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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%
Objective To investigate the synthesis process of Acalabrutinib. Methods 2-Chloro-3-cyanopyrazine (Ⅸ) was used as the starting material to obtain 3-chloropyrazine-2-methylamine hydrochloride (VIII) by sodium borohydride reduction. (S) -tert-butyl (S) -benzyl-2- (3-chloropyridine-2-methylcarbamoyl) pyrrolidine-1-carboxylate is obtained by acylation reaction of (S) -Benzyl-2- (8-chloroimidazo [1,5-a] pyridine) pyrrolidine-1- Tert-Butyl 2- (1-bromo-8-chloroimidazo [1,5-a] pyridine) pyrrolidine- 1 -carboxylate (V). Substitution of the chlorine atom in V with an amino group gives tert-butyl (S) -benzyl-2- (1 -amino-8-chloroimidazo [1,5-a] pyridine) pyrrolidine- (S) -benzyl-2- (8-amino-1- (4- (pyridin-2-ylcarbamoyl) (III) undergoes an acyl hydrolysis reaction to give (S) -4- (8-amino) pyridazin-3-yl) pyrrolidine- (II) with (2) and (2) with 2 - butynoic acid to give Acalabrutinib1 (Ⅰ). Results and Conclusion The target product Acalabrutinib was obtained with a total yield of 2.25%