2,7-二氮杂-螺[3,5]壬烷-2-甲酸叔丁酯的合成  

Synthesis of 2,7-Diaza-spiro[3,5]nonane-2-carboxylic acid tert-butyl ester

作　　者：胡涛[1] 梁慧兴[1] 罗宏军 HU Tao;LIANG Hui-xing;LUO Hong-jun(Yangtze River Pharmaceutical Group Co.,Ltd.,Taizhou,225321,China)

机构地区：[1]扬子江药业集团有限公司,江苏泰州225321

出　　处：《精细化工中间体》2020年第2期41-44,共4页Fine Chemical Intermediates

摘　　要：报道了2,7-二氮杂-螺[3,5]壬烷-2-甲酸叔丁酯一种新的合成方法。以双(2-氯乙基)胺盐酸盐(1)为起始原料,经氮苄基化后与氰乙酸乙酯双烷基化生成4,4-双取代的N-苄基哌啶(3),哌啶甲酸乙酸酯(3)经硼氢化钠还原成羟基化合物(4),随后对甲苯磺酰化成磺酸酯(5),氰基经氢化铝锂还原后发生分子内协同反应环化成2-氮杂螺环丁烷(6),经与二碳酸叔丁酯反应生成2-N-Boc产物(7),最后氢解脱去苄基等7步反应得到标题化合物2,7-二氮杂-螺[3,5]壬烷-2-甲酸叔丁酯,总收率为36%,1H NMR和MS确证了中间体和目标产物结构。A novel synthetic approach of 2,7-diaza-spiro[3,5]nonane-2-carboxylic acid tert-butyl ester was described.N-Benzylation product 2 of bis(2-chloroethyl)amine hydrochloride 1 was reacted with ethyl 2-cyanoacetate,giving 1-benzyl-4-cyano-4-ethoxycarbonylpiperidine 3.This ester was reduced into alcohol 4 with sodium tetrahydroborate and the following sulfonylation with 4-methylbenzenesulfonyl chloride provided Tos product 5.The subsequent reduction with lithium aluminum hydride gave intra-cyclized aztidine 6,followed by Boc carboxylation and hydrogenolysis debenzyl afforded titled compound TM with an overall yield of 36%.The related intermediates and compounds were confirmed by 1H NMR and MS.

关 键 词：双(2-氯乙基)胺 氰乙酸乙酯 硼氢化钠 氢化铝锂 氮螺杂环丁烷 

分 类 号：TQ463[化学工程—制药化工]