* 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.
Stage #1: With sodium hydride In tetrahydrofuran; acetonitrile at 0℃; for 0.5 h; Stage #2: at 0 - 20℃;
To a solution of sodium hydride (480 mg, 12.00 mmol, 1.10 equiv, 60percent) in tetrahydrofuran (50 mL), a solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (2 g, 10.64 mmol, 1.00 equiv) in tetrahydrofuran (50 mL) was slowly added. The resulting solution was stirred at 0° C. for 30 min followed by the addition of methyl iodide (1.66 g, 11.70 mmol, 1.10 equiv) at 0° C. The mixture was stirred at room temperature overnight. After completion, 20 mL of water was added to the mixture and the solution was extracted with ethyl acetate and washed with brine. The organic phase was dried over anhydrous sodium sulfate, filtered and then concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1:5) to afford 2.1 g (98percent) of 2,4-dichloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine as a white solid. LC-MS (ES, m/z): 202 [M+H]
97.2%
Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; for 0.333333 h; Stage #2: at 20℃; for 3 h;
[00237] To a solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (1.5 g, 7.98 mmol) in THF (30 ml) at 0 °C was added sodium hydride (60percent oil suspension, 383 mg, 9.57 mmol) and stirred at 0 °C to r.t. for 20 mins. lodomethane (0.6 ml, 9.57 mmol) was added and stirred at r.t. for 3 h. [00238] The mixture was quenched by addition of saturated ammonium chloride solution (20 mL). EtOAc was then added resulting in formation of a precipitate. The precipitate was filtered and the filtrate extracted with EtOAc (x2). The combined organic fractions were washed with water, dried over Na2S04, filtered and concentrated in vacuo to afford the title compound (1.65 g, 97.2percent) as a yellow powder. [00239] Method A: LC-MS m/z = 201.90, 203.90 [M + H]+; RT = 1.21 min.
96%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 0.5 h; Stage #2: at 20℃; for 3 h;
Step 1 : To a stirred solution of 2,4-dichloro-7/-/-pyrrolo[2,3-c]pyrimidine (2 g, 10.638 mmol) in DMF (20 mL) was added 60 percent NaH (0.63 g, 15.957 mmol, 1.5 equiv) at 0 °C and stirred for 30 min at room temperature. Methyl iodide (0.79 mL, 12.765 mol, 1.2 equiv) was added and allowed to stir at room temperature for 3 h. The reaction was quenched with ice water (200 mL) and the precipitated solid was filtered and dried in vacuo to obtain 2,4-dichloro-7-methyl- 7H-pyrrolo[2,3-c]pyrimidine as an off white solid (2.06 g, 96 percent). LCMS (ES) m/z = 202.1 , 204.0 [M+H]+. H NMR (400 MHz, DMSO-d6) δ ppm 3.80 (s, 3H), 6.66 (d, J = 3.2 Hz, 1 H), 7.73 (d, J = 3.2 Hz, 1 H).
93%
With triethylamine In tetrahydrofuran at 25℃; for 6 h;
A solution of2,4-Dichloro-7H-pyrrolo [2,3-d] pyrimidine (5.0 g, 26.6 mmol) was dissolved in tetrahydrofuran (50 mL)Triethylamine (4.0 g, 39.5 mmol) was added,Methyl iodide (4.2 g, 29.6 mmol) was added dropwise,After the addition was complete, the temperature was raised to 25 ° C and reacted for 16 hours.After the reaction was completed, the reaction solution was poured into water (100 mL)The precipitated solid was filtered,drying,The product (5.0 g, 93percent yield) was obtained.
93%
Stage #1: With sodium hydroxide In tetrahydrofuran at 0℃; for 0.25 h; Stage #2: at 20℃;
A 0 °C solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (1.00 g, 5.32 mmol) in THF (8 mL) was stirred for 5 mm, then to the solution was added sodium hydroxide (255 mg, 6.38 mmol). The mixture was stirred for further 15 mm, and iodomethane (8.50 g, 53.20 mmol) was added. The mixture was stirred at rt overnight. To the reaction mixture was added H20 (100 mL), and the mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo dry,and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 10/1) to give the title compound as a white solid (1.00 g, 93 percent).MS (ESI, pos. ion) m/z: 202.95 [M+Hfb.
93%
Stage #1: With sodium hydride In tetrahydrofuran at 0℃; for 0.25 h; Stage #2: at 20℃;
2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidine (1.00 g, 5.32 mmol)Dissolved in THF (8 mL), and the resulting solution was stirred at 0 ° C for 5 min.Then sodium hydride (255 mg, 6.38 mmol) was added thereto.The resulting reaction solution was stirred for 15 minutes.Methyl iodide (8.50 g, 53.20 mmol) was added thereto.The resulting reaction solution was transferred to room temperature and stirred overnight.The reaction was quenched by H2O (EtOAc) (EtOAc)The combined organic phases were washed with brine (80 mL).Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure.The residue was chromatographed on silica gel ( petroleum ether / ethyl acetate (v/v) = 10/1)Purification to give the title compound as a white solid(1.00g, 93percent).
93%
Stage #1: With sodium hydride In tetrahydrofuran at 0℃; for 0.25 h; Stage #2: at 20℃;
A solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (1.00 g, 5.32 mmol) in THF (8 mL) was stirred at 0 °C for 5 mm. Then sodium hydride (255 mg, 6.38 mmol) was added. The resulting mixture was stirred for 15 mm, then iodomethane (8.50 g, 53.20 mmol) was added. The reaction mixture was warmed to rt and stirred overnight. H20 (100 mL) was added to quench the reaction, and the resulting mixture was extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine (80 mL), dried over anhydrous Na2504, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatograph (PE/EtOAc (v/v) = 10/1) to give the tilte compound as a white solid (1.00 g, 93 percent).MS (ESI, pos. ion) m/z: 203.0 [M+H]t
93%
Stage #1: With sodium hydride In tetrahydrofuran at 0℃; for 0.25 h; Stage #2: at 0 - 20℃;
A solution of 2, 4-dichloro-7H-pyrrolo [2, 3-d] pyrimidine (1.00 g, 5.32 mmol) in THF (8 mL) was stirred for 5 min at 0 , then sodium hydride (255 mg, 6.38 mmol) was added. The mixture was stirred for 15 min, and then iodomethane (8.50 g, 53.20 mmol) was added. The resulting mixture was warm to rt and stirred overnight, then the reaction was quenched with H2O (100 mL) . The mixture was extracted with ethyl acetate (50 mL × 3) . The combined organic layers were washed with saturated brine (80 mL) , dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v) =10/1) to give the title compound as a white solid (1.00 g, 93percent) .MS (ESI, pos. ion) m/z: 203.0 [M+H]+.
84.1%
Stage #1: With sodium hydride In tetrahydrofuran at 0℃; for 0.5 h; Stage #2: at 0 - 20℃;
To a solution of 60percent NaH (750 mg) in dry THF (20 mL), a solution of 18a (1.7 g) in dry THF (50 mL) was slowly added. The resulting solution was stirred at 0 °C for 30 min followed by the addition of MeI (0.79 mL) at 0 °C. The mixture was stirred at room temperature overnight. After the addition of 20 mL water, the solution was extracted with ether (3.x.10 mL) and washed with saturated brine. The organic phase was dried with anhydrous sodium sulfate and filtered. Ether was evaporated in vacuo to yield a crude residue, which was purified by silica gel chromatography (PE/EA= 10/1) to give 18d (1.53 g, yield: 84.1percent). ESI-MS calculated for (C7H5Cl2N3) [M+H]+, 202.0, found 202.1.
74.1%
Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 0℃; Stage #2: at 20℃;
A solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (3.00 g, 16.0 mmol) in anhydrous tetrahydrofuran (45 mL) was cooled to 0° C. and treated with a 60percent dispersion of sodium hydride in mineral oil (0.83 g, 20.8 mmol). The reaction was stirred at 0° C. for 20-30 min. The reaction was then treated with iodomethane (3.65 g, 1.6 mL, 25.7 mmol), and the reaction stirred at room temperature overnight. The reaction was diluted with a saturated aqueous ammonium chloride solution (50 mL) and water (50 mL) and was extracted with a 10percent methanol in methylene chloride solution (4×50 mL). The combined organic layers were dried over magnesium sulfate, filtered and rinsed with methylene chloride, and concentrated in vacuo onto Celite®. Flash chromatography (80 g silica gel column, 0-15percent ethyl acetate/hexanes) afforded 2,4-dichloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine as a light yellow solid (2.39 g, 74.1percent). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.81 (s, 3H) 6.70 (d, J=3.51 Hz, 1H) 7.76 (d, J=3.51 Hz, 1H). LC-MS calcd. for C7H6Cl2N3 [(M+H)+] 202, obsd. 202.0.
58%
Stage #1: With sodium hydride In acetonitrile at 0 - 20℃; for 0.333333 h; Stage #2: at 20℃; for 1 h;
To a solution of 2,4-dichloro-7H-pyrrolo[2,3-djpyrimidine 34 (237 mg, 1.26 mmol) in CH3CN (1 mL) was added NaH (33.3 mg, 1.39 mmol) portion- wise at 0 °C. The reaction mixture was stirred at room temperature for 20 mm until gas evolution was ceased. Methyl iodide (86.4 i.il, 1.39 mmol) was added and stirred the reaction mixture for 1 h at room temperature. To the reaction mixture was added water and extracted with ethyl acetate (2 x 30 mL). The combined organic layers were dried over Mg504, and then concentrated under vacuum. The resultant crude residue was purified by silica-gel column chromatography to afford 35 (144 mg, 58percent) as white solid. ‘H-NMR (400 MHz, DMSO-d6) ö 7.76 (d, J = 3.6 Hz, 1H), 6.71 (d, J = 3.6 Hz, 1H), 3.81 (s, 3H); MS: (m/z) [M+Hjb 204.02.
Reference：
[1] Patent: US2015/57260, 2015, A1, . Location in patent: Paragraph 0436; 0437; 0588; 0589
[2] Patent: WO2015/25026, 2015, A1, . Location in patent: Page/Page column 118
[3] Patent: WO2017/59191, 2017, A1, . Location in patent: Paragraph 00235-00239
[4] Patent: WO2017/46739, 2017, A1, . Location in patent: Page/Page column 51
[5] Patent: CN107226808, 2017, A, . Location in patent: Paragraph 0366-0369
[6] Patent: WO2018/33082, 2018, A1, . Location in patent: Paragraph 00262
[7] Patent: CN108276401, 2018, A, . Location in patent: Paragraph 0554; 0556; 0557; 0920; 0922; 0923
[8] Patent: WO2018/127096, 2018, A1, . Location in patent: Paragraph 00273; 00370
[9] Patent: WO2018/157830, 2018, A1, . Location in patent: Paragraph 00243
[10] European Journal of Medicinal Chemistry, 2012, vol. 52, p. 205 - 212
[11] Journal of Medicinal Chemistry, 2014, vol. 57, # 1, p. 144 - 158
[12] Patent: US2013/331375, 2013, A1, . Location in patent: Paragraph 0153-0154
[13] Liebigs Annalen der Chemie, 1984, # 4, p. 722 - 733
[14] Patent: WO2018/137036, 2018, A1, . Location in patent: Paragraph 00235; 00236
[15] Patent: WO2010/38060, 2010, A1, . Location in patent: Page/Page column 90-91
2
[ 90213-66-4 ]
[ 90213-67-5 ]
Yield
Reaction Conditions
Operation in experiment
93%
Stage #1: With sodium hydride In tetrahydrofuran at 0℃; for 0.25 h; Stage #2: at 20℃;
A 0 oc solution of 2,4-dichloro-7 H-pyrrolo[2,3-d]pyrimidine ( 1.00 g, 5.32 mmol) inTHF (8 mL) was stirred at 0 oc for 5 min. Then sodium hydride (255 mg, 6.38 mmol) was added.The resulting mixture was stirred for 15 min, then iodomethane (8.50 g, 53.20 mmol) was added.The reaction mixture was warmed to rt and stirred overnight. To the reaction mixture was addedwater (60 mL) to quench the reaction, and the resulting mixture was extracted with ethyl acetate(50 mL x 3). The combined organic layers were washed with saturated brine (80 mL), dried overanhydrous sodium sulfate and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 1011) to give the title compound as awhite solid (1.00 g, 93 percent ).MS (ESI, pos. ion) m/z: 202.0[M+Ht.
83%
With potassium hydroxide In dimethyl sulfoxide at 20℃; for 1 h;
Example 2 (1 g, 5.318 mmol) and powdered KOH (446 mg, 7.978 mmol) was dissolved in 4 mL anhydrous DMSO. After 1 h at RT, the reaction mixture was quenched with water and the aqueous layer was extracted with EtOAc (2x).The organics were combined, dried (MgSO4), filtered and the volatiles were removed in vacuo. The residue was purified by flash chromatography (Siψ2, hexanes/EtOAc, 2:1 ) to provide the desired product (892 mg, 83percent) as a colourless solid. 1H NMR (CZ6-DMSO) δ 7.76 (1 H, d, J = 3.6 Hz), 6.70 (1 H, d, J= 3.6 Hz), 3.82 (3H, s).
With N-ethyl-N,N-diisopropylamine; trichlorophosphate In toluene at 70 - 106℃; for 18.5 h;
Example 15; Preparation of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine:; A reactor was equipped with 7H-pyrrolo[2,3-d]pyrimidine-2,4-diol(10.0g, 66.2 mmol) and toluene (30 ml) with stirring. Phosphorusoxychloride (18.5 ml, 198.5 mmol) was added and the reactor was warmed to 7O0C. Diisopropylethylamine (23.0 m, 132.3 mmol) was added over 2.5 h to control the exotherm. After completion of the base addition, the reactor was heated to 1060C and stirred at temperature for 16 h. The mixture was cooled to 250C and added slowly to a flask containing water (230 ml) and ethyl acetate (120ml) at room temperature, then stirred overnight at room temperature. After filtration through Celite, the layers were separated the aqueous layer was extracted with ethyl acetate (3 x 75ml). The organic layers were combined and washed with brine (100ml). Darco KBB (1.24 g) was added to the organics, then filtered through Celite and dried over sodium sulfate (10.0 g). The solution was concentrated in vacuo to obtain the title compound (52percent yield).
43%
With N,N-diethylaniline; trichlorophosphate In <i>N</i>,<i>N</i>-dimethyl-aniline at 120℃; for 0.5 h; Microwave irradiation
Step 2: Synthesis of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine To a 20 mL vial were added 7H-pyrrolo[2,3-d]pyrimidine-2,4-diol (2.5 g, 16.6 mmol), POCl3 (10 mL, 107 mmol) and N,N-dimethylaniline (1 mL, 7.9 mmol). The resulting mixture was heated at 120° C. for 30 min in microwave oven. The reaction mixture was cooled to room temperature, and poured into ice, and neutralized by the addition of concentrated ammonium hydroxide to pH 5-7. The resulting solid was filtered, and washed with water to give the title compound as brown solid (1.323 g, 43percent yield). MS(ESI, M+1) m/z 188.2.
