted with 150 mL of dichloromethane and washed with water (200 mL), saturated aqueous sodium sulfite (200 mL), and brine (100 mL). The organic layers were dried over MgSO4, filtered, and concentrated. The column was run using 1:1 Hex/EtOAc as the eluent to give a white solid (3.1 g, 11.2 mmol, 95percent yield). (Rf: 0.22; 1:1 Hex/EtOAc). mp: 195 - 199 °C (decomposition). 1H-NMR ([(CD3)2SO], 600 MHz): σ 7.94 (s, 1H), 8.59 (s, 1H). 13C-NMR ([(CD3)2SO], 150 Mz): σ 51.7, 115.8, 133.9, 150.4, 150.7, 151.5. HRMS (FAB): expected for C6H3ClN3I (M+H)+:279.91329. Found: 279.91316. IR(neat): vmax 3061, 2819, 1593, 1158 cm-1. Elemental Analysis for C6H3ClIN3: Found: C, 26.33; H, 1.13; N: 14.94. Calculated: C, 25.79; H, 1.08; N, 15.04.
95%
With N-iodo-succinimide In N,N-dimethyl-formamide for 25 h; Inert atmosphere; Darkness
4-Chloro-5-iodo-7H-pyrrolo[2,3]pyrimidine 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (1.8 g 11.9 mmol) and N- iodosuccinamide (3g, 13.1 mmol) were mixed in a round bottomed flask. The flask was dried under high vacuum for 5 h and then back-filled with argon. To this mixture, dry DMF (100 mL) was added and the resulting mixture was stirred in the dark for 20 h. The reaction was quenched with methanol and concentrated in vacuo. The residue was diluted with 150 mL of DCM and washed with water (200 mL), saturated aqueous sodium sulfite (200 mL), and brine (100 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (50percent ethyl acetate / hexanes) to afford the desired product (3.1 g, 95percent yield) as a white solid. ESI-MS m/z: 279.5 [M + H]+.
95%
With N-iodo-succinimide In N,N-dimethyl-formamide for 20 h; Inert atmosphere; Darkness
4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (1.8 g 11.9 mmol) and Niodosuccinamide (3g, 13.1 mmol) were mixed in a round bottomed flask. The flask was dried under high vacuum for 5 h and then back-filled with argon. To this mixture, dryDMF (100 mL) was added and the resulting mixture was stirred in the dark for 20 h. The reaction was quenched with methanol and concentrated in vacuo. The residue was diluted with 150 mL of DCM and washed with water (200 mL), saturated aqueous sodium sulfite (200 mL), and brine (100 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash columnchromatography on silica gel (50percent ethyl acetate / hexanes) to afford the desired product (3.1 g, 95percent yield) as a white solid. ESI-MS m/z: 279.5 [M + H].
90%
With N-iodo-succinimide In N,N-dimethyl-formamide at 20℃; for 18 h; Darkness
To a stirred solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine 41a (7.19 g, 46.8 mmol) in 70 mL of DMF was added N-iodosuccinimide (11.06 g, 49.2 mmol). The solution was stirred in the dark for 18 h at rt before being poured into 100 mL of H2O. The resulting tan precipitate was collected by suction filtration and dried under high vacuum to afford iodide 41b (11.8 g, 90percent) as a tan solid.
86.9%
With N-iodo-succinimide In N,N-dimethyl-formamide at 20℃;
Example 1; Preparation of 2-(2'-methyl-β-D-ribofuanosyl)-2,6-dihydro-2,3,5,6-tetraaza-benzo[cd]azulen-7-one (Compound 301); Step 1; 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine 10.75 g (70 mmol) and N-iodosuccinimide (16.8 g, 75 mmol) were dissolved in 400 mL of dry DMF and left at ambient temperature in the darkness over night. The solvent was evaporated. The yellow residue was suspended in hot 10percent solution of Na2SO3, filtered, washed twice with hot water and crystallized from ethanol to yield 14.6 g (74.6percent) of the title compound as off-white crystals. The mother liquid was evaporated up to volume and crystallized again from ethanol to give 2.47 g (12.3percent) of the target product. The total yield is close to 100percent; Tm 212-214° C. (dec); UV λmax: 307, 266, 230, 227 nm (methanol); MS: 277.93 (M-H), 313 (M+Cl); 1H-NMR (DMSO-d6): 12.94 (s, 1H, NH), 8.58 (s, 1H, H-2), 7.94 (s, 1H, H-8).
86%
With N-iodo-succinimide In N,N-dimethyl-formamide at 20℃;
To a solution of 4-chloro-7H-pyrrolo[2, 3-D]pyrimidine1 (39 mmol) in DMF (50 ml_) was added in several portions /V-iodosuccinimide (8.8 g). After stirring overnight at 200C, EtOAc (500 ml) was added and the solution was washed three times with water (150 ml). The organic layer was filtered through a short silica column and concentrated in vacuo. Yield: 86percent (9.3 g); MS: 279 1' Available from Toronto Research Chemicals
85.8%
at 20℃; for 3 h;
A mixture of 249 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (500 g, 3255.84 mmol) and 250 NIS (805.74 g, 3581.43 mmol) in 21 DMF (3.3 L) was stirred at rt for 3 hrs. The mixture was poured into ice water (20 L) and resulting solid was filtered, washed with saturated sodium thiosulphate solution (4×2.5 L), water (4×2.5 L) and dried under vacuum to afford the 237 title compound as an off white solid (780 g, 85.8percent). 1HNMR (400 MHz, DMSO-d6): 7.94 (s, 1H), 8.59 (s, 1H). LCMS m/z=279.6 [MH]+
85%
With N-iodo-succinimide In N,N-dimethyl-formamide at 22℃; for 2.5 h; Inert atmosphere
N,N-Dimethylformamide (DMF) (47mL) was added to a mixture of 56 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (4.60g, 29.8mmol) and 57 N-iodosuccinimide (6.82g, 30.3mmol) under a nitrogen atmosphere. The solution was stirred at 22°C for 2.5h before the mixture was poured into ice water (150mL). The precipitate was filtered, washed with water and n-pentane and dried to give 7.05g (25.2mmol, 85percent) of 12 1 as a pale brown powder; mp. 187–188°C (dec.) (lit [39]. 196–199°C), Rf=0.16 (n-pentane/EtOAc, 10/1). 1H NMR (400MHz, DMSO‑d6): 12.94 (br s, 1H), 8.59 (s, 1H), 7.94 (d, J=2.5, 1H). The spectroscopic data corresponded well with that reported previously [39].
85%
With N-iodo-succinimide In dichloromethane for 2 h; Heating / reflux
With N-iodo-succinimide In N,N-dimethyl-formamide at 20℃;
Preparation 109; 4-Chloro-5-iodo-7H-pyrrolo|"2.3-2SO3. Wash the organic fraction with 10 percent Na2SO3 (2x100 mL), saturate aqueous sodium chloride solution (150 mL), dry over Na2SO4 and evaporate. Crystalize the yellow residue from ethanol to yield 16.2 g (83percent) of 4-chloro-5-iodo-7H-pyrrolo[2,3-
82%
With N-iodo-succinimide In chloroform for 1 h; Heating / reflux
METHOD P 4-Chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine To a stirred solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (30 g/0.02 mol) dissolved in 80 mL of chloroform was added 4.5 grams (0.02 mol) of N-iodosuccinimide and the resulting mixture heated at reflux for 1 hour. After cooling to room temperature, the percipitate was removed by filtration and dried under reduced pressure affording 4.6 grams (82percent) of the title compound.
82%
With N-iodo-succinimide In dichloromethane at 20℃; for 1 h;
To a vigorously stirred solution of 11 (1.0 g; 6.51 itimol) in CH2Cl2 (55 itiL) was added 95percent N-iodosuccimide (1.70 g; 7.18 mmol) . The reaction mixture was stirred at room temperature for 1 h, during which time more precipitate appeared. The solid was filtered and recrystallized in hot methanol to afford 12 as slightly grey crystals (1.49 g; 82percent yield): 1H NMR (400 MHz, DMSO-d6) δ 12.96 (s br, IH, NH), 8.59 (s, IH, 2-H) , 7.94 (s, IH, 6-H) ; 13C NMR (100 MHz, DMSO-d6) δ 151.2, 150.4, 150.2, 133.6, 115.5, 51.7; HRMS (FAB+) calcd for C6H4N3ClI (M+H+) : 279.9139, found: 279.9141.
82%
With N-iodo-succinimide In N,N-dimethyl-formamide at 20℃; for 3 h; Inert atmosphere
Take a 250 mL two-necked flask, add compound 5 (5 g, 33 mmol), argon,Anhydrous DMF solution was added slowly and NIS (8.1 g, 36 mmol, 1.1 equiv.) In anhydrous DMF was added slowly and stirred at room temperature for 3 h. Add saturated sodium thiosulfate solution(50 mL). The EA (100 mL) was added, the organic phase was collected, washed with saturated brine, extracted, dried over anhydrous sodium sulfate, (PE: EA = 4: 1) to give 7.4 g of product as a white solid in 82percent yield.
77%
With N-iodo-succinimide In N,N-dimethyl-formamide at 20℃; for 10 h;
(e) 5 g (32.56 mmol) of 4-chloropyrrolo[2,3-d]pyrimidine and 11 g (50 mmol) of N-iodosuccinimide are dissolved in 60 ml of DMF, and the mixture is stirred at RT for 10 hours. The mixture is worked up using aqueous sodium thiosulfate solution and extracted with ether. The organic phase is washed with aqueous sodium thiosulfate solution and ammonium chloride solution. The solid which finally remains behind is recrystallized from methanol, giving 7 g (77percent) of 4-chloro-5-iodopyrrolo[2,3-d]pyrimidine in the form of a pale-brownish solid which melts at 195-196° C.
74.6%
With N-iodo-succinimide In DMF (N,N-dimethyl-formamide) at 20℃;
4-Chloro-7H-pyrrolo[2,3-d]pyrimidine 10.75 g (70 mmol) and N-iodosuccinimide (16.8 g, 75 mmol) were dissolved in 400 ml of dry DMF and left at ambient temperature in the darkness over night. The solvent was evaporated. The yellow residue was suspended in hot 10percent solution of Na2SO3, filtered, washed twice with hot water and crystallized from ethanol to yield 14.6 g (74.6percent) of the title compound as off-white crystals. The mother liquid was evaporated up to volume and crystallized again from ethanol to give 2.47 g (12.3percent) of the title product. The total yield is close to 100percent. Tm 212-214 (dec). UV λmax: 307, 266, 230, 227 nm (methanol). MS: 277.93 (M-H), 313 (M+Cl). 1H-NMR (DMSO-d6): 12.94 (s, 1H, NH), 8.58 (s, 1H, H-2), 7.94 (s, 1H, H-8).
74%
With N-iodo-succinimide In N,N-dimethyl-formamide at 20℃; for 2 h;
Compound 13a (5.0 g, 32.56 mmol, 1.00 equiv) was taken up in DMF 60 mL. and to the resulting solution was added N-iodosuccinimide (7.3 g, 32.45 mmol, 1.00 equiv) in portions at room temperature. The resulting reaction was allowed to stir for 2 hours at room temperature, and then was concentrated in vacuo. The resulting residue was purified using flash column chromatography on silica gel and eluted with ethyl acetate/petroleum ether (1:3) to provide 6.7 g (74percent) of compound 13b as a white solid.
72%
With N-iodo-succinimide In N,N-dimethyl-formamide at 20℃; Darkness
Step 1: 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine A mixture of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (3.0 g, 20 mmol) and NIS (4.9 g, 20.1 mmol) in DMF (100 mL) was stirred in darkness at room temperature overnight. Then the mixture was concentrated in vacuo. The residue was treated with 10percent Na2SO3 and filtered to give 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (4.0 g, yield 72percent) as a yellow solid.
52%
With N-iodo-succinimide In dichloromethane at 20℃; for 2 h; Darkness
Synthesis of 7-(2-nitrobenzyloxy)methyl-7-deaza-2′-deoxyadenosine-5′-triphosphate 6-Chloro-7-iodo-7-deazapurine (dA.23): Compound dA.23 was synthesized according to the procedure described by Ju et al. (2006, which is incorporated herein by reference). To a suspension of 6-chloro-7-deazapurine (1.00 g, 6.51 mmol) in anhydrous CH2Cl2 (55 mL) was added N-iodosuccinimide (1.70 g, 7.56 mmol). The reaction was protected from light while stirring at room temperature for two hours. The reaction was then concentrated down in vacuo. The material was re-crystallized from hot methanol to yield 6-chloro-7-iodo-7-deazapurine dA.23 (0.94 g, 52percent).
13.57 g
With N-iodo-succinimide In N,N-dimethyl-formamide at 20℃; for 1 h;
Step 1 Synthesis of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine N-Iodosuccinimide (11.6 g) was added to a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (7.52 g) in DMF (49 ml) at room temperature. The mixture was stirred at the same temperature for 1 hour, and water (150 ml) was added to the reaction mixture. The resulting precipitate was collected by filtration, washed with water, and dried to obtain the title compound as a light-yellow solid (13.57 g). ESI-MS m/z 280, 282 (MH+).
2.8 g
With N-iodo-succinimide In N,N-dimethyl-formamide at 20℃; for 1 h;
4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (2 g, 13.02 mmol) was charged in DCM (60 mL) and was added N-iodosuccinimide (3.80g, 16.92 mmol). To this reaction mixture was added DMF (6 mL) and the reaction mixture was stuffed at RT for 1 h. The progress of reaction was monitored by TLC and NMR. After completion of reaction, the solid obtained was filtered off and washed with pentane (30 mL). The solid obtained was dried under vacuum to get 4-chloro-5-iodo-7H-pyrrolo [2, 3-d] pyrimidine (2.8 g).
Step 1:4-Chloro-7H-pyrrolo[2,3-d]pyrimidine 10.75 g (70 mmol) and N-iodosuccinimide (16.8 g, 75 mmol) were dissolved in 400 mL of dry DMF and left at ambient temperature in the darkness over night. The solvent was evaporated. The yellow residue was suspended in hot 10percent solution of Na2SO3, filtered, washed twice with hot water and crystallized from ethanol to yield 14.6 g (74.6percent) of the title compound as off-white crystals. The mother liquid was evaporated up to volume and crystallized again from ethanol to give 2.47 g (12.3percent) of the target compound. The total yield is close to 100percent;Tm 212-214° C. (dec);UV λmax: 307, 266, 230, 227 nm (methanol);MS: 277.93 (M-H), 313 (M+Cl);1H-NMR (DMSO-d6): 12.94 (s, 1H, NH), 8.58 (s, 1H), 7.94 (s, 1H).
With Selectfluor In acetic acid; acetonitrile at 20 - 70℃; for 14 h;
4-CHLORO-7H-PYRROLOPYRIMIDINE 1 (5 g, 32.7 mmol) and Selectfluor (17.35 g, 49 mmol) were placed in a round bottom flask, followed by the addition of dry acetonitrile (250 mL) and ACOH (50 mL). The solution was then heated at 70 °C for 14 h under N2. After cooling to room temperature, the solvent was removed in vacuo and co-evaporated with toluene (50 mL x 2). The solid was dissolved in a mixture of DCM : EtOAc (1: 1) and filtered through a pad of silica gel which was thoroughly washed. The combined washings were evaporated. And the crude product was then subjected to column chromatography with DCM: EtOAc (4: 1) to give 3.3 g (59percent yield) of 2 as a white SOLID. 1H NMR (DMSO-d6) 8 7.73 (s, 1H), 8.64 (s, 1H), 12.5 (br s, 1H); 13C NMR (DMSO-d6) 8 105.3 (d, J= 14.3 Hz), 111.0 (d, J= 25. 5 Hz), 139.6 (d, J= 244.5 Hz), 146.7 (d, J= 1.5 Hz), 148. 5 (d, J= 3.8 Hz), 151.0 ; 19F NMR (DMSO-D6) 8-170. 7 ( d, J= 1.6 Hz): Mass spectroscopy (MS) measured for C6H3C1FN3 (M+H): 172.0, observed: 172.0.
58%
With acetic acid; Selectfluor In acetonitrile at 70℃; for 18 h; Inert atmosphere
To a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (2.00 g) in acetonitrile (100 mL) were added acetic acid (20 mL) and N-fluoro-N'-(chloromethyl)triethylenediamine bis(tetrafluoroborate) (6.92 g), and the mixture was stirred under nitrogen atmosphere at 70°C for 18 hours. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. To the residue was added methylene chloride/ethyl acetate (1/1), and the solution was passed through a column packed with silica gel (100 mL) and then extracted with methylene chloride/ethyl acetate = 1/1 (2 L). The extract was concentrated, and the resulting residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 70/30 to 35/65) to give 4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine (1.30 g) as a powder (yield: 58percent). MS(APCI)m/z; 172/174[M+H]+.
41%
With acetic acid; Selectfluor In acetonitrile at 70℃;
PREPARATION 144-chloro-5-fluoro-1 /-/-pyrrolo[2,3-c ]pyrimidineA mixture of 6-chloro-7-deazapurine (0.5 g, 3.26 mmol) and Selectfluor.(R). (1.730 g, 4.88 mmol) in CH3CN (25 mL) was treated with AcOH (5 mL) and heated at 70 °C overnight before being cooled and concentrated. Toluene was added and the mixture was concentrated. The residue was dissolved in 1 :1 EtOAc/CH2CI2 and filtered through a pad of silica gel. The filtrate was concentrated and purified via flash column chromatography (20percent EtOAc/CH2CI2) to afford the title compound (0.226 g, 41 percent) as a pink solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.50 (br. s, 1 H), 8.60 - 8.66 (m, 1 H), 7.73 (t, J = 2.51 Hz, 1 H); MS (m/z) 171.9 (M+H+).
26%
With acetic acid; Selectfluor In acetonitrile at 70℃; for 16 h;
The solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimi- dine Q-1 (10 g, 65.1 mmol) and Selectfluor (27.7 g, 78.1 mmol) in CH3CN (500 mE) and AcOH (100 mE) was stirred at 70° C. for 16 h. (The reaction was done four times, 10 g of Q-1 in each vessel). The reaction solution turned from colorless to black. TEC (CH2C12/CH3OH=20: 1) showed 20percent of the starting material remained, and then the reaction solution was concentrated to give crude solid. The solid was dissolved in EtOAc (1 E), washed with H20 (300 mEx2). The organic layer was concentrated to give Q-2 (7 g) as brown solid. The combined batch four batches were purified by prep-HPEC (0.225percent formic acid/acetonitrile) to give Q-2 (11.6 g, 26percent) as a white solid. ECMS [M+1] 172; ‘H NMR (400 MHz, DMSO-d5) ö ppm 12.47 (s, 1H), 8.62 (s, 1H), 7.72 (d, 1H)
Reference：
[1] Nucleosides, Nucleotides and Nucleic Acids, 2004, vol. 23, # 1-2, p. 161 - 170
[2] Patent: WO2005/16878, 2005, A2, . Location in patent: Page/Page column 12
[3] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 24, p. 7297 - 7298
[4] Patent: EP2390254, 2011, A1, . Location in patent: Page/Page column 54
[5] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 5, p. 2052 - 2062
[6] Journal of the American Chemical Society, 2008, vol. 130, # 41, p. 13639 - 13648
[7] Patent: WO2011/149827, 2011, A1, . Location in patent: Page/Page column 67
[8] Patent: US2016/244475, 2016, A1, . Location in patent: Paragraph 0310; 0311
[9] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 18, p. 4518 - 4522
[10] Antimicrobial Agents and Chemotherapy, 2010, vol. 54, # 7, p. 2932 - 2939
[11] Patent: WO2011/146882, 2011, A1, . Location in patent: Page/Page column 111
[12] Patent: US2012/122838, 2012, A1, . Location in patent: Page/Page column 81
[13] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 24, p. 7742 - 7747
[14] Patent: WO2015/143712, 2015, A1,
[15] Patent: US2016/244475, 2016, A1,
Reference：
[1] European Journal of Pharmaceutical Sciences, 2014, vol. 59, # 1, p. 69 - 82
[2] Patent: WO2015/959, 2015, A1,
26
[ 3680-69-1 ]
[ 876343-09-8 ]
Reference：
[1] European Journal of Pharmaceutical Sciences, 2014, vol. 59, # 1, p. 69 - 82
[2] Patent: WO2015/89327, 2015, A1,
[3] Patent: WO2018/88780, 2018, A1,
27
[ 98-09-9 ]
[ 3680-69-1 ]
[ 876343-09-8 ]
Reference：
[1] Patent: WO2015/959, 2015, A1,
28
[ 3680-69-1 ]
[ 98-59-9 ]
[ 479633-63-1 ]
Yield
Reaction Conditions
Operation in experiment
97%
With sodium hydroxide In water; acetone at 0 - 20℃; for 6 h;
EXAMPLE 13-((3Λ,4Λ)-4-Methyl-3-(methyl(7H-pyrrolo[2,3-rf]pyrimidin-4- yl)amino)piperidin-l-yl)-3-oxopropanenitrile mono citrate salt (CP-690550 citrate salt)Step 1[00151] 4-Chloro-7-tosyl-7H-pyrrolor2,3-6πpynmidine: At about O 0C, sodium hydroxide (2 mol/L in water, 8 mL, 1.20 equiv.) was added to a solution of 4- methylbenzene-1-sulfonyl chloride (2.7 g, 13.9 mmol, 1.10 equiv.) and 4-chloro- 7H-pyrrolo[2,3-J]pyrimidine (2 g, 12.8 mmol, 1.00 equiv.) in acetone (20 mL). The resulting solution was stirred at about 20 0C for about 6 hours. The solids were collected by filtration and washed with acetone/water to give the title product as a white solid (4.0 g; yield = 97percent). 1H NMR (300 MHz, CDCl3) δ: 8.78 (s, IH), 8.11 (d, J = 8.4 Hz, 2H), 7.80 (d, J = 4.2 Hz, IH), 7.34 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 4.2 Hz, IH), 2.42 (s, 3H). LC-MS: m/z = 308/310 (M+H)+.
95%
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 2 h;
Example 1; 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine; A slurry of 1 (307 mg, 2.00 mmol), Tosyl-chloride (418 mg, 2.20 mmol) and freshly ground K2CO3 (1.1 g, 8.0 mmol) in DMF (5.0 mL) was stirred at R.T. for 2 h. The mixture was partitioned between water and EtOAc and the organic phase was washed with brine (2.x.), dried (Na2SO4), filtered, and concentrated to provide the title compound (583 mg, 1.89 mmol, 95percent yield) as a white solid.
95%
With sodium hydroxide In acetone at 20℃;
Dissolve 4-chloro-pyrrolo[2,3-d]pyrimidine or intermediate 2 (10 mmol) in acetone (35 mL), add p-toluenesulfonyl chloride (1 mmol) in an ice bath, and then add 2.0 mol/L NaOH solution (12·5 mmol, 6.2 mL) was stirred overnight at room temperature. After the reaction was completed, a large amount of white solids precipitated, which was filtered. The filter cake was washed with 20 mL of acetone/water (1:1) and dried to obtain Intermediate 3. 4-Chloro-7-p-toluenesulfonyl 7H-pyrrolo[2,3-d]pyrimidine (3a) White solid, 95percent yield
90.1%
With sodium hydroxide In water; acetone at -5 - 30℃; for 5 h;
Example 7; Preparation of 4-chloro-7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidine:; To a clean, dry, nitrogen-purged reactor were charged acetone (87.5 ml), p-toluenesulfonyl chloride (17.1 g, 0.09 mol) and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (25.0 g, 0.16 mol). The reactor was cooled to between -5.0 to 5.00C and 2.5 M sodium hydroxide (78.1 ml) was added at a rate to maintain the temperature below 5.00C. The reactor was warmed to between 20-300C and stirred for a minimum of 5 hours. The resulting solids were isolated by filtration and washed with acetone/water (1 :1 , 25 ml each). After drying for a minimum of 12 hours under vacuum at 40-500C with slight nitrogen bleed, 44.9 g (90.1percent) of the title compound were isolated. Mp 140.2-147.70C. Anal. Calcd. for C13H10CIN3O2S: C, 50.73; H, 3.28; N, 13.65. Found: C,50.50; H, 3.06; N, 13.63. 1H NMR (400 MHz, CZ6-DMSO): δ 8.79 (s, 1 H), 8.09 (d, J=4.2 Hz, 1 H), 8.01 (d, J=8.5 Hz, 2H), 7.43 (d, J=8.5 Hz, 2H), 6.92 (d, J=4.2 Hz, 1 H), 2.32 (s, 3H). 13C NMR (400 MHz, dg- DMSO): δ 153.2, 152.7, 151.2, 147.2, 134.3, 131.0, 129.3, 128.5, 119.9, 103.9, 21.8.
90%
With sodium hydroxide In water; acetone at 0 - 20℃; for 6 h;
P-toluenesulfonyl chloride (67.5 g, 348 mmol, 1.10 eq.) and 4-chloro-7-Hpyrrolo[2,3-d]pyrimidine (50 g,320 mmol, 1.0 eq.) was dissolved in acetone (500 ml), sodium hydroxide solution (2 Min water, 200 ml, 1.20 eq.) was slowly added thereto at 0°C, and the reaction was stirred at 20°C for 6 hours to precipitate the solid. Filtration and washing with acetone and water gave the white target compound (90 g, yield = 90percent).
80%
With sodium hydroxide In acetone at 20℃;
A mixture of 4-c oro-7B~pyrfolo[2.s3-dJpyrimidme (10.0 g, 65 mraol), TsCl (13.7 g, 72 iirniol) and NaOH (40 ml,, 2N) in acetone (100 mL) was stirred at room temperature overnight. The resulting solid w s collected by filtration and washed with acetone and then with water to give the title compound as a white solid (16 g„ 80percent). H NM (400 MHz, CDCh) 5 8.7? (s, I B), 8.09 id J 8 0 Hz, 20), 7.77 (d, J 4.0 Hz, 1.H), 7.33 (4 J .0 1 . 2Π ). 6,70 (d, -4.0 1 / , 2H). 2.40 (s, 3H),
79.2%
With triethylamine In dichloromethane at 20℃; for 5 h;
The mixture of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (3.0g, 20mM), NEt3 (6.1g, 60mM) and p-toluene sulfonyl chloride (2.6g, 24mM) were stirred at room temperature in dichloromethane (100mL). After 5h, TLC analysis showed the complete consumption of 4-chloro-7H-pyrrolo [2, 3-d] pyrimidine. The reaction mixture was quenched by the addition of water (70mL). After quenching the reaction, the reaction mixture was poured into separator funnel and the aqueous layer was extracted with dichloromethane (100mL×3). The combined organic layers were evaporated in vacuo and purified by silica gel column chromatography to get the product 2a (4.9g, 79.2percent) as a white solid. ESI-MS m/z: 308.0 [M+H]+. 1H NMR (300MHz, DMSO‑d6): δ 2.37 (3H, s, CH3), 6.96 (1H, d, pyrrolyl-H, J=4.0Hz), 7.48 (2H, d, ArH, J=8.1Hz), 8.05 (2H, d, ArH, J=8.1Hz), 8.12 (1H, d, pyrrolyl-H, J=4.0Hz), 8.82 (1H, s, pyrimidiny-H).
45%
With sodium hydroxide In water; acetone at 0 - 20℃; for 6 h;
[0152] To a stirred solution of TsCI (1.35 g, 7.0 mmol) and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1.0 g, 6.4 mmol) in acetone (10 mL) was added 2.0 M aqueous NaOH (8 mL, 16 mmol) at 0°C. The mixture was stirred at ambient temperature for 6 hours yielding a suspension. The solid product was collected by filtration and washed with acetone/water to afford the title compound as a white solid (0.9 g, 45percent). MS (ESl) calcd for C13H10C1N3025: 307.0; found:308.1[M+H]. 1H NMR (400 MHz, CDCI3) 6 8.77 (s, 1H), 8.09 (d, J = 8.0 Hz, 2H), 7.78 (d, J = 4.0Hz, 1H), 7.33 (d, J = 8.0 Hz, 2H), 6.71 (d, J = 4.0 Hz, 1H), 2.41 (s, 3H).
