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[ CAS No. 3680-69-1 ] {[proInfo.proName]}

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Chemical Structure| 3680-69-1
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Product Citations

Pieterse, Lianie ; Beteck, Richard M. ; Baratte, Blandine , et al. DOI: PubMed ID:

Abstract: Protein kinases, including CDK9/CyclinT and Haspin, are regarded as potential drug targets in cancer therapy. Findings from a previous study suggested 7-azaindole as a privileged scaffold for producing inhibitors of CDK9/CyclinT and Haspin. Inspired by these findings, the current study synthesized and evaluated thirteen (13) C6-substituted 7-azaindole and twenty (20) C4-substituted structurally related 7H-pyrrolo[2,3-d]pyrimidine derivatives against a panel of protein kinases, including CDK9/CyclinT and Haspin. Eleven of the 7H-pyrrolo[2,3-d]pyrimidine derivatives exhibited activity toward CDK9/CyclinT, while 4 of compounds had activity against Haspin. The best CDK9/CyclinT (IC50 of 0.38 μM) and Haspin (IC50 of 0.11 μM) activities were achieved by compounds 7d and 7f, resp. Hence, these compounds may be valuable starting points for development of new anti-cancer drugs.

Keywords: 7-Deazapurine ; Anticancer ; CDK9/CylinT ; Haspin ; Protein kinase

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Product Details of [ 3680-69-1 ]

CAS No. :3680-69-1 MDL No. :MFCD01686865
Formula : C6H4ClN3 Boiling Point : -
Linear Structure Formula :- InChI Key :BPTCCCTWWAUJRK-UHFFFAOYSA-N
M.W : 153.57 Pubchem ID :5356682
Synonyms :
4-Chloro-7H-pyrrolo[2,3-d]pyrimidine
Chemical Name :4-Chloro-7H-pyrrolo[2,3-d]pyrimidine

Calculated chemistry of [ 3680-69-1 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 10
Num. arom. heavy atoms : 9
Fraction Csp3 : 0.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 2.0
Num. H-bond donors : 1.0
Molar Refractivity : 38.9
TPSA : 41.57 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.09 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.43
Log Po/w (XLOGP3) : 1.62
Log Po/w (WLOGP) : 1.61
Log Po/w (MLOGP) : 0.78
Log Po/w (SILICOS-IT) : 2.24
Consensus Log Po/w : 1.54

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -2.48
Solubility : 0.51 mg/ml ; 0.00332 mol/l
Class : Soluble
Log S (Ali) : -2.11
Solubility : 1.21 mg/ml ; 0.00785 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.14
Solubility : 0.112 mg/ml ; 0.000728 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.27

Safety of [ 3680-69-1 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P264-P271-P280-P302+P352-P304+P340-P305+P351+P338-P312-P362-P403+P233-P501 UN#:N/A
Hazard Statements:H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 3680-69-1 ]

* 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.

  • Upstream synthesis route of [ 3680-69-1 ]
  • Downstream synthetic route of [ 3680-69-1 ]

