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A kind of method of synthesizing cariprazine

A technology of piperazine and dichlorophenyl, applied in the field of synthesizing cariprazine, can solve the problems of long total reaction steps, expensive reagents and equipment requirements, etc., and achieve the effect of increasing the total yield and shortening the process steps

Active Publication Date: 2020-06-12
成都福柯斯医药技术有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It has been reported that there are following deficiencies or defects in the synthetic route: step 1, the reduction of nitrophenylacetic acid requires high temperature and pressure and a large amount of palladium / platinum catalyst, expensive reagents and high equipment requirements; and after reduction, esterification and recrystallization are required to obtain relatively Pure trans-configuration product
This process provides a method for the preparation of high-purity trans-configuration intermediates, but the overall reaction steps are longer

Method used

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  • A kind of method of synthesizing cariprazine
  • A kind of method of synthesizing cariprazine
  • A kind of method of synthesizing cariprazine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Example 1: 3-(trans-4-{2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-2-oxo-ethyl}-cyclohexyl)- Synthesis of 1,1-dimethylurea:

[0035]

[0036] Suspend trans-2-(4-(3,3-dimethylureido)cyclohexyl)acetic acid (105g, 0.46mol) in dichloromethane (500ml), slowly add thionyl chloride (82.1 g, 0.69mol), after addition, the system was heated to reflux and stirred for 4h. The reaction solution was concentrated to dryness under reduced pressure, and 300 ml of dichloromethane was added to obtain an acid chloride solution, which was set aside.

[0037] In another reaction flask was added 1-(2,3-dichlorophenyl)piperazine hydrochloride (135.4g, 0.51mol), triethylamine (116.2g, 1.15mol) and dichloromethane (1.3L) , cooled in an ice-water bath. Control the temperature < 15°C and add the prepared acid chloride solution dropwise. After the addition is complete, react at room temperature for 2 hours. After the reaction was completed, the organic phase was poured into water (1 L), separa...

Embodiment 2

[0039] Example 2: 3-(trans-4-{2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-2-oxo-ethyl}-cyclohexyl)- Synthesis of 1,1-dimethylurea:

[0040]

[0041] Suspend trans-2-(4-(3,3-dimethylureido)cyclohexyl)acetic acid (10g, 43.8mmol) in dichloromethane (80ml), add triethylamine (6.6g, 65.7mmol ), the reaction solution was cooled to <-15°C, and isobutyl chloroformate (6g, 44mmol) was slowly added. After the addition, the temperature was controlled at -15~-10°C and stirred for 1 h to obtain a mixed anhydride solution, which was set aside.

[0042] Add 1-(2,3-dichlorophenyl)piperazine hydrochloride (12.9g, 48.2mmol), triethylamine (5.3g, 53mmol) and dichloromethane (60ml) in another reaction flask, stir Uniformly and slowly drop into the prepared mixed anhydride solution, temperature control <5°C. After the addition was completed, the mixture was naturally warmed to room temperature and stirred for 2h. After the reaction was completed, the reaction solution was quenched by adding 1...

Embodiment 3

[0043] Example 3: 3-(trans-4-{2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-2-oxo-ethyl}-cyclohexyl)- Synthesis of 1,1-dimethylurea:

[0044]

[0045] Suspend trans-2-(4-(3,3-dimethylureido)cyclohexyl)acetic acid (10g, 43.8mmol) in dichloromethane (80ml), add triethylamine (6.6g, 65.7mmol ), the reaction solution was cooled to <-5°C, and carbonyldiimidazole (8.5 g, 52.6 mmol) was added in batches. After the addition, the temperature of the reaction solution was raised to 10-15°C and stirred for 1-2 hours, and 1-(2,3-dichlorophenyl)piperazine hydrochloride (12.9 g, 48.2 mmol) was added in batches, and the temperature was controlled to <15°C. After the addition was completed, the mixture was naturally warmed to room temperature and stirred for 2h. After the reaction was completed, the reaction solution was quenched by adding 100 ml of water, adjusted to acidity with 6N hydrochloric acid solution, and the organic phase was separated. The organic phase was concentrated to obtain...

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Abstract

The invention belongs to the technical field of organic synthesis, and provides a novel method for synthesizing cariprazine. The novel method comprises the following steps: firstly, carrying out condensation reaction on trans-2-(4-(3,3-dimethyl ureido) cyclohexyl) acetic acid and 1-(2,3-dichlorophenyl) piperazine to obtain 3-(trans-4-{2-[4-(2,3-dichlorophenyl)-piperazine-1-yl]-2-oxo-ethyl}-cyclohexyl)-1,1-dimethylurea; and secondly, reducing 3-(trans-4-{2-[4-(2,3-dichlorophenyl)-piperazine-1-yl]-2-oxo-ethyl}-cyclohexyl)-1,1-dimethylurea by using borane to obtain the cariprazine. The method hasthe advantages that process steps are greatly shortened, the purity of a final product is ensured and the total yield is obviously increased.

Description

technical field [0001] The invention belongs to the field of organic synthesis, and in particular relates to a method for synthesizing cariprazine. Background technique [0002] Cariprazine (Cariprazine, CAS registration number: 839712-12-8), is a third-generation antipsychotic new drug jointly developed by Allergan of the United States and Gedeon Richter Pharmaceutical Company of Hungary, for the treatment of schizophrenia, mania, and severe depression syndrome; on September 17, 2015, it was approved for marketing by the US Food and Drug Administration. Its chemical name is trans-4-{2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl}-N,N-dimethylformyl-cyclohexyl Amine, the structural formula is as follows: [0003] [0004] 国际专利WO2015056164、WO20111060363、WO2010070370、WO2010070371、WO2008142461和WO2005012266以及文献JMC2013,56(22),9199-9221,Bioorganic&Medicinal Chemistry Letters,22,(2012),3437-3440均报道了卡利拉嗪的合成方法, Summarized as follows: [0005] [0006] Among them, Compound ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D295/135
CPCC07D295/135
Inventor 黄湘川宁兆伦魏庚辉
Owner 成都福柯斯医药技术有限公司
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