Ca. 2 kg
With sodium hydroxide In acetone at -5 - 30℃; for 1 h; Autoclave; Large scale
Autoclave, 3.5L of acetone, p-toluenesulfonyl chloride and 1.36kg 1kg compound 7, followed by stirring under cooling to 0 ~ -5 , maintained at below 5 2.5M sodium hydroxide solution was added dropwise 3.5L, warmed to completion of the dropwise 20-30 deg.] C for 1 h, TLC monitoring completion of the reaction was filtered, washed with 50percent acetone, slurried, filtered, drained, and dried in vacuo 50 ° to give compound 6 about 2kg.
124 g
With tetrabutyl-ammonium chloride; potassium carbonate In dichloromethane; water at 20℃;
A mixture of 66 g (0.43 mol) 4-chloro-7H-pyrrolo[2,3-d]pyrimidine, 607 g dichloromethane, 3.0 g tetrabutylammonium chloride, 90 g tosyl chloride, 85 g potassium carbonate and 381 g water is stirred efficiently at room temperature until reaction is complete. The phases are separated and the organic phase is washed with 340 g water. The organic phase is treated with 6.0 g of activated charcoal, completed with 318 g water and the organic solvent removed by distillation. The mixture is supplemented by 318 g heptane and the product is centrifuged, washed with heptane and water and vacuum dried at a temperature of not more than 8o°C, yielding 124 g (yield: 0.40 mol, 94percent conversion rate) of 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine having a purity of 99.9 area-percent measured by HPLC.
Reference：
[1] Patent: WO2010/123919, 2010, A2, . Location in patent: Page/Page column 49
[2] Patent: US2006/183761, 2006, A1, . Location in patent: Page/Page column 25
[3] Patent: CN107556318, 2018, A, . Location in patent: Paragraph 0101; 0108-0111
[4] Patent: WO2007/12953, 2007, A2, . Location in patent: Page/Page column 21
[5] Patent: CN103896946, 2018, B, . Location in patent: Paragraph 0080; 0081; 0082
[6] Journal of Heterocyclic Chemistry, 2016, vol. 53, # 4, p. 1259 - 1263
[7] Patent: WO2016/44323, 2016, A1, . Location in patent: Paragraph 0258
[8] European Journal of Medicinal Chemistry, 2019, p. 243 - 255
[9] Patent: WO2016/126869, 2016, A1, . Location in patent: Paragraph 0152
[10] Patent: CN105294698, 2016, A, . Location in patent: Paragraph 0037
[11] Patent: WO2018/29641, 2018, A1, . Location in patent: Page/Page column 7-8
[12] Patent: WO2006/101783, 2006, A2, . Location in patent: Page/Page column 23-24
[13] Patent: WO2006/124462, 2006, A2, . Location in patent: Page/Page column 24; 31; 33-34
Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 10℃; for 1 h; Cooling with ice; Inert atmosphere Stage #2: at 10 - 20℃;
Under cooling with an ice-salt bath, sodium hydride (340 mg, 60percent) was added in two portions to a solution of 4-chloropyrrolopyrimidine (3a) (1.0 g, 6.5 mmol) in DMF (15 mL) while keeping the temperature of the reactants no higher than 10°C, and the reaction was stirred under nitrogen atmosphere protection for 1 h. SEMCI (1.4 g, 8.5 mmol) was slowly added via a syringe while keeping the temperature no higher than 10°C. The reaction was warmed to room temperature, and stirred overnight. The reaction was quenched with water, extracted with EA, dried over anhydrous sodium sulfate, and the organic phase was concentrated, and purified by preparative flash chromatography (PE:EA=19:1), to afford 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (3b) (1.834 g, oil product), yield: 97percent,. MS (ESI, m/z): 284 [M+H]+.
96.4%
Stage #1: With potassium <i>tert</i>-butylate In tetrahydrofuran at -30 - 20℃; Stage #2: at 20℃;
Potassium t-butoxide (328.81 g, 2.93 mol)and tetrahydrofuran were added to the reaction flask at -30 ° C to -20 ° C,a solution of 4-chloro-7H-pyrrolo [2,3-d] pyrimidine (300 g, 1.95 mol) in tetrahydrofuran was added dropwise to the reaction flask. after completion of the dropwise addition, the mixture was stirred at room temperature for 4 to 6 hours to control the reaction flask the temperature is not higher than -15° C -5° C ,2- (trimethylsilyl) ethoxymethyl chloride (390.80g, 2.34mol)Is added to the reaction flask, and after completion of the dropwise addition, the temperature is raised to room temperature and the reaction is stirred at that temperature for 3 to 5 hours.After completion of the reaction, the reaction was quenched to neutral with dilute hydrochloric acid, concentrated in tetrahydrofuran in the reverse solution, stirred with ethyl acetate and the aqueous phase was separated. The aqueous phase was extracted with ethyl acetate once, and the reaction solution was cooled and filtered to obtain a wet product. The wet product was crystallized from n-hexane and dried to obtain 534.50 g of product, purity: 99.70percent, and the residue was purified. Yield: 96.40percent.
90.4%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 20℃; for 1 h; Cooling with ice Stage #2: for 1 h; Cooling with ice
To a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (20.0 g, 130.4 mmol, 1.0 eq.) in dry DMF was added NaH (6.6 g, 57percent content, 156.8 mmol, 1.2 eq.), under stirring in an ice bath. After the reactants were stirred for 1 hr at room temperature, SEMCl (26.1 g, 156.5 mmol, 1.2 eq.) was added dropwise under the cooling of an ice bath. After the addition was completed, the reactants were stirred for 1 hr in an ice bath, then the reaction was quenched by adding water, and the resulting mixture was extracted with ethyl acetate. The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was separated by column chromatography on silica gel column to give 4-chloro-7-[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (33.43 g, 90.4percent yield). 1HNMR (400MHz, CDCl3) δ 8.67 (s, 1H), 7.39 (d, J =3.6 Hz, 1H), 6.67 (d, J =3.6 Hz, 1H), 5.65 (s, 2H), 3.53 (dd, J =9.2 Hz, J =8.0 Hz, 2H), 0.91 (t, J =8.4 Hz, 2H), 0.00 (s, 9H). m/z=284[M+1]+.
90%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 20℃; for 1 h; Cooling with ice Stage #2: for 1 h; Cooling with ice
With ice bath,To a solution of 4-chloro-7H-pyrrolo [2,3-d] pyrimidine (20.0 g, 130.4 mmol, 1.0 eq.In dry DMF, NaH (6.6 g, 57percent content, 156.8 mmol, 1.2 eq) was added. The reaction was stirred at room temperature for 1 hour,Further, SEMCl (26.1 g, 156.5 mmol, 1.2 eq.) Was added dropwise with cooling in an ice bath.After the addition was completed, the reaction mixture was stirred in an ice bath for 1 hour, quenched with water,Extraction with ethyl acetate and washing of the combined organic phases with brine,Dried over sodium sulfate, filtered and concentrated in vacuo.Column chromatography silica gel column isolated4-Chloro-7 - [2- (trimethylsilyl) ethoxy] methyl} -Pyrrolo [2,3-d] pyrimidine (33.4 g, 90percent yield).
88.9%
Stage #1: With sodium hydride In n-heptane; ISOPROPYLAMIDE at 0 - 20℃; Cooling with ice/brine bath Stage #2: at 0 - 5℃;
To a flask equipped with a nitrogen inlet, an addition funnel, a thermowell, and the mechanical stirrer was added 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 600 g, 3.91 mol) and N,N-dimethylacetimide (DMAC, 9.6 L) at room temperature. The mixture was cooled to 0-5° C. in an ice/brine bath before solid sodium hydride (NaH, 60 wt percent, 174 g, 4.35 mol, 1.1 equiv) was added in portions at 0-5° C. The reaction mixture went to a dark solution during 15 minutes. Trimethylsilylethoxymethyl chloride (2, SEM-Cl, 763 mL, 4.31 mol, 1.1 equiv) was then added slowly via an addition funnel at a rate that the internal reaction temperature did not exceed 5° C. The reaction mixture was then stirred at 0-5° C. for 30 minutes. When the reaction was deemed complete determined by TLC and HPLC, the reaction mixture was quenched by water (1 L). The mixture was then diluted with water (12 L) and MTBE (8 L). The two layers were separated and the aqueous layer was extracted with MTBE (8 L). The combined organic layers were washed with water (2*4 L) and brine (4 L) and dried over sodium sulfate (Na2SO4). The solvents were removed under reduced pressure. The residue was then dissolved in heptane (2 L), filtered and loaded onto a silica gel (SiO2, 3.5 Kg) column eluding with heptane (6 L), 95percent heptane/ethyl acetate (12 L), 90percent heptane/ethyl acetate (10 L), and finally 80percent heptane/ethyl acetate (10 L). The fractions containing the pure desired product were combined and concentrated under reduced pressure to give 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (3, 987 g, 1109.8 g theoretical, 88.9percent yield) as a pale yellow oil which partially solidified to an oily solid on standing at room temperature.
88.9%
Stage #1: With sodium hydride In N,N-dimethyl acetamide; mineral oil at -5℃; Inert atmosphere Stage #2: at 5℃; Inert atmosphere
4-Chloro-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (3a).; To a flask equipped with a nitrogen inlet, addition funnel, thermowell, and mechanical stirrer was added 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 600 g, 3.91 mol) and dimethylacetimide (9.6 L). The mixture was cooled to -5° C. in an ice/brine bath and sodium hydride (NaH, 60 wt percent, 174 g, 4.35 mol, 1.1 equiv) was added in portions as a solid. The mixture went to a dark solution during 15 minutes and trimethylsilylethoxymethyl chloride (2, 763 mL, 4.31 mol, 1.1 equiv) was added slowly via an addition funnel at a rate that the temperature did not exceed 5° C. The reaction was stirred for 30 minutes, determined to be complete by TLC and HPLC, and water (1 L) was slowly added to quench the reaction. The mixture was then diluted with water (12 L) and MTBE (8 L). The layers were separated and the aqueous was re-extracted with MTBE (8 L). The combined organic layers were washed with water (2.x.4 L) and brine (4 L), dried over sodium sulfate (NaSO4), and solvents removed under reduced pressure.The residue was dissolved in heptane (2 L), filtered and loaded onto a silica gel (3.5 kg) column eluting with heptane (6 L), 95percent heptane/ethyl acetate (12 L), 90percent heptane/ethyl acetate (10 L), and finally 80percent heptane/ethyl acetate (10 L). The pure fractions were combined and concentrated under reduced pressure to give 4-chloro-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (3a, 987 g, 1109.8 g theoretical, 88.9percent yield) as a pale yellow oil that partially solidified to an oily solid on standing at room temperature. For 3a: 1H NMR (DMSO-d6, 300 MHz) δ ppm 8.67 (s, 1H), 7.87 (d, 1H, J=3.8 Hz), 6.71 (d, 1H, J=3.6 Hz), 5.63 (s, 2H), 3.50 (t, 2H, J=7.9 Hz), 0.80 (t, 2H, J=8.1 Hz), 1.24 (s, 9H); 13C NMR (DMSO-d6, 100 MHz) δ ppm 151.3, 150.8, 150.7, 131.5, 116.9, 99.3, 72.9, 65.8, 17.1, -1.48; C12H18ClN3OSi (MW 283.83), LCMS (EI) m/e 284/286 (M++H).
88.9%
Stage #1: With sodium hydride In N,N-dimethyl acetamide; mineral oil at 0 - 5℃; for 0.25 h; Stage #2: at 0 - 5℃; for 0.5 h;
Step 1. 4-Chlow-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (3) To a flask equipped with a nitrogen inlet, an addition funnel, a thermowell, and the mechanical stirrer was added 4-chloro-7H-pyirolo[2,3-c/]pyrirnidine (1, 600 g, 3.91 mol) and N,N-dimethylacetimide (DMAC, 9.6 L) at room temperature. The mixture was cooled to 0 - 5 °C in an ice/brine bath before solid sodium hydride (NaH, 60 wtpercent, 174 g, 4.35 mol, 1.1 equiv) was added in portions at 0 - 5 °C. The reaction mixture turned into a dark solution after 15 minutes. Trimethylsilylethoxymethyl chloride (2, SEM-C1, 763 mL, 4.31 mol, 1.1 equiv) was then added slowly via an addition funnel at a rate that the internal reaction temperature did not exceed 5 °C. The reaction mixture was then stirred at 0 - 5 °C for 30 minutes. When the reaction was deemed complete determined by TLC and HPLC, the reaction mixture was quenched by water (1 L). The mixture was then diluted with water (12 L) and methyl tert-b ty] ether (MTBE) (8 L). The two layers were separated and the aqueous layer was extracted with MTBE (8 L). The combined organic layers were washed with water (2 x 4 L) and brine (4 L) and solvent switched to 1-butanol. The solution of crude product (3) in 1 -butanol was used in the subsequent Suzuki coupling reaction without further purification. Alternatively, the organic solution of the crude product (3) in MTBE was dried over sodium sulfate (Na2SC>4). The solvents were removed under reduced pressure. The residue was then dissolved in heptane (2 L), filtered and loaded onto a silica gel (S1O2, 3.5 Kg) column eluting with heptane (6 L), 95percent heptane/ethyl acetate (12 L), 90percent heptane/ethyl acetate (10 L), and finally 80percent heptane/ethyl acetate (10 L). The fractions containing the pure desired product were combined and concentrated under reduced pressure to give 4-chloro-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-i/]pyrimidine (3, 987 g, 1 109.8 g theoretical, 88.9percent yield) as a pale yellow oil which partially solidified to an oily solid on standing at room temperature. For 3: NMR (DMSO-af6, 300 MHz) δ 8.67 (s, 1 H), 7.87 (d, 1 H, J = 3.8 Hz), 6.71 (d, 1 H, J= 3.6 Hz), 5.63 (s, 2H), 3.50 (t, 2H, J= 7.9 Hz), 0.80 (t, 2H, J= 8.1 Hz), 1.24 (s, 9H) ppm; 13C NMR (DMSO-cfe, 100 MHz) δ 151.3, 150.8, 150.7, 131.5, 1 16.9, 99.3, 72.9, 65.8, 17.1 , -1 .48 ppm; C,2H,8ClN3OSi (MW 283.83), LCMS (EI) m/e 284/286 (M+ + H).
87%
With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 1.5 h;
General procedure: To a mixture of sodium hydride (60percent dispersion in mineral oil; 276 mg; 6.89 mmol) in DMF (10 mL) at 0 °C was added drop-wise a solution of 4-chloro-2-methylsulfanyl-7H-pyrrolo[2,3-d]pyrimidine [prepared as detailed in Ref. 45] (1.145 g; 5.74 mmol) in anhydrous DMF (20 mL). When the addition was complete, 2-(trimethylsilyl)ethoxymethyl chloride (1.32 ml; 7.46 mmol) was added drop-wise and the reaction mixture was stirred at 0 °C for 1.5 h then allowed to warm to ambient temperature. The reaction mixture was partitioned between water (100 mL) and ethyl acetate (100 mL). The organic phase was separated, dried over Na2SO4 and then filtered and the filtrate solvents evaporated in vacuo. The crude product was purified by flash chromatography on silica gel (70 g) eluting with a solvent gradient of 05percent ethyl acetate in hexane to afford the title compound 42 (1.73 g, 91percent) as a colourless oil.
81%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 0℃; for 2 h; Stage #2: at 20℃;
To a solution of NaH (3 g, 0.13 mol) in DMF (60 mL)Suspension is slowSlow to join 1(10 g, 0.066 mol) in DMF (40 mL).The reaction mixture was stirred at 0 & lt; 0 & gt; CStirring for 2 hours,A light brown cloudy mixture was obtained.And then slowly added to the mixture2- (trimethylsilyl) ethoxymethyl chloride (SEMCl) (12.7 g, 0.08 mol)Stirred overnight at room temperature,The reaction was quenched with water and extracted with ethyl acetate,The filtrate was concentrated under reduced pressure. Purification by flash chromatography gave intermediate 2(15 g, 81percent),As a pale yellow oil;
79%
Stage #1: With sodium hydride In N,N-dimethyl acetamide; mineral oil at 0 - 5℃; for 0.416667 h; Inert atmosphere Stage #2: at 4 - 7℃; for 1.75 h; Inert atmosphere
4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (1.5g, 9.77 mmol) was stirred in anhydrous N,N- dimethylacetamide (30ml), under nitrogen, with cooling to between 0°C and 5 °C as sodium hydride (60percent dispersion, 430mg, 10.75 mmol) was added in portions. After all effervescence had ceased (25 min.), (2-chloromethoxy-ethyl)-trimethylsilane (1.79g, 10.75 mmol) was added dropwise, maintaining the temperature between 4 °C and 7 °C. After stirring for a further lh 45 min. saturated aqueous NH4C1 and a little water were added and the product was extracted with 2 portions of t-butyl methyl ether. The extracts were washed with water, brine, dried over Na2S04 and the solvent evaporated. Purification on a Si-SPE ® cartridge (70g) eluting with EtOAc- cyclohexane (1 : 10 followed by 1 :6) afforded the title compound as a colourless oil (2.19g, 79percent) LCMS (Method 1, ESI): Rt 4.11 min., m/z 325 [M+42]+, 284 [M+H]+, 1H NMR (400 MHz, CDCI3): δ 8.67 (1H, s), 7.39 (1H, d, J = 3.5Hz), 6.67 (1H, d, J = 3.5Hz), 5.65 (2H, s), 3.50-3.56 (2H, m), 0.88-0.93 (2H, m), -0.06 (9H, s).
75%
Stage #1: With sodium hydride In N,N-dimethyl acetamide at -10℃; for 0.5 h; Stage #2: at 20℃; for 2 h;
2L three-neck flask, 4-chloropyrrolopyrimidine (280 g, 1.83 mol) and N, N-dimethylacetamide (500 mL) were added, Cooling to -10 deg C, NaH (84 g) was added in triplicate, Plus, Stir for 0.5 hours. 2-(trimethylsilyl)ethoxymethyl chloride (385 mL, 1.98 mol) was added, Plus, After 2 hours of reaction at room temperature, The reaction solution was poured into 1 L of water, 500 mL of ethyl acetate was added, Stirring and extracting the ester layer, Washed with 300 mL of saturated sodium chloride once, Dried over anhydrous sodium sulfate, filter, Concentrated under reduced pressure to give 390 g of red product, Yield 75percent.
70%
With sodium hydride In N,N-dimethyl acetamide at 5℃; for 4.25 h;
Under ice-cooling conditions, 2.0g of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine was dissolved in 50mL N,N-dimethylacetamide. 0.58g of NaH was added dropwise to the solution and stirred for 15 minutes. 2.2g of 2-chloromethoxyethyl trimethylsilane was added and the reaction was continued maintaining the temperature at 5°C for 4h. The solution was then quenched with saturated ammonium chloride solution. The aqueous phase was extracted with ethyl acetate. The organic phase was washed with water. Each 100mL saline solution was washed three times. The organic phase was dried over anhydrous magnesium sulfate overnight. The mixture was filtered and the solvent was distilled off under reduced pressure to give a crude product. The product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 50:1) to give 2.6g of intermediate 2 as a colorless liquid, yield: 70percent.
66%
Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.25 h; Stage #2: at 0 - 20℃; for 1 h;
To a stirred solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (5.0 g, 32.56 mmol, 1 equiv) in DMF (50 mL) was added 60percent sodium hydride (1.5 g, 39.07 mmol, 1.2 equiv) at 000 and stirred for 15 mm followed by addition of (2-(chloromethoxy)ethyl)trimethylsilane(5.7 mL, 32.56 mmol, 1.0 equiv) at same temperature. The reaction mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was quenched with ice water. The crude product was extracted in to ethyl acetate. The organic layer was dried over sodium sulphate and evaporated to obtain 4-chloro-7-((2-(trimethylsilyl) ethoxy) methyl)-7H-pyrrolo [2,3-d]pyrimidine as brown liquid (8.0 g, 66.0 percent). LCMS (ES) m/z =284.10 [M+H]. 1H NMR (400 MHz, DMSO-d6) O ppm -0.11 (s, 9H), 0.79-0.81 (m, 2H),3.50 (t, J= 8.0 Hz, 2H), 5.62 (s, 1H), 6.68-6.69 (m, 1H), 7.85 (d, J=4.0 Hz, 1H), 8.62 (s, 1H).
0.96%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 0.25 h; Reflux Stage #2: for 0.5 h;
2.00 g of 4-hydroxypiperidine was added to a 100-mL round-bottomed flask, and then 20.0 mL of dichloromethane (CH2Cl2) and 20.0 mL of a saturated sodium hydrogen carbonate (NaHCO3) solution were added thereto. After 4.32 g of di-tert-butyl dicarbamate (Boc2O) was added thereto, the reaction mixture was vigorously stirred for about 15 hours and then concentrated under reduced pressure. The aqueous phase was extracted with 20.0 mL of ethyl acetate (EtOAc) to collect an organic phase. The collected organic phase was washed with 10.0 mL of deionized water and 15.0 mL of saturated brine. The organic phase was then filtered with sodium sulfate (Na2SO4). The resulting filtrate was distilled under reduced pressure. As a result, 3.871 g of tert-butyl 4-hydroxypiperidine-1-carboxylate was obtained with a yield of about 97.2percent. (0319) 300 mg of 6-chloro-7-deazapurine was added to a 50-mL round-bottomed flask, and then 3.75 mL of N,N-dimethylformamide was added. After 86.0 mg of sodium hydride (60wtpercent) was added thereto at about 0°C, the reaction mixture was refluxed at room temperature for about 15 minutes. After 0.403 mL of 2-(trimethylsillyl)ethoxymethyl chloride) was added thereto, the reaction mixture was stirred for about 30 minutes and concentrated under reduced pressure. The reaction mixture was extracted with 4.50 mL of ethyl acetate (EtOAc) and 4.50 mL of deionized water to collect an organic phase. The collected organic phase was filtered with magnesium sulfate (MgSO4). The resulting filtrate was distilled under reduced pressure. As a result, 534 mg of 4-chloro-7-((2-(trimethylsillyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine was obtained with a yield of about 96.6percent. (0320) 408 mg of tert-butyl 4-hydroxypiperidine-1-carboxylate was added to a 50-mL round-bottomed flask, and 5.60 mL of dimethyl sulfoxide (DMSO) was added thereinto. After 61.4 mg of sodium hydride (60wtpercent) was added thereinto at about 0°C, the reaction mixture was refluxed at room temperature for about 1.5 hours. Then, a solution of 574 mg of 4-chloro-7-((2-(trimethylsillyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine dissolved in 4.60 mL of dimethyl sulfoxide (DMSO) was slowly dropwise added into the reaction mixture, and the reaction mixture was stirred at about 50°C for about 2 hours and then cooled down to room temperature. The reaction mixture was then extracted with 10.0 mL of ethyl acetate (EtOAc) and 10.0 mL of deionized water to collect an organic phase. The collected organic phase was filtered with sodium sulfate (Na2SO4). The resulting filtrate was distilled under reduced pressure, and then the resulting residue was purified by flash column chromatography (EtOAc:Hexane=1:5). As a result, 457 mg of tert-butyl 4-((7-((2-(trimethylsillyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)piperidine-1-carboxylate was obtained with a yield of about 66.6percent. (0321) 452 mg of tert-butyl 4-((7-((2-(trimethylsillyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)piperidine-1-carboxylate was added to a 50-mL round-bottomed flask, and 5.00 mL of tetrahydrofuran was added thereinto. After 20.4 mL of a solution of 1.0 M tetrabutylammonium fluoride in tetrahydrofuran was added thereinto, the reaction mixture was refluxed at room temperature for about 5 hours and then cooled down to room temperature. The reaction mixture was concentrated under reduced pressure and then extracted with 100 mL of ethyl acetate (EtOAc) and 100 mL of deionized water to collect an organic phase. The collected organic phase was filtered with sodium sulfate (Na2SO4). The resulting filtrated was distilled under reduced pressure, and then the resulting residue was purified by flash column chromatography (EtOAc:Hexane=1:6). As a result, 310 mg of tert-butyl 4-((7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)piperidine-1-carboxylate was obtained with a yield of about 95.7percent. (0322) 310 mg of tert-butyl 4-((7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)piperidine-1-carboxylate was added to a 50-mL round-bottomed flask, and 6.00 mL of 1,4-dioxane was added thereinto. After 10.0 mL of 4N HCI solution was added thereinto, the reaction mixture was stirred at room temperature for about 2 hours. Then, 20.0 mL of ethyl acetate (EtOAc) was added into the reaction mixture and a 10percent ammonium hydroxide solution was added to basify the reaction mixture. An organic phase was filtered with sodium sulfate (Na2SO4). The resulting filtrate was distilled under reduced pressure. As a result, 230 mg of 4-(piperidine-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidine was obtained with a quantitative yield. (0323) 177 mg of 4-(piperidine-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidine was added to a 25-mL round-bottomed flask and then dissolved with 3.00 mL of dichloromethane (CH2Cl2). After 0.0480 mL of chloroacetyl chloride was added into the solution, the reaction mixture was treated with 0.211 mL of N,N-diisopropylethylamine and then stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by flash column chromatography (EtOAc:Hexane=1:6). The resulting fraction was concentrated under reduced pressure and then further under vacuum. As a result, 56.0 mg of 1-(4-((7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)piperidine-1-yl)-2-chloroethane-1-one was obtained with a yield of about 23.5percent. (0324) 55.6 mg of 1-(4-((7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)piperidine-1-yl)-2-chloroethane-1-one was added to a 25-mL round-bottomed flask and then dissolved with 1.00 mL of N,N-dimethylformamide. After 24.3 mg of potassium cyanide was added into the solution, the reaction mixture was stirred overnight at about 30°C to 40°C. The reaction mixture was concentrated under reduced pressure, and then the resulting residue was purified by flash column chromatography (EtOAc:Hexane=1:1). The resulting fraction was concentrated under reduced pressure and then further under vacuum. As a result, 35.4 mg of 3-(4-((7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)piperidine-1-yl)-3-oxopropanenitrile was obtained with a yield of about 49.4percent. (0325) 1H NMR (400 MHz, CDCl3) δ12.03 (s, 1H), 8.34 (s, 1H), 7.35 (t, J = 3.2 Hz, 1H), 6.47 (q, J = 2.0, 3.6 Hz, 1H), 5.58-5.43 (m , 1H), 4.08 (s, 2H), 3.90-3.86 (m, 1H), 3.63-3.59 (m, 1H), 3.47-3.32 (m, 2H), 2.09-2.00 (m, 2H), 1.82-1.77 (m, 1H), 1.69-1.61 (m, 1H). (0326) LRMS (ESI) calcd for (C14H15N5O2 + H+) 286.1, found 286.1.
Reference：
[1] Patent: EP3360878, 2018, A1, . Location in patent: Paragraph 0094; 0095
[2] Patent: CN107226814, 2017, A, . Location in patent: Paragraph 0051-0052
[3] Journal of Medicinal Chemistry, 2017, vol. 60, # 20, p. 8336 - 8357
[4] Patent: EP3235819, 2017, A1, . Location in patent: Paragraph 0122; 0123
[5] Patent: CN107513067, 2017, A, . Location in patent: Paragraph 0082; 0083; 0084; 0085
[6] Organic Letters, 2009, vol. 11, # 9, p. 1999 - 2002
[7] Patent: US2009/233903, 2009, A1, . Location in patent: Page/Page column 61
[8] Patent: US2010/190981, 2010, A1, . Location in patent: Page/Page column 73
[9] Patent: WO2013/36611, 2013, A1, . Location in patent: Page/Page column 23; 24
[10] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 22, p. 6770 - 6789
[11] Patent: CN106905322, 2017, A, . Location in patent: Paragraph 0052; 0053; 0054
[12] Patent: WO2013/7765, 2013, A1, . Location in patent: Page/Page column 182-183
[13] Patent: CN106554363, 2017, A, . Location in patent: Paragraph 0123; 0124; 0125
[14] Patent: CN105418616, 2016, A, . Location in patent: Paragraph 0106; 0107
[15] Patent: WO2017/46738, 2017, A1, . Location in patent: Page/Page column 68; 69
[16] Patent: US2011/224190, 2011, A1, . Location in patent: Page/Page column 37
[17] Patent: WO2012/22265, 2012, A1, . Location in patent: Page/Page column 31
[18] Patent: WO2012/22045, 2012, A1, . Location in patent: Page/Page column 26-27
[19] Patent: WO2013/85802, 2013, A1, . Location in patent: Page/Page column 140-141
[20] Patent: US2013/210831, 2013, A1, . Location in patent: Paragraph 0198; 0199
[21] Patent: WO2014/28756, 2014, A1, . Location in patent: Paragraph 45
[22] Patent: US2015/246046, 2015, A1, . Location in patent: Paragraph 0132
[23] Patent: WO2016/35014, 2016, A1, . Location in patent: Page/Page column 26
[24] Patent: TW2018/2094, 2018, A, . Location in patent: Page/Page column 68
[25] Patent: EP3327021, 2018, A1, . Location in patent: Paragraph 0317-0326
35
[ 3680-69-1 ]
[ 1072027-36-1 ]
Reference：
[1] Archiv der Pharmazie, 2016, vol. 349, # 5, p. 356 - 362
[2] European Journal of Medicinal Chemistry, 2017, vol. 138, p. 543 - 551
[3] Patent: WO2008/128072, 2008, A2,
[4] Patent: CN108997351, 2018, A,
Reference：
[1] Journal of Medicinal Chemistry, 2015, vol. 58, # 18, p. 7431 - 7448
38
[ 3680-69-1 ]
[ 1100318-96-4 ]
Yield
Reaction Conditions
Operation in experiment
91%
With hydrogen iodide In water at 20℃; for 48 h;
4-Chloro-7H-pyrrolo[2,3-d]pyrimidine was dissolved in 57 wt. percent hydriodic acid in H2O. The solution was stirred for 48 h at room temperature, and the solid was removed by filtering. The suspension in cold water was brought to pH 8 with NH3 (aq) solution. The solid was filtered, washed with water and dried.
