第 50 卷第 3 期 Vol. 50 No. 3 2020 年 6 月 Jun 2020

所属栏目：医药及中间体 2-叔丁氧羰基-9-乙氧羰基-2，7-二氮杂-螺［4.4］壬烷的合成

胡 涛，梁慧兴，朱晓鹤 （扬子江药业集团有限公司，江苏 泰州 225321）

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。

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

中图分类号：TQ463　　文献标识码：A　　文章编号：1009-9212（2020）03-0039-05

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

HU Tao, LIANG Hui-xing, ZHU Xiao-he (Yangtze River Pharmaceutical Group Co., Ltd., Taizhou 225321, China)

Abstract：A synthetic approach of 2-tert-butoxycarbonyl-9-ethoxycarbonyl-2,7-diaza-spiro[4.4] nonane was reported. After the Michael-Addition product 3 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 of α, 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.

Key words：glycineethylester Dieckmann Condensation; Witting-Horner-Emmons reaction; 1,3-dipolar cycloaddition; spirocyclic pyrrolidines

作者简介：胡 涛（1975-），男，河南信阳人，高级工程师，博士，主要从事药物合成及工艺开发研究（E-mail：hutao@yangzijiang.com）。

收稿日期：2020-01-10