2-叔丁氧羰基-9-乙氧羰基-2,7-二氮杂-螺[4.4]壬烷的合成  

Synthesis of 2-tert-Butoxycarbonyl-9-ethoxycarbonyl-2,7-diaza-spiro[4.4]nonane

作　　者：胡涛[1] 梁慧兴[1] 朱晓鹤[1] HU Tao;LIANG Hui-xing;ZHU Xiao-he(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3期39-43,共5页Fine Chemical Intermediates

摘　　要：报道了2-叔丁氧羰基-9-乙氧羰基-2,7-二氮杂-螺[4.4]壬烷的合成方法,即以甘氨酸乙酯盐酸盐(1)为起始原料,与丙烯酸乙酯(2)经迈克尔加成、Boc保护和分子内迪克曼缩合生成3-乙氧羰基-4-吡咯酮(5a)和2-乙氧羰基-3-吡咯酮(5b)后,经Krapcho脱羧反应生成N-Boc-3-吡咯酮(6),随后与磷酰乙酸三乙酯经Witting-Horner-Emmons反应生成α,β-不饱和羧酸乙酯(7),再经[1,3]-偶极环加成反应生成螺环双吡咯烷(8),最后经氢解脱去苄基等7步反应得到标题化合物2-叔丁氧羰基-9-乙氧羰基-2,7-二氮杂-螺[4.4]壬烷(TM),总收率为11%,中间体和目标产物结构经~1H NMR和MS确证。A synthetic approach of 2-tert-butoxycarbonyl-9-ethoxycarbonyl-2,7-diaza-spiro[4.4]nonane was reported.After the Michael-Addition product(1)prepared from glycineethylester hydrochloride and ethyl acrylate was protected by Boc group,the intramolecular Dieckmann Condensation of compound 4 gave a mixture of 3-ethoxycarbonyl-4-oxopyrrolidine(5a)and 2-ethoxycarbonyl-3-oxopyrrolidine(5b),which afforded N-Boc-3-oxopyrrolidine(6)by Krapcho Decarboxylation.The following Witting-Horner-Emmons reaction of compound(6)with triethyl phosphonoacetate provided a mixture ofα,β-unsaturated ethyl carboxylate(Z and E)with a yield of 92%,which gave spirocyclic bispyrrolidine(7)via 1,3-dipolar cycloaddition.The final hydrogenolysis debenzylation afforded titled compound TM with an overall yield of 11%.The related intermediates and compounds were confirmed by^1H NMR and MS.

关 键 词：甘氨酸乙酯 迪克曼缩合 Witting-Horner-Emmons反应 [1 3]-偶极环加成 螺环吡咯烷 

分 类 号：TQ463[化学工程—制药化工]