91%
With hydrogen iodide In water at 20℃; for 48 h;
4-Chloro-7H-pyrrolo [2,3-d] pyrimidine was dissolved in 57percent by weight hydriodic acid in H 2 O. The solution was stirred at room temperature for 48 hours. The solid was filtered off. The suspension in cold water was brought to pH 8 with NH3 (aq) solution. The solids were filtered, washed with water and then the solids were dried.
410 mg
at 20℃; for 16 h;
a) 4-iodo-7H-pyrrolo[2,3-d]pyrimidineA mixture of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (336 mg, 2.15 mmol) and 3.5 ml_ of 57percent hydriodic acid was stirred at room temperature for 16 hours. The solid was filtered off, suspended in 3 ml_ of water and brought to pH = 8 with aqueous ammonia solution. The suspension was cooled down to 0 5C and the solid was filtered off, washed with cold water and dried to give the desired product (410 mg). The product contains about 10percent of the starting material.
Reference：
[1] ACS Combinatorial Science, 2015, vol. 17, # 1, p. 5 - 10
[2] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 21, p. 5036 - 5046
[3] Patent: KR2016/124034, 2016, A, . Location in patent: Paragraph 0054; 0055
[4] Patent: WO2009/9740, 2009, A1, . Location in patent: Page/Page column 62
[5] Patent: EP2570125, 2013, A1, . Location in patent: Paragraph 0154
[6] Patent: WO2013/37960, 2013, A1, . Location in patent: Page/Page column 74
39
[ 1143534-59-1 ]
[ 3680-69-1 ]
[ 1143532-39-1 ]
Yield
Reaction Conditions
Operation in experiment
42.5%
With N-ethyl-N,N-diisopropylamine In butan-1-ol at 60℃; for 18 h;
Example 9 alternative route 1: (S)-4-amino-N-Q-(4-chlorophenyl)-3-hvdroxypropyl)- l-(7H-pyrrolo [2,3-dl pyrimidin-4-yl)piperidine-4-carboxamideN-Ethyldiisopropylamine (1.676 ml, 9.62 mmol) was added to (S)-4-amino-N-(l-(4- chlorophenyl)-3-hydroxypropyl)piperidine-4-carboxamide (Intermediate 49) (Ig, 3.21 mmol) and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.493 g, 3.21 mmol) in butan-1-ol (15 ml). The resulting solution was stirred at 600C for 18 hours. The reaction mixture was diluted with EtOAc (50 mL), and washed sequentially with water (25 mL) and saturated brine (25 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 6percent MeOH with ammonia in DCM. Pure fractions were evaporated to dryness to afford (S)-4-amino-N-(l-(4-chlorophenyl)-3-hydroxypropyl)-l-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperidine-4-carboxamide (842mg) as a white foam. (S)-4-amino-N-(l- (4-chlorophenyl)-3-hydroxypropyl)-l-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4- carboxamide was stirred in ethyl acetate (7 mL) for 18 hours. The solid was collected by filtration, washed with a small amount of ethyl acetate and vacuum oven dried at 55°C for 18 hours to afford (S)-4-amino-N-(l-(4-chlorophenyl)-3-hydroxypropyl)-l-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (0.585 g, 42.5 percent) as a white solid, m/z (ES+) (M+H)+ = 429; HPLC tR= 1.60 min. IH NMR (400.13 MHz, DMSO-d6) δ 1.39 - 1.47 (2H, m), 1.80 - 2.02 (4H, m), 2.17 (2H, s), 3.35 - 3.40 (2H, m), 3.50 - 3.59 (2H, m), 4.34 - 4.41 (2H, m), 4.53 (IH, t), 4.88 (IH, d), 6.57 (IH, m), 7.14 - 7.16 (IH, m), 7.31 - 7.37 (4H, m), 8.12 (IH, s), 8.42 (IH, d), 11.62 (IH, s)
Reference：
[1] Journal of Medicinal Chemistry, 2013, vol. 56, # 5, p. 2059 - 2073
41
[ 18997-19-8 ]
[ 3680-69-1 ]
[ 1146629-75-5 ]
Yield
Reaction Conditions
Operation in experiment
98.85%
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 14 h;
4-chloro-7H-pyrrolo[2,3-d]pyrimidine (25 g; Formula III), potassium carbonate (27 g), and chloromethyl pivalate (27 g; Formula IV) were added to a reaction vessel containing N,N-dimethylformamide (100 mL) at ambient temperature. The reaction mixture was stirred for 14 hours. The progress of the reaction was monitored by thin layer chromatography. Water (250 mL) was added to the reaction mixture, and then the mixture was stirred for 2 hours. The reaction mixture was filtered, then washed with water (50 mL), and then dried under reduced pressure at 40°C to 45°C for 12 hours to obtain (4- chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2,2-dimethylpropanoate. Yield: 98.85percent
91%
Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; Inert atmosphere Stage #2: at 0 - 20℃; Inert atmosphere
(4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (3f).; To a oven dried 2 L 4-neck round bottom flask equipped with overhead stirring, septa, thermocouple, 500 mL addition funnel and nitrogen inlet was charged sodium hydride (NaH, 60 wt percent, 29.7 g, 0.742 mol, 1.34 equiv) and anhydrous tetrahydrofuran (THF, 400 mL, 5.0 mol) and the resulting mixture was cooled to 0-3° C. To a oven dried 1 L round bottom flask was charged 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 85.0 g, 0.553 mol) and tetrahydrofuran (600 mL, 7.0 mol) resulting in a slurry. This resulting slurry was then portion wise added to the suspension of sodium hydride in THF via large bore canula over 27 minutes at 0-5° C. The resulting solution was heterogeneous and green in color. Following the addition, the cold bath was removed and the mixture was gradually warmed to room temperature and allowed to stir at room temperature for 1 hour before being cooled to 0-5° C. Chloromethyl pivalate (pivaloyloxymethyl chloride, POM-Cl, 103 ml, 0.692 mol, 1.25 equiv) was added portion wise into the reaction mixture over 25 minutes via syringe with stirring at 0-5° C. The addition of chloromethyl pivalate (POM-Cl) was mildly exothermic and the reaction temperature went to as high as 14° C. After addition of chloromethyl pivalate (POM-Cl), the cooling bath was removed and the reaction mixture was allowed to return to room temperature and stirred at room temperature for overnight. When the reaction was deemed complete after about 16 hours, the reaction was quenched with 20percent aqueous brine (250 mL) and ethyl acetate (250 mL) producing a slurry. Additional amount of water (250 mL) was added until the mixture becomes a homogeneous solution. The two layers were separated and the aqueous layer was extracted with ethyl acetate (250 mL). The combined organic fractions were dried over magnesium sulfate (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 10percent to 15percent ethyl acetate/hexane gradient elution) to afford the desired product as yellow, crystalline solids (155 g). The combined solids were treated with hexanes (750 mL) and the resulting slurry was warmed to 55° C. to produce a homogeneous solution. The resulting solution was then gradually cooled to room temperature and stirred at room temperature for overnight before being cooled to 0-5° C. for 2 h. The solids were collected by filtration, washed with pre-cooled hexanes (2.x.30 mL), dried in vacuum to afford 4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (3f, 134.9 g, 148.0 g theoretical, 91percent yield) as white solids. For 3f: 1H NMR (DMSO-d6, 400 MHz) δ ppm 8.71 (s, 1H), 7.83 (d, 1H, J=3.7 Hz), 6.73 (d, 1H, J=3.8 Hz), 6.23 (s 2H), 1.06 (s, 9H); 13C NMR (DMSO-d6, 100 MHz) δ ppm 176.9, 151.2, 151.1, 151.0, 131.6, 117.1, 99.9, 66.9, 38.3, 26.5; C12H14ClN3O2 (MW, 267.71), LCMS (EI) m/e 268/270 (M++H).
91.6%
Stage #1: With sodium t-butanolate In tetrahydrofuran at -10 - 20℃; Inert atmosphere Stage #2: at 20℃;
Under inert gas protection,Sodium tert-butoxide (40.7 g, 0.424 mol) and tetrahydrofuran (500 ml) were added to the reaction flask, stirred for 0.5 to 3 hours,Chloro-7H-pyrrolo [2,3-d] pyrimidine (50 g, 0.326 mol) was dissolved in tetrahydrofuran (500 ml)a solution of 4-chloro-7H-pyrrolo [2,3-d] pyrimidine in tetrahydrofuran was added dropwise to the reaction flask at -10 ° C to 5 ° C,after completion of the dropwise addition, the mixture was allowed to stand at room temperature and stirred at that temperature for 5 to 8 hours and then cooled to -10 ° C to 5 ° C,the chloromethyl pivalate (58.8g, 0.39mol) was added to the reaction flask,after completion of the dropwise addition, the reaction was allowed to stand at room temperature and the reaction was stirred at that temperature for 10 to 12 hours.After completion of the reaction, the reaction was quenched with water, concentrated in tetrahydrofuran in the reverse solution, stirred with ethyl acetate and the aqueous phase was separated. The aqueous phase was extracted with ethyl acetate once and the organic phase was separated,Then, the ethyl acetate in the reaction solution was replaced with n-heptane, the reaction solution was cooled, filtered to obtain a wet product,The wet product was crystallized from n-heptane and dried to obtain 79.8 g of product, purity: 99.3percent, yield: 91.6percent.
170 mg
Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.166667 h; Stage #2: at 0 - 20℃; for 1.5 h;
4-chloro-7H-pyrrolo[2,3-d]pyrimidine (100 mg, 0.651 mmol) was dissolved in tetrahydrofuran (5 mL). The temperature was lowered to 0° C., and sodium hydride (60percent in mineral oil, 52 mg, 1.30 mmol) was added to the reaction solution. After 10 minutes, chloromethyl pivalate (0.19 mL, 1.30 mmol) was added at 0° C. After stirring for 1.5 hours at room temperature, the reaction solution was put into a saturated ammonium chloride aqueous solution. The organic layers were separated and the aqueous solution layer was extracted with ethyl acetate. The collected organic layers were washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, EA:Hx=1:4) to obtain (4-chloro-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl pivalate (170 mg, 0.635 mmol) as a white solid. MS m/z [M+1] 268.01.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,4-dioxane; water at 80 - 85℃; for 5 h;
4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (0.8 g; Formula IX) was added into a reaction vessel containing a solution of potassium carbonate (2.1 g) in water (30 mL) at about 20°C to about 25°C. A solution of { l-(ethylsulfonyl)-3-[4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl]azetidin-3-yl}acetonitrile (2.0 g; Formula V) in 1,4-dioxane (30 mL) was added into the reaction mixture at about 20°C to about 25 °C, followed by the addition of tetrakis(triphenylphosphine)palladium(0) (0.1 g). The reaction mixture was stirred at about 80°C to about 85°C for about 5 hours. On completion of the reaction, 1,4-dioxane was recovered from the reaction mixture under reduced pressure at about 45°C to obtain a residue. Ethyl acetate (50 mL) was added into the residue, and then the contents were stirred for about 5 minutes. The organic and aqueous layers were separated. The organic layer was concentrated under reduced pressure at about 45°C to obtain baricitinib. Yield: 99.0percent
90%
With tetrakis(triphenylphosphine) palladium(0); cesium fluoride In water; toluene; <i>tert</i>-butyl alcohol at 100℃; for 48 h; Inert atmosphere
Compound 5 (0.092g, 0 . 24mmol), compound 11 (0.037g, 0 . 24mmol), cesium fluoride (0.129g) and Pd (PPh 3) 4 (0.028g) adding toluene, tertiary butyl alcohol and water (1:1:1) in the mixed solvent, nitrogen protection, 100 °C reflux reaction 48 hours, cooling to room temperature, a diatomite filter. Ethyl acetate for flushing diatomite, collect filtrate, separating organic layer, the aqueous layer extracted with ethyl acetate, the organic layer concentrated, drying, column chromatography purification to obtain white solid 0.060g, yield 90percent.
90%
With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 In tetrahydrofuran; water at 90℃; for 19 h; Autoclave; Inert atmosphere
2~yl)-lH-pyrazol-l-yl]azetidm-3-yl}acetonitrile (5.00 g, 13.15 mmol), potassium phosphate tribasic (2.80 g, 13.19 mmol) and a mixture of dichloro[l, - bis(dicyclohexylphosphino)ferrocene] palladium(ll) with potassium phosphate tribasic (2.84 g of the mixture containing 50 mg total with 0.07 mmol palladium catalyst). THF (21 mL) is added to the autoclave followed by water (5.3 mL). The autoclave is sealed and the contents are heated to 90 °C for 19 hours. The reaction mixture is cooled and the resulting suspension is diluted with THF (40 mL) and water (10 mL). The solution is filtered through a mixture of diatomaceous earth (0.4 g) and carbon (0.2 g). The filtrate is concentrated under vacuum to remove THF. An aqueous buffer solution (pH = 7, 30 mL) is added followed by l-butanol (30 mL). The mixture is heated to 85 °C with stirring to dissolve residual solids. Stirring is stopped and the lower aqueous layer is removed. Water (10 mL) is added to the stirred l-butanol layer. Stirring is discontinued and the lower aqueous layer is removed. The l-butanol layer is cooled to 75 °C and stirred for 30 minutes. The solution is further cooled to 20 °C over 6 hours and the resulting slurry is held at that temperature overnight. The solids are collected by filtration, washed with 9: 1 v/v 1 -butane i/water (10 mL) and dried at 40 °C to give the title compound (3.45 g, 70.6percent). The title compound (2.5 g, 6.73 mmol) is combined with l-butanol (12.6 mL) and water (3.8 mL). The mixture is heated to 85 °C and stirred for 30 minutes. The solution is cooled to 20 °C over 7 hours to provide a slurry. The solids are collected by filtration then washed with 1-butanol followed by water. The solids are dried to give the title compound (2.25 g, 90percent after recrystallization of 2.5 g).
84%
With tetrakis(triphenylphosphine) palladium(0); cesium fluoride In water; toluene; <i>tert</i>-butyl alcohol for 48 h; Reflux; Inert atmosphere
To a flask were added 2-{1-(ethylsulfonyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (12) (870 mg, 2.3 mmol, 1.1 equiv.), 4-chloro-7-H-pyrrolo[2,3-d]pyrimidine (5) (290 mg, 0.19 mmol), caesium fluoride (1120 mg), tetrakis(triphenylphosphine)palladium (240 mg, 0.1 equiv.), tertbutanol (10 mL), water (10 mL) and toluene (10 mL) at ambient temperature. The resulting reaction mixture was heated to reflux under nitrogen for 48 h. Then the reaction mixture was cooled to room temperature and filtered through a Celite bed. The Celite bed was washed with ethyl acetate and the aqueous layer was extracted with ethyl acetate. The combined organic layers were concentrated under reduced pressure to remove solvents and the crude product was purified by flash chromatography on a silica gel column eluting with methanol in dichloromethane (0–60percent) to afford baricitinib: Yield 560mg (84percent); m.p. 193–195 °C; IR: 3203, 3113, 2998, 2847, 2363, 1584, 1328, 1137 cm–1. Anal. calcd for C16H17N7O2S: C, 51.74; H, 4.61; N, 26.40; found: C, 51.91; H, 4.49; N, 26.57percent. MS (m/z): 372 [M + H]+;1H NMR (300 MHz, DMSO-d6): δ 1.25 (t, J = 7.3 Hz, 3H), 3.23 (m, J= 7.3 Hz, 2H), 3.69 (s, 2H), 4.24 (d, J = 9.0 Hz, 2H), 4.61 (d, J = 9.0 Hz,2H), 7.08 (s, 1H), 7.62 (s, 1H), 8.47 (s, 1H), 8.71 (s, 1H), 8.92 (s, 1H),12.12 (s, 1H); 13C NMR (125 MHz, DMSO-d6): δ 7.4, 24.9, 39.3, 43.4, 58.5, 99.9, 113.0, 116.6, 126.9, 129.5, 139.9, 149.3, 150.9, 152.2.
Reference：
[1] Patent: WO2016/125080, 2016, A2, . Location in patent: Page/Page column 12
[2] Patent: CN105541891, 2016, A, . Location in patent: Paragraph 0117; 0120; 0121; 0122; 0129; 0130
[3] Patent: WO2016/205487, 2016, A1, . Location in patent: Page/Page column 32-33
[4] Journal of Chemical Research, 2016, vol. 40, # 4, p. 205 - 208
43
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[ 1187594-09-7 ]
Yield
Reaction Conditions
Operation in experiment
73%
With palladium diacetate; caesium carbonate; [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane In N,N-dimethyl acetamide; water at 95 - 100℃; Inert atmosphere
A solution of 2-(3-(4-(5,5-dimethyl-1,3,2-dioxaborate-2-yl)-1H-pyrazol-1-yl)-1(ethylsulfonyl)azetidin-3-yl)acetonitrile (36.62 g, 1OO mmol)4-chloro-7H-pyrrolo[2,3-d]pyrimidine (16.12 g, 105 mmol)Cesium carbonate (52.92 g, 150 mmol),N, N-dimethylacetamide (180 mL) and water (36 mL)Stirring dissolved after vacuum switch nitrogen 3 times,Palladium acetate (113 g, 0.5 mmol) was added under nitrogen atmosphere,Ligand XtanPhos(289 mg, 0.5 mmol),And then vacuum switch nitrogen 3 times,Then heated to 95 ~ 100 ° C for 5-6 hours,The reaction was quenched by adding water (180 mL) and the mixture was extracted twice with ethyl acetate (180 mL). The combined organic phase was washed twice with water (180 mL), filtered through celite and concentrated to recrystallize with isopropanol and water Biti products (27. llg, 73percent).
Reference：
[1] Patent: CN106946917, 2017, A, . Location in patent: Paragraph 0097-0099
44
[ 3680-69-1 ]
[ 1187594-09-7 ]
Reference：
[1] Patent: WO2016/205487, 2016, A1,
[2] Patent: CN107176955, 2017, A,
[3] Patent: CN108129482, 2018, A,
With tetrakis(triphenylphosphine) palladium(0); sodium hydrogencarbonate In 1,4-dioxane; water at 85℃; Inert atmosphere
2-(3-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile (8) [0148] To a 25-mL flask equipped with a nitrogen inlet, a thermocouple, an additional funnel, and a magnetic stirrer were added 2-(1-(1-(3-fluoro-2-(trifluoromethyl)-isonicotinoyl)piperidin-4-yl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (11, 307 mg, 0.546 mmol), 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (4, 84.8 mg, 0.548 mmol, 1.0 equiv), sodium bicarbonate (NaHCO3, 229 mg, 2.72 mmol, 5.0 equiv), water (1.6 mL), and 1,4-dioxane (1.6 mL) at ambient temperature. The mixture was then treated with tetrakis(triphenylphosphine)palladium(0) (12.8 mg, 0.011 mmol, 0.02 equiv) at ambient temperature and the resulting reaction mixture was de-gassed and refilled with nitrogen for 3 times before being heated to 85° C. The reaction mixture was stirred at 85° C. under nitrogen for overnight. When the reaction was complete as monitored by HPLC, the reaction mixture was concentrated to dryness under reduced pressure and the desired product, 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile (8 free base, 135 mg, 302.2 mg theoretical, 44.6percent), was obtained as off-white solids by direct silica gel (SiO2) column chromatography (0-10percent of ethyl acetate in hexane gradient elution) purification of the dried reaction mixture. The compound obtained by this synthetic approach is identical in every comparable aspect to the compound 8 manufactured by the synthetic method as described above in Example 1.
Step 1: Synthesis of 2R,3S,5R)-5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(((4-methylbenzoyl)oxy)methyl)tetrahydrofuran-3-yl 4-methylbenzoateTo a suspension of sodium hydride (60percent dispersion in mineral oil, 0.272 g, 6.79 mmol) in anhydrous acetonitrile (50 ml) under argon atmosphere in a 250 ml three necked round-bottom flask, was added 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.948 g, 6.17 mmol) and the mixture was stirred at ambient temperature for 30 minutes. (2R,3S,5R)-5-chloro-2-(((4-methylbenzoyl)oxy)methyl)tetrahydrofuran-3-yl 4-methylbenzoate (2.4 g, 6.17 mmol) was added in portions with stirring. The reaction mixture was heated to 50 °C and stirred for 2 hours. The reaction progress was monitored by TLC & LCMS. Evaporation of the reaction mixture gave an oily residue, which was purified by silica-gel chromatography with ethyl acetate/petroleum ether (1 :6, v/v) to give the title compound. H-NMR: (300MHz, COCh, ppm): delta 8.64 (s, 1H), 7.98 (d, J=8.1Hz, 2H), 7.92 (d, J=8.1Hz, 2H), 7.43 (d, J=3.6Hz, 1H), 7.20-7.30 (m, 4H), 6.82 (dd, J=5.7Hz, J=8.1Hz, 1H), 6.60 (d, J=3.9Hz, 1H), 4.60-4.76 (m, 3H), 2.86-2.96 (m, 1H), 2.74-2.82 (m, 1H), 2.43 (d, J=5.4Hz, 6H). LC-MS: (ES, m/z): 506.43 [M+H]+.
1.95 g
To a round bottomed flask was added powdered KOH (1.28 g, 22.8 mmol), anhydrous acetonitrile (50 mL), tris(2-(2-methoxyethoxy)ethyl)amine (0.29 mL, 0.91 mmol) and the mixture was stirred at RT for 5 min. To the resulting suspension was added 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1 g, 6.5 mmol) and stirring continued at RT for 5 more minutes. To the resulting suspension was added (2R,3S,5R)5 -chloro-2-( ( ( 4-methylbenzoy l)oxy )methy l)tetrahydrofuran-3-yl 4-methylbenzoate (Carbosynth, 2.53 g, 6.51 mmol) portionwise over a 5 minute period and stirring continued at RT for 30 minutes. The reaction mixture was then filtered and the residue was washed with MeCN. The filtrate was concentrated and purified by silica gel chromatography using a 120 g ISCO column (27 min gradient, with 0-50percent ethyl acetate in hexanes). The product containing fractions were combined and concentrated in vacuo to afford Intermediate 6A (1.95 g, 3.85 mmol) as a colorless solid. 1 H NMR (499 MHz, DMSO-d6) ll 8.65 (s, lH), 7.99-7.94 (m, 3H), 7.85 (d, 1=8.1 Hz, 2H), 7.38 (d, 1=8.0 Hz, 2H), 7.31 (d, 1=8.0 Hz, 2H), 6.80-6.74 (m, 2H), 5.76 (dt, 1=6.3, 2.4 Hz, lH), 4.66-4.50 (m, 3H), 3.21-3.13 (m, lH), 2.77 (ddd, 1=14.3, 6.1, 2.5 Hz, lH), 2.41 (s, 3H), 2.38 (s, 3H). LCMS, [M+Hr=506.2, tR: 1.17 min, Analytical LCMS method A.
With caesium carbonate; In DMF (N,N-dimethyl-formamide); at 20℃; for 1h;
lodomethane (12.2 mL, 195 MMOL) was added to a solution of 4-Chloro-7H- pyrrolo [2,3-d] pyrimidine (15.0 g, 97.7 MMOL) and cesium carbonate (47.7 g, 146.5 MMOL) IN DMF (200 mL). The reaction mixture was stirred at room temperature 1 h, quenched with H20 (500 mL), and extracted with EtOAc (3X200ML). The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash column chromatography (silica, 2: 8X3 : 7 EtOAc: hexanes) provided the title compound as an off-white solid (15.4 g, 94%). MS: 168.5 (MH+) ; HPLC Rf : 3.45 min. (HPLC method 4); HPLC purity: 96%.
83%
Step 1 : To a stirred solution of 4-chloro-7/-/-pyrrolo[2,3-d]pyrimidine (4 g, 26.143 mmol) in THF (40 mL) was added potassium tertiary butoxide (3.8 g, 33.986 mmol, 1.3 equiv) at 0C. The reaction mixture was allowed to stir at room temperature for 20 min. Methyl iodide (2.4 mL, 39.215 mol, 1.5 equiv) was added at 0C to the reaction mixture and stirred for 4h at room temperature. The solvent was evaporated, diluted with ice water (50 mL) and the precipitated solid was filtered & dried in vacuo to give 4-chloro-7-methyl- 7H-pyrrolo[2,3-d]pyrimidine as off white solid (3.6 g, 83 %). LCMS (ES) m/z = 168.1 [M+H]+. H NMR (400 MHz, DMSO-d6) delta ppm 3.84 (s, 3H), 6.62 (d, J = 3.2 Hz, 1 H), 7.72 (d, J = 3.2 Hz, 1 H), 8.62 (s, 1 H).
81%
With caesium carbonate; In 1-methyl-pyrrolidin-2-one; at 15 - 23℃; for 4.5h;
Add Cs2CO3(845 g, 2.60 mol) at 15 C to a solution of 4-chloro-7H-pyrrolo[2,3- d]pyrimidine (200 g, 1.29 mol) in N-methyl-2-pyrrolidone (1.20 L). Warm to 23 C, add Mel (202 g, 1.43 mol) dropwise over 30 min, and stir for 4 h. After this time, pour onto ice-water (2.00 L) and stir for 30 min. Filter, then slurry material in H20 (1.00 L). Filter and dry to give the title compound (180 g, 81%). ES/MS m/z (35C1) 168.0 (M+H).
With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 0 - 20℃; for 3h;
4-chloro-7-methyl-7H-p yrrolo[2,3-d ID yrimidineTo 4-chloro-1 H-pyrrolo[2,3-d]pyrimidine (15.2 g, 99 mmol) in N,N-Dimethylformamide (DMF) (100 mL) at 0 C was added 60% NaH (5.15 g, 129 mmol) portionwise. After H2 bubbling stopped, iodomethane (6.81 mL, 109 mmol) was added dropwise, and then the reaction mixture was allowed to warm to room temperature. After 3 hours, the reaction mixture was poured slowly onto water (-800 mL; Caution: H2 evolution due to quenching excess NaH). The resulting solid was filtered and washed with water followed by hexanes to afford 4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine (12.2 g) as an off-white solid.
With sodium hydride; In tetrahydrofuran; at 0 - 20℃; for 3h;
Iodomethane (0.04 ml, 0.6 mmol) was added to a solution of 1a (92 mg, 0.6 mmol), NaH (24 mg 60%, 0.6 mmol) in 5 mL dry THF at 0 C. After stirring for 3 h at room temperature, the reaction went to completion according to TLC. Water (10 mL) was added and the mixture was extracted with ethyl acetate (3 * 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which was added to a solution of amino-phenol (66 mg, 0.6 mmol) and Cs2CO3 (585 mg, 1.8 mmol) in 10 mL DMSO without further purification. After stirring for 6 h at 80 C, the mixture was cooled to room temperature and extracted with ethyl acetate (3 * 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which was further purified by column chromatography (petroleum ether/ethyl acetate 2:1) to afford compound 3c as a yellow solid (104 mg, 72% over two steps): 1H NMR (300 MHz, CDCl3) delta 8.40 (s, 1H), 7.02-6.91 (m, 3H), 6.67 (d, J = 8.6 Hz, 2H), 6.31 (d, J = 3.5 Hz, 1H), 3.80 (s, 3H), 2.82 (s, 2H).; 13C NMR (100 MHz, d6-DMSO) delta 162.4, 152.3, 150.2, 146.1, 142.8, 128.7, 122.2, 114.4, 104.4, 97.6, 31.1.; HRMS [M]+ calcd for C13H12N4O 240.1011, found 240.1009. The purity of the compound was >98% by HPLC.
