Acalabrutinib的合成工艺初探

New Synthetic Method of Acalabrutinib

目的对Acalabrutinib合成工艺进行探究。方法以2-氯-3-氰基吡嗪(Ⅸ)为起始原料,通过硼氢化钠还原得到3-氯吡嗪-2-甲胺盐酸盐(Ⅷ),再以Ⅷ和Z-L-脯氨酸发生酰化反应得到(S)-苄基-2-(3-氯吡啶-2-甲基氨基甲酰基)吡咯烷-1-甲酸叔丁酯(Ⅶ),然后将(Ⅶ)通过环化得到(S)-苄基-2-(8-氯咪唑[1,5-a]吡啶)吡咯烷-1-甲酸叔丁酯(Ⅵ),通过溴代Ⅵ生成(S)-苄基-2-(1-溴-8-氯咪唑并[1,5-a]吡啶)吡咯烷-1-甲酸叔丁酯(Ⅴ)。将Ⅴ上的氯原子取代为氨基生成(S)-苄基-2-(1-氨基-8-氯咪唑并[1,5-a]吡啶)吡咯烷-1-甲酸叔丁酯(Ⅳ),再用Ⅳ与4-(吡啶-2-基)甲酰氨苯基硼酸反应得到(S)-苄基-2-(8-氨基-1-(4-(吡啶-2-基氨基甲酰基)苯基)咪唑并[1,5-a]吡啶-3-基)吡咯烷-1-甲酸叔丁酯(Ⅲ),(Ⅲ)发生酰基水解反应得到(S)-4-(8-氨基-3-(吡咯烷-2-基)咪唑并[1,5-a]吡啶-1-基)-N-(吡啶-2-基)苯甲酰胺(Ⅱ),最后用(Ⅱ)与2-丁炔酸发生酰化反应得到Acalabrutinib1(Ⅰ)。结果与结论最终得到目标产物Acalabrutinib,总产率为2.25%

Aim Investigating a new synthetic method of acalabrutinib. Method 3-chloropyrazine-2-carbonitrile(IX) was reduced by NaBH4 to produce( 3-Chloropyrazin-2-yl)methanamine hydrochloride(VIII). Acylation of VIII with Z-Pro-OH generated( 5)-benzyl 2-((3-chloropyrazin-2-yl)methylcarbamoy1)pyrrolidine-1-carboxylate(VII). VII cyclized to form( S)-Benzyl 2-(8-chloroimidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate(VI). Bromination of VI with NBS produced( S)-Benzyl 2-(1-bromo-8-chloroimidazo[l ,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate(V).Amination of V with ammonia generated( S)-Benzyl 2-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate(IV). IV reacted with4-(pyridin-2-yl-aminocarbonyl)benzeneboronic acid to produce( S)-benzyl 2-(8-amino-1-(4-(pyridin-2-ylcarbamoyl)phenyl)imidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate(III). Hydrolysis of III to produced( S)-4-(8-Amino-3-(pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide(II). Acylation of II with 2-butynoic acid generated the title compound. Result The final product is acalabrutinib, yield 2.25%.