硼替佐米合成工艺改进  

Improved Synthetic Process of Bortezomib

作　　者：刘灿寅 文浩 祝士国 张乃华 张贵民 LIU Canyin;WEN Hao;ZHU Shiguo;ZHANG Naihua;ZHANG Guimin(Xiangya School of Pharmaceutical Sciences,Central South University,Changsha 410013;National Engineering and Technology Research Center of Chirality Pharmaceutical,Lunan Pharmaceutical Group Co.,Ltd.,Linyi 273400)

机构地区：[1]中南大学湘雅药学院,湖南长沙410013 [2]鲁南制药集团股份有限公司,国家手性制药工程技术研究中心,山东临沂273400

出　　处：《中国医药工业杂志》2025年第2期181-186,共6页Chinese Journal of Pharmaceuticals

摘　　要：以异戊醛(14)和(R)-(+)-叔丁基亚磺酰胺(15)为原料,经缩合反应得希夫碱(16)。随后,联硼酸频哪醇酯(B2Pin2)在五水硫酸铜和三环己基膦四氟硼酸盐的催化下,与16选择性加成得频哪醇(R)-1-(R)-叔丁基亚磺酰胺基-3-甲基丁基硼酸酯(17),再经氯化氢-乙酸乙酯溶液脱保护后,得关键中间体(R)-1-氨基-3-甲基丁烷-1-硼酸频哪醇酯盐酸盐(2)。以L-苯丙氨酸(4)为另一起始原料,与2-甲酸吡嗪(5)缩合得N-(2-吡嗪基羰基)-L-苯丙氨酸(12)。12与2缩合得[(1R)-3-甲基-1-[[(2S)-1-氧代-3-苯基-2-[(吡嗪基羰基)氨基]丙基]氨基]丁基]频哪醇硼酸酯(18),18经酯交换反应脱保护后,得目标产物硼替佐米(1)。总收率62%(以15计),液相纯度>99.7%。该路线通过经济易得、合成难度较小的2来构建手性α-氨基硼酸C片段,且省略了烦琐的柱色谱分离操作,同时使用甲基硼酸替代异丁基硼酸,可有效降低成本。Schiff base(16) was obtained from isovaleraldehyde(14) and (R)-(+)-2-methyl-2-propanesulfinamide(15)through condensation.Pinacol (R)-1-(R)-tert-butylsulfonamido-3-methylbutylborate(17) was synthesized byselective addition of bis(pinacolato)diboron(B_2Pin_2) and 16 in the presence of copper(Ⅱ) sulfate pentahydrate andtricyclohexylphosphonium tetrafluoroborate,and then the deprotection with ethyl acetate solution of hydrogen chloride afforded the key intermediate (R)-1-amino-3-methylbutane-1-borate pinalol hydrochloride(2).N-(2-Pyrazinylcarbonyl)-L-phenylalanine(12) was synthesized from L-phenylalanine(4) and 2-pyrazinecarboxylic acid(5) via condensation.Compound 12reacted with 2 to generate[(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarboxy)amino]propyl]amino]butyl]-pinathol borate(18).Compound 18 was deprotected to obtain bortezomib(1) by transesterification reaction.The total yield of 1 was 62% (based on 15) with the purity more than 99.7%.In this route,the chiral α-aminoboronic acid C fragment was constructed from 2,which was inexpensive and easy to be synthesized,and some complicated column chromatography operations were eliminated.Meanwhile,utilization of methylboronic acid instead of isobutylboronic acid could effectively reduce costs.

关 键 词：硼替佐米 多发性骨髓瘤 合成 工艺改进 

分 类 号：R979.19[医药卫生—药品] TQ460.6[医药卫生—药学]