[ 3680-69-1 ] Synthesis Path-Upstream   1~49

  • 1
  • [ 3680-69-1 ]
  • [ 69-33-0 ]
Reference: [1] Journal of Heterocyclic Chemistry, 1988, vol. 25, # 6, p. 1893 - 1898
[2] Tetrahedron Letters, 1987, vol. 28, # 43, p. 5107 - 5110
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  • [ 3680-69-1 ]
  • [ 35808-68-5 ]
Reference: [1] Patent: WO2012/158795, 2012, A1,
[2] Patent: WO2012/158764, 2012, A1,
[3] Patent: WO2013/191965, 2013, A1,
[4] Patent: WO2014/22569, 2014, A1,
[5] Patent: US8673925, 2014, B1,
[6] Patent: WO2014/184069, 2014, A1,
[7] Beilstein Journal of Organic Chemistry, 2016, vol. 12, p. 1103 - 1110
[8] Patent: WO2017/46738, 2017, A1,
  • 3
  • [ 3680-69-1 ]
  • [ 271-70-5 ]
YieldReaction ConditionsOperation in experiment
98% With hydrogen In methanol for 16 h; 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
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YieldReaction ConditionsOperation 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.
Reference: [1] Patent: EP795556, 1997, A1,
  • 5
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  • [ 3680-69-1 ]
  • [ 271-70-5 ]
Reference: [1] Patent: EP795556, 1997, A1,
  • 6
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  • [ 1618-36-6 ]
Reference: [1] Helvetica Chimica Acta, 1994, vol. 77, # 4, p. 897 - 903
[2] Patent: WO2012/80735, 2012, A1,
[3] Patent: WO2015/143712, 2015, A1,
  • 7
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  • [ 74-88-4 ]
  • [ 7781-10-4 ]
YieldReaction ConditionsOperation in experiment
94% 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
  • 10
  • [ 3680-69-1 ]
  • [ 16019-34-4 ]
Reference: [1] Tetrahedron Letters, 1998, vol. 39, # 32, p. 5685 - 5688
  • 11
  • [ 3680-69-1 ]
  • [ 1500-85-2 ]
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 ]
YieldReaction ConditionsOperation 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 Scheme 4 Synthesis of 5-Pyrrolidine-pyrrolor2,3-d1pyrimidine compoundsmιn 1 INTERMEDIATE; 5-Bromo-4-chloro-7H-pyrrolor2.3-dlpyrimidine.Chemical Formula: C6H3BrCIN3 Exact Mass: 230.921H-NMR (DMSO-d6/400 MHz): 12.97 (s, IH), 8.62 (s, IH), 7.95 (d, J-2.8 Hz, IH).
91.5% 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).

