| 第 50 卷第 3 期 |  | Vol. 50 No. 3 | | 2020 年 6 月 | Jun 2020 |
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所屬欄目：醫藥及中間體
2-叔丁氧羰基-9-乙氧羰基-2，7-二氮雜-螺［4.4］壬烷的合成 |
| 胡 濤，梁慧興，朱曉鶴
（揚子江藥業(yè)集團有限公司，江蘇 泰州 225321） |
| 摘 要：報道了2-叔丁氧羰基-9-乙氧羰基-2，7-二氮雜-螺［4.4］壬烷的合成方法，即以甘氨酸乙酯鹽酸鹽（1）為起始原料，與丙烯酸乙酯（2）經(jīng)邁克爾加成、Boc保護和分子內迪克曼縮合生成3-乙氧羰基-4-吡咯酮（5a）和2-乙氧羰基-3-吡咯酮（5b）后，經(jīng)Krapcho脫羧反應生成N-Boc-3-吡咯酮（6），隨后與磷酰乙酸三乙酯經(jīng)Witting-Horner-Emmons反應生成α，β-不飽和羧酸乙酯（7），再經(jīng)［1，3］-偶極環(huán)加成反應生成螺環(huán)雙吡咯烷（8），最后經(jīng)氫解脫去芐基等7步反應得到標題化合物2-叔丁氧羰基-9-乙氧羰基-2，7-二氮雜-螺［4.4］壬烷（TM），總收率為11%，中間體和目標產(chǎn)物結構經(jīng)1H NMR和MS確證。 |
| 關(guān)鍵詞：甘氨酸乙酯；迪克曼縮合；Witting-Horner-Emmons反應；［1，3］-偶極環(huán)加成；螺環(huán)吡咯烷 |
| 中圖分類(lèi)號：TQ463 文獻標識碼：A 文章編號：1009-9212（2020）03-0039-05 |
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| 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 |
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作者簡(jiǎn)介：胡 濤（1975-），男，河南信陽(yáng)人，高級工程師，博士，主要從事藥物合成及工藝開(kāi)發(fā)研究（E-mail：hutao@yangzijiang.com）。
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收稿日期：2020-01-10
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