28%
at 180℃; for 4 h;
A suspension of 7H-Pyrrolo[2,3-d]pyrimidine-2,4-diol (2.25 g, 0.015 mol) in phenylphosphinic dichloride (PhPOCl2) (15 mL) was heated at 180° C. for 4 h. The resulting dark syrup was poured slowly to ice water, the black precipitates were filtered off, and the filtrate was extracted with ether. The ether layers were combined, washed sequentially with sat. NaHCO3, brine, dried over Na2SO4 and concentrated to give 2,4-Dichloro-7H-Pyrrolo[2,3-d]pyrimidine (0.8 g, 28percent yield).
28%
at 165 - 180℃; for 6 h;
A suspension of 7H-pyrrolo [2,3-d]pyrimidine-2,4-diol (2.25 g, 0.015 mol) in PhPOCl2 was heated at 165 0C for 3 h and 180 °C for additonal 3 h, the resulting dark syrup was poured slowly to ice water, the black precipitates were filtered off, and the filtrate was extracted with ether. Ether layers were combined, washed with Sat NaHCO3, brine, dried over Na2SO4 and concentrated to give 2, 4-dichloro-7H-pyrrolo[2,3-
28%
at 165℃; for 2 h;
Step 3 2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidineA solution of 7H-Pyrrolo[2,3-d]pyrimidine-2,4-diol (1.28 g; 8.5 mmol) in phenylphosphonic dichloride (7 ml) was heated at 165 0C for 2 h. The hot reaction mixture was then poured slowly onto ice water (150 ml) and extracted with ethyl acetate (2 x 100 ml). The organic extract was washed with water (100 ml) followed by sat. sodium chloride (aq) solution (100 ml). The organic phase was dried over Na2SO4 then filtered and filtrate solvents evaporated in vacuo. The crude product was purified by flash chromatography on silica gel (2Og) eluting with 75percent ethyl acetate in hexane to afford the desired product as a yellow solid, (0.45 g; 28percent). LC/MS: RT = 1.98 min; m/z = 188 [M+H]+. Total run time 3.75 mins
Reference：
[1] European Journal of Medicinal Chemistry, 2012, vol. 52, p. 205 - 212
[2] Patent: WO2007/12953, 2007, A2, . Location in patent: Page/Page column 24
[3] Patent: US2010/3250, 2010, A1, . Location in patent: Page/Page column 20
[4] Journal of Medicinal Chemistry, 2010, vol. 53, # 8, p. 3169 - 3182
[5] Patent: US2009/54425, 2009, A1, . Location in patent: Page/Page column 21
[6] Patent: WO2009/131687, 2009, A2, . Location in patent: Page/Page column 131
[7] Patent: WO2007/104944, 2007, A1, . Location in patent: Page/Page column 38
[8] Journal of Medicinal Chemistry, 1988, vol. 31, # 8, p. 1501 - 1506
[9] ACS Medicinal Chemistry Letters, 2015, vol. 6, # 5, p. 584 - 589
[10] Patent: WO2016/130920, 2016, A2, . Location in patent: Page/Page column 114; 115
4
[ 84955-31-7 ]
[ 90213-66-4 ]
Yield
Reaction Conditions
Operation in experiment
43%
Stage #1: With antimony(III) chloride In 1,2-dichloro-ethane at -10℃; for 0.0833333 h; Stage #2: With tert.-butylnitrite In 1,2-dichloro-ethane at -10℃; for 3 h;
Example 7 EPO <DP n="32"/>2,4-dichIoro-7H-pyrrolo[2,3-d]pyrimidine. To a suspension of 4-chloro-7H-pyrrolo[2,3- d]pyrimidin-2-ylamine (500 mg, 2.97 mmol) in 1,2-dichloroethane (40 niL) at -1O0C under argon was added antimony chloride (750 mg, 3.29 mmol). After stirring for 5 min, tert- butylnitrite (2.50 mL, 20.8 mmol) was added to the solution. The reaction was stirred at -1O0C for 3 h. The reaction was diluted with CHCl3 (100 mL) and poured into ice water (50 mL). The CHCl3 layer was separated, washed with brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc = 50:50) yielded 239 mg (43percent) of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine as a tan solid.
Reference：
[1] Patent: WO2006/122003, 2006, A2, . Location in patent: Page/Page column 30-31
[2] Liebigs Annalen der Chemie, 1984, # 4, p. 722 - 733
[3] Liebigs Annalen der Chemie, 1985, p. 312 - 320
[4] Patent: WO2012/45195, 2012, A1, . Location in patent: Page/Page column 60
5
[ 39929-79-8 ]
[ 90213-66-4 ]
Yield
Reaction Conditions
Operation in experiment
48%
With N-ethyl-N,N-diisopropylamine; trichlorophosphate In toluene at 70 - 108℃; for 16.5 h; Inert atmosphere
To a suspension of 33 (5.75 g, 38.0 mmol) in toluene (30 mL) under argon, was added POd3 (10.6 mL, 114 mmol). To the mixture DIPEA (13.3 mL, 76.1 mmol) was added drop-wise over a period of 2.5 h at 70 °C, and then the temperature was increased to 108 °C and stirring continued for 14 h. The reaction mixture was cooled to room temperature and then poured into a mixture of 150 mL ethyl acetate and 200 mL ice cold water, and then filtered through a pad of Celite. The aqueous layer was extracted with ethyl acetate (3 x 200 mL) and the combined organic layers were washed with brine and concentrated to give the 34 (3.42 g, 48percent) as a light- brown solid. ‘H-NMR (400 MHz, DMSO-d6) ö 12.79 (s, 1H), 7.94 — 7.24 (m, 1H), 6.66 (ddd, J= 5.3, 3.5, 1.7 Hz, 1H); MS (m/z): [Mdi 188.03.
Reference：
[1] Tetrahedron, 2014, vol. 70, # 33, p. 4947 - 4956
[2] Patent: WO2018/137036, 2018, A1, . Location in patent: Paragraph 00234; 00235
[3] Journal of the American Chemical Society, 1984, vol. 106, # 21, p. 6379 - 6382
Reference：
[1] European Journal of Medicinal Chemistry, 2012, vol. 52, p. 205 - 212
[2] Patent: WO2007/104944, 2007, A1,
9
[ 102879-75-4 ]
[ 90213-66-4 ]
Reference：
[1] Patent: WO2007/104944, 2007, A1,
10
[ 90213-66-4 ]
[ 335654-06-3 ]
Yield
Reaction Conditions
Operation in experiment
73.54%
With acetic acid; zinc In acetonitrile at 80℃; for 14 h; Large scale
Zinc powder (8700 · 0g, 133πο1, 10 · Oeq •) was added portionwise to glacial acetic acid (3 · 3L, 53 · 2mo1.4 · Oeq ·) and acetonitrile (30 · 0L) mixture was added to complete the reaction temperature was raised to 80 ° C for 14 hours, the reaction was complete by TLC.87] The reaction mixture was cooled to 25 ° C, suction filtration, the filtrate was concentrated under reduced pressure and added to 30L of ice water, precipitated a large number of pink solid, filtration, the filter cake washed with water (5L X 3), dried to give a white solid 1501.7g. Yield: 73.54percent.
63.86%
With acetic acid; zinc In methanol at 70℃; for 16 h; Large scale
Zincpowder (3480.0g, 53.2mol, 4.0eq.) At room temperature control (25 )was added to the next batch compound II-1Mixture(2500.0g, 13.3mol, 1.0eq.) In acetic acid (5.0L, 79.8mol, 6.0eq.) And methanol(30.0L), the plusAfterthe reaction temperature was raised to 70 16 hours, TLCmonitored the reaction was complete. The reaction mixture was cooled to 25 ,filtration, the filtrate was concentrated30L wasadded to ice water, and precipitated a lot of pink solid, filtration, thefilter cake washed with water (5L × 3), drying, compound I-1 whiteThe solid 1304.0g,Yield: 63.86percent.
Reference：
[1] Patent: CN105949196, 2016, A, . Location in patent: Paragraph 0044; 0065; 0083-0087
[2] Patent: CN105859726, 2016, A, . Location in patent: Paragraph 0030; 0031; 0032
[3] Patent: WO2010/7116, 2010, A2, . Location in patent: Page/Page column 91-92
[4] Patent: WO2010/7114, 2010, A2, . Location in patent: Page/Page column 125-126
[5] Patent: JP2016/124825, 2016, A,
11
[ 90213-66-4 ]
[ 1053228-29-7 ]
Yield
Reaction Conditions
Operation in experiment
80.1%
With acetic acid; Selectfluor In acetonitrile at 80℃; for 24 h;
After 2,4-dicMoro-7H-pyrrolo[2,3-d]pyrimidine (200 mg, 1.06 mmol) was dissolved in acetonitrile (5.0 mL), l-chloromethyl-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (561.6 mg, 1.6 mmol) and acetic acid (1 mL) were added thereto. The mixture was heated at 80 °C and stirred for 24 hours, and then the organic layer was isolated, treated with magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was isolated by column chromatography to obtain a title compound (170.0 mg, yield: 80.1percent). (0795) NMR (500MHz,CD3OD) δ 7.36(s, 1H)
22.82%
With acetic acid; Selectfluor In [D3]acetonitrile at 60℃; for 16 h; Inert atmosphere
A mixture of 2,4-dichloro-7H-pyrrolo[2,3- djpyrimidine (7 g, 37.23 mmol) and selectfluor (13.19 g, 37.23 mmol) in CH3CN (360 mL) and AcOH (72 mL) was degassed and then the mixture was stirred at 60 °C for 16 h under N2. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (200 mL), adjusted to pH=7 with aq. NaHCC , and extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with brine (300 mL), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (PE:EtOAc := 10: 1 to 5: 1) to give 2,4- dichloro-5~fluoro-7H"pyrroio[2,3-d]pyrimidine (2.5 g, 22.82percent) as a yellow oil. LCMS: RT 0.732 min,im/z = 206.0 [M+Hf.
1.23 g
With acetic acid; Selectfluor In acetonitrile at 60℃;
2,4-Dchloro-7H-pyrrolo[2,3-d]pyrimidine (5.0 g, 27 mmol) was suspended in MeCN (300 mL) and AcOH (60 mL); to this was added selectfluor (1-chloromethyl-4-fluoro-1 ,4- diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate), 1.4 eq, 13.2 g) in one portion. The reaction mixture was stirred at 60 °C overnight. HPLC monitoring indicated complete conversion. After the solvents were evaporated to the volume of -100 mL, toluene (20 mL) was added and the suspension was filtered. The filtrate was evaporated to dryness and re-evaporated with toluene (2 χ 20 mL). The residue was then purified via a short silica pad (washing with 1/1 DCM/EtOAc) and column chromatography (ISCO machine, EtOAc/DCM, EtOAc on a 0-100percent gradient) to give the crude product. Upon standing the pure product was seen to precipitate from the column fractions. These were filtered and the mother liquors were combined to precipitate a 2nd crop. Total 1.23 g of the product 64 was obtained (22percent yield, ~ 90percent pure, Cl-isomer was the main impurity).
With N-iodo-succinimide In dichloromethane at 16 - 20℃; for 16.34 h;
A 50-L jacketed reactor was charged with 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (950 g, 5053 mmol) and DCM (16 L). The resulting tan suspension was cooled to 16° C., and N-iodosuccinimide (1598 g, 7104 mmol) was added portionwise over 20 min. The reaction mixture was stirred at room temperature for 16 h, after which time TLC analysis (2:1 hexane/ethyl acetate) indicated complete reaction. The resulting precipitate was filtered, washed with DCM (3×1.5 L), and dried under reduced pressure at 40° C. for 64 h to afford 1447 g (Yield: 91percent) of target compound as a beige solid. MS (ESI) m/z 314.0 [M+1]+.
64%
With N-iodo-succinimide In dichloromethane at 25℃; for 16 h;
To a suspension of 2.4-dichloro-7H--pvrro]o[2,3-dipyrimidine (7.2 g, 38 rnmoi) in DCM (120 mL) was added N4odosuccinimide (12.0 g. 53.3 rnmol) in portions over 30 mm. The mixture was stirred at 25 °C for 16 h. The mixture was filtered, the filtered cake was washed with DCM to give 2,4-dichioro-5-iodo--7H-pyrroio[2,3-d]pyrimidine (131a) (76 g, 24 mmoi, 64percent yield) as a white solid. LCMS [M-FF{]: 3139.
30 g
With N-iodo-succinimide In N,N-dimethyl-formamide at 20℃;
To a stirred solution of 2,4-dichloro-7H-pyrrrolo[2,3-(f]pyrimidine (25 g) in DMF (100 mL) was charged N-Iodosuccinamide (31.41g). The reaction mixture was stirred for 3-4 h at ambient temperature and poured into water. Precipitates were filtered and washed with water (500 mL). Filtered solid was suck dried and extracted into ethylacetate (800 mL) and washed with water (300 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under vacuum. Trituration of the solid with hexanes (125 mL) followed by filtration and drying afforded an off-white solid (30 g).
With sodium hydroxide In dichloromethane; water at 18 - 25℃; for 0.5 h;
Intermediate 92,4-Dichloro-7-[(4-methylphenyl)sulfonyll-7H-pyrrolo[2,3-(i]pyrimidine2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidine (1.00 g, 5.32 mmol), 4-methylbenzene-l-sulfonyl chloride (1.115 g, 5.85 mmol) and tetra-butylammonium hydrogen sulfate (0.090 g, 0.27 mmol) were dissolved in DCM (20 mL) at r.t., and NaOH (50percent aq., 1 mL) was added. The reaction mixture stirred at room temperature for 30 minutes. After completion of the reaction as indicated 103496-1Pby TLC, the reaction mixture diluted with H2O and DCM and separated. The organic layer was evaporated in vacuo to obtain a light yellow solid, which was purified by column chromatography (100percent DCM) to provide the title product (1.76 g, 97percent) as a white solid. LCMS: 342 [M+H] +. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 8.14 (d, J=8.59 Hz, 2 H) 7.78 (d, J=3.79 Hz, 1 H) 7.39 (d, J=8.59 Hz, 2 H) 6.70 (d, J=3.79 Hz, 1 H) 2.45 (s, 3 H).
95%
With sodium hydroxide In water; acetone at 0 - 20℃;
EXAMPLE 23-((3No.,4No.)-4-Methyl-3-(d3-methyl(2-dr7H-pyrrolo[2, 3-<;f|pyrimidin-4- yl)amino)piperidin-l-yl)-3-oxopropanenitrile mono citrate salt(CP-690550-6?4 citrate salt)Step 1[00163] 4-Chloro-7-tosyl-7H-pyrrolor2,3-6πpyrimidine: 4-Methylbenzene-l- sulfonyl chloride (3.7 g, 19.32 mmol, 1.20 equiv.) was added to a solution of 2,4- dichloro-7H-pyrrolo[2,3-<;i]pyrimidine 1 (3g, 16.1 mmol, 1.00 equiv.) in acetone (20 mL). At about 0 0C, an aqueous sodium hydroxide solution (2 mol/L, 12mL) was added dropwise to the solution. The solution was then stirred at ambient temperature for about 3 hours. The solids were collected by filtration and washed with acetone/water to give the title product as a white solid (5.2 g; yield = 95percent). LC-MS: m/z = 342 (M+Η)+.
