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Synlett 2003(13): 1965-1966  
DOI: 10.1055/s-2003-41488
LETTER
© Georg Thieme Verlag Stuttgart · New York

A Concise Synthesis of Gabapentin via Intramolecular C-CH Insertion Reaction

Zhenliang Chen, Zhiyong Chen, Yaozhong Jiang, Wenhao Hu*
Key Laboratory for Asymmetric Synthesis and Chirotechnology of Sichuan Province, Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, P. R. China
Fax: +86(28)85229250; e-Mail: huwh@cioc.ac.cn;
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Publication History

Received 29 July 2003
Publication Date:
08 October 2003 (online)

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Abstract

A concise and efficient synthesis of Gabapentin was achieved with an overall yield of 56% by 6 N HCl mediated hydrolysi­s of the corresponding g-lactam (6), obtained from the intramolecula­r C-CH insertion reaction of N-tert-butyl-N-cyclohexylmethy­l diazoacetamide (5) with 0.02 mol% Rh2(OAc)4 catalyst.

Key words

C-CH insertion - g-lactam - GABA - gabapentin

8

A General Procedure for Intramolecular C-CH Insertion Reaction of Diazoacetamide: To a solution of catalyst (1 mol%) in CH2Cl2 (10 mL) at reflux was added diazoacet-amide (5, 72 mg, 0.3 mmol) in CH2Cl2 (5 mL) via a syringe pump over a 2 h period. After addition of the diazoacetamide was complete, the reaction mixture was stirred for an additional 0.5 h, and then the solvent was removed under reduced pressure. Silica gel column chromatography [eluent: 20% EtOAc in petroleum ether (b.p. 60-90 °C)] afforded the C-CH insertion product 6 as a pale yellow oil. 1H NMR (CDCl3, 300 MHz): δ = 3.17 (s, 2 H), 2.20 (s, 2 H), 1.46-1.36 (m, 19 H). 13C NMR (CDCl3, 75 MHz): δ = 175.08, 68.70, 54.43, 37.42, 35.93, 28.48, 26.54, 26.38, 23.58. FT IR: 1686 (C=O) cm-1.; MS (EI): m/z = 209 [M+].