巴瑞替尼杂质20

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: tert-Butyl 3-(cyanomethylidene)azetidine-1-carboxylate (5.0 g, 26 mmol) was dissolved in 4M HCl in dioxane (25.7 mL) and allowed to stir at ambient temperature for 16 hours. The mixture was concentrated to dryness in vacuo, then dissolved in DCM (30.0 mL) and cooled to −10° C. DIPEA (11.6 g, 90.0 mmol) was added followed by ethanesulfonyl chloride (5.0 g, 39 mmol). The resulting mixture was allowed to stir for 7 hours before the mixture was diluted with water and extracted with DCM. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 5-70% EtOAc/heptane). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound. The mixture was concentrated to dryness in vacuo dissolved in DCM (30.0 mL) cooled to −10° C to stir for 7 hours before the mixture extracted with DCM The organic layer was dried over anhydrous Na2SO4 filtered concentrated in vacuo The residue was purified by MPLC on silica gel ( a gradient elution of 5-70% EtOAc/heptane) concentrated in vacuo

实验步骤: 投料: 将2-[1-(乙基磺酰基)-3-氮杂环丁亚基]乙腈(7.38g,39.63mmol,1.0eq)和4-(1H-吡唑-4-基)-7-((2-(三甲基硅烷基)乙氧基)-甲基)-7H-吡咯并[2,3-D]嘧啶(10g,31.7mmol,0.8eq)溶于ACN(80mL,10v)（不溶，微粉浊）,RT下加入DBU(6.03g/5.92ml,39.63mmol,1.0eq)（溶，淡黄澄，后立即变为红棕澄清），RT搅拌。\n监测: 搅拌1h，取样+ACN LCMS(C4X-226017-1-2-1)，原料消耗完，反应完全，有产物信号\n后处理: 用150mL EA和150mL 水萃取，有机相用150mL 饱和食盐水洗涤1次，有机相干燥过滤旋干，得到红棕色固体。 16:30 用150mL PE打浆1h后过滤后旋干1h得微粉黄色固体17.5g

实验步骤: 投料: 将2-[1-(乙基磺酰基)-3-氮杂环丁亚基]乙腈(2.77g,14.49mmol,1.0eq)和4-(1H-吡唑-4-基)-7-((2-(三甲基硅烷基)乙氧基)-甲基)-7H-吡咯并[2,3-D]嘧啶(3.65g,11.6mmol,0.8eq)溶于ACN(30mL,10v)（不溶，微粉浊）,RT下加入DBU(2.2g/1.98ml,14.49mmol,1.0eq)（溶，淡黄澄，后立即变为红棕澄清），RT搅拌。\n监测: 搅拌1h，取样+ACN LCMS(C4X-226017-1-1-1)，原料消耗完，反应完全，有产物信号\n投料: 将2-[1-(乙基磺酰基)-3-氮杂环丁亚基]乙腈(4.69g,25.16mmol,1.0eq)和4-(1H-吡唑-4-基)-7-((2-(三甲基硅烷基)乙氧基)-甲基)-7H-吡咯并[2,3-D]嘧啶(6.35g,20.13mmol,0.8eq)溶于ACN(50mL,10v)（不溶，微粉浊）,RT下加入DBU(3.83g/3.76ml,25.16mmol,1.0eq)（溶，淡黄澄，后立即变为红棕澄清），RT搅拌。\n监测: 搅拌1h，取样+ACN LCMS(C4X-226017-1-1-2)，原料消耗完，反应完全，有产物信号\n后处理: 合并一起处理，用150mL EA和150mL 水萃取，有机相用150mL 饱和食盐水洗涤1次，有机相干燥过滤旋干，得到红棕色固体。 水相还有紫外，取水相LCMS（C4X-226017-1-1-W）,非产物信号 8/12 9:30 用150mL PE打浆1h后过滤得微粉黄色固体16.09g 10:54 取样+CDCL3 HNMR（C4X-226017-1-1），解谱正确。