95%
With dmap; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 2 h; Inert atmosphere
A stirred solution of S-1 (2.00 g, 10.7 mmol) in CH2Cl2(20 mL) taken in a round- bottom flask was charged with DIPEA (3.7 mL, 21.4 mmol), DMAP (0.039 g, 0.32 mmol) and p-toluene sulfonyl chloride (2.25 g, 11.7 mmol) successively at ambient temperature under nitrogen atmosphere. The reaction mixture was stirred for 2 h at same temperature. The reaction mixture was diluted with CH2Cl2(100 mL) and was washed with water (40 mL) and HCl (1 N, 40 mL). The combined organic layer was washed with brine (1 × 50 mL), dried over anhydrous Na2SO4and was concentrated under reduced pressure. The obtained residue was washed with hexanes (2 × 50 mL) and was dried under vacuum to afford S-2 (3.50 g, 95percent, AMRI lot IN-SKY-C-03) as an off-white solid. The compound was characterized by1H NMR analysis.1H NMR (400 MHz, CDCl3): δ 8.03 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 4 Hz, 1H), 7.29 (d, J = 8.12 Hz, 2H), 6.60 (d, J = 4 Hz, 1H), 2.36 (s, 3H).
90%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.0833333 h; Stage #2: at 20℃; for 1 h;
In a flask 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (1.0 g, 5.3 mmol) in DMF (30 rnL) was added NaH (60percent in mineral oil, 0.21 g, 5.3 mmol). After stirring 5 min at room temperature the reaction mixture was added tosyl chloride (1.0 g, 5.3 mmol) and stirred 1 h at room temperature. The reaction mixture was diluted with H2O (100 mL) and filtered. The filtered solid was washed with H2O (20 mL) and dried 5 h under house vacuum at 80 0C to afford the title compound as a yellow solid (1.6 g, 90percent). 1H NMR (500 MHz, DMSO-d6): δ 2.38 (s, 3H), 6.98 (d, J = 4.1 Hz, IH), 7.50 (d, J = 8.3 Hz, 2H), 8.03 (d, J = 8.5 Hz, 2H), 8.11 (d, J = 4.1 Hz, IH) MS (ES+): m/z 343 (M+H)+
90%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.0833333 h; Stage #2: at 20℃; for 1 h;
To a solution of 2,4-dichloro-7H-pyrrolo[2,3-J]pyrimidine (1.0 g, 5.3 mmol) in DMF (30 mL) was added NaH (60percent in mineral oil, 0.21 g, 5.3 mmol). The mixture was stirred for 5 min at room temperature and added tosyl chloride (1.0 g, 5.3 mmol). The mixture was stirred for 1 h at room temperature, diluted with H2O (100 mL), and filtered. The solid was washed with H2O (20 mL), and dried under vacuum 5 h at 80 0C to afford the title compound as a yellow solid (1.6 g, 90percent). <n="47"/>[0158] 1H NMR (500 MHz, DMSO-J6): δ 2.38 (s, 3H), 6.98 (d, J = 4.1 Hz, IH), 7.50 (d, J = 8.3 Hz, 2H), 8.03 (d, J = 8.5 Hz, 2H), 8.12 (d, J = 4.1 Hz, IH)[0159] MS (ES+): m/z 342 (M+H)+
89%
With dmap; triethylamine In dichloromethane at 20℃; for 5 h; Cooling with ice
In the ice bath conditions,A solution of 2,4-dichloro-7H-pyrrole [2,3-d] pyrimidine 1.0 gWas dissolved in 50 mL of dichloromethane,To the above mixed solution, 1.06 g of p-toluenesulfonyl chloride was added slowly,Triethylamine 1.08 g,N, N-dimethylpyridin-4-amine, 0.019 g,The mixed solution was stirred at room temperature for 5 h,After the reaction is complete,To the above solution was poured into 150 mL, the organic phase was washed with water,Citric acid aqueous solution and brine solution were washed three times each. The organic phase was dried with anhydrous magnesium sulfate overnight, and the solvent was evaporated under reduced pressure to obtain crude product.Recrystallization from petroleum ether gave 1.6 g of pure white product.Yield 89percent.
86%
Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5 h; Stage #2: at 20℃;
To a solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (500 mg, 2.66 mmol) in DMF (5 mL) was added NaH (120 mg, 2.93 mmol, 60percent) at 0 °C, and the mixture was stirred at this temperature for 30 mm. Then paratoluensulfonyl chloride (608 mg, 3.19 mmol) was added to the mixture, and the resulting mixture was stirred at rt overnight. To the reaction mixture was added water (50 mL) to quench the reaction, and the resulting mixture was partitioned. The aqueous layer was extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 10/1) to give the title compound as a yellow solid (780 mg, 86 percent).MS (ESI, pos. ion) m/z: 343.90 [M+H]+1H NMR (400 MHz, CDC13) (ppm): 8.13 (d, J = 8.3 Hz, 2H), 7.77 (d, J = 4.0 Hz, 1H), 7.38 (d, J = 8.2 Hz, 2H), 6.70 (d, J = 4.0 Hz, 1H), 2.45 (s, 3H).
84%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.0833333 h; Stage #2: at 20℃; for 1 h;
To a solution of 2,4-dichloro-7Hpyrrolo[2,3-d]pyrimidine (4.5 g, 23.93 mmol) in DMF (140 mL) was added NaH (0.957g, 23.93 mmol). After stirring for 5 min at room temperature, 4-methylbenzene-1-sulfonyl chloride (4.56 g, 23.93 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with water (450 mL) and filtered. The solid was washed with water (90 mL) and dried to give the title compound 1a (7 g,84 percent yield) as a white solid. LCMS: 342 [M+H]+.
80%
With sodium hydroxide In acetone at 0 - 20℃; for 2 h;
After 2,4-dicWoro-7H-pyrrolo[2,3-d]pyrimidine (3.0 g, 16.0 mmol) was dissolved in acetone (20.0 mL), 4- methylbenzenesulfonyl chloride (4.6 g, 23.9 mmol) was added thereto. After cooling to 0 °C, 2 M sodium hydroxide solution (12.0 mL) was slowly added dropwise and then stirred at room temperature for 2 hours. The organic layer was isolated, treated with magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was isolated by column chromatography to obtain a title compound (2.9 g, yield: 80.0percent). [H NMR (500MHz,CD3OD) δ 8.12(d, 2H), 7.76(d, 1H), 7.37(d, 2H), 6.68(d, 1H), 2.43(s, 3H)
1.5 g
With sodium hydroxide In water; acetone at 0 - 30℃; for 2 - 3 h;
To a suspension of 2,4-dichloro-7H-pyrrolo[2,3-d] pyrimidine (l g, 0.005 mol) and toluene sulfonylchloride (1.3gm, 0.007) in 10 ml acetone cooled to about 0-5 °C , a solution of sodium hydroxide in water (0.32gm in 4ml water) was added slowly at about 0-5 °C .The temperature of the reaction mass was raised to 25-30 °C and stirred for 2-3 hrs. The progress of the reaction was monitored by TLC. After completion of the reaction the reaction mass was filtered and washed with a mixture of acetone and water. The solid was dried under vacuum at about 50-55 °C for about 10 hrs to afford 1.5 gm of 2,4-dichloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3- d]pyrimidine as yellow colored solid. (HPLC purity >98.0percent)
Stage #1: With sodium hydride In tetrahydrofuran at 0 - 20℃; Stage #2: at 20℃; for 18 h;
REFERENCE EXAMPLE 2 fR)-2-Choro-4-[3-(Λf,Wdimethy[amino)pyrrolidin-1-yl]-7-[(4-toiLfy.)suifony.- pyrτolo[2,3-d]pyrimidine a) 2,4-Dichloro-7-[(4-toiuyl)suJfonyI]-pyrro[o[2t3-d|pynmidine 6.39 g of NaH 60 percent (158 mmol) were slowly added at 0 0C over a 2,4-dichloro-7H- pyrrolo[2,3-d]pyrimidine solution (15 g, 78.9 mmol) in THF (300 mL). The reaction mixture was stirred at room temperature for 1 h. After this time p-toluensulfonyl chloride (16.4 g, 86 mmoi) was added and it was stirred at room temperature for 18 h. The solvent was evaporated to dryness, the crude product was diluted with H2O and extracted thrice with EtOAc. The combined organic phases were separated, dried over Na2SO4 and the solvent evaporated to dryness. The desired compound was obtained in quantitative yield and used without further purification. LC-MS (Method 1 ): tR = 2.72 min; m/z = 340 (MH").
With N-chloro-succinimide In tetrahydrofuran; dichloromethane at 90℃; for 2.5 h; Microwave irradiation
To a solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (2.0 g, 10.64 mmol) indichloromethane/tetrahydrofuran (DCM/THF) (15 mL/6 mL) was added NCS (1 .70g, 12.76mmol). The mixture was heated to 90 °C under microwave irradiation for 2.5 hr. The solvent was removed in vacuo and the crude product was purified by flash column chromatography using a9:1 v/v Hexane:Ethyl acetate to afford the title compound (2.2 g, 93percent yield) as a white crystalline solid. MS m/z 223.48 [M+1].
93.4%
With N-chloro-succinimide In N,N-dimethyl-formamide at 20℃; for 24 h;
2,4-dicUoro-7H-pyrrolo[2,3-d]pyrimidine (5.0 g, 26.6 mmol) and N- cWorosuccinimide (5.3 g, 39.9 mmol) were dissolved in N,N-dimethylformamide (50.0 mL) and then stirred at room temperature for 24 hours. The organic layer was isolated, treated with magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was isolated by column chromatography to obtain a title compound (5.5 g, yield: 93.4percent). H NMR (500MHz, CD3OD) δ 7.54(s, 1H)
63.37%
With N-chloro-succinimide In tetrahydrofuran; dichloromethane at 25 - 90℃; for 2.5 h; Microwave irradiation
To a mixture of 2,4-dicholo-7H-pyrrolof2,3- djpyrimidine (1 g, 5.32 mmol) in THF (3 mL) and DCM ( 12 mL) was added NCS (852 mg, 6.38 mmol) in one portion at 25°C. The mixture was stirred under microwave at 90 °C for 2.5 h. LC/MS showed the reaction was completed. Two new peaks were shown on LC/MS and 74percent of desired (M+Ff" = 221 .9) was detected. The mixture was added to brine and extracted with DCM. The organics were dried over anhydrous Na^SO, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 50: 1-5 : 1), to yield the desired product as a yellow? solid (750 mg, 63.37percent). MI R (400 MHz, CDC13): δ 10,70 (s„ 1 H) 8.16 (s, 1 H) 4.14 (s, 3 H).
55%
With N-chloro-succinimide In N,N-dimethyl-formamide at 20℃; for 48 h;
Example 14: Synthesis of Compound XIII-12; Step 1: Synthesis of 2,4,5-trichloro-7H-pyrrolo[2,3-d]pyrimidine (2); 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine ( 1 , 2 g, 10.6 mmol) was dissolved in DMF ( 10 mL), NCS (2.13 g, 15.9 mmol) was added and stirred at RT for 48 h. Ice was added to the reaction mixture, scratched the solid, filtered and dried to afford 2,4,5-trichloro-7H-pyrrolo[2,3-d]pyrimidine (2, 1.29 g, 55percent). NMR (400 MHz, DMSO): δ 13.15 (s, 1 H, D20 exchangeable), 7.95 (s, I H).
Reference：
[1] Chemistry - A European Journal, 2015, vol. 21, # 34, p. 11976 - 11979
[2] ACS Medicinal Chemistry Letters, 2015, vol. 6, # 5, p. 584 - 589
[3] Patent: WO2016/130920, 2016, A2, . Location in patent: Page/Page column 115
[4] Patent: WO2018/4306, 2018, A1, . Location in patent: Page/Page column 127
[5] Organic Letters, 2016, vol. 18, # 9, p. 1976 - 1979
[6] Journal of the American Chemical Society, 2014, vol. 136, # 19, p. 6908 - 6911
[7] Patent: WO2017/87905, 2017, A1, . Location in patent: Page/Page column 170
[8] Patent: WO2011/140338, 2011, A1, . Location in patent: Page/Page column 75
[9] Helvetica Chimica Acta, 2008, vol. 91, # 6, p. 1083 - 1105
[10] Patent: US2010/204221, 2010, A1, . Location in patent: Page/Page column 18
Example 7 EPO <DP n="32"/>2,4-dichIoro-7H-pyrrolo[2,3-d]pyrimidine. To a suspension of 4-chloro-7H-pyrrolo[2,3- d]pyrimidin-2-ylamine (500 mg, 2.97 mmol) in 1,2-dichloroethane (40 niL) at -1O0C under argon was added antimony chloride (750 mg, 3.29 mmol). After stirring for 5 min, tert- butylnitrite (2.50 mL, 20.8 mmol) was added to the solution. The reaction was stirred at -1O0C for 3 h. The reaction was diluted with CHCl3 (100 mL) and poured into ice water (50 mL). The CHCl3 layer was separated, washed with brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc = 50:50) yielded 239 mg (43%) of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine as a tan solid.
Example 1C2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidineIn a stirred solution of Example IB (20 g, 0.12 mol) and 25% aqueous HC1 (200 ml) at 0C was added a mixture of NaN02 (12.32 g, 0.17mol) and water (15 ml) slowly. The mixture was stirred at 0C for 15 minutes. Then the mixture was added to a stirred solution of CuCl (17.8 g, 0.17 mol) and water (15 ml) at 0C. Then it was heated to 80C for 2 hours. After cooling to room temperature, the pH was adjusted to 8.0 with concentrated NH4OH, and the mixture was extracted with ethyl acetate. The organic layer was concentrated to provide the title compound. MS (ESI)(+) m/z 188.7 (M+H)+.
