盐酸伊伐布雷定关键手性中间体的新合成方法  

New Synthesis of the Key Chiral Intermediate of Ivabradine Hydrochloride

作　　者：霍领雁 张洒洒 贾海军 时江华 张贵民 HUO Lingyan;ZHANG Sasa;JIA Haijun;SHI Jianghua;ZHANG Guimin(National Engineering and Technology Research Center of Chirality Pharmaceutical,Lunan Pharmaceutical Group Co.,Ltd.,Linyi 273400)

机构地区：[1]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》2020年第10期1266-1270,共5页Chinese Journal of Pharmaceuticals

摘　　要：本研究报道了盐酸伊伐布雷定关键手性中间体(S)-4,5-二甲氧基-1-氰基苯并环丁烷(1)的新合成方法。以3,4-二甲氧基苯乙酸(2)为原料,经碘代、酰胺化、环合得3,4-二甲氧基双环[4.2.0]辛-1,3,5-三烯-7-酮(5),5在(S)-1-甲基-3,3-二苯基-1H,3H-四氢吡咯并[1,2-c][1.3.2]噁唑硼烷的催化下,与N,N-二乙基苯胺硼烷反应得到(R)-3,4-二甲氧基双环[4.2.0]辛-1,3,5-三烯-7-醇(6)。6与三甲基氰基硅烷反应得构型翻转的目标产物1,纯度99.85%,ee 99.32%。本研究利用不对称合成的方法得到了尚未见文献报道的化合物6。该法反应条件温和,所得产物手性纯度高,总收率75%(以2计)。A new synthesis of(S)-4,5-dimethoxy-1-cyanobenzocyclobutane(1),the key chiral intermediate of ivabradine hydrochloride,was developed in this report.3,4-Dimethoxyphenylacetic acid was used as starting material to synthesize 3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-one(5)by iodination,amidation and cyclization.Compound 5 reacted with N,N-diethylanilineborane in the presence of(S)-1-methyl-3,3-diphenyltetrahydro-1H,3H-pyrrolo[1,2-c]-[1,3,2]oxazaborole as catalyst to obtain(R)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-ol(6).Compound 6 reacted with trimethylsilyl cyanide to give 1 with inversion of configuration,in a purity of 99.85%and ee value of 99.32%.In this paper,compound 6 was obtained by asymmetric synthesis which had not been reported in literature.This process had mild reaction conditions,by which the final product was obtained with high ee value and the total yield of 75%(based on 2).

关 键 词：盐酸伊伐布雷定 中间体 手性 不对称合成 

分 类 号：R914.5[医药卫生—药物化学]