To a stirred solution of Preparation Ria (8 g, 52.1 mmol) in abs. DMF (50 ml) wascooled down to 0 C, then sodium-hydride (3.13 g, 60 % disp. in mineral oil, 78.2 mmol,1.5 eq.) was added, and stirred for 20 minutes at r.t. under Ar. Methyl iodide (8.2 g,57.2 mmol, d=2.28, 3.6 ml) was added to the reaction mixture and stirred for 1.5 hours atr.t. The mixture was poured into water (50 ml). Solid compound was formed, which was filtered off.
4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (Preparation R1a; 1.84 g, 12 mmol, 1 eq.)Sodium hydride (720 mg, 60% dispersion in mineral oil, 18 mmol, 1.5 eq.) was added to a stirred solution in dry DMF (15 ml) and stirred at room temperature under Ar for 10 minutes. An alkylating agent (13.18 mmol) was added to the reaction mixture and stirred at room temperature for 1-6 hours. The mixture was poured into water (150 ml) and then it was extracted with EEO (3 x 150 ml). The combined organic layers were washed with water, brine, dried over MgSO4 and evaporated.The preparation of R2b was achieved using general procedure 1 starting with the preparation of R1a and methyl iodide as the alkylating agent.
With N-chloro-succinimide; In N,N-dimethyl-formamide; at 20℃; for 72h;
General procedure: To a solution of readily available 3a (20mmol) in N, N-dimethylformamide (DMF) (15mL) was added NCS/NBS (21mmol) and the reaction mixture was stirred at room temperature for 72h. Then ice water (150mL) was poured into the mixture, the precipitate was filtered, washed with water (3×100mL), and dried to give 3b and 3c.
95%
With N-chloro-succinimide; In N,N-dimethyl-formamide; at 20℃; for 12h;
Dissolve 4-chloro-pyrrolo[2,3-d]pyrimidine (20 mmol) in DMF (6 mL), add NBS or NCS (21 mmol) in portions on ice bath, react at room temperature for 12 h, and pour the reaction mixture into 80 mL of ice. In the water, a large number of off-white solids precipitated and were filtered. The filter cake was washed with 15 mL of water and dried to give Intermediate 2. 4,5-dichloro-pyrrolo[2,3-d]pyrimidine (2a) Gray solid, yield 95%
88%
With N-chloro-succinimide; In dichloromethane; for 72h;Heating / reflux;
3H, m), 2.4 (3H, s), 1.31 (3H, J=6.8 Hz, d); MS (ES+) [M+H]+=455.6.15. Example 15(S)-N-(3-bromophenyl)-4-(5-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N'-cyano-2-methylpiperazine-1-carboximidamide A. Preparation of 4,5-dichloro-7H-pyrrolo[2,3-d]pyrimidine: 4-Chloro-pyrrolo[2,3-d]pyrimidine (0.5 g, 3.26 mmol) was suspended in anhydrous CH2Cl2 (25 ml), and N-chlorosuccinimide (0.87 g, 6.52 mmol) was added. The reaction mixture was refluxed for 3 days, then cooled to room temperature. The white solid was collected by filtration to give 5-dichloro-7H-pyrrolo[2,3-d]pyrimidine (0.54 g, 2.9 mmol, 88%).1H NMR (CD3OD): delta 8.57 (1H, s), 7.60 (1H, s); MS (ES+) [M+H]+=188.
80%
With N-chloro-succinimide; In dichloromethane; at 20℃; for 6h;Heating / reflux;
PREPARATION 7; 4,5-dichloro-7H-pyrrolor2,3-dlpyrimidineN-Chlorosuccinimide (4.78 g, 35.81 mmol) was added portionwise to a stirred suspension of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (5g, 32.56 mmol) in DCM, dry (125ml) at room temperature. The resulting suspension was stirred for 1 hour then heated to reflux for 5 hours, then allowed to cool down and left to stir at room temperature overnight. The reaction mixture was evaporated and suspended in water (50 mL). The suspension was filtered giving crude product as a grey solid. The solid was suspended in hot methnol and filtered. The solid was then suspended in hot ethyl acetate and filtered to give 4,5- dichloro-7H-pyrrolo[2,3-d]pyrimidine (4.87 g, 80 %) as a grey solid. IH NMR (400.13 MHz, DMSO-d6) delta 7.91 (IH, s), 8.64 (IH, s), 12.87 (IH, s) MS m/e MH+ 188
80%
With N-chloro-succinimide; In dichloromethane; at 20℃;Heating / reflux;
PREPARATION I4,5-dichloro-7H-pyrrolor2,3-dlpyrimidine; N-Chlorosuccinimide (4.78 g, 35.81 mmol) was added portionwise to a stirred suspension of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (5g, 32.56 mmol) in DCM, dry (125ml) at room temperature. The resulting suspension was stirred for 1 hour then heated to reflux for 5 hours, then allowed to cool down and left to stir at room temperature overnight. The reaction mixture was evaporated and suspended in water (50 mL). The suspension was filtered giving crude product as a grey solid. The solid was suspended in hot methnol and filtered. The solid was then suspended in hot ethyl acetate and filtered to give 4,5- dichloro-7H-pyrrolo[2,3-d]pyrimidine (4.87 g, 80 %) as a grey solid. IH NMR (400.13 MHz, DMSO-d6) delta 7.91 (IH, s), 8.64 (IH, s), 12.87 (IH, s) MS m/e MH+ 188
72%
With N-chloro-succinimide; In dichloromethane; at 20℃; for 18h;
METHOD I 4,5-Dichloro-7H-pyrrolo[2,3-d]pyrimidine 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (154 mg, 1.0 mmol) was suspended in 6.0 mL of dry dichloromethane in a flame-dried flask and to this mixture was added N-chlorosuccinimide (147 mg, 1.1 mmol) in one portion. The resulting mixture stirred at room temperature for 18 h, at which time the solvent was removed under reduced pressure. The residue was triturated with water and isolated by filtration to afford 137 mg (72%) of the title compound as a gray solid, mp 224-227 C.(dec). LRMS: 188 (M+1).
With N-chloro-succinimide; In dichloromethane; for 18h;Reflux;
C. Preparation of 4,5-dichloro-7H-pyrrolo[2,3-d]pyrimidine. To a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (154 mg, 1.0 mmol) in CH2Cl2 (6 mL) was added NCS (134 mg, 1.0 mmol). The reaction mixture was refluxed for 18 hours, filtered, and concentrated under vacuum to give the title compound, which was carried on crude. MS (ES+) [M+H]+=189.
With N-chloro-succinimide; In dichloromethane; at 20 - 60℃; for 38h;
4-cUoro-lH-pyrrolo[2,3-d]pyrirddine( lg, 6.5mmol, commercially available from e.g. Sigma- Aldrich, Apollo or Alfa Aesar) was dissolved in DCM ( 30ml) and then NCS (1.04g, 7.8mmol) was added . The reaction mixture was stirred at room temperature for 16 hours, and then heated at 60C for 22 hours. After cooling a light yellow solid was obtained by filtration of the desired product in 1.2g. LCMS [MH+] 188.0 (at) 1.42 min ( 5 min run)
With N-chloro-succinimide; In dichloromethane; at 40℃; for 16h;Inert atmosphere;
Step l:Synthesis of 4,5-dichloro-7H-pyrrolo[2,3-d]pyrimidineTo a mixture of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (2.5 g, 16.28 mmol) in dry DCM (100 mL) was added NCS (4.35 g, 32.6 mmol) at 25 C. The resulting mixture was stirred for 16 hours at 40 C under argon atmosphere. When the 4-chloro-7H-pyrrolo[2,3-d]pyrimidine was consumed, the mixture was filtered directly without cooling. The solid was collected, washed with DCM (20 ml), dried under vacuum to give 4,5-dichloro-7H-pyrrolo[2,3-d]pyrimidine as a solid. LC-MS: (ES, /// r): 188.01 [M+H]+. H- MR: (300MHz, d6-OMSO, ppm): delta 12.90 (br, 1H), 8.65 (s, 1H), 7.93 (d, J= 2.7Hz, 1H).
1.08 g
With N-chloro-succinimide; In dichloromethane; for 72h;Reflux;
To a solution of 4-chloro-7H-pyrrolo[2,3-djpyrimidine (2.0 g, 13.04 mmol) in DCM (80 mL) was added N-chlorosuccinimide (1.7 g, 13.04 mmol). The reaction mixture was refluxed 3 days. The reaction mixture was dissolved in water and extracted with EtOAc (3 x 50 mL). Combined organic layers were dried over Mg504, filtered and evaporated to afford 4,5-dichloro-7H-pyrrolo[2,3- djpyrimidine (1.08 g). LCMS: MW (calcd): 186.97; MS (ES, m/z): 187.98 (M+H).
With potassium carbonate; In N,N-dimethyl-formamide;
METHOD L 7-Benzyl-4-chloro-7H-pyrrolo[2,3-d]pyrimidine To a stirred solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (250 mg/1.63 mmol) in 12 mL of DMF was added 676 mg (4.89 mmol) of potassium carbonate and the resulting mixture stirred at room temperature for 20 min. Benzylchloride (310 mg/2.45 mmol) was added and the new mixture stirred at room temperature for 24 h then filtered, concentrated and the residue purified by silica gel chromatography (3:1 hexanes/ethyl acetate) affording 318 mg (80%) of the title compound. LRMS: 244.1 (M+1).
With hydrogen;palladium 10% on activated carbon; In methanol; under 760.051 Torr; for 16h;
As shown in Figure 1-step i, 4-chloro-7H-pyrrolo[2,3-d]pyrimidine(compound 1001) (130 mg, 0.847 mmol) was dissolved in 3 mL of methanol and hydrogenated under 1 atm of hydrogen over Pd-C 10% for 16 hours. Concentration to dryness provided 100 mg (98%) of 7H-pyrrolo[2,3-d ]pyrimidine [compound 1002, 1H-NMR(CD3OD): delta 9.4 (s, IH); 9.1 (s, IH); 7.9 (s, IH); 7.1 (s, IH)].
97%
With ammonium formate;20% Pd(OH)2 on carbon; In methanol; for 2h;Heating / reflux;
(R)-6-Pyrrolidin-2-ylmethyl-7H-pyrrolo[2,3-d]pyrimidine.(Compound 95) Commercially available 6-chloro-7-deazapurine (1.58 g, 10.3 mmol), 3.25 g ammonium formate (51.6 mmol) and 20% Pd(OH)2/C (140 mg) were combined in MeOH (50 ml) and warmed to reflux for 2 hours. The mixture was cooled, filtered, concentrated and re-dissolved in MeOH. Filtration over 25 g SCX-2 (MeOH followed by 1 N NH3/MeOH), followed by flash chromatography (ethyl acetate/MeOH (9/1)) afforded compound 90 (1.2 g, 4.02 mmol, 97%) amorphous material. 1H-NMR (400 MHz, CDCl3): delta 11.1 (bs, 1H), 9.1 (bs, 1H), 9.0 (bs, 1H), 7.45-7.40 (m, 1H), 6.68-6.62 (m, 1H).
With hydrogen;palladium 10% on activated carbon; In methanol; at 20℃;
Synthesis of compound 5B-1; Compound 5B-2 (5 g, 32.6 mmol) was dissolved in MeOH (100 mL), 10%Pd/C was added. The reaction was stirred under H2 at room temperature for overnight. The reaction was filtered, and concentrated. The crude product (compound 5B-1) was used directly in the next step (3.88 g).
With Selectfluor; In acetic acid; acetonitrile; at 20 - 70℃; for 14h;
4-CHLORO-7H-PYRROLOPYRIMIDINE 1 (5 g, 32.7 mmol) and Selectfluor (17.35 g, 49 mmol) were placed in a round bottom flask, followed by the addition of dry acetonitrile (250 mL) and ACOH (50 mL). The solution was then heated at 70 C for 14 h under N2. After cooling to room temperature, the solvent was removed in vacuo and co-evaporated with toluene (50 mL x 2). The solid was dissolved in a mixture of DCM : EtOAc (1: 1) and filtered through a pad of silica gel which was thoroughly washed. The combined washings were evaporated. And the crude product was then subjected to column chromatography with DCM: EtOAc (4: 1) to give 3.3 g (59% yield) of 2 as a white SOLID. 1H NMR (DMSO-d6) 8 7.73 (s, 1H), 8.64 (s, 1H), 12.5 (br s, 1H); 13C NMR (DMSO-d6) 8 105.3 (d, J= 14.3 Hz), 111.0 (d, J= 25. 5 Hz), 139.6 (d, J= 244.5 Hz), 146.7 (d, J= 1.5 Hz), 148. 5 (d, J= 3.8 Hz), 151.0 ; 19F NMR (DMSO-D6) 8-170. 7 ( d, J= 1.6 Hz): Mass spectroscopy (MS) measured for C6H3C1FN3 (M+H): 172.0, observed: 172.0.
58%
With acetic acid; Selectfluor; In acetonitrile; at 70℃; for 18h;Inert atmosphere;
To a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (2.00 g) in acetonitrile (100 mL) were added acetic acid (20 mL) and N-fluoro-N'-(chloromethyl)triethylenediamine bis(tetrafluoroborate) (6.92 g), and the mixture was stirred under nitrogen atmosphere at 70C for 18 hours. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. To the residue was added methylene chloride/ethyl acetate (1/1), and the solution was passed through a column packed with silica gel (100 mL) and then extracted with methylene chloride/ethyl acetate = 1/1 (2 L). The extract was concentrated, and the resulting residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 70/30 to 35/65) to give 4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine (1.30 g) as a powder (yield: 58%). MS(APCI)m/z; 172/174[M+H]+.
47%
With acetic acid; Selectfluor; In acetonitrile; at 70℃; for 16h;
Step 1 : Preparation of compound 41b Select?] uor (34.6 g, 97.7 mmol) and AcOH (100 ml.) were added to a solution of 4-chloro- 7H-pyrrolo[2,3-d]pyrimidine [CAS 3680-69-1] (41a, 10.0 g, 65.1 mmol) in dry MeCN (500 mL), the mixture was stirred at 70 C until complete conversion (ca. 16 h). After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and co-evaporated with anhydrous toluene. The resulting solid was dissolved in a DCM / EtOAc (1 : 1 ) solvent mixture, the obtained solution was filtered through a pad of Diatomaceous earth which was thoroughly washed. The combined filtrates were concentrated under reduced pressure. Purification was done by column chromatography over silica gel (gradient elution: 0 - 1% MeOH in DCM) to give compound 41b as an off- white solid (5.2 g, yield: 47%). NMR (500 MHz, DMSO-t/e) d ppm 12.49 (s, 1H), 8.63 (s, 1H), 7.73 (t, .7 = 2.8 Hz, 1H); ESI-MS: m/z 169.8 [M-H] .
41%
With acetic acid; Selectfluor; In acetonitrile; at 70℃;
PREPARATION 144-chloro-5-fluoro-1 /-/-pyrrolo[2,3-c ]pyrimidineA mixture of 6-chloro-7-deazapurine (0.5 g, 3.26 mmol) and Selectfluor (1.730 g, 4.88 mmol) in CH3CN (25 mL) was treated with AcOH (5 mL) and heated at 70 C overnight before being cooled and concentrated. Toluene was added and the mixture was concentrated. The residue was dissolved in 1 :1 EtOAc/CH2CI2 and filtered through a pad of silica gel. The filtrate was concentrated and purified via flash column chromatography (20% EtOAc/CH2CI2) to afford the title compound (0.226 g, 41 %) as a pink solid. 1H NMR (400 MHz, DMSO-d6) delta ppm 12.50 (br. s, 1 H), 8.60 - 8.66 (m, 1 H), 7.73 (t, J = 2.51 Hz, 1 H); MS (m/z) 171.9 (M+H+).
26%
With acetic acid; Selectfluor; In acetonitrile; at 70℃; for 16h;
The solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimi- dine Q-1 (10 g, 65.1 mmol) and Selectfluor (27.7 g, 78.1 mmol) in CH3CN (500 mE) and AcOH (100 mE) was stirred at 70 C. for 16 h. (The reaction was done four times, 10 g of Q-1 in each vessel). The reaction solution turned from colorless to black. TEC (CH2C12/CH3OH=20: 1) showed 20% of the starting material remained, and then the reaction solution was concentrated to give crude solid. The solid was dissolved in EtOAc (1 E), washed with H20 (300 mEx2). The organic layer was concentrated to give Q-2 (7 g) as brown solid. The combined batch four batches were purified by prep-HPEC (0.225% formic acid/acetonitrile) to give Q-2 (11.6 g, 26%) as a white solid. ECMS [M+1] 172; ?H NMR (400 MHz, DMSO-d5) oe ppm 12.47 (s, 1H), 8.62 (s, 1H), 7.72 (d, 1H)
With acetic acid; Selectfluor; In acetonitrile; at 70℃; for 16h;Inert atmosphere;
Method FGeneral method for the synthesis of 4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine:[00376] 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (E-1) (5.01 g, 32.6 mmol, 1 eq) and Selectrluor (17.32 g,48.9 mmol, 1.5 eq) are dissolved in a mixture of dry acetonitrile (250 mL) and AcOH (50 mL). The resulting mixture is stirred at 70 C under argon for 16 h. The mixture is concentrated in vacuo. The residue is dissolved in a mixture of DCM -ethyl acetate (1 :1, 50 mL) and filtered through celite. The filtrate is concentrated in vacuo and the residue is purified by flash chromatography on silica gel (0-0.7% MeOH-DCM) to afford the product, 4-chloro-5-fluoro-7H- pyrrolo[2,3-d]pyrimidine (F-1) as a pink solid.
With acetic acid; Selectfluor; In acetonitrile; at 70℃; for 16h;Inert atmosphere;
General conditions for the preparation of 4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine :4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (F-1) (5.01 g , 32.6 mmol , 1 eq ) and selectfluor (17.32 g , 48.9 mmol , 1.5 eq ) are dissolved in a mixture of anhydrous acetonitrile (250 mL ) and AcOH (50 mL ). The resulting mixture is stirred at 70 C. under argon for 16 h . The mixture is concentrated in vacuo. The residue is dissolved in a mixture of DCM-ethyl acetate (v/v=1/1, 50 mL ) and filtered through celite. The filtrate is concentrated in vacuo and the residue is purified by flash chromatography on silica gel (0-0.7% MeOH-DCM ) to afford the product , 4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine (F-2) .
With acetic acid; Selectfluor; In acetonitrile; at 70℃; for 16h;Inert atmosphere;
A mixture of compound Int-4-1 (14.5 g, 94.42 mmol, 1 eq.) and Selectfluor (50.17 g, 141.63 mmol, 1.5 eq.) was addedACN (725 mE),AcOH (152.25 g, 2.54 mol, 145 mE, 26.85 eq.) and degassed and purged with N2 for 3 times, and then the mixture was stirred at 70 C. for 16 hr under N2 atmosphere. ECMS showed no compound Int-4-1 was remained. Several new peaks were shown on ECMS and 45% of desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with toluene (200 mE) and concentrated under reduced pressure to remove solvent twice. The residue was purified by column chromatography (Si02, petroleum ether/ethyl acetate=30/1 to 8/1) to give compound Int-4 (10 g, 54.46 mmol, 57.68% yield, ECMS purity 93.43%) as a yellow solid. ?H NMR (400 MHz, DMSO-d5) oe ppm 12.49 (br s, 1H) 8.55-8.67 (m, 1H) 7.71 (t, J=2.63 Hz, 1H); ECMS: (M+Hj: 171.9.
4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1-(toluene-4-sulfonyl)-1H-pyrrole-2-carboxylic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 170℃; for 0.166667h;Microwave irradiation;
Example 2; Preparation of PyrroIyl-PyrroIo[2,3-i/]Pyrimidines of the Invention; [ 0238] 4-(7ff-IVr<>K2^^pyrimidin^-yl)-l-(toluene-4-sulfonyl)-lJy- pyrrole-2-carboxylic acid methyl ester (3'); Under N2, Compound 1 ' (1.3 g, 8.49 mmol) and compound T (1.1 equivalent, 9.34 mmol) and K2CO3 (3.3 equivalent, 28 mmol) were dissolved into 9 mL of dioxane and 3 mL of H2O in a microwave. To this reaction mixture, catalytic amount of Pd(PPh3^ was added and the tube was under <n="69"/>microwave irradiation at 1700C for 10 min. After cooled down the reaction mixture, the product crashed out and filtered off the solid, washed with H2O and CH3CN respectively to obtain title compound 3' quantatively. MS +1 = 397.2.
With sodium hydroxide; In water; acetone; at 0 - 20℃; for 6h;
EXAMPLE 13-((3Lambda,4Lambda)-4-Methyl-3-(methyl(7H-pyrrolo[2,3-rf]pyrimidin-4- yl)amino)piperidin-l-yl)-3-oxopropanenitrile mono citrate salt (CP-690550 citrate salt)Step 1[00151] 4-Chloro-7-tosyl-7H-pyrrolor2,3-6?pynmidine: At about O 0C, sodium hydroxide (2 mol/L in water, 8 mL, 1.20 equiv.) was added to a solution of 4- methylbenzene-1-sulfonyl chloride (2.7 g, 13.9 mmol, 1.10 equiv.) and 4-chloro- 7H-pyrrolo[2,3-J]pyrimidine (2 g, 12.8 mmol, 1.00 equiv.) in acetone (20 mL). The resulting solution was stirred at about 20 0C for about 6 hours. The solids were collected by filtration and washed with acetone/water to give the title product as a white solid (4.0 g; yield = 97%). 1H NMR (300 MHz, CDCl3) delta: 8.78 (s, IH), 8.11 (d, J = 8.4 Hz, 2H), 7.80 (d, J = 4.2 Hz, IH), 7.34 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 4.2 Hz, IH), 2.42 (s, 3H). LC-MS: m/z = 308/310 (M+H)+.
97.7%
With dmap; triethylamine; In dichloromethane; at 0 - 20℃; for 0.5h;Large scale;
4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (2kg, 12.96mol) and dichloromethane (40L) were added to the reaction flask at room temperature, stirred and dissolved.Triethylamine (3.88 kg, 38.4 mol) and 4-dimethylaminopyridine (157.6 g, 1.28 mol) were added in that order, and after stirring and dissolved, p-toluenesulfonyl chloride (2.6 kg, 13.6 mol) was added dropwise at 0 C. The chloromethane (30 L) solution was added dropwise, and the mixture was stirred at room temperature for 30 min. After the TLC was applied, the mixture was washed with water (16L×3). The title product (3.9 kg, yield 97.7%) was obtained after drying under reduced pressure.
97.7%
With dmap; triethylamine; In dichloromethane; at 0 - 20℃;Industrial scale;
4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (2 kg, 12.96 mol) and dichloromethane (40 L) were added to a reaction flask at room temperature, and stirred to dissolve. Triethylamine (3.88 kg, 38.4 mol) and 4-dimethylaminopyridine (157.6 g, 1.28 mol) were added successively, and stirred to dissolve. A solution of p-toluenesulfonyl chloride (2.6 kg, 13.6 mol) in dichloromethane (30 L) was added dropwise at 0 C., followed by stirring at room temperature for 30 minutes. After TLC showed that the reaction was completed, the reaction solution was washed with water (16 L×3). The organic phases were combined, dried over anhydrous sodium sulfate and filtrated. The filtrate was concentrated and dried under reduced pressure to obtain the title product (3.9 kg, yield 97.7%). (0109) MS m/z (ESI): 309.0 [M+1] (0110) 1H-NMR (400 MHz, CDCl3) delta 8.77 (s, 1H), 8.10-8.08 (d, 2H), 7.79-7.78 (d, 1H), 7.34-7.32 (d, 2H), 6.72-6.71 (d, 1H), 2.41 (s, 3H).
95%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 2h;
Example 1; 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine; A slurry of 1 (307 mg, 2.00 mmol), Tosyl-chloride (418 mg, 2.20 mmol) and freshly ground K2CO3 (1.1 g, 8.0 mmol) in DMF (5.0 mL) was stirred at R.T. for 2 h. The mixture was partitioned between water and EtOAc and the organic phase was washed with brine (2×), dried (Na2SO4), filtered, and concentrated to provide the title compound (583 mg, 1.89 mmol, 95% yield) as a white solid.
95%
With sodium hydroxide; In acetone; at 20℃;
Dissolve 4-chloro-pyrrolo[2,3-d]pyrimidine or intermediate 2 (10 mmol) in acetone (35 mL), add p-toluenesulfonyl chloride (1 mmol) in an ice bath, and then add 2.0 mol/L NaOH solution (12·5 mmol, 6.2 mL) was stirred overnight at room temperature. After the reaction was completed, a large amount of white solids precipitated, which was filtered. The filter cake was washed with 20 mL of acetone/water (1:1) and dried to obtain Intermediate 3. 4-Chloro-7-p-toluenesulfonyl 7H-pyrrolo[2,3-d]pyrimidine (3a) White solid, 95% yield
90.1%
With sodium hydroxide; In water; acetone; at -5 - 30℃; for 5h;
Example 7; Preparation of 4-chloro-7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidine:; To a clean, dry, nitrogen-purged reactor were charged acetone (87.5 ml), p-toluenesulfonyl chloride (17.1 g, 0.09 mol) and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (25.0 g, 0.16 mol). The reactor was cooled to between -5.0 to 5.00C and 2.5 M sodium hydroxide (78.1 ml) was added at a rate to maintain the temperature below 5.00C. The reactor was warmed to between 20-300C and stirred for a minimum of 5 hours. The resulting solids were isolated by filtration and washed with acetone/water (1 :1 , 25 ml each). After drying for a minimum of 12 hours under vacuum at 40-500C with slight nitrogen bleed, 44.9 g (90.1%) of the title compound were isolated. Mp 140.2-147.70C. Anal. Calcd. for C13H10CIN3O2S: C, 50.73; H, 3.28; N, 13.65. Found: C,50.50; H, 3.06; N, 13.63. 1H NMR (400 MHz, CZ6-DMSO): delta 8.79 (s, 1 H), 8.09 (d, J=4.2 Hz, 1 H), 8.01 (d, J=8.5 Hz, 2H), 7.43 (d, J=8.5 Hz, 2H), 6.92 (d, J=4.2 Hz, 1 H), 2.32 (s, 3H). 13C NMR (400 MHz, dg- DMSO): delta 153.2, 152.7, 151.2, 147.2, 134.3, 131.0, 129.3, 128.5, 119.9, 103.9, 21.8.
90%
With sodium hydroxide; In water; acetone; at 0 - 20℃; for 6h;
P-toluenesulfonyl chloride (67.5 g, 348 mmol, 1.10 eq.) and 4-chloro-7-Hpyrrolo[2,3-d]pyrimidine (50 g,320 mmol, 1.0 eq.) was dissolved in acetone (500 ml), sodium hydroxide solution (2 Min water, 200 ml, 1.20 eq.) was slowly added thereto at 0C, and the reaction was stirred at 20C for 6 hours to precipitate the solid. Filtration and washing with acetone and water gave the white target compound (90 g, yield = 90%).
80%
With sodium hydroxide; In acetone; at 20℃;
A mixture of 4-c oro-7B~pyrfolo[2.s3-dJpyrimidme (10.0 g, 65 mraol), TsCl (13.7 g, 72 iirniol) and NaOH (40 ml,, 2N) in acetone (100 mL) was stirred at room temperature overnight. The resulting solid w s collected by filtration and washed with acetone and then with water to give the title compound as a white solid (16 g? 80%). H NM (400 MHz, CDCh) 5 8.7? (s, I B), 8.09 id J 8 0 Hz, 20), 7.77 (d, J 4.0 Hz, 1.H), 7.33 (4 J .0 1 . 2Pi ). 6,70 (d, -4.0 1 / , 2H). 2.40 (s, 3H),
79.2%
With triethylamine; In dichloromethane; at 20℃; for 5h;
The mixture of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (3.0g, 20mM), NEt3 (6.1g, 60mM) and p-toluene sulfonyl chloride (2.6g, 24mM) were stirred at room temperature in dichloromethane (100mL). After 5h, TLC analysis showed the complete consumption of 4-chloro-7H-pyrrolo [2, 3-d] pyrimidine. The reaction mixture was quenched by the addition of water (70mL). After quenching the reaction, the reaction mixture was poured into separator funnel and the aqueous layer was extracted with dichloromethane (100mL×3). The combined organic layers were evaporated in vacuo and purified by silica gel column chromatography to get the product 2a (4.9g, 79.2%) as a white solid. ESI-MS m/z: 308.0 [M+H]+. 1H NMR (300MHz, DMSO-d6): delta 2.37 (3H, s, CH3), 6.96 (1H, d, pyrrolyl-H, J=4.0Hz), 7.48 (2H, d, ArH, J=8.1Hz), 8.05 (2H, d, ArH, J=8.1Hz), 8.12 (1H, d, pyrrolyl-H, J=4.0Hz), 8.82 (1H, s, pyrimidiny-H).