Step 1: Synthesis of (2R,35,5R)-5-(2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(((4-methylbenzoyl)oxy)methyl)tetrahydrofuran-3-yl 4-methylbenzoateTo a stirred suspension of sodium hydride (60percent dispersion in mineral oil, 0.509 g, 12.73 mmol) in anhydrous acetonitrile (125 ml) was added 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (2.176 g, 1 1.57 mmol) in portions under argon atmosphere and the mixture was stirred at ambient temperature for 30 minutes. To the above clear solution was added Intermediate A (4.5 g, 1 1.57 mmol) batch wise with stirring. The reaction mixture was allowed to stir at ambient temperature for 2 hours. The reaction progress was monitored by TLC. Evaporation of the reaction mixture gave an oily residue, which was purified by silica-gel column chromatography using ethyl acetate/petroleum ether (1/6, v/v) to give the title compound. LC-MS: (ES, m/z): 540.20 [M+H]+. H- MR: (400MHz, C , ppm): delta 8.01 (d, J = 8.0Hz, 2H), 7.93 (d, J= 8.0Hz, 2H), 7.43 (d, J = 3.6 Hz, 1H), 7.22-7.37 (m, 4H), 6.80 (dd, J = 6.0Hz, J= 8.0Hz, 1H), 6.61 (d, J = 4.0Hz, 1H), 5.76 (t, J= 2.8Hz, 1H), 4.76 (dd, J = 3.6Hz, J = 12.0Hz, 1H), 4.63-4.69 (m, 2H), 2.76-2.86 (m, 2H), 2.47,2.45 (2s, 6H).
To a solution of sodium hydride (480 mg, 12.00 mmol, 1.10 equiv, 60%) in tetrahydrofuran (50 mL), a solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (2 g, 10.64 mmol, 1.00 equiv) in tetrahydrofuran (50 mL) was slowly added. The resulting solution was stirred at 0 C. for 30 min followed by the addition of methyl iodide (1.66 g, 11.70 mmol, 1.10 equiv) at 0 C. The mixture was stirred at room temperature overnight. After completion, 20 mL of water was added to the mixture and the solution was extracted with ethyl acetate and washed with brine. The organic phase was dried over anhydrous sodium sulfate, filtered and then concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1:5) to afford 2.1 g (98%) of 2,4-dichloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine as a white solid. LC-MS (ES, m/z): 202 [M+H]
97.2%
[00237] To a solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (1.5 g, 7.98 mmol) in THF (30 ml) at 0 C was added sodium hydride (60% oil suspension, 383 mg, 9.57 mmol) and stirred at 0 C to r.t. for 20 mins. lodomethane (0.6 ml, 9.57 mmol) was added and stirred at r.t. for 3 h. [00238] The mixture was quenched by addition of saturated ammonium chloride solution (20 mL). EtOAc was then added resulting in formation of a precipitate. The precipitate was filtered and the filtrate extracted with EtOAc (x2). The combined organic fractions were washed with water, dried over Na2S04, filtered and concentrated in vacuo to afford the title compound (1.65 g, 97.2%) as a yellow powder. [00239] Method A: LC-MS m/z = 201.90, 203.90 [M + H]+; RT = 1.21 min.
96%
Step 1 : To a stirred solution of 2,4-dichloro-7/-/-pyrrolo[2,3-c]pyrimidine (2 g, 10.638 mmol) in DMF (20 mL) was added 60 % NaH (0.63 g, 15.957 mmol, 1.5 equiv) at 0 C and stirred for 30 min at room temperature. Methyl iodide (0.79 mL, 12.765 mol, 1.2 equiv) was added and allowed to stir at room temperature for 3 h. The reaction was quenched with ice water (200 mL) and the precipitated solid was filtered and dried in vacuo to obtain 2,4-dichloro-7-methyl- 7H-pyrrolo[2,3-c]pyrimidine as an off white solid (2.06 g, 96 %). LCMS (ES) m/z = 202.1 , 204.0 [M+H]+. H NMR (400 MHz, DMSO-d6) delta ppm 3.80 (s, 3H), 6.66 (d, J = 3.2 Hz, 1 H), 7.73 (d, J = 3.2 Hz, 1 H).
93%
With triethylamine; In tetrahydrofuran; at 25℃; for 6h;
A solution of2,4-Dichloro-7H-pyrrolo [2,3-d] pyrimidine (5.0 g, 26.6 mmol) was dissolved in tetrahydrofuran (50 mL)Triethylamine (4.0 g, 39.5 mmol) was added,Methyl iodide (4.2 g, 29.6 mmol) was added dropwise,After the addition was complete, the temperature was raised to 25 C and reacted for 16 hours.After the reaction was completed, the reaction solution was poured into water (100 mL)The precipitated solid was filtered,drying,The product (5.0 g, 93% yield) was obtained.
93%
A 0 C solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (1.00 g, 5.32 mmol) in THF (8 mL) was stirred for 5 mm, then to the solution was added sodium hydroxide (255 mg, 6.38 mmol). The mixture was stirred for further 15 mm, and iodomethane (8.50 g, 53.20 mmol) was added. The mixture was stirred at rt overnight. To the reaction mixture was added H20 (100 mL), and the mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo dry,and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 10/1) to give the title compound as a white solid (1.00 g, 93 %).MS (ESI, pos. ion) m/z: 202.95 [M+Hfb.
93%
2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidine (1.00 g, 5.32 mmol)Dissolved in THF (8 mL), and the resulting solution was stirred at 0 C for 5 min.Then sodium hydride (255 mg, 6.38 mmol) was added thereto.The resulting reaction solution was stirred for 15 minutes.Methyl iodide (8.50 g, 53.20 mmol) was added thereto.The resulting reaction solution was transferred to room temperature and stirred overnight.The reaction was quenched by H2O (EtOAc) (EtOAc)The combined organic phases were washed with brine (80 mL).Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure.The residue was chromatographed on silica gel ( petroleum ether / ethyl acetate (v/v) = 10/1)Purification to give the title compound as a white solid(1.00g, 93%).
93%
A solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (1.00 g, 5.32 mmol) in THF (8 mL) was stirred at 0 C for 5 mm. Then sodium hydride (255 mg, 6.38 mmol) was added. The resulting mixture was stirred for 15 mm, then iodomethane (8.50 g, 53.20 mmol) was added. The reaction mixture was warmed to rt and stirred overnight. H20 (100 mL) was added to quench the reaction, and the resulting mixture was extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine (80 mL), dried over anhydrous Na2504, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatograph (PE/EtOAc (v/v) = 10/1) to give the tilte compound as a white solid (1.00 g, 93 %).MS (ESI, pos. ion) m/z: 203.0 [M+H]t
93%
A solution of 2, 4-dichloro-7H-pyrrolo [2, 3-d] pyrimidine (1.00 g, 5.32 mmol) in THF (8 mL) was stirred for 5 min at 0 , then sodium hydride (255 mg, 6.38 mmol) was added. The mixture was stirred for 15 min, and then iodomethane (8.50 g, 53.20 mmol) was added. The resulting mixture was warm to rt and stirred overnight, then the reaction was quenched with H2O (100 mL) . The mixture was extracted with ethyl acetate (50 mL × 3) . The combined organic layers were washed with saturated brine (80 mL) , dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v) =10/1) to give the title compound as a white solid (1.00 g, 93%) .MS (ESI, pos. ion) m/z: 203.0 [M+H]+.
84.1%
To a solution of 60% NaH (750 mg) in dry THF (20 mL), a solution of 18a (1.7 g) in dry THF (50 mL) was slowly added. The resulting solution was stirred at 0 C for 30 min followed by the addition of MeI (0.79 mL) at 0 C. The mixture was stirred at room temperature overnight. After the addition of 20 mL water, the solution was extracted with ether (3×10 mL) and washed with saturated brine. The organic phase was dried with anhydrous sodium sulfate and filtered. Ether was evaporated in vacuo to yield a crude residue, which was purified by silica gel chromatography (PE/EA= 10/1) to give 18d (1.53 g, yield: 84.1%). ESI-MS calculated for (C7H5Cl2N3) [M+H]+, 202.0, found 202.1.
74.1%
A solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (3.00 g, 16.0 mmol) in anhydrous tetrahydrofuran (45 mL) was cooled to 0 C. and treated with a 60% dispersion of sodium hydride in mineral oil (0.83 g, 20.8 mmol). The reaction was stirred at 0 C. for 20-30 min. The reaction was then treated with iodomethane (3.65 g, 1.6 mL, 25.7 mmol), and the reaction stirred at room temperature overnight. The reaction was diluted with a saturated aqueous ammonium chloride solution (50 mL) and water (50 mL) and was extracted with a 10% methanol in methylene chloride solution (4×50 mL). The combined organic layers were dried over magnesium sulfate, filtered and rinsed with methylene chloride, and concentrated in vacuo onto Celite. Flash chromatography (80 g silica gel column, 0-15% ethyl acetate/hexanes) afforded 2,4-dichloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine as a light yellow solid (2.39 g, 74.1%). 1H NMR (400 MHz, DMSO-d6) delta ppm 3.81 (s, 3H) 6.70 (d, J=3.51 Hz, 1H) 7.76 (d, J=3.51 Hz, 1H). LC-MS calcd. for C7H6Cl2N3 [(M+H)+] 202, obsd. 202.0.
58%
To a solution of 2,4-dichloro-7H-pyrrolo[2,3-djpyrimidine 34 (237 mg, 1.26 mmol) in CH3CN (1 mL) was added NaH (33.3 mg, 1.39 mmol) portion- wise at 0 C. The reaction mixture was stirred at room temperature for 20 mm until gas evolution was ceased. Methyl iodide (86.4 i.il, 1.39 mmol) was added and stirred the reaction mixture for 1 h at room temperature. To the reaction mixture was added water and extracted with ethyl acetate (2 x 30 mL). The combined organic layers were dried over Mg504, and then concentrated under vacuum. The resultant crude residue was purified by silica-gel column chromatography to afford 35 (144 mg, 58%) as white solid. ?H-NMR (400 MHz, DMSO-d6) oe 7.76 (d, J = 3.6 Hz, 1H), 6.71 (d, J = 3.6 Hz, 1H), 3.81 (s, 3H); MS: (m/z) [M+Hjb 204.02.
Intermediate 46; 2,4-Dichloro-7-methyl-7H-pyrrolor2,3-d1pyrimidine 103496-1P2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidine (2370 mg, 12.61 mmol) was dissolved in acetonitrile (8320 mul) and sodium hydride (529 mg, 13.24 mmol) was added portion- wise. The reaction mixture was stirred at room temperature for 30 minutes until gas evolution ceased. Methyl iodide (867 mul, 13.87 mmol) was added and the resulting mixture was stirred for 30 minutes. The reaction mixture was then poured into water and extracted with DCM/MeOEta. Concentration of the organic layers under reduced pressure provided a residue, which was purified utilizing ISCO (0%-» 100% DCM/EtOAc) to afford the title product (2. Ig). LCMS: 204 [M+Eta]+.
With N-iodo-succinimide; In dichloromethane; at 16 - 20℃; for 16.34h;
A 50-L jacketed reactor was charged with 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (950 g, 5053 mmol) and DCM (16 L). The resulting tan suspension was cooled to 16 C., and N-iodosuccinimide (1598 g, 7104 mmol) was added portionwise over 20 min. The reaction mixture was stirred at room temperature for 16 h, after which time TLC analysis (2:1 hexane/ethyl acetate) indicated complete reaction. The resulting precipitate was filtered, washed with DCM (3×1.5 L), and dried under reduced pressure at 40 C. for 64 h to afford 1447 g (Yield: 91%) of target compound as a beige solid. MS (ESI) m/z 314.0 [M+1]+.
64%
With N-iodo-succinimide; In dichloromethane; at 25℃; for 16h;
To a suspension of 2.4-dichloro-7H--pvrro]o[2,3-dipyrimidine (7.2 g, 38 rnmoi) in DCM (120 mL) was added N4odosuccinimide (12.0 g. 53.3 rnmol) in portions over 30 mm. The mixture was stirred at 25 C for 16 h. The mixture was filtered, the filtered cake was washed with DCM to give 2,4-dichioro-5-iodo--7H-pyrroio[2,3-d]pyrimidine (131a) (76 g, 24 mmoi, 64% yield) as a white solid. LCMS [M-FF{]: 3139.
With N-iodo-succinimide; In dichloromethane; at 20℃; for 1h;
Example 21 1-(4-(4-(4-(1H-indazol-6-ylamino)-5-ethyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone To a suspension of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (2.0 g, 10.6 mmol) in CH2Cl2 (32 mL) was added N-iodosuccinimide (NIS) (2.4 g, 10.6 mmol) at room temperature. After stirring for 1 h, the resulting precipitates were collected by filtration to give 2,4-dichloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (1.8 g).
With N-iodo-succinimide; In dichloromethane; at 20℃; for 1h;Product distribution / selectivity;
To a suspension of 2, 4-dichloro-7H-pyrrolo[2,3-<i]pyrimidine (2.0 g, 10.6 mmol) in DCM (32 mL) was added NIS (2.4 g, 10.6 mmol) at room temperature. After stirring for 1 h, the resulting precipitate was collected by filtration to give 2, 4-dichloro-5-iodo-7H- pyrrolo[2,3-<f|pyrimidine (1.8 g).
Compound 20.2 (3.80 g, 20.0 mmol) was dissolved in THF (200 mL) and cooled to- 20C for 20 min. N-IODOSUCCINIMIDE (7. 0g, 30.0 mmol) was slowly added and the resulting mixture was stirred at room temperature. After 2h, the mixture was evaporated to dryness and the residue was re-dissolved in ethyl acetate, washed with 5% sodium thiosulphate, saturated sodium chloride solution and then dried over sodium sulfate and evaporated to dryness. The crude product was purified by silica gel column chromatography using 20 % ethyl acetate in hexane to give 4.6 g of compound 20.3 as a yellowish solid.
With N-iodo-succinimide; In N,N-dimethyl-formamide; at 0 - 25℃; for 1.5h;Inert atmosphere;
To a mixture of 2,4-dichloro-7H- pyrrolo[2,3-d]pyrimidine (7 g, 37.23 mmol) in DMF (37 mL) was added NIS (8,79 g, 39.09 mmol) in one portion at 0 C under N2. The mixture was stirred at 25 C for 1.5 h. The reaction solution was poured into ice-water ( 100 mL), and the resulting precipitate was isolated by filtration. The filter cake was washed with ice water (2 chi 50 mL) and dried under reduced pressure to give 2,4-dichloro-5-iodo-7H- pyrrolo[2,3-d]pynmidme as a yellow solid. LCMS: RT 0,771 min, m/z = 313.9 [M+H]+. NMR (400 MHz, DMSO): delta 13.12 (br. s, 1 H), 7.97 (d, J=2.01 Hz, 1 H).
30 g
With N-iodo-succinimide; In N,N-dimethyl-formamide; at 20℃;
To a stirred solution of 2,4-dichloro-7H-pyrrrolo[2,3-(f]pyrimidine (25 g) in DMF (100 mL) was charged N-Iodosuccinamide (31.41g). The reaction mixture was stirred for 3-4 h at ambient temperature and poured into water. Precipitates were filtered and washed with water (500 mL). Filtered solid was suck dried and extracted into ethylacetate (800 mL) and washed with water (300 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under vacuum. Trituration of the solid with hexanes (125 mL) followed by filtration and drying afforded an off-white solid (30 g).