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of 4-(1H-pyrrol-3-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (0.100 g, 0.318 mmol) and [1-(ethylsulfonyl)azetidin-3-ylidene]acetonitrile (0.118 g, 0.636 mmol, prepared as in Example 68) in acetonitrile (1 mL) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (24 μL, 0.16 mmol). The mixture was stirred for 4 hours. The solvent was evaporated. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution, then extracted with two further portions of ethyl acetate. The combined extracts were dried over sodium sulfate, decanted and concentrated. The crude product was stirred with 25% TFA/DCM (8 mL) overnight. The solvents were evaporated. The product was then stirred with ethylenediamine (0.3 mL) in methanol (5 mL). Preparative HPLC-MS (eluting with a gradient of methanol and water containing 0.15% NH4OH) was used to purify the product. 1H NMR (300 MHz, CDCl3): δ 8.59 (s, 1H), 7.54 (dd, 1H), 7.27 (d, 1H), 6.95 (dd, 1H), 6.82 (dd, 1H), 6.74 (d, 1H), 4.49 (d, 2H), 4.15 (d, 2H), 3.24 (s, 2H), 3.02 (q, 2H), 1.33 (t, 3H); LCMS (M+H)+: 371.1. The solvent was evaporated The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution extracted with two further portions of ethyl acetate The combined extracts were dried over sodium sulfate decanted concentrated The crude product was stirred with 25% TFA/DCM (8 mL) overnight The solvents were evaporated The product was then stirred with ethylenediamine (0.3 mL) in methanol (5 mL) Preparative HPLC-MS (eluting with a gradient of methanol and water containing 0.15% NH4OH) to purify the product

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a suspension of [4-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methyl pivalate (19, 10.0 g, 33.4 mmol) and 2-(1-(ethylsulfonyl)azetidin-3-ylidene)acetonitrile (11, 6.22 g, 33.4 mmol, 1.0 equiv) in N,N-dimethylformamide (DMF, 20 mL) was added DBU (254 mg, 1.67 mmol, 0.05 equiv) drop wise to keep the reaction temperature between 15-25° C. After adding DBU, the reaction mixture became homogeneous within 90 min. The reaction mixture was stirred for 3 h at room temperature. When HPLC showed that the reaction was deemed complete, the reaction mixture was quenched with water (120 mL) and acetonitrile (80 mL). The resulting mixture was stirred at room temperature for an additional 30 min. The solids were collected by filtration, washed with a mixture of acetonitrile and water (⅔ by volume, 2×20 mL), and dried in vacuum oven at 40-45° C. for 24 h to afford crude (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (20, 14.5 g, 16.2 g theoretical, 89.5% yield) as white solids, which was found to be sufficiently pure (>98.0% by HPLC) for the subsequent reaction without further purification. For 20: between 15-25° C the reaction mixture was quenched with water (120 mL) and acetonitrile (80 mL) The resulting mixture was stirred at room temperature for an additional 30 min The solids were collected by filtration washed with a mixture of acetonitrile and water (⅔ by volume, 2×20 mL) dried in vacuum oven at 40-45° C. for 24 h

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a suspension of 4-(1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (5, 440 g, 1.395 mol) and 2-(1-(ethylsulfonyl)azetidin-3-ylidene)acetonitrile (11, 312.4 g, 1.68 mol, 1.2 equiv) in acetonitrile (4.4 L) was added DBU (249.8 mL, 1.67 mol, 1.2 equiv) drop wise to keep the reaction temperature between 15-25° C. After adding DBU, the reaction mixture became homogeneous, but a precipitate appeared in 30 min. The reaction mixture was stirred for 3 h at room temperature. When HPLC showed that the reaction was deemed complete, the reaction mixture was quenched with water (11 L). The resulting mixture was stirred at room temperature for additional 30 min and then filtered. The solid cake was washed with water (4 L), MTBE (2 L) and dried in vacuum oven at 35° C. for 24 h to afford crude 2-(1-(ethylsulfonyl)-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (12, 681 g, 699.8 g theoretical, 97.3% yield) as white solids, which was found to be sufficiently pure for the subsequent reaction without further purification. For 12: 1HNMR (CDCl3, 300 MHz), δ 8.86 (s, 1H), 8.45 (s, 1H), 8.35 (s, 1H), 7.43 (d, 1H), 6.80 (d, 1H), 5.68 (s, 2H), 4.65 (d, 2H), 4.27 (d, 2H), 3.55 (s, 2H), 3.4 (t, 2H), 3.07 (m, 2H), 1.42 (m, 3H), 0.92 (m, 2H), −0.05 (s, 9H) ppm; C22H31N7O3SSi (MW, 501.68), LCMS (EI) m/e 502 (M++H). between 15-25° C the reaction mixture was quenched with water (11 L) The resulting mixture was stirred at room temperature for additional 30 min filtered The solid cake was washed with water (4 L), MTBE (2 L) dried in vacuum oven at 35° C. for 24 h

