罗拉匹坦关键中间体的合成工艺改进  

Improved Synthetic Process of the Key Intermediate of Rolapitant

作　　者：秦若松 肖国荣 张连第 QIN Ruosong;XIAO Guorong;ZHANG Liandi(School of Pharmacy,Xuzhou Medical University,Xuzhou 221004;Jiangsu Fspharm Ltd.,Nanjing 210033)

机构地区：[1]徐州医科大学药学院,江苏徐州221004 [2]江苏福锌雨医药科技有限公司,江苏南京210033

出　　处：《中国医药工业杂志》2023年第8期1193-1197,共5页Chinese Journal of Pharmaceuticals

摘　　要：N-苄氧羰基-L-苯甘氨酸(2)与苯甲醛二甲缩醛缩合,得(2R,4S)-5-氧代-2,4-二苯基噁唑烷-3-羧酸苄酯(3),将原路线中异丙醚更换成乙腈作为反应溶剂,无需二次反应和打浆,简化了操作,缩短了生产周期。3经取代、还原反应,得(2R,4S)-4-[[(R)-1-[3,5-双(三氟甲基)苯基]乙氧基]甲基]-5-羟基-2,4-二苯基唑烷-3-羧酸苄酯(5)。替换原路线经水解再进行Wittig反应的方法,利用半缩醛与醛的平衡,5直接与溴甲烷三苯基膦盐(叶立德试剂)进行“一锅法”Wittig反应,得[(S)-1-[(R)-1-[3,5-双(三氟甲基)苯基]乙氧基]-2-苯基丁-3-烯-2-基]氨基甲酸苄酯(7),收率由54%提高至90%(以5计),同时反应时间由24 h缩至6 h。7经氨基脱保护、成盐,生成罗拉匹坦关键中间体(S)-1-[(R)-1-[3,5-双(三氟甲基)苯基]乙氧基]-2-苯基丁-3-烯-2-胺马来酸盐(1)。优化后的工艺总收率达59%,纯度99.8%,更适合工业化生产。Benzyl(2R,4S)-5-oxo-2,4-diphenyloxazolidine-3-carboxylate(3)was obtained from N-carbobenzoxy-L-phenylglycine(2)by substitution with benzadehyde dimethyl acetal.In this reaction,acetonitrile was used as the reaction solvent instead of di-isopropyl ether in the original literature,which greatly simplified the operation and shortened the reaction time.Benzyl(2R,4S)-4-[[(R)-1-[3,5-bis(trifiuoromethyl)phenyl]ethoxy]methyl]-5-hydroxy-2,4-diphenyloxazolidine-3-carboxylate(5)was generated by substitution and reduction of compound 3.Compound 5,without hydrolysis,reacted directly with methyl bromide triphenylphosphine salt(Ylide reagent)in the"one pot"Wittig reaction to generate benzyl[(S)-1-[(R)-1-[3,5-bis(trifiuoromethyl)phenyl]ethoxy]-2-phenylbut-3-en-2-yl]carbamate(7).This reaction increased the yield from 54%to 90%,and shorted the reaction time from 24 h to 6 h.After amino deprotection and salt production,the key intermediate of rolapitant,(S)-1-[(R)-1-[3,5-bis(trifiuoromethyl)-phenyl]ethoxy]-2-phenylbutyl-3-en-2-amine maleate(1)was obtained with the overall yield of 59%and the purity of 99.8%.The improved process was more suitable for industrial application.

关 键 词：神经激肽-1受体抑制剂 罗拉匹坦 中间体 合成 

分 类 号：R979.1[医药卫生—药品] TQ460.6[医药卫生—药学]