45%
With sodium hydroxide; In water; acetone; at 0 - 20℃; for 6h;
[0152] To a stirred solution of TsCI (1.35 g, 7.0 mmol) and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1.0 g, 6.4 mmol) in acetone (10 mL) was added 2.0 M aqueous NaOH (8 mL, 16 mmol) at 0C. The mixture was stirred at ambient temperature for 6 hours yielding a suspension. The solid product was collected by filtration and washed with acetone/water to afford the title compound as a white solid (0.9 g, 45%). MS (ESl) calcd for C13H10C1N3025: 307.0; found:308.1[M+H]. 1H NMR (400 MHz, CDCI3) 6 8.77 (s, 1H), 8.09 (d, J = 8.0 Hz, 2H), 7.78 (d, J = 4.0Hz, 1H), 7.33 (d, J = 8.0 Hz, 2H), 6.71 (d, J = 4.0 Hz, 1H), 2.41 (s, 3H).
Ca. 2 kg
With sodium hydroxide; In acetone; at -5 - 30℃; for 1h;Autoclave; Large scale;
Autoclave, 3.5L of acetone, p-toluenesulfonyl chloride and 1.36kg 1kg compound 7, followed by stirring under cooling to 0 ~ -5 , maintained at below 5 2.5M sodium hydroxide solution was added dropwise 3.5L, warmed to completion of the dropwise 20-30 deg.] C for 1 h, TLC monitoring completion of the reaction was filtered, washed with 50% acetone, slurried, filtered, drained, and dried in vacuo 50 to give compound 6 about 2kg.
124 g
With tetrabutyl-ammonium chloride; potassium carbonate; In dichloromethane; water; at 20℃;
A mixture of 66 g (0.43 mol) 4-chloro-7H-pyrrolo[2,3-d]pyrimidine, 607 g dichloromethane, 3.0 g tetrabutylammonium chloride, 90 g tosyl chloride, 85 g potassium carbonate and 381 g water is stirred efficiently at room temperature until reaction is complete. The phases are separated and the organic phase is washed with 340 g water. The organic phase is treated with 6.0 g of activated charcoal, completed with 318 g water and the organic solvent removed by distillation. The mixture is supplemented by 318 g heptane and the product is centrifuged, washed with heptane and water and vacuum dried at a temperature of not more than 8oC, yielding 124 g (yield: 0.40 mol, 94% conversion rate) of 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine having a purity of 99.9 area-% measured by HPLC.
With triethylamine;dmap; In dichloromethane; for 0.5h;
Into a solution of 6-chloro deazapurine (2.0 g, 13 mmol, 1.0 eq.) in dichloromethane (65 ml) are added triethylamine (1.98 ml, 14.3 mmol, 1.1 eq.) and 4- dimethylamino pyridine (catalytic). Tosyl chloride (2.55 g, 13.4 mmol, 1.03 eq.) is added in portions into the reaction mixture which is further equilibrated for 30 minutes. The reaction mixture is then partitioned between dichloromethane and water. The organic layer is separated and the aqueous layer is extracted with dichloromethane. The combined organic extracts are washed with water, dried over Na2SO4, filtered and concentrated to afford the 4- chloro-7-(toluene-40sulfonyl)-7H-pyrrolo[2,3-d]pyrimidine which is used in the next step without further purification.
With triethylamine;dmap; In dichloromethane; for 0.5h;Product distribution / selectivity;
To a solution of 6-chloro deazapurine (2.0 g, 13 mmol, 1.0 eq.) in dichloromethane (65 ml) is added triethylamine (1.98 ml, 14.3 mmol, 1.1 eq.) and A- dimethylamino pyridine (catalytic). Tosyl chloride (2.55 g, 13.4 mmol, 1.03 eq.) is added in portions into the reaction mixture which is further equilibrated for 30 minutes. The reaction mixture is then partitioned between dichloromethane and water. The organic layer is separated and the aqueous layer is extracted with dichloromethane. The combined organic extracts are washed with water, dried over Na2SO4, filtered and concentrated to afford the title product 2. The titled compound is used in the next step without further purification.; 5. 4-Chloro-7-(toluene-4-sulfonyl)-7H-py rrolo [2,3-d] py rimidine[00115] Into a solution of 6-chloro deazapurine (4, 10.0 g, 65 mmol, 1.0 eq.) in dichloromethane (325 ml) are added triethylamine (9.9 ml, 71.5 mmol, 1.1 eq.) and 4- dimethylamino pyridine (catalytic). Tosyl chloride (12.76 g, 66.9 mmol, 1.03 eq.) is added in portions into the reaction mixture which is further equilibrated for 30 minutes. The reaction mixture is then partitioned between dichloromethane and water. The organic layer is separated EPO <DP n="35"/>and the aqueous layer is extracted with dichloromethane. The combined organic extracts are washed with water, dried over Na2SO4, filtered and concentrated to afford the title product which is used in the next step without further purification.
In acetone; at 20℃; for 8h;
Weigh 10 grams of 4-chloropyrrole[2,3-d]pyrimidine and 18.6 grams of p-methylsulfonyl chloride into a three-necked flask, measure 20 ml of acetone solution as a solvent, and stir at room temperature for 8 h to obtain Ts protection 4-chloropyrrole[2,3-d]pyrimidine, when the reaction system is too hot, the temperature can be lowered by taking an ice bath.
With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 100℃; for 25.67h;
4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (0.4 M, 300 ul, 120 umol) and benzyl 1,2-dihydro- I'H-spirotindole-S^'-piperidinel-r-carboxylate (0.4 M, 300 ul, 120 umol) in DMSO were mixed together. DIEA (neat, 75 ul, 431 umol) was added. The contents were concentrated to dryness in a Genevac and the reaction vial was capped and heated at 1000C for 25 h, 40 min to form benzyl 1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1 ,2-dihydro-1Eta-spiro[indole-3,4'-piperidine]-1'- carboxylate. THF (0.5 ml) was added to the mixture, followed by lithium aluminum hydride (1 M in THF, 0.24 ml, 240 umol). The resulting solution was shaken at room temperature for 2 h, 20 min. Water (2 ml) and dichloroethane (2 ml) were added to the reaction mixture and the layers EPO <DP n="71"/>were separated. The aqueous layer was re-extracted with dichloroethane (2 ml). The combined organic layers were concentrated to dryness to afford 27.5 mg of a crude product. The material was dissolved in DMSO (1 ml) and purified by HPLC to afford 9.4 mg of the title compound as a TFA salt (18% overall yield after two steps). APCI LCMS: Observed mass: 320.13 (M+1). Retention time: 1.9 min (Method E).
With dmap; bis(trichloromethyl) carbonate; In chlorobenzene; at 50 - 60℃; for 6h;Inert atmosphere;
To a 2000 ml four-neck flask was added 135.1 g (1 mol) of <strong>[3680-71-5]4-hydroxy-7H-pyrrolo[2,3-d]pyrimidine</strong>. Protected with nitrogen, chlorobenzene (540 g) was added, and 178.1 g (0.60 mol) of bis(trichloromethyl)carbonate (BTC) was added.49.3 g (0.4 mol) of 4-dimethylaminopyridine was added, heated to 50-60°C, and stirred at 50-60°C for 6 hours. Cool down to 5-15°C, add 10percent liquid caustic soda to adjust the pH to 8-9, control the temperature <30°C, and complete the addition.Stir at 30-40°C for 0.5-1 hour. It was suction filtered, washed with water and dried in vacuum at 80°C for 8 hours.An approximately 144.7 g of white solid was obtained with a yield of 94.2percent and a purity of 99.0percent.
93%
With trichlorophosphate;
(d) The mixture of 5 g (37 mmol) of <strong>[3680-71-5]7H-pyrrolo[2,3-d]pyrimidin-4-ol</strong> in 50 ml of POCl3 is warmed until the starting material is completely in solution. The mixture is then stirred for a further 45 minutes without further supply of heat, and finally the POCl3 is removed in vacuo. The residue is taken up in ice-water, rendered alkaline using NaHCO3 and extracted with ether. The organic phase is dried and evaporated, giving 5.28 g (93percent) of 4-chloropyrrolo[2,3-d]pyrimidine in the form of a greenish solid which melts at 187-188° C.
91.5%
With trichlorophosphate; at 110℃; for 1h;
Into a 100ml single neck flask was added 3.375g (25mmol) 4- hydroxy-pyrrolo [2,3-d] pyrimidine, and then phosphorous oxychloride was slowly added 50g (326.2mmol), and then was slowly warmed to 110 deg.] C, with stirring at reflux 1h Thereafter, the reaction system by the suspension becomes dark supernatant.Reduced pressure after ice-cooling phosphorus oxychloride was evaporated to dryness, to the residue was added 15mL of water after, the ice bath was slowly added 10percent NaOH aqueous solution was slowly adjusted to PH = 7-8, a large amount of brown solid precipitated, pumping filtered off, washed with water (10mL * 2) and dried.Wherein NaOH aqueous solution is not limited to, use in adjusting the PH can have KOH, CsOH is equally capable of adjusting pH of an aqueous solution of an alkaline substance.After To the dried solid was added 20mL 100mLEA and petroleum ether, and heated to 50 , 1h while stirring until substantially dissolved, 1.2g of activated carbon was added and heating continued for 30 minutes followed by filtration the organic phase under reduced pressure after dried and concentrated to give a yellow solid, which was with ethyl acetate / petroleum ether = 1/3 mixed solvent (20 mL) were successively beating, suction filtration, washed with petroleum ether, and dried to give 3.5g (theoretical yield 3.84 g) as a pale yellow solid, yield 91.5 percent.
88%
With trichlorophosphate; at 85℃;
56.4 g (0.4 mol) of <strong>[3680-71-5]4-hydroxy-7H-pyrrolo[2,3-d]pyrimidine</strong> was dissolved in phosphorus oxychloride,Heat to about 85 degrees, after the reaction is over, distill out excess phosphorus oxychloride.Cool down to about 0 degrees and quench with ice water.Adjust the pH to 7-8 with a saturated solution of sodium bicarbonate, filter, and recrystallize from methanol water.Drying gave 56.1 g of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine in a yield of 88percent.
67.8%
4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (1).; 4-Hydroxy-7H-pyrrolo[2,3-d]pyrimidine (7, 306 g, 2.25 mol) was added in portions over 20 min to phosphorus oxychloride (1050 ml, 1727 g, 11.26 mol, 5.0 equiv). Stirring was continued at room temperature for 15 min then this suspension was slowly heated to reflux and the evolving hydrochloric acid was scrubbed through 20percent sodium hydroxide solution. Reflux was continued for 30 min after all material went in solution. The reaction mixture was allowed to cool to 60° C. and it was poured onto ice (5 Kg) with stirring. Stirring was continued for 20 min and potassium carbonate was slowly added in portions to adjust pH to 7.5. Ice was added as needed to keep the temperature below 20° C. The precipitate was collected by filtration, washed well with water and dried in a vacuum oven (30° C.). The crude material was taken in ethyl acetate and stirred at 50° C. for 1.5 hrs. This solution was treated with charcoal, stirred at 50° C. for an additional 20 min and filtered hot through celite. The resulting solution was concentrated to 900 ml and cooled in an ice bath with stirring. The precipitate was collected by filtration, washed with small volume of cold ethyl acetate and dried in a vacuum oven (40° C.) to afford 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 227g, 334.8 g theoretical, 67.8percent) as yellow to brown crystalline solids. Further concentration of the mother liquor produces an additional crop of the desired product (5-10percent) as yellow to brown crystals of less purity. For 1: 1H NMR (DMSO-d6, 400 MHz) delta ppm 12.58 (bs, 1H), 8.58 (s,1H), 7.69 (d,1H, J=3.5 Hz), 6.59 (d, 1H, J=3.5 Hz); C6H4ClN3 (MW, 153.57), LCMS (EI) m/e 154/156 (M++H).
62%
With trichlorophosphate; at 100℃; for 2.5h;Inert atmosphere;
Phosphorous oxychloride (20 mL) was added to <strong>[3680-71-5]7H-pyrrolo[2,3-d]pyrimidine-4-ol</strong> (1.15 g, 8.5 mmol) and the reaction was heated under N2 atmosphere to 100 °C for 2.5 hours. The initial suspension becomes an homogeneous dark liquid which was then allowed to cool to room temperature. Excess phosphorous oxychloride was removed in vacuo and the residue was cooled in ice bath and crushed ice was added with stirring. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic extracts were washed with sat NaCl (aq) solution, then dried over anhydrous Na2SO4. Mixture was filtered and filtrate solvents removed in vacuo to afford the title compound as a white solid (0.811 g; (62percent): LC/MS: RT = 1.619 min; m/z = 154 [M+H]+. Total run time 3.75 mins; 1H NMR (d6 DMSO): d 6.60 (dd, 1H, J = 3.5, 1.8Hz); 7.69 (dd, 1H, J = 3.6, 2.3 Hz); 8.59 (s,1H), 12.57 (brs 1H).
62%
With trichlorophosphate; at 100℃; for 2.5h;
Step 3 4-Chloro-7H-Pyrrolo[2,3-d]pyrimidinePhosphorous oxychloride was added to 7H-Pyrrolo[2,3-d]pyrimidine-4-ol (1.15 g, 8.5 mmol) and the reaction was heated under N2 atmosphere to 100 0C for 2.5 hours. The initial suspension becomes homogeneous dark suspension which was then allowed to cool to room temperature. Excess phosphorous oxychloride was removed in vacuo and the residue was cooled in ice bath and crushed ice was added with stirring. The mixture was diluted with water (20 ml) and extracted with ethyl acetate (2 x 30 ml). The combined organic extracts were washed with sat NaCI (aq) solution, then dried over anhydrous Na2SO4. Mixture was filtered and filtrate solvents removed in vacuo to afford a white solid (0.811 g; (62percent).LC/MS: RT = 1.619 min; m/z = 154 [M+H]+. Total run time 3.75 mins. 1H NMR (dbeta DMSO): delta 6.60 (dd, 1H, J = 3.5, 1.8Hz); 7.69 (dd, 1H, J = 3.6, 2.3 Hz); 8.59 (s,1H), 12.57 (brs 1 H).
43.4%
d. A suspension of <strong>[3680-71-5]7H-pyrrolo[2,3-d]pyrimidin-4-ol</strong> (84) (5 g, 37.00 mmol) in Phosphorous oxy chloride (50 mL) was heated at reflux with stirring for 1.5 h. The reaction mixture was cooled and concentrated in vacuum to remove Phosphorous oxy chloride. To the residue obtained was added ice cold water and stirred for 30 min. The reaction mixture was extracted with diethyl ether (2 x 500 mL). The organic layers were combined, washed with water (2 x 200 mL); brine (100 mL) dried and concentrated in vacuum. The residue was triturated with hexanes, and the solid obtained was collected by filtration to afford on drying in vacuum 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (85) (2.467 g, 43.4percent) as a white crystalline solid.'HNMR (300 MHz, DMSO) delta 12.58 (s, IH, D2O exchangeable), 8.60 (s, IH), 7.70 (d, J= 3.5, IH), 6.61 (d, J= 3.5, IH); HPLC [Column: Zorbax SBC3, 3.0 x 150 mm, 5 mum, with a ZGC SBC3, 2.1 x 12.5 mm guard cartridge. Mobile phase: 0.1 M Ammonium Acetate /Acetonitrile) Rt = 12.76 min. (97.97 percent).
42%
With trichlorophosphate; for 1.5h;Heating / reflux;
To <strong>[3680-71-5]7H-pyrrolo[2,3-d]pyrimidin-4-ol</strong> (0.425 g, 3.14 mmol) was added phosphorus oxychloride (4 ml). The mixture was heated at reflux for 90 minutes and then cooled to room temperature. The solution was poured onto cracked ice, and extracted with chloroform (3 x 50 ml) and ethyl acetate (100 ml). The extracts were EPO <DP n="126"/>then dried and concentrated, and the residue obtained triturated with hot ethyl acetate (200 ml) to yield the desired product (0.204 g, 42percent).
42%
With trichlorophosphate; for 1.5h;Heating / reflux;
2D. 4-Chloro-7H-pyrrolor2.3-</1pyrimidineTo 7H-pyrrolo[2,3-</Jpyrimidin-4-ol (0.425 g, 3.14 mmol) was added phosphorus oxychloride (4 ml). The mixture was heated at reflux for 90 minutes and then cooled to room temperature. The solution was poured onto cracked ice, and extracted with chloroform (3 x 50 ml) and ethyl acetate (100 ml). The extracts were then dried and concentrated, and the residue obtained triturated with hot ethyl acetate (200 ml) to yield the title compound (0.204 g, 42percent).
42%
With trichlorophosphate; for 1.5h;Heating / reflux;
To 7H-pyrrolo[2,3-cT]pyrimidin-4-ol (0.425 g, 3.14 mmol) was added phosphorus oxychloride (4 ml). The mixture was heated at reflux for 90 minutes and then cooled to room temperature. The solution was poured onto cracked ice, and extracted with chloroform (3 x 50 ml) and ethyl acetate (100 ml). The extracts were then dried and concentrated, and the residue obtained triturated with hot ethyl acetate (200 ml) to yield the title compound (0.204 g, 42percent).
42%
With trichlorophosphate; for 1.5h;Heating / reflux;
12D. 4-Chloro-7H-pyrrolor2.3-cfiPyrimidineTo 7H-pyrrolo[2,3-c(|pyrimidin-4-ol (0.425 g, 3.14 mmol) was added phosphorus oxychloride (4 ml). The mixture was heated at reflux for 90 minutes and then cooled to room temperature. The solution was poured onto cracked ice, and extracted with chloroform (3 x 50 ml) and ethyl acetate (100 ml). The extracts were then dried and concentrated, and the residue obtained triturated with hot ethyl acetate (200 ml) to yield the title compound (0.204 g, 42percent).
42%
With trichlorophosphate; for 1.5h;Heating / reflux;
18D. 4-Chloro-7H-pyrrolor2,3-d]pyrimidine; To 7W-pyrrolo[2,3-cfjpyrimidin-4-ol (0.425 g, 3.14 mmol) was added phosphorus oxychloride (4 ml). The mixture was heated at reflux for 90 minutes and then cooled to room temperature. The solution was poured onto cracked ice, and extracted with chloroform (3 x 50 ml) and ethyl acetate (100 ml). The extracts were then dried and concentrated, and the residue obtained triturated with hot ethyl acetate (200 ml) to yield the desired product (0.204 g, 42percent).
82 g
With N-ethyl-N,N-diisopropylamine; trichlorophosphate; In toluene; at 50℃;
A mixture of 86 g (0.64 mol) <strong>[3680-71-5]7H-pyrrolo[2,3-d]pyrimidin-4-ol</strong>, 185 g phosphoryl chloride and 373 g toluene are warmed to 50°C. 97 g of Nu, Nu-diisopropylethylamine are added in portions. Temperature is kept at 50°C until reaction is complete. The batch is poured onto 770 g water at a maximal temperature of 35°C, made alkaline (pH 8-9) by addition of concentrated potassium hydroxide solution and is aged at a temperature below 35°C for a minimum of 1 hour. The product is then centrifuged, washed with water and dried under vacuum at a temperature below 8o°C, yielding 82 g (yield: 0.54 mol, 84percent conversion rate) of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine having a purity of 99.9 area-percent, measured by HPLC.
With potassium hydroxide; In aqueous potassium hydroxide;
Example 3 4-(2-tetralyloxy)-7H-pyrrolo[2,3-d]pyrimidine. To a solution of 2-hydroxytetralin (1.482 g, 10 mM) in 80 ml of aqueous potassium hydroxide solution containing 1.683 g (30 mM) of solid potassium hydroxide is added 4-chloro-pyrrolo[2,3-d]pyrimidine (1.536 g, 10 mM). The reaction mixture is stirred for about 0.5 h at room temperature until most of the 6-chloro-pyrido[2,3-d]pyrimidine dissolves and then heated on the steam bath for further 0.5 h. The mixture is cooled, filtered and the residue recrystallized from hot aqueous ethanol to give pure title compound in 65% yield. MS m/z 265.
Example 4 4-(2-tetralylthio)-7H-pyrrolo[2,3-d]pyrimidine. To a solution of 4-chloropyrrolo[2,3-d]pyrimidine (1.536 g, 10 mM) in methanol (30 ml) is added a solution of 2-mercaptotetralin (4.928 g, 30 mM) in methanolic potassium hydroxide (60 ml containing 1.608g (30 mM) solid potassium hydroxide). The reaction mixture is stirred for 0.5 h at room temperature and then boiled for 0.5 h at reflux. The solution is concentrated under vacuum and then cooled to give crystalline title compound in about 65% yield. MS m/z 281.
With sodium 4-methylbenzenesulfinate; In dimethyl sulfoxide; at 100℃; for 17.0h;
Commercially available 4-chloro-7H-pyrrolo[2,3-<f|pyrimidine (1 g, 6.51 mmol) was dissolved in DMSO (15 mL) then p-toluenesulfinic acid, sodium salt (1.16 g, 6.51 mmol) and KCN (635 mg, 9.76 mmol) were added. The reaction mixture was heated at 100 0C for 17 h, cooled to RT and diluted with water. The mixture was extracted with EtOAc. The organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo to give 7H-pyrrolo[2,3-(f]pyrimidine-4-carbonitrile as a light yellow solid.
In dimethyl sulfoxide; at 150℃; for 8.0h;
To a solution of 6-Cl-7-deazapurine (0.3 g, 1.96 mmol) in DMSO (6.0 niL) is added KCN (0.64 g, 5.0 eq.). The reaction is heated to 15O0C for a period of 8 h. The mixture is partitioned between ethyl acetate (20 mL) and water. The organic extracts are washed with brine, dried over Na2SO4, filtered and concentrated. The residue is purified by column chromatography (silica gel, eluting with hexanes/ ethyl acetate) to afford the title compound. MS m/z 145.1 (M + I)-
N-(2,3-dihydro-1H-inden-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
5%
To a stirred solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.075 g, 0.488 mmol) and <strong>[32202-61-2]4-aminoindan</strong> (0.072 g, 0.537mmol) in isopropanol (1 ml) was added concentrated HCl (2 drops). The reaction was heated at 600C for 5 h, then cooled to room temperature and concentrated to dryness. The reaction was diluted with ethyl acetate (5 ml) and washed with saturated aqueous NaHCO3 solution (3 x 5 ml). The organic extract was washed with H2O (5 ml), washed with brine (5 ml), dried (Na2SO4), and concentrated. The crude material was purified by column chromatography on silica gel (0-5 percent DCM/MeOH). The resulting material was recrystallized from ethyl acetate/hexanes to give the desired product (0.0060 g, 5percent) as a white solid.1H NMR (300 MHz, CD3OD) delta ppm: 2.06 (t, J = 7 Hz, 2 H), 2.82 (t, J = 7 Hz, 2 H), 2.99 (t, J = 7 Hz, 2 H), 6.29 (d, J = 4 Hz, 1 H), 7.09 (d, J = 4 Hz, 1 H), 7.16 - 7.23 (m, 3 H), 8.10 (s, 1 H). HPLC: 100percent at 2.100 minutes; Sunfire C18 4.6 x 50 mm; 10-90percent methanol: water with 0.1percent TFA; Gradient time = 2 min; 3.5 ml/ min; 254 nm. MS = 251 M+H+.
5%
To a stirred solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.075 g, 0.488 mmol) and <strong>[32202-61-2]4-aminoindan</strong> (0.072 g, 0.537mmol) in isopropanol (1 ml) was added concentrated HCl (2 drops). The reaction was heated at 600C for 5 h, then cooled to room temperature and concentrated to dryness. The reaction was diluted with ethyl acetate (5 ml) and washed with saturated aqueous NaHCO3 solution (3 x 5 ml). The organic extract was washed with H2O (5 ml), washed with brine (5 ml), dried (Na2SO4), and concentrated. The crude material was purified by column chromatography on silica gel (0-5 percent DCM/MeOH). The resulting material was recrystallized from ethyl acetate/hexanes to give the desired product (0.0060 g, 5percent) as a white solid.1H NMR (300 MHz, CD3OD) delta ppm: 2.06 (t, J = 7 Hz, 2 H), 2.82 (t, J = 7 Hz, 2 H), 2.99 (t, J = 7 Hz, 2 H), 6.29 (d, J = 4 Hz, 1 H), 7.09 (d, J = 4 Hz, 1 H), 7.16 - 7.23 (m, 3 H), 8.10 (s, 1 H). HPLC: 100percent at 2.100 minutes; Sunfire C18 4.6 x 50 mm; 10-90percent methanol: water with 0.1percent TFA; Gradient time = 2 min; 3.5 ml/ min; 254 nm. MS = 251 M+H+.
With triethylamine;dmap; In dichloromethane; for 0.5h;
Into a solution of 6-chloro deazapurine (2.0 g, 13 mmol, 1.0 eq.) in dichloromethane (65 ml) are added triethylamine (1.98 ml, 14.3 mmol, 1.1 eq.) and 4-dimethylamino pyridine (catalytic). Tosyl chloride (2.55 g, 13.4 mmol, 1.03 eq.) is added in portions into the reaction mixture which is further equilibrated for 30 minutes. The reaction mixture is then partitioned between dichloromethane and water. The organic layer is separated and the aqueous layer is extracted with dichloromethane. The combined organic extracts are washed with water, dried over Na2SO4, filtered and concentrated to afford the 4-chloro-7-(toluene-40sulfonyl)-7H-pyrrolo[2,3-d]pyrimidine which is used in the next step without further purification.
Step 1:4-Chloro-7H-pyrrolo[2,3-d]pyrimidine 10.75 g (70 mmol) and <strong>[516-12-1]N-iodosuccinimide</strong> (16.8 g, 75 mmol) were dissolved in 400 mL of dry DMF and left at ambient temperature in the darkness over night. The solvent was evaporated. The yellow residue was suspended in hot 10percent solution of Na2SO3, filtered, washed twice with hot water and crystallized from ethanol to yield 14.6 g (74.6percent) of the title compound as off-white crystals. The mother liquid was evaporated up to volume and crystallized again from ethanol to give 2.47 g (12.3percent) of the target compound. The total yield is close to 100percent;Tm 212-214° C. (dec);UV lambdamax: 307, 266, 230, 227 nm (methanol);MS: 277.93 (M-H), 313 (M+Cl);1H-NMR (DMSO-d6): 12.94 (s, 1H, NH), 8.58 (s, 1H), 7.94 (s, 1H).
With hydrogen iodide; at 20℃; for 80h;Inert atmosphere;
Add 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (7.00 g, 45.6 mmol) to 58% hydroiodic acid (51.1 g, 228 mmol), to get a cloudy suspension. The mixture was stirred at room temperature under a nitrogen atmosphere for 80 hours. The suspension was then neutralized with a 50% sodium hydroxide solution, and the solid was collected by filtration. The filter cake was washed with cold water and dried under vacuum. The filtrate was extracted with dichloromethane (3 x 50 ml). The combined organic phases were dried over sodium sulfate, filtered to remove the drying agent, and desolvated under reduced pressure. The obtained solid was combined with the precipitate to obtain the target compound 1B (10.9 g, pale yellow solid) in a yield of 98%.
91%
With hydrogen iodide; In water; at 20℃; for 48h;
4-Chloro-7H-pyrrolo[2,3-d]pyrimidine was dissolved in 57 wt. % hydriodic acid in H2O. The solution was stirred for 48 h at room temperature, and the solid was removed by filtering. The suspension in cold water was brought to pH 8 with NH3 (aq) solution. The solid was filtered, washed with water and dried.