反应条件: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (9, 1000 g, 5.2 mol) in acetonitrile (7 L) and a 3 N aqueous HCl solution (7 L) was stirred at room temperature for 18 h. When HPLC showed that all the starting material (9) was consumed, the reaction mixture was concentrated under reduced pressure to dryness. The residue, which contains the crude desired deprotection product (10), was then suspended in acetonitrile (12 L) and the resulting suspension was cooled to 0-5° C. Diisopropyethylamine (DIEA, 3.14 L, 18.03 mol, 3.5 equiv) was then slowly added while keeping the internal temperature below 5° C. The resulting homogeneous solution was allowed to cool down to 0° C. and ethane sulfonyl chloride (EtSO2Cl, 730 mL, 7.73 mol, 1.5 equiv) was added over 1 h while keeping the internal temperature below 5° C. The resulting reaction mixture was allowed to gradually warm to room temperature and stirred at room temperature for overnight. When HPLC showed that the reaction was complete, the reaction mixture was concentrated under reduced pressure to a volume of approximately 2 L. The bath temperature of the rotary evaporator is set to not exceed 45° C. The concentrated residue was then diluted with dichloromethane (CH2Cl2, 10 L) and the resulting dichloromethane solution was washed with aqueous sodium chloride solution (10 L). The aqueous phase was back extracted with dichloromethane (CH2Cl2, 5 L). The combined organic layers were dried over anhydrous sodium sulfate (Na2SO4) and the residue was absorbed onto silica gel (SiO2, 1 Kg) under reduced pressure. The bath temperature of the rotary evaporator was set to not exceed 45° C. The material was then loaded onto a silica gel column (SiO2, 2.5 Kg) and eluted with 20-60% ethyl acetate in heptane to afford 2-(1-(ethylsulfonyl)azetidin-3-ylidene)acetonitrile (11, 882 g, 968.4 g theoretical, 91% yield) as off-white solids. For 11: 1H NMR (CDCl3, 300 MHz) δ 5.46 (m, 1H), 4.77 (m, 2H), 4.70 (m, 2H), 3.05 (q, 2H), 1.39 (t, 3H) ppm; C7H10N2O2S (MW, 186.23), LCMS (EI) m/e 187 (M++H). was consumed the reaction mixture was concentrated under reduced pressure to dryness the internal temperature below 5° C to cool down to 0° C. the internal temperature below 5° C The resulting reaction mixture to gradually warm to room temperature the reaction mixture was concentrated under reduced pressure to a volume of approximately 2 L The bath temperature of the rotary evaporator exceed 45° C The concentrated residue was then diluted with dichloromethane (CH2Cl2, 10 L) the resulting dichloromethane solution was washed with aqueous sodium chloride solution (10 L) The aqueous phase was back extracted with dichloromethane (CH2Cl2, 5 L) The combined organic layers were dried over anhydrous sodium sulfate (Na2SO4) the residue was absorbed onto silica gel (SiO2, 1 Kg) under reduced pressure The bath temperature of the rotary evaporator exceed 45° C eluted with 20-60% ethyl acetate in heptane

