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Practical synthesis method of 3-benzyl-3-aza-bicyclo[2,1,0]hexane

A technology of azabicyclo and benzyl, applied in the field of practical synthesis of 3-benzyl-3-azabicyclo[2,1,0]hexane, which can solve troublesome post-processing, complicated operation, unsuitable issues of mass production

Inactive Publication Date: 2012-05-02
SUZHOU KANGRUN PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] The present invention develops a synthesis method of 3-benzyl-3-azabicyclo[2,1,0]hexane, which avoids the high cost, low yield, complicated operation and troublesome post-treatment of the existing route, and is not suitable for large-scale production. Disadvantages such as mass production

Method used

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  • Practical synthesis method of 3-benzyl-3-aza-bicyclo[2,1,0]hexane

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Embodiment 1

[0025] Step 1: Synthesis of N-benzyl-5-oxopyrrolidine-3-carboxylic acid methyl ester

[0026] Dissolve dimethyl itaconate (158 g, 1 mol) in 1200 ml of methanol and slowly add benzylamine (107 g, 1 mol). After the addition is complete, the reaction solution is stirred at room temperature overnight. The solvent is spin-dried to remove the residue The material was poured into petroleum ether and stirred, and the mixture was filtered to obtain a white solid of methyl N-benzyl-5-oxopyrrolidine-3-carboxylate (230 g, 98.7%).

[0027] 1 HNMR(400MHz, CDCl 3 ): 2.66-2.81(m, 2 H), 3.18-3.23 (m,1 H), 3.45-3.49 (m, 2 H), 3.70 (s, 3 H), 4.40-4.52(m, 2 H), 7.22-7.35 (m, 5 H).

[0028] Step 2: Synthesis of N-benzyl-4-hydroxymethylpyrrolidin-2-one

[0029] Methyl N-benzyl-5-oxopyrrolidine-3-carboxylate (100 g, 0.43 mol) was dissolved in 2000 ml of methanol and sodium borohydride (33 g, 0.86 mol) was added in portions. After the reaction is complete, add 10% HCl solution until the reaction solution i...

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Abstract

The invention relates to a practical synthesis method of 3-benzyl-3-aza-bicyclo[2,1,0]hexane. The method comprises the following synthesis processes of: condensing dimethyl itaconate, serving as a raw material, with benzylamine to obtain ester, and reducing to obtain alcohol; reacting the ester with methanesulfonyl chloride to generate methanesulfonyl ester; reacting the methanesulfonyl ester with lithium hexamethyl disilazide to obtain corresponding 3-benzyl-3-aza-bicyclo[2,1,0]hexane-2-one; and reducing by lithium aluminum hydride to obtain the 3-benzyl-3-aza-bicyclo[2,1,0]hexane. Due to the adoption of the method, the defects of low yield, complexity in operation, difficulty in post-treatment and amplification and the like in the conventional document process are overcome. The practical synthesis method of the 3-benzyl-3-aza-bicyclo[2,1,0]hexane provided by the invention has the advantages of simple synthesis route, reasonable process selection, low cost of the raw material, easiness in obtaining of the raw material, convenience for operation and post-treatment, high total yield, easiness in amplification, and application to large-scale production. In the method, the dimethyl itaconate serves as the raw material.

Description

technical field [0001] The invention relates to a practical synthesis method of 3-benzyl-3-azabicyclo[2,1,0]hexane. Background technique [0002] 3-Benzyl-3-azabicyclo[2,1,0]hexane is an important intermediate in organic synthesis, it can be obtained by catalytic hydrogenation of 3-azabicyclo[2,1,0] Hexane. The derivatives of 3-azabicyclo[2,1,0]hexane are good DP Ⅳ inhibitors, and DP Ⅳ inhibitors are good therapeutic drugs for cancer and metabolic diseases (WO2007054577). In recent years, it is one of the hotspots in the field of medicinal chemistry to search for some active screening drugs by linking 3-azabicyclo[2,1,0]hexane with some specific structures. Such research literature and patents are also Emerge in endlessly (J.M.C., 2005,48,5009; WO200433451; WO201045212; US200947252 etc. [0003] At present, the synthesis of 3-benzyl-3-azabicyclo[2,1,0]hexane is mainly through the condensation of methyl chloroacetate and methyl acrylate to generate cis dimethyl cyclomalonat...

Claims

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Application Information

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IPC IPC(8): C07D209/52
Inventor 徐卫良左兵徐炜政
Owner SUZHOU KANGRUN PHARMA
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