Reference: [1] Organic Letters, 2003, vol. 5, # 20, p. 3587 - 3590
[2] Synthesis, 2011, # 9, p. 1442 - 1446
[3] Archiv der Pharmazie, 2016, vol. 349, # 5, p. 356 - 362
[4] European Journal of Medicinal Chemistry, 2017, vol. 138, p. 543 - 551
[5] Patent: CN107556318, 2018, A, . Location in patent: Paragraph 0101-0103; 0106; 0107
[6] Patent: WO2018/85833, 2018, A2, . Location in patent: Paragraph 0353
[7] Patent: CN108997351, 2018, A, . Location in patent: Paragraph 0075; 0112; 0149; 0150
[8] Patent: WO2008/128072, 2008, A2, . Location in patent: Page/Page column 39
[9] Patent: WO2014/60432, 2014, A1, . Location in patent: Page/Page column 146; 147
[10] Patent: US6635762, 2003, B1, . Location in patent: Page/Page column 26
[11] Journal of Medicinal Chemistry, 1988, vol. 31, # 11, p. 2086 - 2092
[12] Patent: EP2390254, 2011, A1, . Location in patent: Page/Page column 56
[13] Patent: WO2008/75007, 2008, A1, . Location in patent: Page/Page column 81
[14] Journal of Medicinal Chemistry, 2011, vol. 54, # 24, p. 8328 - 8342
[15] Patent: US2009/264450, 2009, A1, . Location in patent: Page/Page column 7
[16] Patent: US2009/42893, 2009, A1, . Location in patent: Page/Page column 14
[17] Helvetica Chimica Acta, 1994, vol. 77, # 4, p. 897 - 903
[18] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 19, p. 5607 - 5612
[19] Patent: WO2005/51304, 2005, A2, . Location in patent: Page/Page column 117
[20] Patent: WO2005/51304, 2005, A2, . Location in patent: Page/Page column 117
[21] Patent: US2016/244475, 2016, A1, . Location in patent: Paragraph 0310; 0312
[22] Patent: US9630968, 2017, B1, . Location in patent: Page/Page column 28; 29
[23] Patent: WO2017/111787, 2017, A1, . Location in patent: Paragraph 00140
[24] Patent: TW2017/22956, 2017, A, . Location in patent: Paragraph 0139; 0140
[25] Patent: WO2011/149827, 2011, A1, . Location in patent: Page/Page column 67
[26] Patent: WO2008/75109, 2008, A1, . Location in patent: Page/Page column 114-115
[27] Patent: WO2008/75110, 2008, A1, . Location in patent: Page/Page column 106-107
[28] Patent: WO2009/47563, 2009, A1, . Location in patent: Page/Page column 118
[29] Patent: US2009/5359, 2009, A1, . Location in patent: Page/Page column 25
[30] Patent: WO2013/12915, 2013, A1, . Location in patent: Paragraph 00939
[31] Journal of Medicinal Chemistry, 2018, vol. 61, # 23, p. 10665 - 10699
[32] Patent: WO2009/80682, 2009, A1, . Location in patent: Page/Page column 30
[33] Patent: WO2010/15643, 2010, A1, . Location in patent: Page/Page column 82
[34] Patent: US2010/144758, 2010, A1, . Location in patent: Page/Page column 61-62
[35] Patent: WO2006/65335, 2006, A2, . Location in patent: Page/Page column 21; 22
[36] Patent: WO2010/135520, 2010, A1, . Location in patent: Page/Page column 139
[37] Patent: WO2011/119663, 2011, A1, . Location in patent: Page/Page column 137
[38] Patent: WO2011/146882, 2011, A1, . Location in patent: Page/Page column 110
[39] Patent: US2012/122838, 2012, A1, . Location in patent: Page/Page column 81-82
[40] Patent: WO2012/80735, 2012, A1, . Location in patent: Page/Page column 7; 23; 24
[41] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 24, p. 7742 - 7747
[42] Patent: WO2013/85802, 2013, A1, . Location in patent: Page/Page column 49
[43] Patent: WO2015/77866, 2015, A1, . Location in patent: Page/Page column 61; 62
[44] Patent: WO2015/143712, 2015, A1, . Location in patent: Page/Page column 39
[45] Patent: WO2017/46739, 2017, A1, . Location in patent: Page/Page column 53
[46] Patent: WO2010/15637, 2010, A1, . Location in patent: Page/Page column 94
  • 13
  • [ 3680-69-1 ]
  • [ 22276-95-5 ]
Reference: [1] Patent: US2002/19526, 2002, A1,
  • 14
  • [ 3680-69-1 ]
  • [ 24391-41-1 ]
Reference: [1] Patent: WO2011/146882, 2011, A1,
[2] Patent: US2012/122838, 2012, A1,
[3] Patent: WO2012/80735, 2012, A1,
[4] Patent: WO2013/12915, 2013, A1,
[5] Patent: WO2010/15637, 2010, A1,
  • 15
  • [ 3680-69-1 ]
  • [ 115093-90-8 ]
YieldReaction ConditionsOperation in experiment
95% 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 ]
YieldReaction ConditionsOperation 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 Scheme 1General Synthesis of 5-Aryl pyπOlor2,3-d1pyrimidine CompoundsP X,Y = H1F , CI.C F31C N. CH3, OCH3, NH2, N(CH3J2, OCF31S F5X,Y = H, F, Cl, CF3,C N, CH3, OCH31N H2, N(CH3)2,O CF3,S F5EXAMPLE 27 4-CHLORO-5-IODO-7-BENZENESULFONYL-7H-PYRROLO[2,3-D]PYRIMIDINE1H-NMR (CD3ODMOO MHz): 8.75 (s, IH), 8.22 (dm, J = 6.5 Hz, 2H), 7.94 (s, IH), 7.68 (tm, J = 8.6 Hz, IH), 7.55 (tm, J = 8.6 Hz, 2H). MS (ES+, m/z): 419.9 (M++l, 100.0).
83% 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).