With N-iodo-succinimide; In N,N-dimethyl-formamide; for 16h;
To a stirred solution of compound (XXIX, 50 g) in DMF (200 mL) was added N-iodosuccinimide (62.14 g) and stirred for 16 hrs. The reaction mixture was poured slowly into water (3.5 L) resulted in precipitation which was filtered, washed with water (1 L) and suck dried. Crude residue was purified by refluxing in ethyl acetate and filtered to give compound(XXX).
With potassium carbonate; In tetrahydrofuran; water; at 110℃; for 10.0h;
To a solution of 2,4-dichloro-7/-/-pyrrolo[2,3-d]pyhmidine (0.50 g, 2.66 mmol) in THF/H2O (1 :1 ) (7 ml_), 3-aminocyclohexane carboxylic acid (0.38 g, 2.66 mmol) and K2CO3 (0.55 g, 3.98 mmol) were added. The reaction was stirred at 11 O0C in a sealed tube for 10 h. The resulting mixture was diluted with H2O and the phases were separated. Aqueous 1 N HCI was added at 0 C until pH = 3 and extracted thrice with EtOAc/MeOH (9:1 ). The combined organic phases were dried over Na2SO4 and concentrated to dryness and the crude product thus obtained was directly used in the next step.LC-MS (method 2): tR = 0.94 min; m/z = 295 (MH+).
With N-Bromosuccinimide; In tetrahydrofuran; at 20℃;Darkness;
(1) Dissolve 200 g of 2,4-dichloro-7H-pyrrolo [2,3-d] pyrimidine in 1500 ml of tetrahydrofuran, and add 210 g of N-bromosuccinimide in batches at room temperature until N-brominated After all the succinimide is added, stir for 1-2 hours in the dark;(2) After stirring, filter, wash with water, and recrystallize ethanol to obtain pure 5-bromo-2,4-dichloro-7H-pyrrolo [2,3-d] pyrimidine, with a purity of more than 98%. 90% yield;
64%
With N-Bromosuccinimide; In dichloromethane; at 20℃; for 4h;
To a solution of compound c-1 (1 g, 5.32 mmol) in 80 mL of dichloromethane was added NBS (1.04 g, 5.85 mmol). The reaction mixture was stirred at room temperature for 4 hours. After the reaction was completed, the mixturewas concentrated under reduced pressure and purified by combiflash to give compound p-1 (900mg, yield 64%). MSm/z(ESI):266[M+H]+.
With N-Bromosuccinimide; In dichloromethane; at 20℃; for 18h;
To a suspension of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (105 mg, 0.560 mmol) in CH2Cl2 (7 niL) at room temperature, NBS (109 mg, 0.610 mmol) was added. The mixture was stirred at room temperature for 18 h. CH2Cl2 was removed in vacuo. The residue was partitioned between water and EtOAc. The organic phase was separated, washed with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give 5-bromo-2,4-dichloro-7H- pyrrolo[2,3-d]pyrimidine (142 mg).
With sodium hydroxide;tetra(n-butyl)ammonium hydrogensulfate; In dichloromethane; water; at 18 - 25℃; for 0.5h;
Intermediate 92,4-Dichloro-7-[(4-methylphenyl)sulfonyll-7H-pyrrolo[2,3-(i]pyrimidine2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidine (1.00 g, 5.32 mmol), 4-methylbenzene-l-sulfonyl chloride (1.115 g, 5.85 mmol) and tetra-butylammonium hydrogen sulfate (0.090 g, 0.27 mmol) were dissolved in DCM (20 mL) at r.t., and NaOH (50% aq., 1 mL) was added. The reaction mixture stirred at room temperature for 30 minutes. After completion of the reaction as indicated 103496-1Pby TLC, the reaction mixture diluted with H2O and DCM and separated. The organic layer was evaporated in vacuo to obtain a light yellow solid, which was purified by column chromatography (100% DCM) to provide the title product (1.76 g, 97%) as a white solid. LCMS: 342 [M+H] +. 1H NMR (400 MHz, CHLOROFORM-D) delta ppm 8.14 (d, J=8.59 Hz, 2 H) 7.78 (d, J=3.79 Hz, 1 H) 7.39 (d, J=8.59 Hz, 2 H) 6.70 (d, J=3.79 Hz, 1 H) 2.45 (s, 3 H).
95%
With sodium hydroxide; In water; acetone; at 0 - 20℃;
EXAMPLE 23-((3No.,4No.)-4-Methyl-3-(d3-methyl(2-dr7H-pyrrolo[2, 3-<;f|pyrimidin-4- yl)amino)piperidin-l-yl)-3-oxopropanenitrile mono citrate salt(CP-690550-6?4 citrate salt)Step 1[00163] 4-Chloro-7-tosyl-7H-pyrrolor2,3-6?pyrimidine: 4-Methylbenzene-l- sulfonyl chloride (3.7 g, 19.32 mmol, 1.20 equiv.) was added to a solution of 2,4- dichloro-7H-pyrrolo[2,3-<;i]pyrimidine 1 (3g, 16.1 mmol, 1.00 equiv.) in acetone (20 mL). At about 0 0C, an aqueous sodium hydroxide solution (2 mol/L, 12mL) was added dropwise to the solution. The solution was then stirred at ambient temperature for about 3 hours. The solids were collected by filtration and washed with acetone/water to give the title product as a white solid (5.2 g; yield = 95%). LC-MS: m/z = 342 (M+Eta)+.
95%
With dmap; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 2h;Inert atmosphere;
A stirred solution of S-1 (2.00 g, 10.7 mmol) in CH2Cl2(20 mL) taken in a round- bottom flask was charged with DIPEA (3.7 mL, 21.4 mmol), DMAP (0.039 g, 0.32 mmol) and p-toluene sulfonyl chloride (2.25 g, 11.7 mmol) successively at ambient temperature under nitrogen atmosphere. The reaction mixture was stirred for 2 h at same temperature. The reaction mixture was diluted with CH2Cl2(100 mL) and was washed with water (40 mL) and HCl (1 N, 40 mL). The combined organic layer was washed with brine (1 × 50 mL), dried over anhydrous Na2SO4and was concentrated under reduced pressure. The obtained residue was washed with hexanes (2 × 50 mL) and was dried under vacuum to afford S-2 (3.50 g, 95%, AMRI lot IN-SKY-C-03) as an off-white solid. The compound was characterized by1H NMR analysis.1H NMR (400 MHz, CDCl3): delta 8.03 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 4 Hz, 1H), 7.29 (d, J = 8.12 Hz, 2H), 6.60 (d, J = 4 Hz, 1H), 2.36 (s, 3H).
90%
In a flask 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (1.0 g, 5.3 mmol) in DMF (30 rnL) was added NaH (60% in mineral oil, 0.21 g, 5.3 mmol). After stirring 5 min at room temperature the reaction mixture was added tosyl chloride (1.0 g, 5.3 mmol) and stirred 1 h at room temperature. The reaction mixture was diluted with H2O (100 mL) and filtered. The filtered solid was washed with H2O (20 mL) and dried 5 h under house vacuum at 80 0C to afford the title compound as a yellow solid (1.6 g, 90%). 1H NMR (500 MHz, DMSO-d6): delta 2.38 (s, 3H), 6.98 (d, J = 4.1 Hz, IH), 7.50 (d, J = 8.3 Hz, 2H), 8.03 (d, J = 8.5 Hz, 2H), 8.11 (d, J = 4.1 Hz, IH) MS (ES+): m/z 343 (M+H)+
90%
To a solution of 2,4-dichloro-7H-pyrrolo[2,3-J]pyrimidine (1.0 g, 5.3 mmol) in DMF (30 mL) was added NaH (60% in mineral oil, 0.21 g, 5.3 mmol). The mixture was stirred for 5 min at room temperature and added tosyl chloride (1.0 g, 5.3 mmol). The mixture was stirred for 1 h at room temperature, diluted with H2O (100 mL), and filtered. The solid was washed with H2O (20 mL), and dried under vacuum 5 h at 80 0C to afford the title compound as a yellow solid (1.6 g, 90%). <n="47"/>[0158] 1H NMR (500 MHz, DMSO-J6): delta 2.38 (s, 3H), 6.98 (d, J = 4.1 Hz, IH), 7.50 (d, J = 8.3 Hz, 2H), 8.03 (d, J = 8.5 Hz, 2H), 8.12 (d, J = 4.1 Hz, IH)[0159] MS (ES+): m/z 342 (M+H)+
89%
With dmap; triethylamine; In dichloromethane; at 20℃; for 5h;Cooling with ice;
In the ice bath conditions,A solution of 2,4-dichloro-7H-pyrrole [2,3-d] pyrimidine 1.0 gWas dissolved in 50 mL of dichloromethane,To the above mixed solution, 1.06 g of p-toluenesulfonyl chloride was added slowly,Triethylamine 1.08 g,N, N-dimethylpyridin-4-amine, 0.019 g,The mixed solution was stirred at room temperature for 5 h,After the reaction is complete,To the above solution was poured into 150 mL, the organic phase was washed with water,Citric acid aqueous solution and brine solution were washed three times each. The organic phase was dried with anhydrous magnesium sulfate overnight, and the solvent was evaporated under reduced pressure to obtain crude product.Recrystallization from petroleum ether gave 1.6 g of pure white product.Yield 89%.
89%
With dmap; triethylamine; In dichloromethane; at 20℃; for 5h;
1.0 g of 2,4-dichloro-7H-pyrrole [2,3-d]pyrimidine was dissolved in 50 mL of dichloromethane under ice bath. To the above mixed solution, 1.06 g of p-toluenesulfonyl chloride, 1.08 g of triethylamine, and 0.019 g of 4-dimethylaminopyridine were slowly added. The mixed solution was stirred at room temperature for 5 h. After the reaction was completed, 150 mL of dichloromethane was poured into the above solution, and the organic phase was washed three times with 100 mL of each of water, aqueous citric acid and brine; The organic phase was dried over anhydrous magnesium sulfate (MgSO4). Recrystallization from petroleum ether gave 1.6 g of white pure product. The yield was 89%.
89.1%
With dmap; triethylamine; In dichloromethane; at 20℃;Inert atmosphere;
Compound 34 (3.0 g, 16.11 mmol) was added to a 250 mL single-mouth bottle with magnetic stirring.And dichloromethane (80 mL), stirred and dissolved, and then added p-toluenesulfonyl chloride (TsCl, 3.18 g, 16.92 mmol), triethylamine (3.24 g, 32.22 mmol)And 4-dimethylaminopyridine (DMAP, 60 mg, 0.48 mmol), plus,The reaction mixture was stirred at room temperature overnight under a nitrogen atmosphere. The reaction was quenched by the addition of water (50 mL).The organic layer was separated, the aqueous layer was extracted with dichloromethane (40 mL×2), and organic phases were combined.Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate.4.8g,The yield was 89.1%.
89.1%
With dmap; triethylamine; In dichloromethane; at 20℃;
Compound 9a (3.0 g, 16.11 mmol) and dichloromethane (80 mL) were added to a 250 mL single-mouth flask with magnetic stirring, and the mixture was stirred and dissolved, and p-toluenesulfonyl chloride was added in sequence.(TsCl, 3.18 g, 16.92 mmol), triethylamine (3.24 g, 32.22 mmol)And DMAP (4-dimethylaminopyridine, 60mg, 0.48mmol), plus,The reaction mixture was stirred at room temperature overnight under a nitrogen atmosphere. The reaction was quenched by the addition of water (50 mL).The organic layer was separated and the aqueous layer was extracted with dichloromethane (40 mL×2).The organic phases were combined, dried over anhydrous sodium sulfate, filtered and evaporated.The residue was passed through a silica gel column to give a white solid4.8 g, yield 89.1%.
86%
To a solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (500 mg, 2.66 mmol) in DMF (5 mL) was added NaH (120 mg, 2.93 mmol, 60%) at 0 C, and the mixture was stirred at this temperature for 30 mm. Then paratoluensulfonyl chloride (608 mg, 3.19 mmol) was added to the mixture, and the resulting mixture was stirred at rt overnight. To the reaction mixture was added water (50 mL) to quench the reaction, and the resulting mixture was partitioned. The aqueous layer was extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 10/1) to give the title compound as a yellow solid (780 mg, 86 %).MS (ESI, pos. ion) m/z: 343.90 [M+H]+1H NMR (400 MHz, CDC13) (ppm): 8.13 (d, J = 8.3 Hz, 2H), 7.77 (d, J = 4.0 Hz, 1H), 7.38 (d, J = 8.2 Hz, 2H), 6.70 (d, J = 4.0 Hz, 1H), 2.45 (s, 3H).
85.3%
With sodium hydride; In tetrahydrofuran; at 0 - 20℃; for 6h;Large scale;
In a 50 L double-layered kettle, Compound II (2500 g, 13.3 mol, 1.0 e.q.) was added to 30 L of THF.Add NaH (797.8 g, 19.95 mol, 1.5 e.q.) in portions at 0 C, add, at 0 C,P-toluenesulfonyl chloride (3042 g, 15.96 mol, 1.2 e.q.) was added dropwise, and the temperature was controlled at 0 to 10 C.After the dropwise addition was completed, the reaction was stirred at 20 C for 6 h, and the reaction was completed by LC-MS.35 L of water was added to the reaction solution, and the mixture was thoroughly stirred, and the organic phase was washed with 30 L of saturated sodium hydrogen carbonate solution.After washing with 30 L of water, the mixture was separated, dried over anhydrous magnesium sulfate, filtered, and evaporated.It was beaten with petroleum ether and dried to give Compound III-2 as a pale yellow solid 3881.3 g.The yield was 85.3%.
84%
To a solution of 2,4-dichloro-7Hpyrrolo[2,3-d]pyrimidine (4.5 g, 23.93 mmol) in DMF (140 mL) was added NaH (0.957g, 23.93 mmol). After stirring for 5 min at room temperature, 4-methylbenzene-1-sulfonyl chloride (4.56 g, 23.93 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with water (450 mL) and filtered. The solid was washed with water (90 mL) and dried to give the title compound 1a (7 g,84 % yield) as a white solid. LCMS: 342 [M+H]+.
80%
With sodium hydroxide; In acetone; at 0 - 20℃; for 2h;
After 2,4-dicWoro-7H-pyrrolo[2,3-d]pyrimidine (3.0 g, 16.0 mmol) was dissolved in acetone (20.0 mL), 4- methylbenzenesulfonyl chloride (4.6 g, 23.9 mmol) was added thereto. After cooling to 0 C, 2 M sodium hydroxide solution (12.0 mL) was slowly added dropwise and then stirred at room temperature for 2 hours. The organic layer was isolated, treated with magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was isolated by column chromatography to obtain a title compound (2.9 g, yield: 80.0%). [H NMR (500MHz,CD3OD) delta 8.12(d, 2H), 7.76(d, 1H), 7.37(d, 2H), 6.68(d, 1H), 2.43(s, 3H)
78%
With sodium hydroxide; In water; acetone; at 20℃;
General procedure: To a solution of S1a (150mg, 0.7978mmol) and p-toluenesulfonyl chloride (183mg, 0.9574) in acetone (10mL) was added 2 M aqueous NaOH (638muL, 1.2765mmol). The mixture was allowed to react overnight at room temperature. The product precipitates upon formation. The next day the solvent was evaporated and water was added. The precipitate was isolated via vacuum filtration, washed with water, and allowed to air dry yielding 2,4-dichloro-5-(p-tolylsulfonyl)pyrrolo[3,2-d]pyrimidine (S2a) as a free flowing solid (142mg, 52%).