91%
With hydrogen iodide; In water; at 20℃; for 48h;
4-Chloro-7H-pyrrolo [2,3-d] pyrimidine was dissolved in 57% by weight hydriodic acid in H 2 O. The solution was stirred at room temperature for 48 hours. The solid was filtered off. The suspension in cold water was brought to pH 8 with NH3 (aq) solution. The solids were filtered, washed with water and then the solids were dried.
[00295] A mixture of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (673 mg, 4.41 mmol) and 7 ml_ of 57% hydriodic acid was stirred at room temperature for 16 hours. The solid was filtered off, suspended in 5 ml_ of water and brought to pH=8 with aqueous ammonia solution. The suspension was cooled down to O0C and the solid was filtered off, washed with cold water and dried to give the product.to yield 970 mg of the product as a white powder. The product contains about 10% of the starting material.
With hydrogen iodide; at 20℃; for 16h;
A mixture of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (336 mg, 2.15 mmol) and 3.5 mL of 57% hydriodic acid was stirred at room temperature for 16 hours. The solid was filtered off, suspended in 3 mL of water and brought to pH = 8 with aqueous ammonia solution. The suspension was cooled down to 0 ºC and the solid was filtered off, washed with cold water and dried to give the desired product (410 mg). The product contains about 10% of the starting material.
410 mg
With hydrogen iodide; at 20℃; for 16h;
a) 4-iodo-7H-pyrrolo[2,3-d]pyrimidineA mixture of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (336 mg, 2.15 mmol) and 3.5 ml_ of 57% hydriodic acid was stirred at room temperature for 16 hours. The solid was filtered off, suspended in 3 ml_ of water and brought to pH = 8 with aqueous ammonia solution. The suspension was cooled down to 0 5C and the solid was filtered off, washed with cold water and dried to give the desired product (410 mg). The product contains about 10% of the starting material.
With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 60.0℃; for 18.0h;Product distribution / selectivity;
Example 9 alternative route 1: (S)-4-amino-N-Q-(4-chlorophenyl)-3-hvdroxypropyl)- l-(7H-pyrrolo [2,3-dl pyrimidin-4-yl)piperidine-4-carboxamideN-Ethyldiisopropylamine (1.676 ml, 9.62 mmol) was added to (S)-4-amino-N-(l-(4- chlorophenyl)-3-hydroxypropyl)piperidine-4-carboxamide (Intermediate 49) (Ig, 3.21 mmol) and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.493 g, 3.21 mmol) in butan-1-ol (15 ml). The resulting solution was stirred at 600C for 18 hours. The reaction mixture was diluted with EtOAc (50 mL), and washed sequentially with water (25 mL) and saturated brine (25 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 6percent MeOH with ammonia in DCM. Pure fractions were evaporated to dryness to afford (S)-4-amino-N-(l-(4-chlorophenyl)-3-hydroxypropyl)-l-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperidine-4-carboxamide (842mg) as a white foam. (S)-4-amino-N-(l- (4-chlorophenyl)-3-hydroxypropyl)-l-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4- carboxamide was stirred in ethyl acetate (7 mL) for 18 hours. The solid was collected by filtration, washed with a small amount of ethyl acetate and vacuum oven dried at 55°C for 18 hours to afford (S)-4-amino-N-(l-(4-chlorophenyl)-3-hydroxypropyl)-l-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (0.585 g, 42.5 percent) as a white solid, m/z (ES+) (M+H)+ = 429; HPLC tR= 1.60 min. IH NMR (400.13 MHz, DMSO-d6) delta 1.39 - 1.47 (2H, m), 1.80 - 2.02 (4H, m), 2.17 (2H, s), 3.35 - 3.40 (2H, m), 3.50 - 3.59 (2H, m), 4.34 - 4.41 (2H, m), 4.53 (IH, t), 4.88 (IH, d), 6.57 (IH, m), 7.14 - 7.16 (IH, m), 7.31 - 7.37 (4H, m), 8.12 (IH, s), 8.42 (IH, d), 11.62 (IH, s)
Intermediate 1: 4-(ert-butoxycarbonylamino)-l-(7H-pyrrolo[2.,3-dlpyrimidin-4- yl)piperidine-4-carboxylic acidTo a mixture of 4-[(2-methylpropan-2-yl)oxycarbonylamino]piperidine-4- carboxylic acid (115.6 g) in CH3CN-H2O (6 L) was added to NaHCO3 (181 g), followed by 4-chloro 7H-pyrrole[2,3-d]pyrimidine (72.7 g). The mixture was heated to reflux overnight under nitrogen for 24 hrs and then extracted with EtOAc (IL x 4). The aqueous layer was concentrated and MeOH (1.5 L) was added. The mixture was shaken for 30 min at 45 0C and filtered. The filtrate was concentrated again and dissolved in H2O (300 mL). 6N HCl was added until the pH reached 4.5 (ca. 80 mL). The mixture was filtered and the cake was dried under vacuum to afford the crude product, which was further purified by silica gel chromatography (eluting with MeOH: DCM=I :3) to yield 4-[(2-methylpropan-2- yl)oxycarbonylamino]-l-(3,5,7-triazabicyclo[4.3.0]nona-2,4,8,10-tetraen-2-yl)piperidine- 4-carboxylic acid as pale grey solid (105g, 63%). IH NMR (400.13 MHz, DMSO-d6) delta 1.40 (9H, s), 1.88 - 1.95 (2H, m), 2.02 - 2.06 (2H, m), 3.44 - 3.51 (2H, m), 4.30 (2H, d), 6.60 - 6.61 (IH, m), 7.16 - 7.18 (IH, m), 7.29 (IH, s), 8.14 (IH, s), 11.68 (IH, s). MS m/e MH+ 362.
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 20 - 95℃;Inert atmosphere;Product distribution / selectivity;
(3R)-Cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propionitrile ((R)-12, free base).; Method C.; To a 25 mL round bottom flask equipped with a stir bar, condenser, and three-way valve connected to nitrogen and vacuum was charged 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 154 mg, 1.00 mmol), (3R)-3-cyclopentyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propanenitrile ((R)-24, 445 mg, 1.41 mmol, 1.41 equiv), 1,4-dioxane(2.78 mL, 35.6 mmol), water (1.39 mL, 77.2 mmol), and potassium carbonate (K2CO3, 693 mg, 5.02 mmol, 5.0 equiv) at room temperature. The resulting mixture was degassed three times back filling with nitrogen each time before being charged tetrakis(triphenylphosphine)palladium(0) (207 mg, 0.180 mmol, 0.18 equiv). The resulting reaction mixture was degassed four times back filling with nitrogen each time and then warmed to 95 C. The reaction mixture was stirred at 95 C. for 17 hours. When the reaction was deemed complete, the reaction mixture was cooled to room temperature before being diluted with ethyl acetate (20 mL) and 20% aqueous brine (11 mL). The mixture was stirred vigorously at room temperature until the majority of solids had gone into solution. The two layers were separated, and the aqueous layer was extracted with ethyl acetate (20 mL). The combined organic extracts were washed with saturated brine (10 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was then purified by flash chromatography (SiO2, 0-100% ethyl acetate/hexanes gradient elution) to afford (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile ((R)-12, 197 mg, 306.4 mg theoretical, 64.3% yield) as colorless oil, which was solidified upon standing at room temperature. For (R)-12: 1H NMR (DMSO-d6, 400 MHz) delta ppm 12.1 (bs, 1H), 8.80 (d, 1H, J=0.42 Hz), 8.67 (s, 1H), 8.37 (s, 1H), 7.59 (dd, 1H, J=2.34, 3.51 Hz), 6.98 (dd, 1H, J=1.40, 3.44 Hz), 4.53 (td, 1H, J=19.5, 4.63 Hz), 3.26 (dd, 1H, J=9.77, 17.2 Hz), 3.18 (dd, 1H, J=4.32, 17.3 Hz), 2.40 (m, 1H), 1.79 (m, 1H), 1.65 to 1.13 (m, 7H); C17H18N6(MW, 306.37) LCMS (EI) m/e 307 [M++H].
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 14h;
4-chloro-7H-pyrrolo[2,3-d]pyrimidine (25 g; Formula III), potassium carbonate (27 g), and chloromethyl pivalate (27 g; Formula IV) were added to a reaction vessel containing N,N-dimethylformamide (100 mL) at ambient temperature. The reaction mixture was stirred for 14 hours. The progress of the reaction was monitored by thin layer chromatography. Water (250 mL) was added to the reaction mixture, and then the mixture was stirred for 2 hours. The reaction mixture was filtered, then washed with water (50 mL), and then dried under reduced pressure at 40C to 45C for 12 hours to obtain (4- chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2,2-dimethylpropanoate. Yield: 98.85%
91%
(4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (3f).; To a oven dried 2 L 4-neck round bottom flask equipped with overhead stirring, septa, thermocouple, 500 mL addition funnel and nitrogen inlet was charged sodium hydride (NaH, 60 wt %, 29.7 g, 0.742 mol, 1.34 equiv) and anhydrous tetrahydrofuran (THF, 400 mL, 5.0 mol) and the resulting mixture was cooled to 0-3 C. To a oven dried 1 L round bottom flask was charged 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 85.0 g, 0.553 mol) and tetrahydrofuran (600 mL, 7.0 mol) resulting in a slurry. This resulting slurry was then portion wise added to the suspension of sodium hydride in THF via large bore canula over 27 minutes at 0-5 C. The resulting solution was heterogeneous and green in color. Following the addition, the cold bath was removed and the mixture was gradually warmed to room temperature and allowed to stir at room temperature for 1 hour before being cooled to 0-5 C. Chloromethyl pivalate (pivaloyloxymethyl chloride, POM-Cl, 103 ml, 0.692 mol, 1.25 equiv) was added portion wise into the reaction mixture over 25 minutes via syringe with stirring at 0-5 C. The addition of chloromethyl pivalate (POM-Cl) was mildly exothermic and the reaction temperature went to as high as 14 C. After addition of chloromethyl pivalate (POM-Cl), the cooling bath was removed and the reaction mixture was allowed to return to room temperature and stirred at room temperature for overnight. When the reaction was deemed complete after about 16 hours, the reaction was quenched with 20% aqueous brine (250 mL) and ethyl acetate (250 mL) producing a slurry. Additional amount of water (250 mL) was added until the mixture becomes a homogeneous solution. The two layers were separated and the aqueous layer was extracted with ethyl acetate (250 mL). The combined organic fractions were dried over magnesium sulfate (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 10% to 15% ethyl acetate/hexane gradient elution) to afford the desired product as yellow, crystalline solids (155 g). The combined solids were treated with hexanes (750 mL) and the resulting slurry was warmed to 55 C. to produce a homogeneous solution. The resulting solution was then gradually cooled to room temperature and stirred at room temperature for overnight before being cooled to 0-5 C. for 2 h. The solids were collected by filtration, washed with pre-cooled hexanes (2×30 mL), dried in vacuum to afford 4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (3f, 134.9 g, 148.0 g theoretical, 91% yield) as white solids. For 3f: 1H NMR (DMSO-d6, 400 MHz) delta ppm 8.71 (s, 1H), 7.83 (d, 1H, J=3.7 Hz), 6.73 (d, 1H, J=3.8 Hz), 6.23 (s 2H), 1.06 (s, 9H); 13C NMR (DMSO-d6, 100 MHz) delta ppm 176.9, 151.2, 151.1, 151.0, 131.6, 117.1, 99.9, 66.9, 38.3, 26.5; C12H14ClN3O2 (MW, 267.71), LCMS (EI) m/e 268/270 (M++H).
91.6%
Under inert gas protection,Sodium tert-butoxide (40.7 g, 0.424 mol) and tetrahydrofuran (500 ml) were added to the reaction flask, stirred for 0.5 to 3 hours,Chloro-7H-pyrrolo [2,3-d] pyrimidine (50 g, 0.326 mol) was dissolved in tetrahydrofuran (500 ml)a solution of 4-chloro-7H-pyrrolo [2,3-d] pyrimidine in tetrahydrofuran was added dropwise to the reaction flask at -10 C to 5 C,after completion of the dropwise addition, the mixture was allowed to stand at room temperature and stirred at that temperature for 5 to 8 hours and then cooled to -10 C to 5 C,the chloromethyl pivalate (58.8g, 0.39mol) was added to the reaction flask,after completion of the dropwise addition, the reaction was allowed to stand at room temperature and the reaction was stirred at that temperature for 10 to 12 hours.After completion of the reaction, the reaction was quenched with water, concentrated in tetrahydrofuran in the reverse solution, stirred with ethyl acetate and the aqueous phase was separated. The aqueous phase was extracted with ethyl acetate once and the organic phase was separated,Then, the ethyl acetate in the reaction solution was replaced with n-heptane, the reaction solution was cooled, filtered to obtain a wet product,The wet product was crystallized from n-heptane and dried to obtain 79.8 g of product, purity: 99.3%, yield: 91.6%.
85%
To a solution of 4-chloro-7H-pyrrolo[2,3-d] pyrimidine (15.4 g,0.100 mol) in tetrahydrofuran, 60% sodium hydride (8.0 g, 0.200 mol)was added in batches under ice bath. The reaction mixture was stirredunder ice bath for 0.5 h, and then chloromethyl pivalate (30.1 g,0.200 mol) was added to the mixture. Subsequently, the reaction wasstirred at room temperature for 1.5 h. After completed, the mixture waspoured into saturated ammonium chloride solution. The mixture wasextracted with ethyl acetate (50 ml×5), the organic layer was washedwith brine, dried over anhydrous Na2SO4, and then filtered and concentratedto yield 4 as a yellow solid (27.5 g, 85.0%). MS (ESI) m/z:268.4 [M+H]+
To a oven dried 3 L 4-neck round bottom flask equipped with a stirring bar, a septa, a thermocouple, a 500 mL addition funnel and the nitrogen inlet was charged solid sodium hydride (NaH, 60 wt % in mineral oil, 32.82 g, 0.82 mol, 1.20 equiv) and anhydrous 1,2-dimethoxyethane (DME, 500 mL, 4.8 mol) and the resulting mixture was cooled to 0-3 C. To a oven dried 1 L round bottom flask was charged 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1,105.0 g, 0.684 mol) and 1,2-dimethoxyethane (DME, 750 mL, 7.2 mol) and the resulting slurry was then portion wise added to the suspension of sodium hydride in DME via large bore cannula over 30 minutes at 5-12 C. The resulting reaction mixture was heterogeneous. Following the addition, the cold bath was removed and the mixture was gradually warmed to room temperature and allowed to stir at room temperature for 1 hour before being cooled to 0-5 C. Chloromethyl pivalate (pivaloyloxymethyl chloride, POM-Cl, 112 ml, 0.752 mol, 1.1 equiv) was then added drop wise into the reaction mixture over 30 minutes with stirring at 0-5 C. The addition of chloromethyl pivalate was mildly exothermic and the reaction temperature went up to as high as 14 C. After addition of chloromethyl pivalate, the cooling bath was removed and the reaction mixture was allowed to return to room temperature and stirred at room temperature for 90 min. When the reaction was deemed complete after confirmed by HPLC, the reaction mixture was carefully quenched with water (100 mL) and this quenched reaction mixture, which contains crude POM-protected chlorodeazapurine (17), was used directly in the subsequent Suzuki coupling reaction without further work-up and purification.
4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (100 mg, 0.651 mmol) was dissolved in tetrahydrofuran (5 mL). After cooling to 0 C, the reaction mixture was added to sodium hydride (60% in mineral oil, 52 mg, 1.30 mmol). 10 minutes later, chloromethyl pivalate (0.19 mL, 1.30 mmol) was added at 0 C. After stirring for 1.5 hours at room temperature, the reaction mixture was added to saturated ammonium chloride aqueous solution. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried with magnesium sulfate, and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, EA:Hx = 1:4) yielded (4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (170 mg, 0.635 mmol) as white solid.MS m/z [M+1] 268.01.
Step 1: (4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (100 mg, 0.651 mmol) was dissolved in tetrahydrofuran (5 mL). After cooling to 0 C., the reaction mixture was added to sodium hydride (60% in mineral oil, 52 mg, 1.30 mmol). 10 minutes later, chloromethyl pivalate (0.19 mL, 1.30 mmol) was added at 0 C. After stirring for 1.5 hours at room temperature, the reaction mixture was added to saturated ammonium chloride aqueous solution. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried with magnesium sulfate, and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, EA:Hx=1:4) yielded (4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (170 mg, 0.635 mmol) as white solid. MS m/z [M+1] 268.01.
170 mg
4-chloro-7H-pyrrolo[2,3-d]pyrimidine (100 mg, 0.651 mmol) was dissolved in tetrahydrofuran (5 mL). The temperature was lowered to 0 C., and sodium hydride (60% in mineral oil, 52 mg, 1.30 mmol) was added to the reaction solution. After 10 minutes, chloromethyl pivalate (0.19 mL, 1.30 mmol) was added at 0 C. After stirring for 1.5 hours at room temperature, the reaction solution was put into a saturated ammonium chloride aqueous solution. The organic layers were separated and the aqueous solution layer was extracted with ethyl acetate. The collected organic layers were washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, EA:Hx=1:4) to obtain (4-chloro-7H-pyrrolo[2,3-d]pyrimidine-7-yl)methyl pivalate (170 mg, 0.635 mmol) as a white solid. MS m/z [M+1] 268.01.
530 g
Under argon protection, 4-chloropyrrolopyridine (308g, 2.0mol, SM-1) was dissolved in 1.5L anhydrous DMAc, cooled to 10C in ice water bath, and added to NaH (104g, 2.6mol, 60%) in batches. The temperature was kept at 10-15 C, and the mixture was stirred for 1 h under the temperature after the dropwise addition was completed. A solution of methyl pivalate in tetrahydrofuran (390g, 2.6mol dissolved in 1.5L anhydrous tetrahydrofuran, SM-2) was slowly added dropwise, and the temperature was maintained below 20C, and the addition was ended after 1h. The reaction solution was warmed to room temperature and reacted for 2h, and the TLC showed the reaction was completed. The reaction was quenched by being added with water drop wise in ice-water bath, and extracted with methyl t-butyl ether. The organic phase was concentrated to obtain white solid 1a (530g).
Under ice-cooling with stirring, 38.4g (250.4mmol, 1.0eq.) 4-chloro-7H-pyrrolo[2,3-d]pyrimidine is dissolved in 200mL dry DMF. 13g (305mmol, 1.2eq) 57% content of NaH was added. The reaction was stirred at room temperature for 1 hour. 50.9g SEMCl was added dropwise under ice-cooling (305mmol, 1.2eq.). After complete addition, the ice bath the reaction was stirred for 1 hour, quenched with water, extracted with ethyl acetate, combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo, column chromatography on a silica column to give the title compound (71g , yield = 100%).
100%
38.4 g (250.4 mmol, 1.0 eq.) with stirring in an ice bath. 4-chloro-7H-pyrrole [2,3-d]pyrimidine is dissolved in 200 mL of dry DMF solution.13 g (305 mmol, 1.2 eq) of 57% NaH was added. The reaction was stirred at room temperature for 1 hour, then 50.9 g of SEMCl (305 mmol, 1.2 eq.).After the addition, the reaction was stirred in an ice bath for 1 hour. quenched with water, extracted with ethyl acetate. the title compound (71 g, yield = 100%) was obtained.
97%
Under cooling with an ice-salt bath, sodium hydride (340 mg, 60%) was added in two portions to a solution of 4-chloropyrrolopyrimidine (3a) (1.0 g, 6.5 mmol) in DMF (15 mL) while keeping the temperature of the reactants no higher than 10C, and the reaction was stirred under nitrogen atmosphere protection for 1 h. SEMCI (1.4 g, 8.5 mmol) was slowly added via a syringe while keeping the temperature no higher than 10C. The reaction was warmed to room temperature, and stirred overnight. The reaction was quenched with water, extracted with EA, dried over anhydrous sodium sulfate, and the organic phase was concentrated, and purified by preparative flash chromatography (PE:EA=19:1), to afford 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (3b) (1.834 g, oil product), yield: 97%,. MS (ESI, m/z): 284 [M+H]+.
97.2%
EXAMPLE 3 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine 450 g of 4-chloropyrrolo[2,3-d]pyrimidine was added to 3.6 L of DMF, and the temperature was lowered to -10 C.?-20 C., and then 144 g of sodium hydride (60%) was added in batches. 586.0 g of 2-(trimethylsilyl)ethoxymethyl chloride was slowly added dropwise to the resulting mixture and stirred to react for 2 hours. After the reaction was completed, the reaction was quenched by dropwise adding 36 g of glacial acetic acid under stirring. Then, the reaction solution was poured into 14.4 L of purified water, and extracted with ethyl acetate, and then the organic layer was washed with saturated brine. The organic layer was concentrated under reduced pressure to remove the solvent, and the residue was purified by using 200300 mesh silica gel column chromatography to obtain 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (808.2 g, 97.2%). 1H-NMR (500 MHz, DMSO-d6): delta=8.69 (s, 1H), 7.85 (d, J=3.8 Hz, 1H), 6.70 (d, J=3.6 Hz, 1H), 5.62 (s,2H), 3.53 (t, J=7.9 Hz, 2H), 0.81 (t, J=8.1 Hz, 2H), 0.23 (s, 9H); MS (ES): 284.10 (M+H+).
96.4%
Potassium t-butoxide (328.81 g, 2.93 mol)and tetrahydrofuran were added to the reaction flask at -30 C to -20 C,a solution of 4-chloro-7H-pyrrolo [2,3-d] pyrimidine (300 g, 1.95 mol) in tetrahydrofuran was added dropwise to the reaction flask. after completion of the dropwise addition, the mixture was stirred at room temperature for 4 to 6 hours to control the reaction flask the temperature is not higher than -15 C -5 C ,2- (trimethylsilyl) ethoxymethyl chloride (390.80g, 2.34mol)Is added to the reaction flask, and after completion of the dropwise addition, the temperature is raised to room temperature and the reaction is stirred at that temperature for 3 to 5 hours.After completion of the reaction, the reaction was quenched to neutral with dilute hydrochloric acid, concentrated in tetrahydrofuran in the reverse solution, stirred with ethyl acetate and the aqueous phase was separated. The aqueous phase was extracted with ethyl acetate once, and the reaction solution was cooled and filtered to obtain a wet product. The wet product was crystallized from n-hexane and dried to obtain 534.50 g of product, purity: 99.70%, and the residue was purified. Yield: 96.40%.
91.8%
A solution of 4-chloropyrrolo[2,3-d]pyrimidine (200 g, 1.3 mol, 1.0 eq.) in N,N-dimethylformamide was added to 60% NaH (62.4 g, 1.56 mol, 1.2 eq.) in an ice bath. After the completion of the addition, the resulting mixture was stirred to react at room temperature for 1 hour. 2-(Trimethylsilyl)ethoxymethyl chloride (SEMC1, 260 g, 1.56 mol, 1.2 eq.) was slowly added dropwise under cooling in an ice bath. After the completion of the addition, the resulting mixture was stirred to react in an ice bath for 1 hour, and the reaction was quenched with water. The resulting mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated salt solution, dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography to obtain 4-chloro-7-{ [2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (312.2 g, 91.8% yield). 1H-NMR (500 MHz, CDCl3): delta8.64 (s, 1H), 7.38 (d, J=3.6 Hz, 1H), 6.65 (d, J=3.6 Hz, 1H), 5.64 (s, 2H), 3.52 (t, J=8.2 Hz, 2H), 0.90(t, J=8.2 Hz, 2H), -0.07 (s, 9H); HRMS (ESI) calcd. for C12H18N3OSi[M+H]+284.0980; Found: 284.0995.
91.8%
To a solution of 4-chloropyrrolo[2,3-d]pyrimidine (200 g, 1.3 mol, 1.0 eq.) in N,N-dimethylformamide was added 60% NaH (62.4 g, 1.56 mol, 1.2 eq.) in an ice bath, and stirred for 1 hour at room temperature after completion of addition. 2-(Trimethylsilyl)ethoxymethyl chloride (SEMCl, 260 g, 1.56 mol, 1.2 eq.) was slowly added drop-wise under cooling in an ice bath. After completion of addition, the reaction was stirred for 1 hour in an ice bath, quenched with water, and extracted with ethyl acetate. The combined organic phase was washed with a saturated brine solution, dried over anhydrous sodium sulfate, and filtrated. The filtrate was concentrated under reduced pressure to obtain residue, which was purified by column chromatography on silica gel to afford 4-chloro-7-[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (2) (312.2 g, yield: 91.8%). 1H-NMR (500 MHz, CDCl3): delta 8.64 (s, 1H), 7.38 (d, J=3.6 Hz, 1H), 6.65 (d, J=3.6 Hz, 1H), 5.64 (s, 2H), 3.52 (t, J=8.2 Hz, 2H), 0.90 (t, J=8.2 Hz, 2H), -0.07 (s, 9H); HRMS (ESI) calcd. for C12H18N3OSi [M+H]+ 284.0980; Found: 284.0995.
90.4%
To a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (20.0 g, 130.4 mmol, 1.0 eq.) in dry DMF was added NaH (6.6 g, 57% content, 156.8 mmol, 1.2 eq.), under stirring in an ice bath. After the reactants were stirred for 1 hr at room temperature, SEMCl (26.1 g, 156.5 mmol, 1.2 eq.) was added dropwise under the cooling of an ice bath. After the addition was completed, the reactants were stirred for 1 hr in an ice bath, then the reaction was quenched by adding water, and the resulting mixture was extracted with ethyl acetate. The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was separated by column chromatography on silica gel column to give 4-chloro-7-[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (33.43 g, 90.4% yield). 1HNMR (400MHz, CDCl3) delta 8.67 (s, 1H), 7.39 (d, J =3.6 Hz, 1H), 6.67 (d, J =3.6 Hz, 1H), 5.65 (s, 2H), 3.53 (dd, J =9.2 Hz, J =8.0 Hz, 2H), 0.91 (t, J =8.4 Hz, 2H), 0.00 (s, 9H). m/z=284[M+1]+.
90%
With ice bath,To a solution of 4-chloro-7H-pyrrolo [2,3-d] pyrimidine (20.0 g, 130.4 mmol, 1.0 eq.In dry DMF, NaH (6.6 g, 57% content, 156.8 mmol, 1.2 eq) was added. The reaction was stirred at room temperature for 1 hour,Further, SEMCl (26.1 g, 156.5 mmol, 1.2 eq.) Was added dropwise with cooling in an ice bath.After the addition was completed, the reaction mixture was stirred in an ice bath for 1 hour, quenched with water,Extraction with ethyl acetate and washing of the combined organic phases with brine,Dried over sodium sulfate, filtered and concentrated in vacuo.Column chromatography silica gel column isolated4-Chloro-7 - [2- (trimethylsilyl) ethoxy] methyl} -Pyrrolo [2,3-d] pyrimidine (33.4 g, 90% yield).
88.9%
To a flask equipped with a nitrogen inlet, an addition funnel, a thermowell, and the mechanical stirrer was added 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 600 g, 3.91 mol) and N,N-dimethylacetimide (DMAC, 9.6 L) at room temperature. The mixture was cooled to 0-5 C. in an ice/brine bath before solid sodium hydride (NaH, 60 wt %, 174 g, 4.35 mol, 1.1 equiv) was added in portions at 0-5 C. The reaction mixture went to a dark solution during 15 minutes. Trimethylsilylethoxymethyl chloride (2, SEM-Cl, 763 mL, 4.31 mol, 1.1 equiv) was then added slowly via an addition funnel at a rate that the internal reaction temperature did not exceed 5 C. The reaction mixture was then stirred at 0-5 C. for 30 minutes. When the reaction was deemed complete determined by TLC and HPLC, the reaction mixture was quenched by water (1 L). The mixture was then diluted with water (12 L) and MTBE (8 L). The two layers were separated and the aqueous layer was extracted with MTBE (8 L). The combined organic layers were washed with water (2*4 L) and brine (4 L) and dried over sodium sulfate (Na2SO4). The solvents were removed under reduced pressure. The residue was then dissolved in heptane (2 L), filtered and loaded onto a silica gel (SiO2, 3.5 Kg) column eluding with heptane (6 L), 95% heptane/ethyl acetate (12 L), 90% heptane/ethyl acetate (10 L), and finally 80% heptane/ethyl acetate (10 L). The fractions containing the pure desired product were combined and concentrated under reduced pressure to give 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (3, 987 g, 1109.8 g theoretical, 88.9% yield) as a pale yellow oil which partially solidified to an oily solid on standing at room temperature.
