Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

The preparation method of trans 4-amino-cyclohexyl acetate derivative

A technology of cyclohexyl acetate and aminocyclohexanone, which is applied in the preparation of pharmaceutical intermediates and the field of preparation of trans 4-amino-cyclohexyl ethyl ester derivatives, can solve the problem of purifying trans products, cariprazine Can not meet the medicinal standards and other problems, to achieve the effect of easy availability of raw materials, great application value, and high purity

Active Publication Date: 2018-04-27
ZHEJIANG JINGXIN PHARMA +2
View PDF7 Cites 0 Cited by
  • 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

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • The preparation method of trans 4-amino-cyclohexyl acetate derivative
  • The preparation method of trans 4-amino-cyclohexyl acetate derivative
  • The preparation method of trans 4-amino-cyclohexyl acetate derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Example 1 Preparation of trans 4-amino-cyclohexyl ethyl acetate hydrochloride

[0042]

[0043] 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, drop (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, 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.

[0044]

[0045] In a 1L single-mouth bottle, add the olefin product from the previous step (24.2g, calculated accor...

Embodiment 2

[0047] Example 2 Preparation of trans-4-amino-cyclohexylacetic acid methyl ester hydrochloride

[0048]

[0049] 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.

[0050]

[0051] 1L single-necked bottle, add the olefin product ...

Embodiment 3

[0054]

[0055] 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.

[0056]

[0057] In a 1L single-necked bottle, add the crude olefi...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

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, and severe depression. It is expected to be launched in the United States as an antischizophrenia drug in 2015. 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 ace...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Patents(China)
IPC IPC(8): C07C227/06C07C229/46
CPCC07C227/06C07C227/10C07C229/46
Inventor 李凤杰徐苗焕黄悦
Owner ZHEJIANG JINGXIN PHARMA
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com