With dmap; triethylamine; In dichloromethane; at 20℃; for 1h;
To a suspension of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (1.59 g, 8.46 mmol), p-toluenesulfonyl chloride (1.93 g, 10.1 mmol) and triethylamine (TEA) (2.35 mL, 16.9 mmol) in CH2Cl2 (15 mL), dimethylaminopyridine (DMAP) (27 mg, 0.22 mmol) was added. As soon as the DMAP was added, the suspension became clear. The solution was then stirred at room temperature for 1 h. It was washed with 1N HCl, then with 5% NaHCO3, dried over Na2SO4 and concentrated in vacuo to give 2,4-dichloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine as a solid (2.55 g).
With dmap; triethylamine; In dichloromethane; at 20℃; for 20h;
To a mixture of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (1.67 g, 8.88 mmol), p- toluenesulfonyl chloride (1.72 g, 9.02 mmol) and triethylamine (2.50 mL, 18.0 mmol) in CH2C2 (15 mL), dimethylaminopyridine (30 mg, 0.24 mmol) was added. It was stirred at room temperature for 20 h. Water and CH2Ci2 were added. The organic phase was separated, washed with IN HCl, then with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give 2,4-dichloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine as a solid (3.03 g).
In N,N-dimethyl-formamide; at 20℃; for 2.15h;
Example 74N-[2-( { [2-({3 -methoxy-4- [(4-methylpiperazin- 1 -yl)carbonyl]phenyl} amino)- 7H- pyrrolo[2,3-d]pyrimidin-4-yl]amino}methyl)phenyl]-N-methylmethanesulfonamideExample 74A 2,4-dichIoro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine Example 1C (0.792 g, 4.21 mmol) was dissolved in N,N-dimethylformamide (15 ml) and 4-methylbenzene-l-sulfonyl chloride (0.803 g, 4.21 mmol) was added. The mixture was stirred at room temperature for 15 minutes then 4-methylbenzene-l-sulfonyl chloride (0.803 g, 4.21 mmol) was added. The mixture was stirred for 2 hours then diluted with 75 ml of ethyl acetate and washed with 50 ml of 2N aqueous HC1. The organic phase was dried over anhydrous Na2S04, filtered, and absorbed on silica gel. The crude material was purified by flash chromatography on silica gel, eluting with a 0 - 50% ethyl acetate / hexanes gradient to yield the title compound. MS ESI(+) m/z 341.7 [M+H]+
1.5 g
With sodium hydroxide; In water; acetone; at 0 - 30℃; for 2 - 3h;
To a suspension of 2,4-dichloro-7H-pyrrolo[2,3-d] pyrimidine (l g, 0.005 mol) and toluene sulfonylchloride (1.3gm, 0.007) in 10 ml acetone cooled to about 0-5 C , a solution of sodium hydroxide in water (0.32gm in 4ml water) was added slowly at about 0-5 C .The temperature of the reaction mass was raised to 25-30 C and stirred for 2-3 hrs. The progress of the reaction was monitored by TLC. After completion of the reaction the reaction mass was filtered and washed with a mixture of acetone and water. The solid was dried under vacuum at about 50-55 C for about 10 hrs to afford 1.5 gm of 2,4-dichloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3- d]pyrimidine as yellow colored solid. (HPLC purity >98.0%)
NaH (1.1 equiv) was slowly added at 0C to a 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (1 equiv) solution in THF. The reaction mixture was stirred at 0C for 0.5h. p-Toluensulfonyl chloride (1 equiv) was then added and it was stirred at 0C for 4h. The solvent was evaporated to dryness, and the crude product was diluted with H2O and extracted thrice with CH2Cl2. The organic layer was washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to obtain the crude product for the next step.
A 0 oc solution of 2,4-dichloro-7 H-pyrrolo[2,3-d]pyrimidine ( 1.00 g, 5.32 mmol) inTHF (8 mL) was stirred at 0 oc for 5 min. Then sodium hydride (255 mg, 6.38 mmol) was added.The resulting mixture was stirred for 15 min, then iodomethane (8.50 g, 53.20 mmol) was added.The reaction mixture was warmed to rt and stirred overnight. To the reaction mixture was addedwater (60 mL) to quench the reaction, and the resulting mixture was extracted with ethyl acetate(50 mL x 3). The combined organic layers were washed with saturated brine (80 mL), dried overanhydrous sodium sulfate and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 1011) to give the title compound as awhite solid (1.00 g, 93 % ).MS (ESI, pos. ion) m/z: 202.0[M+Ht.
83%
With potassium hydroxide; In dimethyl sulfoxide; at 20℃; for 1h;
Example 2 (1 g, 5.318 mmol) and powdered KOH (446 mg, 7.978 mmol) was dissolved in 4 mL anhydrous DMSO. After 1 h at RT, the reaction mixture was quenched with water and the aqueous layer was extracted with EtOAc (2x).The organics were combined, dried (MgSO4), filtered and the volatiles were removed in vacuo. The residue was purified by flash chromatography (Sitheta2, hexanes/EtOAc, 2:1 ) to provide the desired product (892 mg, 83%) as a colourless solid. 1H NMR (CZ6-DMSO) delta 7.76 (1 H, d, J = 3.6 Hz), 6.70 (1 H, d, J= 3.6 Hz), 3.82 (3H, s).
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; N,N-dimethyl-formamide; at 140℃; for 2h;
To a round bottomed flask was charged with 2,4-dichloro-7H-pyrrolo[2,3- d]pyrimidine (0.20 g, 1.1 mmol), <strong>[162607-15-0]4-methylthiophene-2-boronic acid</strong> (0.20 g, 1.4 mmol) and Pd(PPh3 )4 (0.10 g, 0.087 mmol). DMF (6 mL) was added to the above mixture followed by aqueous sodium carbonate (2 M; 1.5 mL, 3.0 mmol). The suspension was heated at 140 0C for 2 h and then allowed to cool to room temperature. The mixture was filtered, the filtered solid washed with DCM and the filtrate concentrated. The residue was purified by flash column chromatography on silica gel (hexanes to 60% EtOAc/hexanes) to afford the title compound as a yellow solid (80 mg, 30%). MS (ES+): m/z 250 (M+eta)+
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; N,N-dimethyl-formamide; at 120℃; for 1h;
To a round bottomed flask was charged with 2,4-dichloro-7H-pyrrolo[2,3- d]pyrimidine (0.40 g, 2.1 mmol), 5-methylthiophene-2-boronic acid (0.50 g, 3.5 mmol) and Pd(PPh3 )4 (0.20 g, 0.17 mmol). DMF (10 mL) was added to the above mixture followed by aqueous sodium carbonate (2 M; 3.0 mL, 6.0 mmol). The suspension was heated at 120 0C for 1 h and then allowed to cool to room temperature. The mixture was filtered, the filtered solid washed with DCM and the filtrate concentrated. The residue was triturated in MeOH and the solid filtered to afford the title compound as a brown solid (0.30 g, 56percent). The material was used in the next step without purification. MS (ES+): m/z 250 (M+eta)+
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; ethanol; water; at 110℃; for 0.333333h;Microwave irradiation;
To a solution of 2,4-dichloro-7H-pyrrolo[2,3-J]pyrimidine (188 mg, 1.0 mmol) in dimethoxyethane (DME, 10 mL) was added a solution of benzo[b]thiophen-2-yl-2-boronic acid (174 mg, 1.1 mmol) in EtOH (5 mL), 2.0 M Na2CO3 (2 mL), and tetrakis(triphenylphosphine)palladium (0) (Pd(PPh3)4, 115 mg, 0.1 mmol). The reaction mixture was heated at 110 0C for 20 min under mu-wave. The hot solution was filtered and the solid was washed with EtOAc. The filtrate was washed with brine (50 mL). The aqueous was extracted with EtOAc (3 x 30 mL). Combined organic layer was dried (Na2SO4). The solvent was removed in vacuo. The residue was added MeOH and sonicated. The solid was collected by filtration. The title compound (165 mg, 62%) was afforded as a yellow solid.
With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 70℃; for 20h;
A solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine ( 188 mg, 1.00 mmol), 2-(4- piperidinyl)acetic acid ethyl ester (171 mg, 1.00 mmol) and DEEA (0.400 mL, 2.30 mmol) in dioxane (6 mL) was stirred at 700C for 20 h. Water and EtOAc were added. The organic phase was separated, washed with IN HCl, dried over Na2SO4, concentrated in vacuo to give ethyl 2-(l-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-yl)acetate (308 mg).
With acetic acid; Selectfluor; In acetonitrile; at 80℃; for 24h;
After 2,4-dicMoro-7H-pyrrolo[2,3-d]pyrimidine (200 mg, 1.06 mmol) was dissolved in acetonitrile (5.0 mL), l-chloromethyl-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (561.6 mg, 1.6 mmol) and acetic acid (1 mL) were added thereto. The mixture was heated at 80 C and stirred for 24 hours, and then the organic layer was isolated, treated with magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was isolated by column chromatography to obtain a title compound (170.0 mg, yield: 80.1%). (0795) NMR (500MHz,CD3OD) delta 7.36(s, 1H)
22.82%
With acetic acid; Selectfluor; In [D3]acetonitrile; at 60℃; for 16h;Inert atmosphere;
A mixture of 2,4-dichloro-7H-pyrrolo[2,3- djpyrimidine (7 g, 37.23 mmol) and selectfluor (13.19 g, 37.23 mmol) in CH3CN (360 mL) and AcOH (72 mL) was degassed and then the mixture was stirred at 60 C for 16 h under N2. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (200 mL), adjusted to pH=7 with aq. NaHCC , and extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with brine (300 mL), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (PE:EtOAc := 10: 1 to 5: 1) to give 2,4- dichloro-5~fluoro-7H"pyrroio[2,3-d]pyrimidine (2.5 g, 22.82%) as a yellow oil. LCMS: RT 0.732 min,im/z = 206.0 [M+Hf.
With acetic acid; Selectfluor; In acetonitrile; at 70℃; for 18h;
A mixture of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (200 mg, 1.06 mmol) and SelectFluor (560 mg, 1.58 mmol) in CH3CN (5 mL) and HOAc (1 mL) was stirred at 70 0C for 18 h. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give 2,4-dichloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine (50 mg).
To a solution of,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidine 90.3 g, 1.6 mmol), Selectfluor (0.848 g, 2.4 mmol) was added acetonitrile (15 mL) and AcOH (2.5 mL). The solution was then heated at 70 C. for 24 h under Ar. After cooling to rt, ice was added and the mixture was neutralized by NaHCO3. Extraction with EtOAc and the organic residue was purified by combiflash (10 g, 0%~100% EtOAc/Hexane). White crystal was obtained. 1H-NMR (300 MHz, (CD3)2CO) 7.60 (d, J=3.6 Hz, 1H). MS-ESI: 206.1, 208.1 (M+H)+
With acetic acid; Selectfluor; In acetonitrile; at 60℃;
Step 1 : 2,4-Dchloro-7H-pyrrolo[2,3-d]pyrimidine (5.0 g, 27 mmol) was suspended in MeCN(300 mL) and AcOH (60 mL); to this was added selectfluor (l -chloromethyl-4-fluoro- l ,4- diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate), 1.4 eq, 13.2 g) in one portion. The reaction mixture was stirred at 60 C overnight. HPLC monitoring indicated complete conversion. After the solvents were evaporated to the volume of ~100 mL, toluene (20 mL) was added and the suspension was filtered. The filtrate was evaporated to dryness and re-evaporated with toluene (2 chi 20 mL). The residue was then purified via a short silica pad (washing with 1/1 DCM/EtOAc) and column chromatography (ISCO machine, EtOAc/DCM, EtOAc on a 0-100% gradient) to give the crude product. Upon standing the pure product was seen to precipitate from the column fractions. These were filtered and the mother liquors were combined to precipitate a 2nd crop. Total 1.23 g of the product 64 was obtained (22% yield, ~ 90% pure, Cl-isomer was the main impurity).
1.23 g
With acetic acid; Selectfluor; In acetonitrile; at 60℃;
2,4-Dchloro-7H-pyrrolo[2,3-d]pyrimidine (5.0 g, 27 mmol) was suspended in MeCN (300 mL) and AcOH (60 mL); to this was added selectfluor (1-chloromethyl-4-fluoro-1 ,4- diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate), 1.4 eq, 13.2 g) in one portion. The reaction mixture was stirred at 60 C overnight. HPLC monitoring indicated complete conversion. After the solvents were evaporated to the volume of -100 mL, toluene (20 mL) was added and the suspension was filtered. The filtrate was evaporated to dryness and re-evaporated with toluene (2 chi 20 mL). The residue was then purified via a short silica pad (washing with 1/1 DCM/EtOAc) and column chromatography (ISCO machine, EtOAc/DCM, EtOAc on a 0-100% gradient) to give the crude product. Upon standing the pure product was seen to precipitate from the column fractions. These were filtered and the mother liquors were combined to precipitate a 2nd crop. Total 1.23 g of the product 64 was obtained (22% yield, ~ 90% pure, Cl-isomer was the main impurity).
With 1-(chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane-1,4-diium tetrafluoroborate; In acetic acid; acetonitrile; at 70℃; under 760.051 Torr; for 36h;Inert atmosphere;
2,4-dichloro-7H-pyrrolo[2,3-<i]pyrimidine (1 g, 5.32 mmol) was massed into a 250 mL round-bottom flask and dried over P205 under vacuum overnight. To this were injected acetonitrile (60 mL) and acetic acid (12 mL) at room temperature, followed by the addition of 1- (chloromethyl)-4-fluoro-l,4-diazabicyclo[2.2.2]octane-l,4-diium tetrafluorob orate (2.64 g, 7.45 mmol) under argon atmosphere. The mixture was heated to 70 C and stirred for 36 hours. The resulting mixture was cooled to 25 C, diluted with DCM (150 mL), washed with water (2 x 50 mL) and brine (2 x 50 mL) successively. The organic layer was collected, dried over anhydrous Na2S04, filtered and the filtrate was concentrated under reduced pressure, silica gel column using ethyl acetate / petroleum ether (0% to 20% EtOAc in Pet. ether) to give a crude solid, which was further purified by CI 8 gel column reverse-phase-chromatography with the following conditions: Column, 60 A, 120 g; mobile phase, water (with 0.05% TFA) and acetonitrile (5% acetonitrile up to 40% in 15 min, 40% up to 47% in 5 min, hold 47% 5 min, up to 95% in 3 min, down to 5% in 5 min); Detector, UV 254 nm. The product-containing fractions were collected, extracted with EtOAc (2 x 50 mL). The organic layer was collected, washed with brine (2 x 30 mL), dried over anhydrous Na2S04, filtered and the filtrate was concentrated under reduced pressure to give 2,4- dichloro-5-fluoro-7H-pyrrolo[2,3-ii]pyrimidine. LC-MS: (ES, m/z): 206.05 [M + H]+. 1H- MR: (300 MHz, d6-OMSO, ppm): delta 12.71 (brs, 1H), 7.77 (d, J= 2.4 Hz, 1H). 19F- MR:(282 MHz, d6- DMSO, ppm): delta -169.79 (s, IF).
