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Method for synthesizing (1R,2R)-(-)-N,N-dimethyl-1,2-cyclohexanediamine oxalate

A technology for the synthesis of cyclohexanediamine oxalate, which is applied in the field of -N, can solve the problems of limited preparation process, low preparation cost, and inability to scale production, and achieve cheap raw materials, short production time, and optimized post-processing The effect of craft

Inactive Publication Date: 2011-11-09
上海药明康德新药开发有限公司 +1
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0021] The object of the present invention is to provide a kind of effective preparation (1R, 2R)-(-)-N, the method for N-dimethyl-1,2-cyclohexanediamine oxalate, solve existing 1R, 2R)- (-)-N, N-dimethyl-1,2-cyclohexanediamine preparation technology is limited to laboratory preparation, the problem that scale production cannot be produced; this method of the present invention has the advantages of simple process, high yield and stable product characteristics; created a new (1R, 2R)-(-)-N, N-dimethyl-1,2-cyclohexanediamine salt preparation method - the preparation of oxalate, and this The method is realized in industrialization, and a kind of (1R, 2R)-(-)-N, N-dimethyl-1,2-cyclohexanediamine oxalate with higher overall yield and lower preparation cost is provided. Industrial preparation method

Method used

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  • Method for synthesizing (1R,2R)-(-)-N,N-dimethyl-1,2-cyclohexanediamine oxalate
  • Method for synthesizing (1R,2R)-(-)-N,N-dimethyl-1,2-cyclohexanediamine oxalate
  • Method for synthesizing (1R,2R)-(-)-N,N-dimethyl-1,2-cyclohexanediamine oxalate

Examples

Experimental program
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example 1

[0030] (1R,2R)-(-)-N,N-Dimethyl-1,2-cyclohexanediamine oxalate

[0031] The first step (amidation): Add 100 g of the raw material to 750 mL of dichloromethane and 500 mL of 13% sodium hydroxide solution at room temperature, then cool it down to 0-10°C, add 75 g of methyl chloroformate dropwise, and react at room temperature for 1-4 hours. Add 100mL of water and 500mL of dichloromethane in turn, static layering, wash the organic layer once with 600mL of water, concentrate the organic layer to 300-400mL, add 1L of n-heptane, concentrate to 300-400mL, then add 1L of n-heptane , concentrated to 300-400 mL, the concentrated solution was stirred at room temperature for 10-12 h, filtered and rinsed once with 100-200 mL of n-heptane, and the solid intermediate A (83 g, 95%) was vacuum-dried.

[0032] The second step (reduction): Add 68g of lithium aluminum tetrahydrogen in batches to 600mL of anhydrous tetrahydrofuran at 0~10°C, stir for 10min, then slowly add a solution of 83g of int...

example 2

[0034] (1R,2R)-(-)-N,N-Dimethyl-1,2-cyclohexanediamine oxalate

[0035] The first step (amidation): Add 100g of raw material to 750mL of dichloromethane and 500mL of 13% sodium hydroxide solution at room temperature, then cool it down to 0-10°C, add 75g of methyl chloroformate dropwise, and react at room temperature for 1-4h , add 100mL of water and 500mL of dichloromethane in turn, static layering, wash the organic layer once with 600mL of water, concentrate the organic layer to 300-400mL, add 1L of n-heptane, concentrate to 300-400mL, then add 1L of n-heptane Alkanes, concentrated to 300-400mL, the concentrated solution was stirred at room temperature for 10-12h, filtered and rinsed once with 100-200mL of n-heptane, and the solid intermediate A (83g, 95%) was vacuum-dried.

[0036] The second step (reduction): Add 82g of lithium aluminum tetrahydrogen in batches to 600mL of anhydrous tetrahydrofuran at 0~10°C, stir for 10min, then slowly add a solution of 83g of intermediate...

example 3

[0038] (1R,2R)-(-)-N,N-Dimethyl-1,2-cyclohexanediamine oxalate

[0039]The first step (amidation): Add 750mL of dichloromethane and 500mL of 13% sodium hydroxide solution to the raw material at room temperature, then cool it down to 0-10°C, add 75g of methyl chloroformate dropwise, react at room temperature for 1-4 hours, and then Add 100mL of water and 500mL of dichloromethane, keep the layers, wash the organic layer once with 600mL of water, concentrate the organic layer to 300-400mL, add 1L of n-heptane, concentrate to 300-400mL, then add 1L of n-heptane, Concentrated to 300-400 mL, the concentrated solution was stirred at room temperature for 10-12 h, filtered and rinsed with 100-200 mL of n-heptane once, and solid intermediate A (83 g, 95%) was vacuum-dried.

[0040] The second step (reduction): Add 68g of lithium aluminum tetrahydrogen in batches to 600mL of anhydrous tetrahydrofuran at 0~10°C, stir for 10min, then slowly add a solution of 83g of intermediate A dissolved...

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Abstract

The invention relates to a method for synthesizing (1R,2R)-(-)-N,N-dimethyl-1,2-cyclohexanediamine oxalate, and solves the problem that the conventional preparation process for the (1R,2R)-(-)-N,N-dimethyl-1,2-cyclohexanediamine is limited to laboratorial preparation and cannot be produced on a large scale. The synthesis method comprises the following two steps of: 1, performing amidation reaction on trans-1,2-diaminocyclohexane and methylclhlorofonmate to obtain an intermediate A; and 2, performing reduction reaction on the intermediate A by using lithium aluminum hydride to obtain (1R,2R)-(-)-N,N-dimethyl-1,2-cyclohexanediamine free alkali, quenching the reduction reaction, concentrating filtrate of (1R,2R)-(-)-N,N-dimethyl-1,2-cyclohexanediamine free alkali, extracting the free alkali, forming salt with oxalate dissolved in a mixed solvent to obtain the stable (1R,2R)-(-)-N,N-dimethyl-1,2-cyclohexanediamine oxalate. The obtained (1R,2R)-(-)-N,N-dimethyl-1,2-cyclohexanediamine oxalate is an important ligand in pharmaceutical chemistry and asymmetric catalysis.

Description

Technical field: [0001] The invention relates to a preparation method of (1R,2R)-(-)-N,N-dimethyl-1,2-cyclohexanediamine. In particular, it relates to an industrial preparation method of (1R,2R)-(-)-N,N-dimethyl-1,2-cyclohexanediamine oxalate. Background technique: [0002] (1R,2R)-(-)-N,N-Dimethyl-1,2-cyclohexanediamine is a very important chiral ligand in medicinal chemistry and asymmetric catalysis, due to its superior catalytic activity And enantioselectivity, more and more people's attention, generally all is to prepare liquid free amine, so far there is no method for preparing this product oxalate, especially industrial preparation. [0003] For the preparation of (1R,2R)-(-)-N,N-dimethyl-1,2-cyclohexanediamine, the representative methods reported in the literature mainly include the following two. [0004] ●Method 1: Use 7-oxo-bicyclo[4.1.0]n-n-heptane as the starting material, react with aqueous methylamine solution, reflux, extract with ether, and distill to obtai...

Claims

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Application Information

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IPC IPC(8): C07C211/36C07C209/28C07C55/07C07C51/41
Inventor 刘淼秀贾默李在兴曾伟鹏黄平陈曦陈民章唐苏翰
Owner 上海药明康德新药开发有限公司
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