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: tert-Butyl 3-(cyanomethylene)azetidine-1-carboxylate (2, 82 g, 0.42 mol) was added to THF (850 mL) and the resulting solution was cooled to 0° C. before a 4 M HCl solution in 1,4-dioxane (850 mL, 3.38 mol, 8.0 equiv) was added over 1 h while keeping the temperature<5° C. The resulting reaction mixture was slowly warmed to room temperature and stirred at room temperature for 18 h. When the reaction was deemed complete, the reaction mixture was concentrated under reduced pressure and the residue was placed under high vacuum for an additional 3 h before being treated with THF (900 mL) and diisopropylethyl amine (183 mL, 1.06 mol, 2.5 equiv) at room temperature. The resulting solution was then cooled to 0° C. and ethanesulfonyl chloride (56 mL, 0.59 mol, 1.4 equiv) was added while keeping the reaction temperature<5° C. The ice bath was removed and the reaction was stirred at room temperature for 18 h. When TLC indicated the reaction was complete, the reaction mixture was diluted with ethyl acetate (1 L) and washed with saturated brine (1 L). The aqueous layer was extracted with ethyl acetate (2×500 mL). The combined organic layers were dried over sodium sulphate and concentrated under reduced pressure. The residue was diluted with dichloromethane and absorbed onto silica gel (150 g). This mixture was purified by column chromatography (1.5 Kg silica gel) eluting with heptane (4 L), 10% EtOAc in heptane (4 L), 20% EtOAc in heptane (8 L), 30% EtOAc in heptane (12 L), and finally with 40% EtOAc in heptane (12 L) to afford 2-(1-(ethylsulfonyl)azetidin-3-ylidene)acetonitrile (4) and 2-(3-chloro-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile (4B) as a off-white solid (58.1 g, 68% yield), which was found to be an approximately one to one mixture of compound 4 and 4B. For 4: 1H NMR (300 MHz, CDCl3) δ 1.38 (t, 3H), 3.05 (q, 2H), 4.72 (m, 2H), 4.79 (m, 2H), 5.41 (m, 1H); MS: m/z calcd. 187.05. found: 187.1. For 4B: 1H NMR (300 MHz, CDCl3) δ1.38 (t, 3H), 3.05 (q, 2H), 3.1 (s, 2H), 4.15 (d, 2H), 4.37 (d, 2H); MS: m/z calcd. 222.9. found: 222.9. was added over 1 h the temperature<5° C The resulting reaction mixture the reaction mixture was concentrated under reduced pressure the residue was placed under high vacuum for an additional 3 h The resulting solution was then cooled to 0° C. the reaction temperature<5° C The ice bath was removed the reaction was stirred at room temperature for 18 h the reaction mixture was diluted with ethyl acetate (1 L) washed with saturated brine (1 L) The aqueous layer was extracted with ethyl acetate (2×500 mL) The combined organic layers were dried over sodium sulphate concentrated under reduced pressure The residue was diluted with dichloromethane absorbed onto silica gel (150 g) This mixture was purified by column chromatography (1.5 Kg silica gel) eluting with heptane (4 L), 10% EtOAc in heptane (4 L), 20% EtOAc in heptane (8 L)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: tert-Butyl 3-(cyanomethylene)azetidine-1-carboxylate (2, 1000 g, 5.2 mol) was diluted with acetonitrile (7 L) and 3 N aqueous HCl (7 L). This resulting reaction mixture was stirred at room temperature for 18 h. When TLC showed the reaction was deemed complete, the reaction mixture was concentrated under reduced pressure. The residual solids were then suspended in acetonitrile (12 L) and cooled to 5° C. Diisopropyethyl amine (2.7 L, 15. 6 mol, 3 equiv) was slowly added to the suspension while keeping the temperature<15° C. The homogeneous solution was allowed to cool to 5° C. and ethanesulfonyl chloride (730 mL, 7.73 mol, 1.5 equiv) was added over 1 h while keeping the reaction temperature<15° C. The resulting solution was allowed to slowly warm to room temperature and stirred at room temperature for overnight. The additional amount of ethanesulfonyl chloride (100 ml, 1.05 mol, 0.2 equiv) was added and the reaction mixture was stirred for an additional 2 h at room temperature. After the reaction was deemed complete, the reaction mixture was concentrated under reduced pressure to a volume of about 4 L. This solution was then placed in a 50 L separatory funnel, diluted with dichloromethane (10 L) and washed with half saturated brine (10 L). The aqueous phase was extracted with dichloromethane (5 L). The combined organic layers were dried over sodium sulphate and absorbed onto silica gel (1 Kg) under reduced pressure. The material was then loaded onto a silica gel column (2.5 Kg) and eluted with 20% ethyl acetate in heptane (40 L), 40% ethyl acetate in heptane (80 L) and finally 60% ethyl acetate in heptane (40 L) to afford pure 2-(1-(ethylsulfonyl)azetidin-3-ylidene)acetonitrile (4, 567 g, 968.4 g theoretical, 58.6% yield) as a off-white solid. For 4: 1H NMR (300 MHz, CDCl3) δ1.38 (t, 3H), 3.05 (q, 2H), 4.72 (m, 2H), 4.79 (m, 2H), 5.41 (m, 1H); MS: m/z calcd. 187.05. found: 187.1. This resulting reaction mixture the reaction mixture was concentrated under reduced pressure cooled to 5° C the temperature<15° C to cool to 5° C. the reaction temperature<15° C to slowly warm to room temperature stirred at room temperature for overnight the reaction mixture was stirred for an additional 2 h at room temperature the reaction mixture was concentrated under reduced pressure to a volume of about 4 L This solution was then placed in a 50 L separatory funnel diluted with dichloromethane (10 L) washed with half saturated brine (10 L) The aqueous phase was extracted with dichloromethane (5 L) The combined organic layers were dried over sodium sulphate absorbed onto silica gel (1 Kg) under reduced pressure eluted with 20% ethyl acetate in heptane (40 L), 40% ethyl acetate in heptane (80 L)