A mixture of 2, 4-Dichloro-7H-pyrrolo[2,3-<i]pyrimidine (0.1 g, 0.53 mmol) in Ammonia (7 N in MeOH, ImL) was heated at 100 0C for 24 h, then it was diluted with EtOAc, washed with Sat. NaetaCO3, brine, dried and concentrated to give 2-chloro-7H- pyrrolo[2,3-d]pyrimidine-4-amine (0.06 g).
With acetic acid; zinc; In acetonitrile; at 80℃; for 14h;Large scale;
Zinc powder (8700 · 0g, 133piomicron1, 10 · Oeq ?) was added portionwise to glacial acetic acid (3 · 3L, 53 · 2mo1.4 · Oeq ·) and acetonitrile (30 · 0L) mixture was added to complete the reaction temperature was raised to 80 C for 14 hours, the reaction was complete by TLC.87] The reaction mixture was cooled to 25 C, suction filtration, the filtrate was concentrated under reduced pressure and added to 30L of ice water, precipitated a large number of pink solid, filtration, the filter cake washed with water (5L X 3), dried to give a white solid 1501.7g. Yield: 73.54%.
63.86%
With acetic acid; zinc; In methanol; at 70℃; for 16h;Large scale;
Zincpowder (3480.0g, 53.2mol, 4.0eq.) At room temperature control (25 )was added to the next batch compound II-1Mixture(2500.0g, 13.3mol, 1.0eq.) In acetic acid (5.0L, 79.8mol, 6.0eq.) And methanol(30.0L), the plusAfterthe reaction temperature was raised to 70 16 hours, TLCmonitored the reaction was complete. The reaction mixture was cooled to 25 ,filtration, the filtrate was concentrated30L wasadded to ice water, and precipitated a lot of pink solid, filtration, thefilter cake washed with water (5L × 3), drying, compound I-1 whiteThe solid 1304.0g,Yield: 63.86%.
Method for svnthesising A.21-PG; 2,4-dichloro-7H-pyrrolo[2,3-J]pyrimidine (500 mg, 2.66 mmol), palladium(II)acetate(70 mg, 0.31 mmol) and BINAP (240 mg, 0.39 mmol) are dissolved in 6 mL TEtaF and stirred for 20 min at 200C. Then TMEDA (300 muL; 2.0 mmol) is added, the mixture is stirred for 20 min and then sodium borohydride (189 mg; 5.11 mmol) dissolved in 10 rnL diglyme is added. After 1 h at 200C the mixture is combined with 1 N HCl and the solvent is eliminated in vacuo. The residue is purified by column chromatography (method prep. HPLC2; 3 % acetonitrile to 55 % in 12 min) and 2-chloro-7H-pyrrolo[2,3-</Jpyrimidine (EtaPLC-MS: tRet. = 1.25 min; MS(M+Eta)+ = 154; method FEC3) is obtained.
Method for svnthesising A.21-PG; A.2I A.2I-PG; 2,4-dichloro-7H-pyrrolo[2,3-J]pyrimidine (500 mg, 2.66 mmol), palladium(II)acetate(70 mg, 0.31 mmol) and BINAP (240 mg, 0.39 mmol) are dissolved in 6 mL TEtaF and stirred for 20 min at 200C. Then TMEDA (300 muL; 2.0 mmol) is added, the mixture is stirred for 20 min and then sodium boro hydride (189 mg; 5.11 mmol) dissolved in 10 rnL diglyme is added. After 1 h at 200C the mixture is combined with 1 N HCl and the solvent is eliminated in vacuo. The residue is purified by column chromatography (method prep. HPLC2; 3 % acetonitrile to 55 % in 12 min) and 2-chloro-7H-pyrrolo[2,3-</Jpyrimidine (EtaPLC-MS: tRet. = 1.25 min; MS(M+Eta)+ = 154; method FEC3) is obtained.
REFERENCE EXAMPLE 2 fR)-2-Choro-4-[3-(Lambdaf,W»dimethy[amino)pyrrolidin-1-yl]-7-[(4-toiLfy.)suifony.- pyrtauolo[2,3-d]pyrimidine a) 2,4-Dichloro-7-[(4-toiuyl)suJfonyI]-pyrro[o[2t3-d|pynmidine 6.39 g of NaH 60 % (158 mmol) were slowly added at 0 0C over a 2,4-dichloro-7H- pyrrolo[2,3-d]pyrimidine solution (15 g, 78.9 mmol) in THF (300 mL). The reaction mixture was stirred at room temperature for 1 h. After this time p-toluensulfonyl chloride (16.4 g, 86 mmoi) was added and it was stirred at room temperature for 18 h. The solvent was evaporated to dryness, the crude product was diluted with H2O and extracted thrice with EtOAc. The combined organic phases were separated, dried over Na2SO4 and the solvent evaporated to dryness. The desired compound was obtained in quantitative yield and used without further purification. LC-MS (Method 1 ): tR = 2.72 min; m/z = 340 (MH").
With potassium phosphate; palladium diacetate; CyJohnPhos In 1,4-dioxane for 4h; Inert atmosphere; Reflux;
4.1.4. 2,4-Diphenyl-7H-pyrrolo[2,3-d]pyrimidine (5a)
General procedure: A solution of compound 1 (0.3 g, 1.60 mmol) in anhydrous dioxane (10 mL) was flushed with argon and 2.0 mol % Pd(OAc)2 and 4.0 mol % (2-biphenyl)dicyclohexylphosphine were added under stirring and argon flow. After 10 min phenylboronic acid (2a) (0.47 g, 3.83 mmol) and K3PO4 (1.62 g, 7.66 mmol) were added. The reaction mixture was stirred under reflux for 4 h. Then dioxane was evaporated under reduced pressure to dryness and water (5 mL) was added to dissolve inorganic salts. The obtained solution was extracted with chloroform (3×25 mL), organic layer was dried with Na2SO4, chloroform removed by distillation under reduced pressure and the solid was purified by column chromatography using benzene as an eluent to give compound 5a (0.28 g, 65%) as a yellowish solid
With sodium carbonate; In water; acetonitrile; for 24.0h;Reflux;
The compound of formula (10) synthesized in the same manner as in Reference Example 2 was added to a mixed solution of water-acetonitrile and the known compound as <strong>[252720-31-3]N-Boc-amino-piperidinyl-1,1-carboxylic acid</strong> and sodium bicarbonate, heat to reflux for 24 hours. The compound of the formula (26) is synthesized by the above steps.
2,4-dichloro-7-(3-chloro-2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
46%
With copper diacetate; In methanol; at 20℃; for 4h;
General procedure: 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (0.5 mmol), respective aryl boronic acid (0.6 mmol) and copper (II) acetate (0.5 mmol) in methanol (10 mL) was stirred at room temperature for 4 hours. Then, the reaction mixture was filtered over celite pad and the solvent was evaporated. The crude product was purified through flash column chromatography on a silica gel using dichloromethane as eluent to yield the respective products.
7-(4-butylphenyl)-2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
53%
With copper diacetate; In methanol; at 20℃; for 4h;
General procedure: 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (0.5 mmol), respective aryl boronic acid (0.6 mmol) and copper (II) acetate (0.5 mmol) in methanol (10 mL) was stirred at room temperature for 4 hours. Then, the reaction mixture was filtered over celite pad and the solvent was evaporated. The crude product was purified through flash column chromatography on a silica gel using dichloromethane as eluent to yield the respective products.
Multi-step reaction with 7 steps
1: potassium carbonate / tetrahydrofuran; water / 12 h / 35 °C / Large scale
2: potassium carbonate / N,N-dimethyl-formamide / 48 h / 35 °C / Large scale
3: tris-(dibenzylideneacetone)dipalladium(0); XPhos; potassium carbonate / <i>tert</i>-butyl alcohol / 6 h / 40 - 85 °C / Inert atmosphere; Large scale
4: sodium hydroxide; water / water; methanol / 4.25 h / 10 - 15 °C / Large scale
5: palladium 10% on activated carbon; hydrogen / tetrahydrofuran / 5 h / 90 - 100 °C / 7500.75 Torr / Inert atmosphere
6: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 1.5 h / -5 - 0 °C
7: ethanol; water / 6 h / 25 - 40 °C / Large scale
Multi-step reaction with 7 steps
1.1: potassium carbonate / tetrahydrofuran; water / 12 h / 35 °C
2.1: potassium carbonate / N,N-dimethyl-formamide / 48 h / 35 °C / Large scale
3.1: potassium carbonate; tris-(dibenzylideneacetone)dipalladium(0); XPhos / 6 h / 40 - 85 °C / Inert atmosphere; Large scale
4.1: sodium hydroxide; water / methanol / 4 h / 10 - 15 °C / Large scale
5.1: palladium on activated charcoal / tetrahydrofuran / 0.5 h / 1500.15 - 6000.6 Torr / Inert atmosphere; Large scale
5.2: 11 h / 85 °C / 1500.15 - 6000.6 Torr / Large scale
6.1: potassium carbonate / tetrahydrofuran; water / 1 h / 10 °C
6.2: 1 h / 10 °C
7.1: water; ethanol / 1 h / 40 °C / Large scale
((2R,3R,4S,5R)-3-(benzoyloxy)-5-(2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-fluorotetrahydrofuran-2-yl)methyl benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
66%
Stage #1: 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine With Tris(3,6-dioxaheptyl)amine; potassium hydroxide In acetonitrile for 0.5h; Inert atmosphere;
Stage #2: 2-deoxy-2-fluoro-3,5-di-O-benzoyl-α-D-arabinofuranosyl bromide In acetonitrile at 20℃; for 18h; Inert atmosphere;
b.ii ii. PREPARATION OF ((2R,3R,4S,5R)-3-(BENZOYLOXY)-5-(2,4- DICHLORO-7H-P YRROLO [2,3-D] PYRIMIDIN-7-YL)-4- FLUOROTETRAHYDROFURAN-2-YL)METHYL BENZOATE (4)
To a mixture of anhydrous acetonitrile (300 mL) and potassium hydroxide (4.92 g, 87.6 mmol, 2.12 eq) was added catalytic Tris[2-(2-methoxyethoxy)ethyl]amine (TDA-1) (0.793 mL, 2.48 mmol, 0.06 eq). The mixture was stirred for 20 min and then the nucleobase 3 (7.77 g, 41.3 mmol, 1.0 eq) was added. The reaction mixture was stirred for 30 min after which time a solution of the brominated sugar 2 (20.99 g, 49.59 mmol, 1.2 eq) in anhydrous acetonitrile (200 mL) was added. The reaction mixture was stirred at 20 °C for 18 hrs. The reaction mixture was quenched with sat NH4CI (300 mL). The organic layer was separated and then evaporated in vacou to afford a tacky solid, which was suspended into the aqueous layer above and then extracted with dichloromethane (3 x 100 mL). The organic extracts were combined and washed with brine (100 mL). The organic layer was separated, dried (Na2S04), fdtered, and then the fdtrate was evaporated under reduced pressure to give 27.78 g of a crude tan tacky solid. Purification by flash chromatography (5 x 120 g silica columns, 100-70% hexane in ethyl acetate, gradient elution) provided 14.4 g (66%) of 4 as a whited foamy solid. NMR (CDCb) d 8.17-8.08 (m, 4H), 7.73-7.39 (m, 7H), 6.80 (dd, J = 22.3, 2.9 Hz, 1H), 6.66 (d, J = 3.8 Hz, 1H), 5.76 (ddd, J = 17.7, 3.1, 0.9 Hz, 1H), 5.36 (ddd, J = 50.1, 3.0, 0.8 Hz, 1H), 4.87-4.76 (m, 2H), 4.57 (td, J = 4.6, 3.0 Hz, 1H); 19F NMR 5F - 198.27 to -198.52 (m, IF); LCMS m/z 530 (M+H)+.
49%
Stage #1: 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine With caesium carbonate In acetonitrile at 20℃; for 1h;
Stage #2: 2-deoxy-2-fluoro-3,5-di-O-benzoyl-α-D-arabinofuranosyl bromide In acetonitrile at 20℃;
65.a
Step a: 2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidine (350 mg, 1.86 mmol) was dissolved in 15 mL of acetonitrile and treated with Cs2CO3 (788 mg, 2.42 mmol, 1.3 equiv.). The mixture was stirred at room temperature for 60 min. 2-Deoxy-2-fluoro- -D-arabinofuranosyl bromide 3, 5-dibenzoate (787 mg, 1.86 mmol, 1 equiv.) was dissolved in 10 mL of acetonitrile and added to the mixture dropwise via an addition funnel. The mixture was allowed to stir overnight at room temperature. The mixture was filtered on a pad of silica gel and concentrated. The residue was adsorbed on silica, purified using column chromatography (hexanes / ethyl acetate) to provide the product as a white solid in 49% yield (480 mg).
3.8 g
Stage #1: 2-deoxy-2-fluoro-3,5-di-O-benzoyl-α-D-arabinofuranosyl bromide With sodium hydride In acetonitrile at 0℃; for 0.333333h;
Stage #2: 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine In acetonitrile at 25℃; for 1.66667h;
107.2 Step 2:
To a solution of compound ((2R,3R,4S,5R)-3-(benzoyloxy)-5-bromo-4-fluorotetrahydrofuran-2-yl)methyl benzoate (1.91 g, 10.18 mmol, 1.2 eq.) inanhydrous MeCN (100 mL) at 0°C was added NaH (407.12 mg, 10.18 mmol, 60% purity, 1.2eq.). The reaction mixture was stirred further for 20 min. A solution of compound 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (3.59 g, 8.48 mmol, 1 eq.) in MeCN (20 mL) wasadded dropwise over 10 min. The mixture was stirred at 25 oc for 1.5 h before it wasquenched with water (30 mL) and extracted with EtOAc (50 mL x 3). The combined organiclayers were washed with brine (20 mL), dried over anhydrous Na2S04, filtered andconcentrated to give a residue as yellow foam. The crude was purified by columnchromatography on a 40 g silica gel column (eluted with 10 -70% ofEtOAc in petroleumether) to provide ((2R,3R,4S,5R)-3-(benzoyloxy)-5-(2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-fluorotetrahydrofuran-2-yl)methyl benzoate (3.8 g, 84% yield) as a whitefoam.