88.9%
4-Chloro-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (3a).; To a flask equipped with a nitrogen inlet, addition funnel, thermowell, and mechanical stirrer was added 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 600 g, 3.91 mol) and dimethylacetimide (9.6 L). The mixture was cooled to -5 C. in an ice/brine bath and sodium hydride (NaH, 60 wt %, 174 g, 4.35 mol, 1.1 equiv) was added in portions as a solid. The mixture went to a dark solution during 15 minutes and trimethylsilylethoxymethyl chloride (2, 763 mL, 4.31 mol, 1.1 equiv) was added slowly via an addition funnel at a rate that the temperature did not exceed 5 C. The reaction was stirred for 30 minutes, determined to be complete by TLC and HPLC, and water (1 L) was slowly added to quench the reaction. The mixture was then diluted with water (12 L) and MTBE (8 L). The layers were separated and the aqueous was re-extracted with MTBE (8 L). The combined organic layers were washed with water (2×4 L) and brine (4 L), dried over sodium sulfate (NaSO4), and solvents removed under reduced pressure.The residue was dissolved in heptane (2 L), filtered and loaded onto a silica gel (3.5 kg) column eluting with heptane (6 L), 95% heptane/ethyl acetate (12 L), 90% heptane/ethyl acetate (10 L), and finally 80% heptane/ethyl acetate (10 L). The pure fractions were combined and concentrated under reduced pressure to give 4-chloro-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (3a, 987 g, 1109.8 g theoretical, 88.9% yield) as a pale yellow oil that partially solidified to an oily solid on standing at room temperature. For 3a: 1H NMR (DMSO-d6, 300 MHz) delta ppm 8.67 (s, 1H), 7.87 (d, 1H, J=3.8 Hz), 6.71 (d, 1H, J=3.6 Hz), 5.63 (s, 2H), 3.50 (t, 2H, J=7.9 Hz), 0.80 (t, 2H, J=8.1 Hz), 1.24 (s, 9H); 13C NMR (DMSO-d6, 100 MHz) delta ppm 151.3, 150.8, 150.7, 131.5, 116.9, 99.3, 72.9, 65.8, 17.1, -1.48; C12H18ClN3OSi (MW 283.83), LCMS (EI) m/e 284/286 (M++H).
88.9%
Step 1. 4-Chlow-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (3) To a flask equipped with a nitrogen inlet, an addition funnel, a thermowell, and the mechanical stirrer was added 4-chloro-7H-pyirolo[2,3-c/]pyrirnidine (1, 600 g, 3.91 mol) and N,N-dimethylacetimide (DMAC, 9.6 L) at room temperature. The mixture was cooled to 0 - 5 C in an ice/brine bath before solid sodium hydride (NaH, 60 wt%, 174 g, 4.35 mol, 1.1 equiv) was added in portions at 0 - 5 C. The reaction mixture turned into a dark solution after 15 minutes. Trimethylsilylethoxymethyl chloride (2, SEM-C1, 763 mL, 4.31 mol, 1.1 equiv) was then added slowly via an addition funnel at a rate that the internal reaction temperature did not exceed 5 C. The reaction mixture was then stirred at 0 - 5 C for 30 minutes. When the reaction was deemed complete determined by TLC and HPLC, the reaction mixture was quenched by water (1 L). The mixture was then diluted with water (12 L) and methyl tert-b ty] ether (MTBE) (8 L). The two layers were separated and the aqueous layer was extracted with MTBE (8 L). The combined organic layers were washed with water (2 x 4 L) and brine (4 L) and solvent switched to 1-butanol. The solution of crude product (3) in 1 -butanol was used in the subsequent Suzuki coupling reaction without further purification. Alternatively, the organic solution of the crude product (3) in MTBE was dried over sodium sulfate (Na2SC>4). The solvents were removed under reduced pressure. The residue was then dissolved in heptane (2 L), filtered and loaded onto a silica gel (S1O2, 3.5 Kg) column eluting with heptane (6 L), 95% heptane/ethyl acetate (12 L), 90% heptane/ethyl acetate (10 L), and finally 80% heptane/ethyl acetate (10 L). The fractions containing the pure desired product were combined and concentrated under reduced pressure to give 4-chloro-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-i/]pyrimidine (3, 987 g, 1 109.8 g theoretical, 88.9% yield) as a pale yellow oil which partially solidified to an oily solid on standing at room temperature. For 3: NMR (DMSO-af6, 300 MHz) delta 8.67 (s, 1 H), 7.87 (d, 1 H, J = 3.8 Hz), 6.71 (d, 1 H, J= 3.6 Hz), 5.63 (s, 2H), 3.50 (t, 2H, J= 7.9 Hz), 0.80 (t, 2H, J= 8.1 Hz), 1.24 (s, 9H) ppm; 13C NMR (DMSO-cfe, 100 MHz) delta 151.3, 150.8, 150.7, 131.5, 1 16.9, 99.3, 72.9, 65.8, 17.1 , -1 .48 ppm; C,2H,8ClN3OSi (MW 283.83), LCMS (EI) m/e 284/286 (M+ + H).
87%
With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 0 - 20℃; for 1.5h;
General procedure: To a mixture of sodium hydride (60% dispersion in mineral oil; 276 mg; 6.89 mmol) in DMF (10 mL) at 0 C was added drop-wise a solution of 4-chloro-2-methylsulfanyl-7H-pyrrolo[2,3-d]pyrimidine [prepared as detailed in Ref. 45] (1.145 g; 5.74 mmol) in anhydrous DMF (20 mL). When the addition was complete, 2-(trimethylsilyl)ethoxymethyl chloride (1.32 ml; 7.46 mmol) was added drop-wise and the reaction mixture was stirred at 0 C for 1.5 h then allowed to warm to ambient temperature. The reaction mixture was partitioned between water (100 mL) and ethyl acetate (100 mL). The organic phase was separated, dried over Na2SO4 and then filtered and the filtrate solvents evaporated in vacuo. The crude product was purified by flash chromatography on silica gel (70 g) eluting with a solvent gradient of 05% ethyl acetate in hexane to afford the title compound 42 (1.73 g, 91%) as a colourless oil.
81%
To a solution of NaH (3 g, 0.13 mol) in DMF (60 mL)Suspension is slowSlow to join 1(10 g, 0.066 mol) in DMF (40 mL).The reaction mixture was stirred at 0 & lt; 0 & gt; CStirring for 2 hours,A light brown cloudy mixture was obtained.And then slowly added to the mixture2- (trimethylsilyl) ethoxymethyl chloride (SEMCl) (12.7 g, 0.08 mol)Stirred overnight at room temperature,The reaction was quenched with water and extracted with ethyl acetate,The filtrate was concentrated under reduced pressure. Purification by flash chromatography gave intermediate 2(15 g, 81%),As a pale yellow oil;
79%
4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (1.5g, 9.77 mmol) was stirred in anhydrous N,N- dimethylacetamide (30ml), under nitrogen, with cooling to between 0C and 5 C as sodium hydride (60% dispersion, 430mg, 10.75 mmol) was added in portions. After all effervescence had ceased (25 min.), (2-chloromethoxy-ethyl)-trimethylsilane (1.79g, 10.75 mmol) was added dropwise, maintaining the temperature between 4 C and 7 C. After stirring for a further lh 45 min. saturated aqueous NH4C1 and a little water were added and the product was extracted with 2 portions of t-butyl methyl ether. The extracts were washed with water, brine, dried over Na2S04 and the solvent evaporated. Purification on a Si-SPE cartridge (70g) eluting with EtOAc- cyclohexane (1 : 10 followed by 1 :6) afforded the title compound as a colourless oil (2.19g, 79%) LCMS (Method 1, ESI): Rt 4.11 min., m/z 325 [M+42]+, 284 [M+H]+, 1H NMR (400 MHz, CDCI3): delta 8.67 (1H, s), 7.39 (1H, d, J = 3.5Hz), 6.67 (1H, d, J = 3.5Hz), 5.65 (2H, s), 3.50-3.56 (2H, m), 0.88-0.93 (2H, m), -0.06 (9H, s).
75%
2L three-neck flask, 4-chloropyrrolopyrimidine (280 g, 1.83 mol) and N, N-dimethylacetamide (500 mL) were added, Cooling to -10 deg C, NaH (84 g) was added in triplicate, Plus, Stir for 0.5 hours. 2-(trimethylsilyl)ethoxymethyl chloride (385 mL, 1.98 mol) was added, Plus, After 2 hours of reaction at room temperature, The reaction solution was poured into 1 L of water, 500 mL of ethyl acetate was added, Stirring and extracting the ester layer, Washed with 300 mL of saturated sodium chloride once, Dried over anhydrous sodium sulfate, filter, Concentrated under reduced pressure to give 390 g of red product, Yield 75%.
70%
With sodium hydride; In N,N-dimethyl acetamide; at 5℃; for 4.25h;
Under ice-cooling conditions, 2.0g of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine was dissolved in 50mL N,N-dimethylacetamide. 0.58g of NaH was added dropwise to the solution and stirred for 15 minutes. 2.2g of 2-chloromethoxyethyl trimethylsilane was added and the reaction was continued maintaining the temperature at 5C for 4h. The solution was then quenched with saturated ammonium chloride solution. The aqueous phase was extracted with ethyl acetate. The organic phase was washed with water. Each 100mL saline solution was washed three times. The organic phase was dried over anhydrous magnesium sulfate overnight. The mixture was filtered and the solvent was distilled off under reduced pressure to give a crude product. The product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 50:1) to give 2.6g of intermediate 2 as a colorless liquid, yield: 70%.
66%
To a stirred solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (5.0 g, 32.56 mmol, 1 equiv) in DMF (50 mL) was added 60% sodium hydride (1.5 g, 39.07 mmol, 1.2 equiv) at 000 and stirred for 15 mm followed by addition of (2-(chloromethoxy)ethyl)trimethylsilane(5.7 mL, 32.56 mmol, 1.0 equiv) at same temperature. The reaction mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was quenched with ice water. The crude product was extracted in to ethyl acetate. The organic layer was dried over sodium sulphate and evaporated to obtain 4-chloro-7-((2-(trimethylsilyl) ethoxy) methyl)-7H-pyrrolo [2,3-d]pyrimidine as brown liquid (8.0 g, 66.0 %). LCMS (ES) m/z =284.10 [M+H]. 1H NMR (400 MHz, DMSO-d6) O ppm -0.11 (s, 9H), 0.79-0.81 (m, 2H),3.50 (t, J= 8.0 Hz, 2H), 5.62 (s, 1H), 6.68-6.69 (m, 1H), 7.85 (d, J=4.0 Hz, 1H), 8.62 (s, 1H).
To a suspension of sodium hydride (36.141 g, 903.62 mmol) in N,N-dimethylacetamide (118 mL) at -5 C. (ice/salt bath) was added a dark solution of 4-chloropyrrolo[2,3-d]pyrimidine (119.37 g, 777.30 mmol) in N,N-dimethylacetamide (237 mL) slowly. The flask and addition funnel were rinsed with N,N-dimethylacetamide (30 mL). A large amount of gas was evolved immediately. The mixture became a slightly cloudy orange mixture. The mixture was stirred at 0 C. for 60 min to give a light brown turbid mixture. To the mixture was slowly added [2-(trimethylsilyl)ethoxy]methyl chloride (152.40 g, 914.11 mmol) and the reaction was stirred at 0 C. for 1 h. The reaction was quenched by addition of 12 mL of H2O slowly. More water (120 mL) was added followed by methyl tert-butyl ether (MTBE) (120 mL). The mixture was stirred for 10 min. The organic layer was separated. The aqueous layer was extracted with another portion of MTBE (120 mL). The organic extracts were combined, washed with brine (120 mL×2) and concentrated under reduced pressure to give the crude product 4-chloro-7-[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine as a dark oil. Yield: 85.07 g (97%); LC-MS: 284.1 (M+H)+. It was carried to the next reaction without purification.
To a solution of 4-chloro-7H-pyrrolo[2,3-</Jpyrimidine (5 g, 32.6 mmol) in THF (50 mL) was added NaH (30%, 4 g, 50.0mmol) at 0 C. The reaction mixture was stirred at 0 C for 1 hour before the addition of (2-(chloromethoxy)ethyl)- trimethylsilane (15 g, 90.0mmol). The reaction was stirred at ambient temperature for 3 hours. It was then treated with water (5 mL) and extracted with EtOAc. The organic layer was concentrated under reduced pressure, and the residue was purified by chromatography to give the title compound. MS (m/z): 284 (M+H)+ (35C1), 286 (M+H)+ (37C1).
Intermediate 5(R)-6-(l-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-< |pyrimidin-4-yl)pyrrolidin-3-ylamino)nicotinonitrile(A) 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-< |pyrimidine [0100] To a solution of 4-chloro-7H-pyrrolo[2,3-<JJpyrimidine (5 g, 32.6 mmol) in THF (50 mL) was added NaH (30%, 4 g, 50.0mmol) at 0 C. The reaction mixture was stirred at 0 C for 1 hour before the addition of (2-(chloromethoxy)ethyl)- trimethylsilane (15 g, 90.0mmol). The reaction was stirred at ambient temperature for 3 hours. It was then treated with water (5 mL) and extracted with EtOAc. The organic layer was concentrated under reduced pressure, and the residue was purified by chromatography to give the title compound. MS (m/z): 284 (M+H)+ (35C1), 286 (M+H)+ (37C1).
To a solution of 4-chloro-7H-pyrrolo[2,3-</]pyrimidine (15.3 g, 99.6 mmol) in tetrahydrofuran (200 mL) was added NaH (60% dispersion in mineral oil, 4.20 g, 105 mmol) at 0 C. The resulting solution was stirred for 1 hour at 0 C and then SEMC1 (16.6 g, 100 mmol) was added dropwise. After stirring for an additional 5 hours at 25 C, the reaction was quenched by addition of 250 mL of water/ice, and extracted with ethyl acetate (x2). The organic layers were combined and dried over anhydrous sodium sulfate and concentrated in vacuo. The reaction was purified by chromatography using silica gel, eluting with 50% EtO Ac/petroleum ether. The product was collected and concentrated in vacuo to afford 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- < ]pyrimidine as a light yellow oil. LR S (ESI) calc'd for [M+H]+: 284, found 284.
(A) 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine To a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (5 g, 32.6 mmol) in THF (50 mL) was added NaH (30%, 4 g, 50.0 mmol) at 0 C. The reaction mixture was stirred at 0 C. for 1 hour before the addition of (2-(chloromethoxy)ethyl)-trimethylsilane (15 g, 90.0 mmol). The reaction was stirred at ambient temperature for 3 hours. It was then treated with water (5 mL) and extracted with EtOAc. The organic layer was concentrated under reduced pressure, and the residue was purified by chromatography to give the title compound. MS (m/z): 284 (M+H)+ (35Cl), 286 (M+H)+ (37Cl).
Step C: 4-Chloro-7-[2-(trimethylsilyl) ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine To a suspension of sodium hydride (36.141 g, 903.62 mmol) in N,N-dimethylacetamide (118 mL) at -5 C. (ice/salt bath) was added a dark solution of 4-chloropyrrolo[2,3-d]pyrimidine (119.37 g, 777.30 mmol) in N,N-dimethylacetamide (237 mL) slowly. The flask and addition funnel were rinsed with N,N-dimethylacetamide (30 mL). A large amount of gas was evolved immediately. The mixture became a slightly cloudy orange mixture. The mixture was stirred at 0 C. for 60 min to give a light brown turbid mixture. To the mixture was slowly added [2-(trimethylsilyl)ethoxy]methyl chloride (152.40 g, 914.11 mmol) and the reaction was stirred at 0 C. for 1 h. The reaction was quenched by addition of 12 mL of H2O slowly. More water (120 mL) was added followed by methyl tert-butyl ether (MTBE) (120 mL). The mixture was stirred for 10 min. The organic layer was separated. The aqueous layer was extracted with another portion of MTBE (120 mL). The organic extracts were combined, washed with brine (120 mL*2) and concentrated under reduced pressure to give the crude product 4-chloro-7-[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine as a dark oil. Yield: 85.07 g (97%); LC-MS: 284.1 (M+H)+. It was carried to the next reaction without purification.
4-Chloro-7H-pyrrolo[2,3- (0221) dimethylacetamide (700 inL) at -10C to 0C to obtain a solution. The solution was added drop-wise to a mixture of sodium hydride (60%, 31.26 g) in dimethylacetamide (200 mL) to obtain a reaction mixture. The reaction mixture was stirred for 1 hour at 0C to -2C. 2-(Trimethylsilyl)ethoxymethyl chloride (119.37 g) was added drop-wise to the reaction mixture at 0C to -10C and the reaction mixture was stirred for 2 hours at 0C to 5C. After completion of the reaction, deionized (DI) water (1000 mL) and methyl fert-butyl ether (1000 mL) were added to the reaction mixture and the reaction mixture was stirred for 10 minutes at 20C to 25C. The layers obtained were separated and the aqueous layer was extracted with methyl fert-butyl ether (500 mL). The combined organic layers were washed with DI water (2 chi 500 mL) and concentrated under reduced pressure at 40C to 45 C to obtain the title compound, which was used as such for next step.
Preparation of R1a (2.81 g, 18.3 mmol) was dissolved in THF (25 ml) cooled to 0C.And NaH (60% dispersion, 1.1 g, 27.4 mmol) was added to the mixture,Stir for 1 hour. Then SEM-Cl (8.1 ml, 45.76 mmol) was added to the mixture,And let it warm up to room temperature. After 2.5 hours, add water (25 ml) to the reaction mixture.And extracted with EEO (2 x 30 ml). The combined organic layers were dried over MgSO4 and evaporated.The residue was purified by flash chromatography (220 g Silica Gold column, heptane-EEO gradient) to give the title product.
Ca.96.6%
2.00 g of 4-hydroxypiperidine was added to a 100-mL round-bottomed flask, and then 20.0 mL of dichloromethane (CH2Cl2) and 20.0 mL of a saturated sodium hydrogen carbonate (NaHCO3) solution were added thereto. After 4.32 g of di-tert-butyl dicarbamate (Boc2O) was added thereto, the reaction mixture was vigorously stirred for about 15 hours and then concentrated under reduced pressure. The aqueous phase was extracted with 20.0 mL of ethyl acetate (EtOAc) to collect an organic phase. The collected organic phase was washed with 10.0 mL of deionized water and 15.0 mL of saturated brine. The organic phase was then filtered with sodium sulfate (Na2SO4). The resulting filtrate was distilled under reduced pressure. As a result, 3.871 g of tert-butyl 4-hydroxypiperidine-1-carboxylate was obtained with a yield of about 97.2%. (0319) 300 mg of 6-chloro-7-deazapurine was added to a 50-mL round-bottomed flask, and then 3.75 mL of N,N-dimethylformamide was added. After 86.0 mg of sodium hydride (60wt%) was added thereto at about 0C, the reaction mixture was refluxed at room temperature for about 15 minutes. After 0.403 mL of 2-(trimethylsillyl)ethoxymethyl chloride) was added thereto, the reaction mixture was stirred for about 30 minutes and concentrated under reduced pressure. The reaction mixture was extracted with 4.50 mL of ethyl acetate (EtOAc) and 4.50 mL of deionized water to collect an organic phase. The collected organic phase was filtered with magnesium sulfate (MgSO4). The resulting filtrate was distilled under reduced pressure. As a result, 534 mg of 4-chloro-7-((2-(trimethylsillyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine was obtained with a yield of about 96.6%. (0320) 408 mg of tert-butyl 4-hydroxypiperidine-1-carboxylate was added to a 50-mL round-bottomed flask, and 5.60 mL of dimethyl sulfoxide (DMSO) was added thereinto. After 61.4 mg of sodium hydride (60wt%) was added thereinto at about 0C, the reaction mixture was refluxed at room temperature for about 1.5 hours. Then, a solution of 574 mg of 4-chloro-7-((2-(trimethylsillyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine dissolved in 4.60 mL of dimethyl sulfoxide (DMSO) was slowly dropwise added into the reaction mixture, and the reaction mixture was stirred at about 50C for about 2 hours and then cooled down to room temperature. The reaction mixture was then extracted with 10.0 mL of ethyl acetate (EtOAc) and 10.0 mL of deionized water to collect an organic phase. The collected organic phase was filtered with sodium sulfate (Na2SO4). The resulting filtrate was distilled under reduced pressure, and then the resulting residue was purified by flash column chromatography (EtOAc:Hexane=1:5). As a result, 457 mg of tert-butyl 4-((7-((2-(trimethylsillyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)piperidine-1-carboxylate was obtained with a yield of about 66.6%. (0321) 452 mg of tert-butyl 4-((7-((2-(trimethylsillyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)piperidine-1-carboxylate was added to a 50-mL round-bottomed flask, and 5.00 mL of tetrahydrofuran was added thereinto. After 20.4 mL of a solution of 1.0 M tetrabutylammonium fluoride in tetrahydrofuran was added thereinto, the reaction mixture was refluxed at room temperature for about 5 hours and then cooled down to room temperature. The reaction mixture was concentrated under reduced pressure and then extracted with 100 mL of ethyl acetate (EtOAc) and 100 mL of deionized water to collect an organic phase. The collected organic phase was filtered with sodium sulfate (Na2SO4). The resulting filtrated was distilled under reduced pressure, and then the resulting residue was purified by flash column chromatography (EtOAc:Hexane=1:6). As a result, 310 mg of tert-butyl 4-((7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)piperidine-1-carboxylate was obtained with a yield of about 95.7%. (0322) 310 mg of tert-butyl 4-((7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)piperidine-1-carboxylate was added to a 50-mL round-bottomed flask, and 6.00 mL of 1,4-dioxane was added thereinto. After 10.0 mL of 4N HCI solution was added thereinto, the reaction mixture was stirred at room temperature for about 2 hours. Then, 20.0 mL of ethyl acetate (EtOAc) was added into the reaction mixture and a 10% ammonium hydroxide solution was added to basify the reaction mixture. An organic phase was filtered with sodium sulfate (Na2SO4). The resulting filtrate was distilled under reduced pressure. As a result, 230 mg of 4-(piperidine-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidine was obtained with a quantitative yield. (0323) 177 mg of 4-(piperidine-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidine was added to a 25-mL round-bottomed flask and then dissolved with 3.00 mL of dichloromethane (CH2Cl2). After 0.0480 mL of chloroacetyl chloride was added into the solution, the reaction mixture was treated with 0.211 mL of N,N-diisopropylethylamine and then stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the re...
With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 0℃; for 1h;Inert atmosphere;
Intermediate 2a. 4-chloro-7-[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine To a stirred suspension of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (3.00 g, 19.5 mmol) in DMF (45 mL) was added SEM-C1 (5.20 mL, 29.3 mmol). The resulting mixture was placed under nitrogen and cooled to 0 C in an ice bath. NaH (0.938 g of a 60% dispersion in mineral oil, 23.4 mmol) was added, the resulting yellow suspension was stirred at 0 C for approximately 1 hour. The reaction was quenched with 10% aqueous NaCl (180 mL), and the resulting mixture was extracted with EtOAc (180 mL). The organic washings were washed with additional 10% aqueous NaCl (180 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to a crude oil. The oil was purified by column chromatography on silica gel eluting with EtOAc/hexane (2-20%) to afford the title compound as an oil. LRMS calc'd for C12H19ClN3OSi [M+H]+, 284; found 284. 1HNMR (500 MHz, CDCl3) delta 8.67 (s,1H), 7.39 (d, 1H), 6.67 (d, 1H), 5.65 (s, 2H), 3.52 (t, 2H), 0.91 (t, 2H), 0.06 (s, 9H).
4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (1 g) was dissolved in N,N-dimethylformamide (7.2 mL), potassium carbonate (1.35 g) and <strong>[66-27-3]methyl methanesulfonate</strong> (0.55 mL) were added, and the mixture was stirred at room temperature for 2 hr. The mixture was partitioned between ethyl acetate (80 mL) and water (80 mL), and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (10 mL), potassium carbonate (990 mg) and 4-amino-2-chlorophenol (857 mg) were added, and the mixture was stirred at 120C for 16 hr. The mixture was partitioned between ethyl acetate (150 mL) and water (100 mL), and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (hexane:ethyl acetate=90:10?20:80) to give the title compound (516 mg) as a pale-red powder. 1H-NMR (CDCl3) delta:3.75 (2H, br s), 3.88 (3H, s), 6.51 (1H, d, J= 3.0 Hz), 6.63 (1H, dd, J= 3.0 Hz, 9.0 Hz), 6.80 (1H, d, J= 3.0 Hz), 7.06 (1H, d, J= 2.0 Hz), 7.09 (1H, d, J= 3.0 Hz), 8.46 (1H, s)
Step 1: 4-methyl-7H-pyrrolo[2,3-d]pyrimidine 150 g of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine and 5.72 g of Pd(bppf)Cl2 were added to 1.5 L of tetrahydrofuran, stirred at room temperature for 0.5 hour, and then cooled down to below 0 C. To the resulting mixture was slowly added dropwise 850 mL of methylmagnesium bromide (3M dissolved in ether). After the addition was completed, the temperature was raised to 6065 C., and the resulting mixture reacted under reflux for 2 hours. Then, the temperature was lowered to below 0 C., and the reaction was quenched by slowly adding dropwise concentrated hydrochloric acid. After the addition was completed, 650 mL of purified water was added to the resulting mixture and stirred for 15 minutes, the phases were separated and the organic phase was discarded. The aqueous phase was adjusted to pH 6 with NaHCO3 and then suction-filtered, the filter cake was washed with 455 mL of purified water, and the filtrate was collected and extracted three times with 1.05 L of ethyl acetate, and then the organic phase was concentrated to obtain 4-methyl-7H-pyrrolo[2,3-d]pyrimidine (109.5 g, 84.2%). 1H-NMR (500 MHz, DMSO-d6): delta=12.00 (bs, 1H), 8.61 (s, 1H), 7.47 (d, J=3.6 Hz, 1H), 6.62 (d, J=3.5 Hz, 1H), 2.64 (d, J=1.6 Hz, 3H); MS (ES): 134.07 (M+H+).
(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In diethyl ether; toluene; at 20 - 60℃;Inert atmosphere;
Into a round bottom flask the catalyst PdCl2(dppf), under an atmosphere of nitrogen, was placed with 15 mL of toluene along with a stir bar. A suspension of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 1.47 g, 9.57 mmol) in 15 mL of toluene was added at room temperature. After stirring for 10 minutes, methylmagnesium bromide (17.00 mL, 3.00 M in ether, 51.00 mmol) was added dropwise. The solution turned from orange to yellow, and was slowly heated to 60 C. and stirred for 3 hrs at 60 C. and then overnight at room temperature. The resulting dark orange reaction mixture was quenched with 1 N hydrochloric acid and adjusted to pH~5, then extracted with ethyl acetate and water saturated with sodium chloride. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluding with ethyl acetate and hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as a yellow solid (42, 202 mg). 1H-NMR(dmso-d6) was consistent with the desired compound. MS(ESI) [M+H+]+=134.3.
Step 1a-Preparation of 4-methyl-7H-pyrrolo[2,3-d]pyrimidine (15)To 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (9, 5.03 g, 32.8 mmol) in 100 mL of toluene, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) 1:1 complex with dichloromethane (0.627 g, 0.328 mmol) is added under an atmosphere of nitrogen. After stirring for 10 minutes, methylmagnesium bromide (62.9 mL, 3.00 M in ether, 189 mmol) is added slowly. The reaction is heated at 55 C. overnight, then cooled to -70 to -80 C. and quenched by adding ammonium chloride dropwise. Then 1N hydrochloric acid is added and the pH is adjusted to 7-8 with the addition of saturated sodium bicarbonate. This is extracted 3× with ethyl acetate. The combined organic layer is washed with saturated ammonium chloride and brine, then dried with magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with ethyl acetate and dichloromethane, then methanol and dichloromethane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound as a tan solid (15). MS (ESI) [M+H+]+=134. This is reacted similarly to steps 2 and 3 of Scheme 4 to provide the desired compound 16.
Step 1 - Preparation of 4-methyl-7H-pyrrolo[2,3-d]pyrimidine (7):[0215] Into a round bottom flask the catalyst [1,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(II), 1 : 1 complex with dichloromethane (70.0 mg, 0.09 mmol), is placed under nitrogen with 15 mL of toluene along with a stir bar. A suspension of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 1.47 g, 9.57 mmol) in 15 mL of toluene is added at room temperature. After stirring for 10 minutes, methylmagnesium bromide (17.00 mL, 3.00 M in ether, 51.00 mmol) is added dropwise. The solution is slowly heated to 60 C and stirred for 3 hrs at 60 C, then overnight at room temperature. The resulting dark orange reaction mixture is quenched with 1 N hydrochloric acid and adjusted to pH ~5, then extracted with ethyl acetate and water saturated with sodium chloride. The organic layer is washed with water and brine, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography eluting with ethyl acetate and hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound as a yellow solid (8, 202 mg). 1H-NMR(dmso-d6) is consistent with the desired compound. MS(ESI)[M+H+]+ = 134.3.
