莫扎伐普坦的合成工艺研究  

Improved synthesis of mozavaptan

作　　者：刘杨[1] 骆伟[1] 孙厉[1] 夏正君 郭春[1] 

机构地区：[1]沈阳药科大学基于靶点的药物设计与研究教育部重点实验室,辽宁沈阳110016 [2]江苏亚邦药业集团技术中心,江苏金坛213200

出　　处：《中国药物化学杂志》2011年第2期130-133,共4页Chinese Journal of Medicinal Chemistry

摘　　要：目的研究莫扎伐普坦的合成工艺。方法以邻氨基苯甲酸甲酯为起始原料,经N-磺酰化、烃化、环合、脱羧、N-甲基化、还原胺化等反应制得关键中间体8;以对氨基苯甲酸甲酯为原料,经N-酰化、酯水解和酰氯化制得另一中间体11;8与11于丙酮中反应制得目标化合物。结果与结论目标化合物的结构经1H-NMR、M S等确证。总收率达14.2%(以邻氨基苯甲酸甲酯计)。该路线操作简便,条件温和,有利于工业应用。Mozavaptan（1）,a new type of vasopressin V2 receptor antagonist,has been used for the treatment of hyponatremia caused by heart failure with good efficiency and reliability.A confluent synthetic route was designed and used to prepare the target compound in this paper.The key intermediate 8,5-N,N-dimethylamino-2,3,4,5-tetrahydro-1H-benzazepine,was synthesized via N-sulfonic acylation,alkylation,cyclization,decarboxylation,N-methylation and reduction amination starting from methyl anthranilate.Another key intermediate 11,4-（2-methylbenzoylamino） benzoyl chloride,was synthesized from methyl p-aminobenzoate via N-acylation,ester hydrolysis and chlorination.Then 8 was reacted with 11 in acetone to give target compound and the overall yield was 14.2%（based on methyl anthranilate）.The structure of the target compound was identified by 1H-NMR and MS.In this improved procedure,the yield of intermediate 3,γ-N-（2-methoxycarbonylphenyl）-N-（4-methylbenzenesulfonylamino） buterate,was increased by 16%,intermediate 6,5-N-methylamino-1-（4-methylbenzenesulfonyl）-2,3,4,5-tetrohydro-1H-benzazepine,was synthesized in a shortened reaction time by adding a catalytic amount of toluenesulfonic acid and intermediate 7,5-N,N-dimethylamino-1-（4-methylbenzenesulfonyl）-2,3,4,5-tetrahydro-1H-benzazepine,was obtained at a lower reaction temperature without any by-product almost.This improved synthetic process has the advantages of mild reaction conditions,relatively convenient operation procedures and being suitable for industrial application.

关 键 词：莫扎伐普坦 血管加压素V2受体拮抗剂 化学合成 工艺改进 

分 类 号：TQ463.2[化学工程—制药化工]