盐酸伊伐布雷定有关物质的合成

Synthesis of the Related Substances of Ivabradine Hydrochloride

为有效控制盐酸伊伐布雷定的质量,基于其合成工艺,制备了5种有关物质:7,8-二甲氧基-3-丙基-1,3-二氢-2H-苯并[d]氮?-2-酮(有关物质A)、3-烯丙基-7,8-二甲氧基-1,3-二氢-2H-苯并[d]氮?-2-酮(有关物质B)、3,3’-(丙烷-1,3-二基)双(7,8-二甲氧基-1,3-二氢-2H-苯并[d]氮?-2-酮)(有关物质C)、(S)-[2-[2-[[3-[[[3,4-二甲氧基二环[4.2.0]辛-1(6),2,4-三烯-7-基]甲基](甲基)氨基]丙基]氨基]乙基]-4,5-二甲氧基苯基]乙酸(有关物质D)及3-(7,8-二甲氧基-2-氧代-1,2,4,5-四氢-3H-苯并[d]氮?-3-基)-N-[[(S)-3,4-二甲氧基双环[4.2.0]八-1(6),2,4-三烯-7-基]甲基]-N-甲基丙烷-1-胺氧化物(有关物质E)。结构均经由MS和;H NMR确证,其中有关物质A和B未见文献报道。

In order to control the quality of ivabradine hydrochloride,five related substances were prepared:7,8-dimethoxy-3-propyl-1,3-dihydro-2H-benzo[d]azepin-2-one(related substance A),3-allyl-7,8-dimethoxy-1,3-dihydro-2H-benzo[d]azepin-2-one(related substance B),3,3’-(propane-1,3-diyl)bis(7,8-dimethoxy-1,3-dihydro-2H-benzo[d]-azepin-2-one)(related substance C),(S)-[2-[2-[[3-[[[3,4-dimethoxybicyclo[4.2.0]octa-1(6),2,4-trien-7-yl]methyl]-(methyl)amino]propyl]amino]ethyl]-4,5-dimethoxyphenyl]acetic acid(related substance D),3-(7,8-dimethoxy-2-oxo-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)-N-[[(S)-3,4-dimethoxybicyclo[4.2.0]octa-1(6),2,4-triene-7-yl]methyl]-N-methylpropan-1-amine oxide(related substance E).The structures were confirmed by MS and ~1H NMR.Among them,both related substance A and B have not found in literature.