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Preparation method for trans 4-amino-cyclohexyl acetate derivative

A technology of cyclohexyl acetate and aminocyclohexanone, which is used in the preparation of pharmaceutical intermediates and the preparation of trans 4-amino-cyclohexyl ethyl ester derivatives, can solve the problem that cariprazine cannot meet pharmaceutical standards , purification of trans products and other issues, to achieve the effect of great application value, easy availability of raw materials and simple operation

Active Publication Date: 2017-04-19
ZHEJIANG JINGXIN PHARMA +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The inventors conducted experiments on this method, and the results showed that the obtained cyclohexylaminoacetic acid compounds were cis: trans = 3:7, and since the amino groups were all substituted, they could not be purified by salt formation to obtain qualified Trans product, so the raw material used in the preparation of cariprazine cannot meet the pharmaceutical standards: the preparation of cariprazine requires the finished product trans:cis at least 99.9:0.1, such a starting material is unsatisfactory

Method used

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  • Preparation method for trans 4-amino-cyclohexyl acetate derivative
  • Preparation method for trans 4-amino-cyclohexyl acetate derivative
  • Preparation method for trans 4-amino-cyclohexyl acetate derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Example 1 Preparation of trans 4-amino-cyclohexyl ethyl acetate hydrochloride

[0043]

[0044] 1L there-necked flask, add 450ml THF, nitrogen protection, ice bath, internal temperature down to 5°C, slowly add (45.0g, 0.39mol, 3.0eq) potassium tert-butoxide, stir to dissolve, dropwise add (45.0g, 0.2mol ,1.5eq) triethyl phosphoroacetate, the internal temperature is less than 10°C, after the addition is completed, rise to room temperature and stir for 0.5h, then add (14.7g, 0.13mol, 1.0eq) raw material 4-aminocyclohexanone II in batches, and react 2 hours until raw material disappears. Add 200ml of water, separate the layers, wash the organic phase with 100ml of saturated sodium chloride, dry over anhydrous sodium sulfate, and spin dry to obtain 24.2g of crude oily product of ethyl 4-amino-cyclohexyl ethylene acid, which is directly put into the next reaction.

[0045]

[0046] In a 1L single-mouth bottle, add the olefin product from the previous step (24.2g, calc...

Embodiment 2

[0048] Example 2 Preparation of trans-4-amino-cyclohexylacetic acid methyl ester hydrochloride

[0049]

[0050] 1L three-necked flask, add 50ml methyl tert-butyl ether, nitrogen protection, ice bath, the internal temperature dropped to 5 ℃, slowly add (1.14g, 14.3mmol, 1.1eq) lithium tert-butoxide, stir to dissolve, drop ( 2.6g, 14.3mol, 1.1eq) trimethyl phosphoacetate, the internal temperature is less than 10°C, after the addition is complete, raise to room temperature and stir for 0.5h, then add (1.47g, 13mmol, 1.0eq) raw material 4-aminocyclohexyl in batches Ketone II, react for 2.5 hours until the raw material disappears. Add 50ml of water, separate the layers, wash the organic phase with 50ml of saturated sodium chloride, dry over anhydrous sodium sulfate, and spin dry to obtain 2.2g of crude oily product of 4-amino-cyclohexylethylene acid methyl ester, which is directly put into the next reaction.

[0051]

[0052] 1L single-necked bottle, add the olefin product ...

Embodiment 3

[0055]

[0056] Add 45ml tetrahydrofuran to a 1L three-necked flask, protect it with nitrogen, and put it in an ice bath. The inner temperature drops to -10°C, slowly add (8.9ml, 14.3mmol, 1.1eq) n-butyllithium hexane solution (1.6M / L), and stir to dissolve After that, (8.74g, 39mol, 3eq) triethyl phosphoroacetate was added dropwise, the internal temperature was less than 10°C, after the addition was completed, it was raised to room temperature and stirred for 0.5h, and (1.47g, 13mmol, 1.0eq) was added in batches (1.47g, 13mmol, 1.0eq) raw material 4- Aminocyclohexanone, reacted for 2 hours until the disappearance of raw materials. Add 50ml of water, separate the layers, wash the organic phase with 50ml of saturated sodium chloride, dry over anhydrous sodium sulfate, and spin dry to obtain 2.41g of crude oily product of ethyl 4-amino-cyclohexyl ethylene acid, which is directly put into the next reaction.

[0057]

[0058] In a 1L single-necked bottle, add the crude olefi...

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Abstract

The invention provides a preparation method for a trans 4-amino-cyclohexyl acetate derivative. The preparation method comprises the following steps that a formula (please see the description for the formula) is provided, wherein R is methyl or ethyl; a compound III is prepared from the raw materials of 4-amino cyclohexanone II and is subjected to hydrogenation reduction, a compound I crude product is obtained, acid is added, and salt is formed; and a compound I is prepared by adding alkali. According to the preparation method, 4-amino cyclohexanone not protected by amino is adopted as raw materials, witting reaction is conducted, and then through catalytic hydrogenation, the trans crude product of the preparation method is obtained. The crude product can be subjected to salifying crystallization so as to obtain the purer trans product, and the trans:syn ratio is 95-99.9:5-0.1. The product compound is high in purity and can be used for preparing cariprazine. Operation is simple, the raw materials are easy to obtain, industrial production is suitable, and large application value is achieved.

Description

technical field [0001] The invention relates to medicinal chemistry, in particular to a preparation method of a drug intermediate, in particular to a preparation method of trans 4-amino-cyclohexyl ethyl ester derivatives. Background technique [0002] Cariprazine (Cariprazine) was jointly developed by Gedeon Richter Ltd and Forest Laboratories. It was first reported that it has a dopamine D3 / D2 partial agonist, and has the characteristics of preferentially binding D3R and DA partial agonists. It is used for the treatment of schizophrenia, Mania, severe depression, expected to be launched in the United States in 2015 as an anti-schizophrenia drug, its chemical name is trans-1-{4-[2-[4-(2,3-dichlorophenyl)- Piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethylurea hydrochloride. Its structural formula is as follows: [0003] [0004] Patent (CN1829703) discloses the preparation method of cariprazine. Use piperazine compound 1 and amino-protected 4-aminocyclohexyl acetaldehyde ...

Claims

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Application Information

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IPC IPC(8): C07C227/06C07C229/46
CPCC07C227/06C07C227/10C07C229/46
Inventor 李凤杰徐苗焕黄悦
Owner ZHEJIANG JINGXIN PHARMA
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