2,4-dichloro-7-(2,3-O-isopropylidene-5-O-tert-butyldimethylsilyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
21%
Stage #1: 5-(tert-butyldimethylsilyloxy)-2,3-isopropylidenedioxy-D-ribofuranose With N,N,N,N,N,N-hexamethylphosphoric triamide In tetrachloromethane; toluene at -50℃; for 2.5h;
Stage #2: 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine With Tris(3,6-dioxaheptyl)amine; potassium hydroxide In tetrachloromethane; toluene at 20℃; for 48h;
A2 Preparation of intermediate 3
To a solution of 5-0-tert-butyldimethylsilyl-2,3-o-isopropylidene-D-ribofuranose (= intermediate 2 = commercial) (79.8 mmol) in CC14 (12.8 mL, 133 mmol) and toluene (200 ml) was added dropwise HMPA( 16.32 g, 100 mmol) at -50°C over 30 minutes. After the mixture was stirred at -50°C for 2 hours, the reaction mixture was quickly washed with ice cold brine (30 mL), dried over anhydrous Na2S04 and added immediately to a heavily stirred mixture of powdered KOH (6.5 g, 117 mmol), 2,4- dichloro-7H-pyrrolopyrimidine (10.0 g, 53 mmol), tris(3,6-dioxaheptyl)amine (8.27 mL, 26.6 mmol) and toluene (200 ml). The mixture was stirred at r.t. for 48 hours. Then the solvent was concentrated. The residue was treated with 250 ml NH4C1 solution and extracted with ethyl acetate (two times 300 ml). The organic layers were combined and dried with Na2S04, filtered and the filtrate was concentrated in vacuum. The residue was purified by column chromatography over silica gel (gradient elution: petroleum ether/ethyl acetate from 25: 1 to 15:1). The product fractions were collected and the solvent was evaporated to give the desired intermediate 3 (6.50 g, 21% yield).
A solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (500 mg, 2.66 mmol) in DMF (5 mL) was stirred at 0C for 5 mm, then to the solution was added sodium hydride (130 mg, 3.25 mmol, weight content 60%). The mixture was stirred for further 15 mm, and<strong>[762-51-6]1-fluoro-2-iodoethane</strong> (680 mg, 3.90 mmol) was added. The mixture was stirred at rt overnight. After the reaction, to the reaction mixture was added H20 (100 mL) to quench the reaction, and the mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo,and the residue was purified by silica gel column chromatography (PE/EtOAc(v/v)=10/1 ) to give the title compound as a white solid (499 mg, 80 %).MS (ESI, pos. ion) m/z: 235.95 [M+Hfb;?H NIVIR (400 IVIFIz, CDC13) (ppm): 7.35 (d, J = 3.4 Hz, 1H), 6.66 (d, J = 3.6 Hz, 1H), 4.83 (t, J = 4.6 Hz, 1H), 4.71 (t, J = 4.6 Hz, 1H), 4.61 (t, J = 4.6 Hz, 1H), 4.54 (t, J = 4.6 Hz, 1H).
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 100℃;Inert atmosphere;
To a RBF was added 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (540 mg, 2.87 mmol),<strong>[1029716-44-6]1-<strong>[1029716-44-6](1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong></strong> (2,1.07 g, 4.02 mmol, 1.5 eq.), sodium carbonate (Na2CO3, 608 mg, 5.74 mmol, 2 eq.),water (H2O, 10 mL) and 1,4-dioxane (30 mL), the resulting reaction mixture wasdegassed three times backfilling with nitrogen each time before being treated withPd(PPh3)4 (199 mg, 0.172 mmol, 0.06 eq.). The resulting reaction mixture was heatedto 100 C overnight. When the reaction was deemed complete determined by TLC,the reaction mixture was gradually cooled down to ambient temperature before beingfiltered through a Celite bed. The Celite bed was washed with DCM (2 x 20 mL)before the filtrates and washing solution were combined. The two layers wereseparated, and the aqueous layer was extracted with DCM (2 x 30 mL). The combinedorganic layers were concentrated under reduced pressure to remove solvents, and thecrude was purified by column chromatography (EA/Hex/DCM, 1/1/1) to yield 31(586 mg, 2.01 mmol, 70%) as a white solid. LRMS (ESI) m/z 292.1 [M+H]+. 1H NMR(400 MHz, CDCl3) ae 11.66 (s, 1H), 8.47 (s, 1H), 8.28 (s, 1H), 7.45-7.44 (m, 1H),6.81-6.79 (m, 1H), 5.61 (d, J = 6.0 Hz, 1H), 3.58 - 3.38 (m, 2H), 1.75 (d, J = 6.0 Hz,3H), 1.19 (t, J = 7.0 Hz, 3H). 13C NMR (101 MHz, CDCl3) ae 153.82, 153.25, 152.95,139.12, 127.87, 126.28, 121.44, 112.89, 100.79, 88.19, 64.52, 22.20, 14.82.
N-[(3R,4R)-1-benzyl-4-methylpiperidin-3-yl]-2-chloro-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93.6%
<strong>[1062580-52-2](3R,4R)-N,4-dimethyl-1-(phenylmethyl)-3-piperidinamine hydrochloride</strong> 234g (0.79 mol), 3000 ml of purified water was added to a 5 L reaction flask.177 g (1.61 mol) of potassium carbonate was added thereto with stirring, and then 150 g (0.79 mol) of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine was added thereto, and the mixture was heated to 98-102 C to stir the reaction.After reacting for 10 h, the temperature was lowered to 20-25 C, stirred for 4 h, filtered, and washed with 750 ml of purified water.Drying at 60-65 C to give an off-white solid ((3R,4R)-1-benzyl-4-methyl-piperidin-3-yl)-methyl-(2-Chloro-7H-pyrido[2,3-d]pyrimidin-4-yl)amine 276.1 g, yield 93.6%.
89.5%
With potassium carbonate; In water; at 90℃;
S1. Add 180 g of <strong>[1062580-52-2](3R,4R)-1-benzyl-N,4-dimethylpiperidine-3-amine dihydrochloride</strong>,200g 2,4-dichloro-7H pyrrole[2,3-D]pyrimidine,153g potassium carbonate and 650mL water, Stir and heat to 90C and monitor the reaction by TLC; After the reaction is complete, Cooling the reaction solution,The aqueous layer was extracted twice with 1000 mL of ethyl acetate. Combined organic phases,Dried over anhydrous magnesium sulfate, Concentrated under reduced pressure, 205 g of compound I was obtained as a pale yellow solid (yield 89.5%, HPLC purity 95.3%);
82.3%
With potassium carbonate; In water; for 10h;Reflux;
20g of compound 5,13.3g of compound 4 is added to the 500ml reaction flask,Add 266 ml of purified water,Add pre-mixed potassium carbonate solution with stirring(20 g of potassium carbonate was dissolved in 40 ml of purified water) and heated to reflux.After stirring and refluxing for 10 hours, TLC detection was started until the reaction was completed.Cool down to 20 ~ 30 C, add 120ml dichloromethane and stir to extract.The mixture was allowed to stand, dried, filtered, and washed to obtain a reaction solution.Add n-heptane with stirring at room temperature.Decreasing to 0 to 10 C for 2 to 4 hours,Filter and wash. Drying at 50-60 C for 6 hours under vacuum to obtain compound 3,Weighing 20.9g,Yield: 82.3%, purity: 99.9%.
4.72 kg
40Kg of purified water was added to a 100L glass reactor.Turn on the agitation,Add 4Kg of <strong>[1062580-52-2](3R,4R)-N,4-dimethyl-1-(phenylmethyl)-3-piperidinamine hydrochloride</strong> (Compound VI), and stir to dilute the system;Then add 9.49Kg potassium carbonate powder slowly.Adding stirring for 10 to 20 minutes;Further 2.61 Kg of 2,4-dichloro-7Hpyrrole[2,3-D]pyrimidine (Compound V) was added.The system is temperature-controlled at 100 ± 5 C for 20 to 24 hours.Sampling HPLC to monitor the reaction,After the reaction is completed, the heating is stopped, the system is cooled to 20 to 30 C, and centrifuged until substantially no solvent is discharged. The filter cake is rinsed with purified water, and centrifuged until no solvent is present; the filter cake is beaten with 20 Kg of purified water for 0.5 hour, and centrifuged until substantially no. The solvent was removed, the filter cake was rinsed with 8.0 Kg of purified water, and centrifuged until no solvent was obtained; the filter cake was added to a mixed solution of 15.8 Kg of absolute ethanol and 20 Kg of purified water, and stirred at 10 to 30 C for 1 to 2 hours, and centrifuged until substantially no. SolventThe filter cake was rinsed with 3.16 Kg of absolute ethanol and centrifuged until substantially solvent free. Transfer the whole batch of wet product to a blast drying oven and dry at 45-55 C for 4-6 hours to obtain a white solid, ie N-((3R,4R)-1-phenyl-4-methylpiperidine-3 -yl)-2-chloro-N-methyl-7H-pyrrole[2,3-d]pyrimidin-4-amine, weighed a total of 4.72 Kg.
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 14h;
2,4-Dichloro-7H-pyrrolo [2,3-d] pyrimidine-2,4-diol(100 mg, 0.53 mmol)To dimethylformamide (2 mL) was addedTo the dissolved solution was added <strong>[15827-56-2]cis-1,4-cyclohexanediamine</strong>(73 mg, 0.64 mmol),K2CO3 (220 mg, 1.59 mmol) was added.The reaction mixture was stirred at 80 C for 14 hours. The reaction mixture was cooled to room temperature, distilled under reduced pressure to remove the solvent, and then chloroform: methanol (1: 1) was added. The resulting solid was removed and the remaining solution was distilled under reduced pressure. The solid (100 mg, 0.38 mmol) was used in the next reaction.To a solution of the obtained solid (100 mg, 0.38 mmol) in dimethylformamide was added acrylic acid (32 mg, 0.45 mmol), HATU (285 mg, 0.75 mmol) andTriethylamine (0.16 mL, 1.13 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was distilled under reduced pressure to remove the solvent and then extracted twice with ethyl acetate. The organic layer was dried over magnesium sulfate and filtered. The solvent was distilled off under reduced pressure, and the solvent was removed. The residue was purified by silica gel column chromatography using hexane / ethyl acetate to obtain a white solid compound (80 mg, 47%, 0.25 mmol).
Multi-step reaction with 3 steps
1.1: potassium carbonate / water / 22 h / 90 °C / Inert atmosphere; Large scale
2.1: hydrogen; 10% palladium hydroxide on charcoal / water / 10 h / 75 - 80 °C / 2550.26 - 2850.29 Torr / Large scale
2.2: 2 h / 55 °C / Inert atmosphere; Large scale
3.1: potassium phosphate / tetrahydrofuran; water / 5 °C / Inert atmosphere
Multi-step reaction with 3 steps
1.1: potassium carbonate / water / 22 h / 90 °C / Large scale
2.1: hydrogen; 10 wt% Pd(OH)2 on carbon / water / 10 h / 75 - 80 °C / 2550.26 - 2850.29 Torr / Inert atmosphere
3.1: potassium phosphate / water; tetrahydrofuran / 0.17 h / 18 - 53 °C / Large scale
3.2: 2 h / 10 - 20 °C / Large scale
3.3: 0.17 h / 20 °C / Large scale
Multi-step reaction with 3 steps
1.1: potassium carbonate / water / 22 h / 90 °C / Inert atmosphere; Large scale
2.1: hydrogen; 10 wt% Pd(OH)2 on carbon / water / 10 h / 75 - 80 °C / 2550.26 - 2850.29 Torr / Large scale
3.1: potassium phosphate / water; tetrahydrofuran / 2 h / 10 - 20 °C / Inert atmosphere; Large scale
3.2: 22 - 25 °C / Inert atmosphere; Large scale
Multi-step reaction with 3 steps
1.1: potassium carbonate / water / 22 h / 90 °C / Inert atmosphere; Large scale
2.1: hydrogen; 10% palladium hydroxide on charcoal / water / 10 h / 75 - 80 °C / 2550.26 - 2850.29 Torr / Large scale
2.2: 2 h / 55 °C / Inert atmosphere; Large scale
3.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran; water / 5 °C / Inert atmosphere
With tris-(dibenzylideneacetone)dipalladium(0); BrettPhos; potassium carbonate In 1,4-dioxane at 80 - 100℃; Inert atmosphere;
4.2.10. Preparation of intermediated 15 and 16
General procedure: 4.2.10.1. N-(tert-butyl)-3-((2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)benzenesulfonamide (15). A 100 mL three-necked roundbottomedflask equipped with a magnetic stir bar was charged withcompound 3 (1.25 g, 5.5 mmol), 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine(0.94 g, 5 mmol), Pd2dba3 (1.83 g, 0.5 mmol), Brettphos (0.54 g, 1mmol) and K2CO3 (1.38 g, 10 mmol). 1,4-dioxane (40 mL), and theresulting mixture was purged with nitrogen then heated to 100 C stirredfor 24 h before being filtered while hot through Celite and then washedwith methyl alcohol. The organic phase was concentrated in vacuo andpurification of this residue by flash chromatography on silica gel (25 gcolumn, gradient: 0-6 % MeOH in DCM) gave 15 (0.95 g, 50 %) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.98 (s, 1H), 9.95 (s,1H), 8.23 (t, J = 2.0 Hz, 1H), 8.11 (ddd, J = 7.9, 2.2, 1.2 Hz, 1H),7.60-7.49 (m, 3H), 7.29 (d, J = 3.5 Hz, 1H), 6.80 (d, J = 3.5 Hz, 1H),1.15 (s, 9H).
50 %
With tris-(dibenzylideneacetone)dipalladium(0); BrettPhos; potassium carbonate In 1,4-dioxane at 80 - 100℃; Inert atmosphere;
4.2.10. Preparation of intermediated 15 and 16
General procedure: 4.2.10.1. N-(tert-butyl)-3-((2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)benzenesulfonamide (15). A 100 mL three-necked roundbottomedflask equipped with a magnetic stir bar was charged withcompound 3 (1.25 g, 5.5 mmol), 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine(0.94 g, 5 mmol), Pd2dba3 (1.83 g, 0.5 mmol), Brettphos (0.54 g, 1mmol) and K2CO3 (1.38 g, 10 mmol). 1,4-dioxane (40 mL), and theresulting mixture was purged with nitrogen then heated to 100 C stirredfor 24 h before being filtered while hot through Celite and then washedwith methyl alcohol. The organic phase was concentrated in vacuo andpurification of this residue by flash chromatography on silica gel (25 gcolumn, gradient: 0-6 % MeOH in DCM) gave 15 (0.95 g, 50 %) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.98 (s, 1H), 9.95 (s,1H), 8.23 (t, J = 2.0 Hz, 1H), 8.11 (ddd, J = 7.9, 2.2, 1.2 Hz, 1H),7.60-7.49 (m, 3H), 7.29 (d, J = 3.5 Hz, 1H), 6.80 (d, J = 3.5 Hz, 1H),1.15 (s, 9H).
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