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YieldReaction ConditionsOperation in experiment
86.9% at 20℃; 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).
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YieldReaction ConditionsOperation in experiment
59% 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)

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[8] Patent: US2016/244475, 2016, A1, . Location in patent: Paragraph 0310; 0311
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[14] Patent: WO2015/143712, 2015, A1,
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YieldReaction ConditionsOperation 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.

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YieldReaction ConditionsOperation in experiment
97%
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
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  • [ 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,
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  • [ 941685-27-4 ]
Reference: [1] Patent: US2011/224190, 2011, A1,
[2] Patent: WO2013/36611, 2013, A1,
[3] Patent: US2015/246046, 2015, A1,
[4] Patent: CN106905322, 2017, A,
[5] Journal of Medicinal Chemistry, 2017, vol. 60, # 20, p. 8336 - 8357
[6] Patent: EP3360878, 2018, A1,
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  • [ 784150-41-0 ]
Reference: [1] Journal of Medicinal Chemistry, 2015, vol. 58, # 18, p. 7431 - 7448
  • 38
  • [ 3680-69-1 ]
  • [ 1100318-96-4 ]
YieldReaction ConditionsOperation 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 ]
YieldReaction ConditionsOperation 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] Patent: WO2009/47563, 2009, A1, . Location in patent: Page/Page column 40
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  • [ 1143532-39-1 ]
Reference: [1] Journal of Medicinal Chemistry, 2013, vol. 56, # 5, p. 2059 - 2073
  • 41
  • [ 18997-19-8 ]
  • [ 3680-69-1 ]
  • [ 1146629-75-5 ]
YieldReaction ConditionsOperation 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.

Reference: [1] Patent: WO2016/88094, 2016, A1, . Location in patent: Page/Page column 10
[2] Organic Letters, 2009, vol. 11, # 9, p. 1999 - 2002
[3] Patent: US2010/190981, 2010, A1, . Location in patent: Page/Page column 73-75
[4] Patent: CN107226814, 2017, A, . Location in patent: Paragraph 0039-0040; 0042; 0044; 0046; 0048; 0050
[5] Patent: US2009/233903, 2009, A1, . Location in patent: Page/Page column 67-68
[6] Patent: WO2011/52923, 2011, A2, . Location in patent: Page/Page column 42
[7] Patent: US2012/271048, 2012, A1, . Location in patent: Page/Page column 21
[8] Patent: US2018/50036, 2018, A1, . Location in patent: Paragraph 0111; 0112; 0113; 0114
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  • [ 1187594-09-7 ]
YieldReaction ConditionsOperation in experiment
99% 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
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  • [ 3680-69-1 ]
  • [ 1187594-09-7 ]
YieldReaction ConditionsOperation 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,
  • 45
  • [ 3680-69-1 ]
  • [ 1207518-63-5 ]
Reference: [1] Patent: WO2010/15637, 2010, A1,
  • 46
  • [ 3680-69-1 ]
  • [ 1266343-30-9 ]
Reference: [1] Patent: WO2011/119663, 2011, A1,
[2] MedChemComm, 2014, vol. 5, # 10, p. 1500 - 1506
[3] Patent: WO2018/194885, 2018, A1,
  • 47
  • [ 3680-69-1 ]
  • [ 1334298-90-6 ]
YieldReaction ConditionsOperation in experiment
44.6% 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.
Reference: [1] Patent: US2014/256941, 2014, A1, . Location in patent: Paragraph 0148
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  • [ 3680-69-1 ]
  • [ 1334298-90-6 ]
Reference: [1] Patent: WO2013/36611, 2013, A1,
[2] Patent: US2014/256941, 2014, A1,
[3] Patent: US2015/246046, 2015, A1,
  • 49
  • [ 3680-69-1 ]
  • [ 1337531-36-8 ]
Reference: [1] Journal of Medicinal Chemistry, 2012, vol. 55, # 16, p. 7193 - 7207