陈会来,李勤,郝希霖,代庆海,贾娴
CHEN Hui-lai,LI Qin,HAO Xi-lin,DAI Qing-hai,JIA Xian(School of Pharmaceutical Engineering

• 1:沈阳药科大学制药工程学院

摘要(Abstract)：

目的研究合成非磺酰脲类促胰岛素分泌剂瑞格列奈的关键中间体(S)-(+)-3-甲基-1-[2-(1-哌啶基)苯基]丁胺的合成工艺。方法以邻氟苯甲醛(1)为起始原料,首先与盐酸羟胺反应生成邻氟苯甲醛肟(2),再经脱水生成邻氟苯腈(3),然后与哌啶进行胺解反应生成邻哌啶基苯腈(4),再与溴代异丁基镁进行格氏反应生成亚胺衍生物(5),最后经硼氢化钠还原生成消旋伯胺(6),经与N-乙酰-L-谷氨酸成盐、拆分、氢氧化钠水解得到目标产物S-(6)。结果以邻氟苯甲醛为起始原料,经6步反应合成了(S)-(+)-3-甲基-1-[2-(1-哌啶基)苯基]丁胺,总收率达15.4%,目标产物结构经ESI-MS、1H-NMR确证。结论本合成方法原料易得,反应条件温和,适合大规模制备。
Objective To synthesize(S)-(+)-3-methyl-[2-(1-piperidinyl)phenyl]butylamine,the key chiral intermediate for the preparation of(S)-repaglinide-an insulin promoting secretion agent.Methods o-Fluoro benzaldehyde(1)was reacted with hydroxylamine hydrochloride to give o-fluorobenzaldoxime(2),followed by the treatment with acetic anhydride to give 2-fluorocyanobenzene(3),which was reacted with piperidine to provide 2-(1-piperidinyl)cyanobenzene(4),and then proceeding Grignard reaction with i-butyl magnesium bromide to afford imine(5),which was followed by reduction reaction with sodium borohydride to give the racemic mixture,then the racemic was saltified with N-acetyl-L-glutamic acid and the resolution procedure was carried out in the mixed-solvents of actetone-methanol,followed by hydrolysis reaction with sodium hydroxide to yield the target S-(6).Results(S)-(+)-3-methyl-[2-(1-piperidinyl)phenyl]butylamine was synthesized through a six-step procedure in a overall yield of 15.4%,and the structure of the target compound was identified by ESI-MS and 1H-NMR.Conclusions The easy availability of the reactants,facile reaction conditions and convenient operation procedures made the process a promising prospect for application in large-scale manufacture.

关键词(KeyWords)： 瑞格列奈;中间体;(S)-(+)-3-甲基-1-[2-(1-哌啶基)苯基]丁胺;合成
repaglinide;intermediate;(S)-(+)-3-methyl-[2-(1-piperidinyl)phenyl]butylamine;synthesis

Abstract:

Keywords:

基金项目(Foundation): 辽宁省自然科学基金资助项目(20102215);; 沈阳市手性药物生物催化合成重点实验室建设资助项目(F11-243-1-00);; 辽宁省教育厅基金资助项目(L2011173)

作者(Author): 陈会来,李勤,郝希霖,代庆海,贾娴
CHEN Hui-lai,LI Qin,HAO Xi-lin,DAI Qing-hai,JIA Xian(School of Pharmaceutical Engineering

DOI: 10.14066/j.cnki.cn21-1349/r.2012.06.008

参考文献(References)：

• [1]郑虎.药物化学[M].6版.北京:人民卫生出版社,2007:354-355.
• [2]李凌维,田东钦.瑞格列奈的疗效研究[J].中国医药指南,2011,9(6):74.
• [3]韩晓风.瑞格列奈治疗2型糖尿病的临床观察[J].临床合理用药,2011,4(2B):40-41.
• [4]KALKOTE U R,GURJAR M K,JOSHI S V,et al.Process for preparing(RS)3-methyl-[(2-piperidinyl)phenyl]butylamine:US,20040192921 A1[P].2004-09-30.
• [5]唐鹤,李美玉,王礼权,等.瑞格列奈的合成[J].中国医药工业杂志,2008,39(10):727-730.
• [6]GRELL W,HUMAUS R,GRISS G,et al.Repaglinideand related hypoglycemic benzoic acid derivatives[J].J Med Chem,1998,41(26):5219-5246.
• [7]赵爽,徐志炳,王恩思,等.抗糖尿病药物瑞格列奈的合成[J].吉林大学学报:理学版,2008,46(3):556-559.
• [8]ALDRICH.Catalog Handbook of Fine Chemicals[M].Wisconsin:Sigma-Aldrich Co,1998-1999:831.
• [9]陈红飙,林原斌.邻氟苯丙酮的合成研究[J].中国药物化学杂志,2002,12(1):30-33.