Preparation method of 2-trifluoromethyl-1-carbobenzoxy-1-aza-cyclane

An azacycloalkane and benzyloxycarbonyl technology is applied in the field of preparation of 2-trifluoromethyl-1-benzyloxycarbonyl-1-azacycloalkane, and can solve the problems of low yield, unsuitability for amplification, α- Problems such as long steps to replace azacycloalkanes, to achieve the effects of low yield, improved drug-like properties, and increased yield

Active Publication Date: 2013-05-01
武汉药明康德新药开发有限公司
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  • Abstract
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  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The method prepares α-substituted azacycloalkane with long steps and low yield, especially for azepane yield as low as 10%
Therefore, this method is not suitable for the amplification of the reaction and has considerable limitations.

Method used

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  • Preparation method of 2-trifluoromethyl-1-carbobenzoxy-1-aza-cyclane
  • Preparation method of 2-trifluoromethyl-1-carbobenzoxy-1-aza-cyclane
  • Preparation method of 2-trifluoromethyl-1-carbobenzoxy-1-aza-cyclane

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] Example 1 : 2-oxa-benzyloxycarbonyl cycloheptylamine 2c preparation

[0020]

[0021] Steps:

[0022] Under nitrogen protection, add compound cycloheptamide in a dry three-necked flask 1c (20 g, 0.23 mol) and tetrahydrofuran (200 mL), slowly added n-butyllithium (94 mL, 0.23 mol, 2.5 M n-hexane solution) under a dry-ice acetone bath. The reaction solution was stirred at -78°C for 60 minutes, and then a solution of benzyl chloroformate (40 g, 0.23 mol) in THF (50 mL) was slowly added. Slowly rise to room temperature and stir for 10 hours, quench with saturated aqueous ammonium chloride, extract with ethyl acetate, and dry and concentrate the organic phase to obtain 53 grams of product 2-oxa-benzyloxycarbonyl cycloheptylamine 2c , the yield is 100%. used directly in the next reaction.

Embodiment 2

[0023] Example 2 : 2-oxa-1-benzyloxycarbonylpyrroline 2a preparation

[0024] When n=1, the operation is the same as in Example 1. The yield is 100%. used directly in the next reaction.

Embodiment 3

[0025] Example 3 : 2-oxa-1-benzyloxycarbonylpiperidine 2b preparation

[0026] When n=2, the operation is the same as in Example 1. The yield is 70%. used directly in the next reaction.

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Abstract

The invention discloses a preparation method of 2-trifluoromethyl-1-carbobenzoxy-1-aza-cyclane, and mainly solves the problems that the step of the preparation of alpha-position trifluoromethyl aza-cyclane is long, the yield is low, and the like. The method comprises the steps that aza-cyclane-2-ketone is taken as starting material; the starting material is conducted to Cbz protection, so as to obtain 2-oxa-1-carbobenzoxy-1-aza-cyclane; the 2-oxa-1-carbobenzoxy-1-aza-cyclane is reacted with trifluoromethylation reagent, so as to obtain 2-hydroxy-2-trifluoromethyl-1-carbobenzoxy-1-aza-cyclane; and the compound is conducted to hydrogenation deprotection, so as to obtain the 2-trifluoromethyl-1-carbobenzoxy-1-aza-cyclane. The overall yield is 13 to 35.8 percent.

Description

technical field [0001] The invention relates to a preparation method of 2-trifluoromethyl-1-benzyloxycarbonyl-1-azacycloalkane. Background technique [0002] Nitrogen-α-substituted azacycloalkanes are an important class of nitrogen-containing heterocyclic rings. Except some exist in natural products, they are also useful groups for constructing a wide variety of biological activities. This type of heterocycle has the characteristics of many alkaloids, and many literatures have reported that compounds containing this type of heterocycle have been studied clinically or preclinically. This type of compound is a class of molecules with a relatively special structure, which can effectively link and integrate key pharmacophore units into its rigid structure to form molecules with special spatial configurations / conformations, which can match the different biomacromolecules in the organism. Spatial structure, resulting in different biological activities or utility. So far, there a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/08C07D211/18C07D223/04
Inventor 公衍之刘德军段建军董径超吴颢马汝建陈曙辉林寿忠
Owner 武汉药明康德新药开发有限公司
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