To 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (17, 5.03 g, 32.8 mmol) in 100 mL of toluene, [1,1?-bis(diphenylphosphino)ferrocene]dichloropalladium(II) 1:1 complex with dichloromethane (0.627 g, 0.328 mmol) was added under nitrogen. After stirring for 10 minutes, methylmagnesium bromide (62.9 mL, 3.00 M in ether, 189 mmol) was added slowly. The reaction was heated at 55 C. overnight, then cooled to -70 to -80 C. and quenched by adding ammonium chloride dropwise. Then 1N hydrochloric acid was added and the pH was adjusted to 7-8 with addition of saturated sodium bicarbonate. This was extracted 3× with ethyl acetate. The combined organic layer was washed with saturated ammonium chloride and brine, then dried with magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with ethyl acetate and dichloromethane, then methanol and dichloromethane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as a tan solid (18). MS (ESI) [M+H?]?=134.
With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; for 4h;
A typical procedure for the preparation of 3a:2-bromopropane (74 mg, 0.6 mmol) was added to a solution of 1a (92 mg, 0.6 mmol) and K2CO3 (110 mg, 0.8 mmol) in 5 mL DMF at 70 C. According to TLC the reaction went to completion after 4 h. The mixture was extracted with ethyl acetate (3 * 10 mL). The combined organic layers were washed with brine(10 mL), dried over anhydrous Na2SO4, filtered and concentrated to give the crude product 2a, which was added to a solution of amino-phenol(66 mg, 0.6 mmol) and Cs2CO3 (585 mg, 1.8 mmol) in 10 mL DMSO without further purification. After stirring for 6 h at 80 C, the mixture was cooled to room temperature and extracted with ethyl acetate (3 * 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which was further purified by column chromatography(petroleum ether/ethyl acetate 2:1) to afford compound 3a as a brown solid(121 mg, 75% over two steps).
With tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; toluene;Reflux;
To a previously degassed solution of 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (418mg, 2.72mmol) and palladium tetrakis (157mg, 0.14mmol) in THF (27mL) was added a solution of trimethylaluminium (2.72mL, 5.44mmol, 2M in toluene). After refluxing overnight, the mixture was cooled to 0C and quenched by slow addition of saturated aqueous ammonium chloride. The medium was diluted with EtOAc. The mixture was filtered and the filtrate was decanted. The organic layer was washed with brine, filtered and concentrated under vacuum to afford impure title compound (338mg). LC/MS (ES+): (0290) 134.1 (M+l).
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; at 80℃; for 20h;Inert atmosphere;
To the mixture of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (300 mg, 1.95 mmol) and 2-fluoro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (653 mg, 2.93 mmol) in ethylene glycol dimethyl ether (40 mL) was added water (10 mL), Na2C03 (414 mg, 3.90 mmol) and Pd(PPh3)4 (5%) under N2 atmosphere. The mixture was stirred at 80C for 20 h, filtered, the solvent was removed in vacuo. The residue was purified with column chromatography (petrol ether: EtOAc = 1 :2) to give the desired product (202 mg, 48%). 1H NMR (DMSO- ?: ? 12.36 (1H, s), 8.89 (1H, s), 8.37-8.44 (1H, m), 7.67-7.68 (1H, m), 7.58-7.61 (1H, m), 6.56-6.58 (1H, m).
48%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; at 80℃; for 20h;Inert atmosphere;
To a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (300 mg, 1.95 mmol) and <strong>[452972-14-4]2-fluoropyridine-3-boronic acid pinacol ester</strong>(10 mL), sodium carbonate (414 mg, 3.90 mmol) and Pd(PPh3)4 (5%) were added to the ethylene glycol dimethyl ether solution (40 mL), and the reaction mixture was purged with nitrogen. The reaction was stirred at 80 C for 20 hours, filtered and concentrated in vacuo to remove the solvent. The resulting residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1: 2) to give the title compound (202 mg, 48%)
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,2-dimethoxyethane; water; at 150℃; for 1h;Microwave irradiation;
In a 20 mL sealable microwave tube, 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (500 mg, 3.26 mmol, Eq: 1.00), tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzylcarbamate (1.6 g, 4.8 mmol, Eq: 1.47) and potassium carbonate (1.8 g, 13.0 mmol, Eq: 4.00) were combined with DME (10 mL) and water (5 mL). Pd(PPh3)4(376 mg, 0.326 mmol, Eq: 0.1) was added and the reaction mixture was heated at 150 C for 60 minutes. The resulting solution was diluted with EtOAc and washed with brine. The combined organic phases were dried over anhydrous sodium sulfate then the solvent was removed under reduced pressure. The crude material was purified by column chromatography (silica, 5-70% ethyl acetate in hexanes). The title compound was obtained as a solid (545 mg, 52% yield). LC/MS: m/z calculated for C18H20N402([M+H]+): 325.3 Found: 325.2
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 1h;
To a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine 31-a (392 mg, 2.5 mmol) and Intermediate 31-b (500 mg, 2.8 mmol) in THF (12.7 mL) were sequentially added triphenylphosphine (2.0 g, 7.6 mmol), and DIAD (1.5 ml, 7.6 mmol). The solution was stirred at room temperature for 1 hour. Volatiles were removed under reduced pressure. Purification by silica gel chromatography provided Intermediate 5-c as a beige oil.
2-(1-(ethanesulfonyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidine-3-yl)acetonitrile[ No CAS ]
[ 3680-69-1 ]
[ 1187594-09-7 ]
Yield
Reaction Conditions
Operation in experiment
99%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 80 - 85℃; for 5h;
4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (0.8 g; Formula IX) was added into a reaction vessel containing a solution of potassium carbonate (2.1 g) in water (30 mL) at about 20C to about 25C. A solution of { l-(ethylsulfonyl)-3-[4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl]azetidin-3-yl}acetonitrile (2.0 g; Formula V) in 1,4-dioxane (30 mL) was added into the reaction mixture at about 20C to about 25 C, followed by the addition of tetrakis(triphenylphosphine)palladium(0) (0.1 g). The reaction mixture was stirred at about 80C to about 85C for about 5 hours. On completion of the reaction, 1,4-dioxane was recovered from the reaction mixture under reduced pressure at about 45C to obtain a residue. Ethyl acetate (50 mL) was added into the residue, and then the contents were stirred for about 5 minutes. The organic and aqueous layers were separated. The organic layer was concentrated under reduced pressure at about 45C to obtain baricitinib. Yield: 99.0%
90%
With tetrakis(triphenylphosphine) palladium(0); cesium fluoride; In water; toluene; tert-butyl alcohol; at 100℃; for 48h;Inert atmosphere;
Compound 5 (0.092g, 0 . 24mmol), compound 11 (0.037g, 0 . 24mmol), cesium fluoride (0.129g) and Pd (PPh 3) 4 (0.028g) adding toluene, tertiary butyl alcohol and water (1:1:1) in the mixed solvent, nitrogen protection, 100 C reflux reaction 48 hours, cooling to room temperature, a diatomite filter. Ethyl acetate for flushing diatomite, collect filtrate, separating organic layer, the aqueous layer extracted with ethyl acetate, the organic layer concentrated, drying, column chromatography purification to obtain white solid 0.060g, yield 90%.
90%
With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; water; at 90℃; for 19h;Autoclave; Inert atmosphere;
2~yl)-lH-pyrazol-l-yl]azetidm-3-yl}acetonitrile (5.00 g, 13.15 mmol), potassium phosphate tribasic (2.80 g, 13.19 mmol) and a mixture of dichloro[l, - bis(dicyclohexylphosphino)ferrocene] palladium(ll) with potassium phosphate tribasic (2.84 g of the mixture containing 50 mg total with 0.07 mmol palladium catalyst). THF (21 mL) is added to the autoclave followed by water (5.3 mL). The autoclave is sealed and the contents are heated to 90 C for 19 hours. The reaction mixture is cooled and the resulting suspension is diluted with THF (40 mL) and water (10 mL). The solution is filtered through a mixture of diatomaceous earth (0.4 g) and carbon (0.2 g). The filtrate is concentrated under vacuum to remove THF. An aqueous buffer solution (pH = 7, 30 mL) is added followed by l-butanol (30 mL). The mixture is heated to 85 C with stirring to dissolve residual solids. Stirring is stopped and the lower aqueous layer is removed. Water (10 mL) is added to the stirred l-butanol layer. Stirring is discontinued and the lower aqueous layer is removed. The l-butanol layer is cooled to 75 C and stirred for 30 minutes. The solution is further cooled to 20 C over 6 hours and the resulting slurry is held at that temperature overnight. The solids are collected by filtration, washed with 9: 1 v/v 1 -butane i/water (10 mL) and dried at 40 C to give the title compound (3.45 g, 70.6%). The title compound (2.5 g, 6.73 mmol) is combined with l-butanol (12.6 mL) and water (3.8 mL). The mixture is heated to 85 C and stirred for 30 minutes. The solution is cooled to 20 C over 7 hours to provide a slurry. The solids are collected by filtration then washed with 1-butanol followed by water. The solids are dried to give the title compound (2.25 g, 90% after recrystallization of 2.5 g).
84%
With tetrakis(triphenylphosphine) palladium(0); cesium fluoride; In water; toluene; tert-butyl alcohol; for 48h;Reflux; Inert atmosphere;
To a flask were added 2-{1-(ethylsulfonyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (12) (870 mg, 2.3 mmol, 1.1 equiv.), 4-chloro-7-H-pyrrolo[2,3-d]pyrimidine (5) (290 mg, 0.19 mmol), caesium fluoride (1120 mg), tetrakis(triphenylphosphine)palladium (240 mg, 0.1 equiv.), tertbutanol (10 mL), water (10 mL) and toluene (10 mL) at ambient temperature. The resulting reaction mixture was heated to reflux under nitrogen for 48 h. Then the reaction mixture was cooled to room temperature and filtered through a Celite bed. The Celite bed was washed with ethyl acetate and the aqueous layer was extracted with ethyl acetate. The combined organic layers were concentrated under reduced pressure to remove solvents and the crude product was purified by flash chromatography on a silica gel column eluting with methanol in dichloromethane (0-60%) to afford baricitinib: Yield 560mg (84%); m.p. 193-195 C; IR: 3203, 3113, 2998, 2847, 2363, 1584, 1328, 1137 cm-1. Anal. calcd for C16H17N7O2S: C, 51.74; H, 4.61; N, 26.40; found: C, 51.91; H, 4.49; N, 26.57%. MS (m/z): 372 [M + H]+;1H NMR (300 MHz, DMSO-d6): delta 1.25 (t, J = 7.3 Hz, 3H), 3.23 (m, J= 7.3 Hz, 2H), 3.69 (s, 2H), 4.24 (d, J = 9.0 Hz, 2H), 4.61 (d, J = 9.0 Hz,2H), 7.08 (s, 1H), 7.62 (s, 1H), 8.47 (s, 1H), 8.71 (s, 1H), 8.92 (s, 1H),12.12 (s, 1H); 13C NMR (125 MHz, DMSO-d6): delta 7.4, 24.9, 39.3, 43.4, 58.5, 99.9, 113.0, 116.6, 126.9, 129.5, 139.9, 149.3, 150.9, 152.2.
With tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; toluene; at 60 - 80℃; for 40h;Inert atmosphere;
A suspension of 4-chloro-7H-pyrrolo[2,3-d]pyri- midine (1.54 g, 10 mmol) and Pd(PPh3)4(ii6 mg, 0.100 mmol) in THF (10.0 mE, iM) was vacuum purged with N2. Then a solution of dimethylzinc (3.82 g, 40.0 mmol, 20.0 mE, 2M in toluene) was added and the mixture was vacuum flushed with N2 and then heated to 60 C. for 16 h. ECMSAPC1(+) showed .-i:i mixture of starting material to product. The reaction was heated to 80 C. for another 24 h, in which ECMS showed a 2: 1 mixture of product to starting material. The reaction mixture was cooled in an ice-water bath then quenched with saturated NaHCO3 (aq) and extracted with EtOAc. The EtOAc was washed with brine, dried with Mg504, filter and concentrated to an oil. The crude material was purified by ISCO-Rf on a 24 g column eluting with 0-100% EtOAc-Heptane to give compound V-1 (561 mg, 42%). ECMS [M+i] 134; ?HNMR (400 MHz, CDC13) oe ppm8.94 (s, iH), 7.42 (d, J=3.4 Hz, iH), 6.68 (d, J=3.4 Hz, iH),2.87 (s, 3H)
2-(3-(4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-pyrazole-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile[ No CAS ]
[ 3680-69-1 ]
[ 1187594-09-7 ]
Yield
Reaction Conditions
Operation in experiment
73%
With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In N,N-dimethyl acetamide; water; at 95 - 100℃;Inert atmosphere;
A solution of 2-(3-(4-(5,5-dimethyl-1,3,2-dioxaborate-2-yl)-1H-pyrazol-1-yl)-1(ethylsulfonyl)azetidin-3-yl)acetonitrile (36.62 g, 1OO mmol)4-chloro-7H-pyrrolo[2,3-d]pyrimidine (16.12 g, 105 mmol)Cesium carbonate (52.92 g, 150 mmol),N, N-dimethylacetamide (180 mL) and water (36 mL)Stirring dissolved after vacuum switch nitrogen 3 times,Palladium acetate (113 g, 0.5 mmol) was added under nitrogen atmosphere,Ligand XtanPhos(289 mg, 0.5 mmol),And then vacuum switch nitrogen 3 times,Then heated to 95 ~ 100 C for 5-6 hours,The reaction was quenched by adding water (180 mL) and the mixture was extracted twice with ethyl acetate (180 mL). The combined organic phase was washed twice with water (180 mL), filtered through celite and concentrated to recrystallize with isopropanol and water Biti products (27. llg, 73%).
With potassium phosphate; copper(l) iodide; (1R,2R)-1,2-diaminocyclohexane; In 1,4-dioxane; at 100℃; for 4h;Inert atmosphere;
The mixture of Preparation Ria (1.0 g, 6.51 mmol)), 2-iodo-6-methoxy-pyridine (2.35 g, 9.77 mmol, 1.5 eq.), copper(I)-iodide (125 mg, 0.65 mmol, 0.1 eq.), potassium-phosphatetribasic (2.76 g, 13 mmol, 2 eq.), (1R,2R)-(-)-1,2-diaminocyclohexane (74 mg, 0.65 mmol,0.1 eq.) in PDO (50 ml) was stirred under inert atmosphere for 4 hours at 100 C. The inorganics was filtered off and the filtrate was evaporated. The resulted residue was purified by flash chromatography (DCM).
With copper(l) iodide; (1R,2R)-1,2-diaminocyclohexane; In 1,4-dioxane; at 100℃; for 4h;Inert atmosphere;
R1a (1.0 g, 6.51 mmol) will be prepared,2-Iodo-6-methoxy-pyridine (2.35 g, 9.77 mmol, 1.5 eq.),Copper iodide (I) (125 mg, 0.65 mmol, 0.1 eq.),Potassium phosphate (2.76 g, 13 mmol, 2 eq.),(1R,2R)-(-)-1,2-diaminocyclohexane (74 mg, 0.65 mmol, 0.1 eq.)The mixture in PDO (50 ml) was stirred at 100C under an inert atmosphere for 4 hours. The inorganic material is filtered off and the filtrate is evaporated.The resulting residue was purified by flash chromatography (DCM).
With potassium carbonate; In water; for 24h;Reflux;
2.00 g of 4-amino-1-benzylpiperidine was added to a 100-mL round-bottomed flask, and then 20.0 mL of deionized water and 20.0 mL of saturated sodium hydrogen carbonate (NaHCO3) were added thereto. After 2.41 g of di-tert-butyl dicarbamate (Boc2O) was added thereto, the reaction mixture was vigorously stirred for about 4 hours and then concentrated under reduced pressure. The aqueous phase was extracted with 20.0 mL of ethyl acetate (EtOAc) obtain an organic phase. The organic phase was washed with 15.0 mL of deionized water and 5.00 mL of saturated brine. The organic phase was filtered with sodium sulfate (Na2SO4). The resulting filtrate was distilled under reduced pressure. As a result, 3.04 g of tert-butyl (1-benzylpiperidine-4-yl)carbamate was obtained with a yield of about 99.7%. (0257) 3.04 g of tert-butyl (1-benzylpiperidine-4-yl)carbamate was added to a 100-mL round-bottomed flask, and then 45.0 mL of tetrahydrofuran was added thereto. After 2.50 g of lithium aluminum hydride (LiAlH4) was added thereto, the reaction mixture was refluxed for about 4 hour and then cooled at room temperature. 4.50 mL of deionized water was slowly added thereto while cooling. After the reaction mixture was stirred for about 5 minutes, 4.50 mL of a 15% sodium hydroxide (NaOH) aqueous solution was added thereto. The reaction mixture was further stirred for about 5 minutes, and then 13.5 mL of deionized water was added thereto to terminate the reaction. The reaction mixture was filtered through a Celite 545 filter agent. The resulting filtrate was distilled under reduced pressure. As a result, 2.22 g of <strong>[7006-50-0]1-benzyl-N-methylpiperidine-4-amine</strong> was obtained with a quantitative yield. (0258) 1.00 g of <strong>[7006-50-0]1-benzyl-N-methylpiperidine-4-amine</strong> was added to a 50-mL round-bottomed flask, and then 20.0 mL of deionized water was added thereto. After 790 mg of 6-chloro-7-deazapurine was added thereto, 1.35 g of potassium carbonate (K2CO3) was added into the reaction mixture. The reaction mixture was refluxed for about 24 hours and then cooled at room temperature. The reaction mixture was then extracted three times with 10.0 mL of dichloromethane (CH2Cl2) to collect an organic phase. The collected organic phase was concentrated under reduced pressure, and then the resulting residue was purified by flash column chromatography (MeOH:CH2Cl2=2:98). As a result, 607 mg of N-(1-benzylpiperidine-4-yl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-4-amine was obtained with a yield of about 38.7%. (0259) 350 mg of N-(1-benzylpiperidine-4-yl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-4-amine was added to a 50-mL round-bottomed flask, and then dissolved with 7.00 mL of methanol and 1.00 mL of dichloromethane (CH2Cl2). After 350 mg of a 10w/w% palladium/ carbon (Pd/C) was added thereto, a hydrogen-containing balloon was installed on the reaction flask. The reaction mixture was vigorously stirred for about 24 hours and then filtered through a Celite 545 filter agent. The resulting filtrate was concentrated under reduced pressure. The resulting fraction was concentrated under reduced pressure and then further under vacuum. As a result, 220 mg of N-methyl-N-(piperidine-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine was obtained with a yield of about 87.7%. (0260) 150 mg of N-methyl-N-(piperidine-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine was added to a 5-mL round-bottomed flask and then dissolved with 1.50 mL of n-butanol. After 0.690 mL of ethyl cyanoacetate was added into the solution, the reaction mixture was treated with 0.0485 mL of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and then heated at about 80C for about 24 hours. After termination of the reaction, the reaction solution was distilled under reduced pressure to remove the solvent. The resulting residue was purified by flash column chromatography (MeOH:CH2Cl2=2:98). The resulting fraction was concentrated under reduced pressure and then further under vacuum. As a result, 6.20 mg of 3-(4-(methyl(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)-3-oxopropanenitrile was obtained with a yield of about 3.20%. (0261) 1H NMR (400 MHz, DMSO) delta12.65 (s, 1H), 8.38 (s, 1H), 7.43 (s, 1H), 6.90 (d, J = 1.6 Hz, 1H), 4.75 (s, 1H), 4.52 (d, J = 12.8 Hz, 1H), 4.08 (s, 2H), 3.81 (d, J = 13.6 Hz, 1H), 3.27-3.20 (m, 3H), 2.82-2.75 (m, 1H), 2.03-1.91 (m, 1H), 1.77 (s, 2H), 1.23-1.18 (m, 2H). (0262) LRMS (ESI) calcd for (C15H18N6O + H+) 299.2, found 299.1.
((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)-N-methyl-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Ca.48.9%
With potassium carbonate; In water; for 24h;Reflux;
500 mg of <strong>[1062580-52-2](3R,4R)-1-benzyl-N,4-dimethylpiperidine-3-amine dihydrochloride</strong> was added to a 25-mL round-bottomed flask, and 5.00 mL of deionized water was added thereto. After 277 mg of 6-chloro-7-deazapurine and 1.08 of potassium carbonate (K2CO3) were added into the reaction mixture, the reaction mixture was refluxed for about 24 hours and then cooled at room temperature. The reaction mixture was extracted three times with 10.0 mL of dichloromethane (CH2Cl2) to collect an organic phase. The collected organic phase was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (MeOH:CH2Cl2=2:98). As a result, 282 mg of N-((3R,4R)-1-benzyl-4-methylpiperidine-3-yl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-4-amine was obtained with a yield of about 48.9%. (0285) 282 mg of N-((3R,4R)-1-benzyl-4-methylpiperidine-3-yl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-4-amine was added to a 25-mL round-bottomed flask, and then dissolved with 3.00 mL of methanol. After 280 mg of a 10w/w% palladium/ carbon (Pd/C) was added thereto, a hydrogen-containing balloon was installed on the reaction flask. The reaction mixture was vigorously stirred for about 24 hours and then filtered through a Celite 545 filter agent. The resulting filtrate was concentrated under reduced pressure. The resulting fraction was concentrated under reduced pressure and then further under vacuum. As a result, 200 mg of N-methyl-N-((3R,4R)-4-methylpiperidine-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine was obtained with a yield of about 97.1%. (0286) 70.0 mg of N-methyl-N-((3R,4R)-4-methylpiperidine-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine was added to a 5-mL round-bottomed flask, and then dissolved with 1.50 mL of dichloromethane (CH2Cl2). After 57.0 mg of 3-cyanobenzenesulfonyl chloride was added into the solution, the reaction mixture was treated with 0.0750 mL of N,N-diisopropylethylamine and then stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and then the resulting residue was purified by flash column chromatography (MeOH:CH2Cl2=2:98). The resulting fraction was concentrated under reduced pressure and then further under vacuum. As a result, 85.9 mg of 3-(((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)sulfonyl)benzonitrile was obtained with a yield of about 73.4%. (0287) 1H NMR (400 MHz, CDCl3) delta10.40 (s, 1H), 8.27 (s, 1H), 8.09-8.08 (m, 1H), 8.03-8.01 (m, 1H), 7.95-7.92 (m, 1H), 7.64 (t, J = 3.6 Hz, 1H), 7.13 (d, J = 3.6 Hz, 1H), 6.66 (d, J = 3.6 Hz, 1H), 5.49 (d, J = 4.8 Hz, 1H), 3.79 (dd, J = 4.4, 12.4 Hz, 1H), 3.68 (s, 3H), 3.10 (dd, J = 4.4, 12.4 Hz, 1H), 2.83-2.77 (m, 1H), 2.20-2.11 (m, 1H), 1.92-1.86 (m, 3H), 0.98 (d, J = 6.8 Hz, 3H). (0288) LRMS (ESI) calcd for (C20H22N6O2S + H+) 411.2, found 411.1.
145 g
With potassium carbonate; In water; at 90℃;
100 gm of 4-Chloro-7H-pyrrolo[2,3-d] pyrimidine and 205 gm of (3R,4R)-l-benzyl-N-4- dim ethyl piperidin-3-amine dihydrochloride, 216 gm of Potassium carbonate was dissolved in water and raise the temperature of about 90.0C. After the end of the reaction, extract the product into Toluene and filter off. Distill off the solvent completely under vacuum and isolated the product in Isopropyl alcohol. Filtered the material and dried to get 145 gm of N-((3R,4R)-l-benzyl-4-methylpiperidin-3-yl)-N- methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine.
tert-butyl (3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)cyclohex-3-en-1-yl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 100℃; for 14h;Inert atmosphere;
To 4-chloro-7H-pyrrolo[2,3-d]pyrimidin (2.97 g), the compound (9.39 g) of Reference Example 1(2a) and tripotassiumphosphate (10.2 g), 1,4-dioxane (66 mL) and water (11 mL) were added, followed by nitrogen substitution, andPdCl2(dppf)CH2Cl2 (1.41 g) was then added to the reaction mixture. The thus obtained mixture was stirred at 100C for14 hours. Thereafter, the reaction mixture was cooled to a room temperature, and ethyl acetate and water were thenadded to the mixture. Thereafter, the thus obtained mixture was filtered through Celite. The filtrate was then extractedwith ethyl acetate, and the gathered organic layer was then washed with water and then with a saturated saline. Theresultant was dried over anhydrous sodium sulfate, and was then concentrated under a reduced pressure. The obtainedresidue was purified by silica gel chromatography (chloroform : methanol) to obtain tert-butyl (3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)cyclohex-3-en-1-yl)carbamate. The above obtained compound was used in the subsequent reaction withoutfurther purification.
General procedure: Preparation Rla (460 mg, 3 mmol, 1 eq.), heteroaryl/aryl-boronic acid (7.5 mmol) and copper(II)-acetate (817 mg, 4.5 mmol) were stirred in pyridine (10 ml) at 50-60 C for 16-72 hours. (0176) Work-up 1 : (0177) The mixture was evaporated to Celite and purified by flash chromatography (heptane:EEO, gradient). (0178) Work-up 2: (0179) The mixture was filtered and the resulted filtrate was purified by preparative LC (on C-18 Gemini-NX 5 pm column, 5 mM aqueous NH4HC03-MeCN, gradient).
Example 87 4-[(7H-Pyrrolo[2,3-d]pyrimidin-4-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester EXAMPLE 87 was prepared from <strong>[157023-34-2]4-aminomethyl-piperidine-1-carboxylic acid benzyl ester</strong> and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (4-chloro-7H-pyrrolo[2,3-d]pyrimidine was prepared according to U. Lupke, F. Seela, Chem. Ber., 112:3832-3839(1979): MS (m+1)=366.
N-(4-nitrophenethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%
With triethylamine; In isopropyl alcohol; at 80℃; for 48h;
4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (100.0 mg, 0.65 mmol), <strong>[29968-78-3]2-(4-nitrophenyl)ethan-1-amine hydrochloride</strong> (132.0 mg, 0.65 mmol) and Et3N (272.0 muL, 1.95 mmol) were added toi-PrOH (6.5 mL). The reaction mixture was stirred at 80 for 2 days. After addition of water, the reaction mixture was extracted with EtOAc, washed with brine, dried with Na2SO4, filtered and distilled under reduced pressure. The residue was purified by C18 reversed-phase silica gel column chromatography (CH3CN:H2O condition) and freeze-dried to obtain the yellow solid compound,N-(4-nitrophenethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (102.0 mg, 55%).[770][771]LC/MS ESI (+): 284 (M+1)
1,1-dichloro-2-cyano-4-methoxy-1,3-butadiene[ No CAS ]
[ 6313-33-3 ]
[ 3680-69-1 ]
Yield
Reaction Conditions
Operation in experiment
91%
With sodium methylate; In methanol; at 25 - 70℃; for 10h;
To a 250 ml four-necked flask equipped with a stirring, thermometer, reflux condenser and constant pressure dropping funnel, 50 g of tetrahydrofuran, 10.5 g (0.13 mol) of formazan hydrochloride, 25.1 g (0.13 mol) of 28 wt% methanol were added. Sodium methanol solution, 25 to 30 C, 17.8 g (0.1 mol) of 1,1-dichloro-2-cyano-4-methoxy-1,3-butane obtained in Example 2 was added dropwise. A solution of the ene (IV) and 80 g of tetrahydrofuran was added dropwise in about 2 hours, and then the reaction was stirred at 25 to 30 C for 4 hours. Then add 21.5 g (0.11 mol) of a 28 wt% sodium methoxide methanol solution, stir the reaction for 4 hours at 65 to 70 C, cool to 20-25 C, filter, wash twice with 20 grams each time, and dry to obtain 13.97 g of 4-chloro- 7H-pyrrolo [2,3-d] pyrimidine (I), the yield was 91.0%, and the liquid purity was 99.5%.
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