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Preparation method of cariprazine

A technology of piperazine and compounds, which is applied in the field of preparation of cariprazine, can solve the problems of long reaction time, complex process of cariprazine intermediates, low yield and purity, and achieve short reaction time, high purity, good safety effect

Pending Publication Date: 2021-10-22
四川弘远药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] Based on the problems of complex process, long reaction time, low yield and purity of cariprazine intermediates in the prior art, the present invention is proposed

Method used

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  • Preparation method of cariprazine
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  • Preparation method of cariprazine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Example 1: (4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-2-oxoethyl}-cyclohexyl)-tert-butyl carbamate preparation of

[0039] Starting material 150.1g (1.0eq) 4-tert-butoxycarbonylamino-cyclohexyl)-acetic acid (SM01), 187.3g (1.2eq) 1-(2,3-dichlorophenyl)piperazine (SM02) , 134.3g (1.2eq) EDCI and 1L dichloromethane were added to a 2L reaction flask, and 202mL (2.3eq) triethylamine was added under stirring, and the temperature was raised to 40°C for reflux reaction. After 2h, the reaction was completed, and stirred overnight at room temperature; Cleared, stirred and separated, the organic phase was concentrated, the crude product was refluxed with methanol for beating, filtered, washed with methanol, and dried to finally obtain 183.70g (4-{2-[4-(2,3-dichloro-phenyl)-piperazine -1-yl]-2-oxoethyl}-cyclohexyl)-tert-butyl carbamate (IM01), yield 66.9%, purity 98.5%.

Embodiment 2

[0040] Example 2: (4-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-2-oxoethyl}-cyclohexyl)-tert-butyl carbamate preparation of

[0041]

[0042] Dissolve the starting material 0.20kg (1.0eq) 4-tert-butoxycarbonylamino-cyclohexyl)-acetic acid (SM01) in tetrahydrofuran, then add 0.18kg (1.2eq) EDCI, 0.13kg (1.2eq) HOBT and 0.24kg (3.0eq) triethylamine, stirred at room temperature for about 1 hour, after the reaction was completed, add 0.25kg (1.2eq) 1-(2,3-dichlorophenyl)piperazine (SM02), and then heated to 50-60 ℃ for the reaction, and the reaction ended after 4 hours; after the reaction was completed, 3 times the volume of tetrahydrofuran was added for crystallization, and then the crude product was obtained by filtration to obtain (4-{2-[4-(2,3-dichloro-phenyl) -piperazin-1-yl]-2-oxoethyl}-cyclohexyl)-tert-butyl carbamate (IM01). Yield 93.90%, purity 99.65%.

[0043] NMR: 1 H NMR (300MHz, CDCl 3 ):δ=7.21-7.13(m,2H),6.93-6.90(m,1H),4.38(s,1H),3.80(s,2H),3.66-3.63(m,2H),...

Embodiment 3

[0044] Example 3: Trans-4-{2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-2-oxo-ethyl}-cyclohexylamine hydrochloride preparation

[0045]

[0046] Add 0.34kg (1.0eq) of IM01 to 1.37kg of acetonitrile, then add 0.2kg (3.0eq) of 37% concentrated hydrochloric acid, heat up to 60-65°C to react, react for 3-4h, after the reaction is complete, cool down, filter, the amount of acetonitrile Rinse the filter cake and dry to obtain trans-4-{2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-2-oxo-ethyl}-cyclohexylamine Hydrochloride (IM02), yield 98.85%, purity 99.86%.

[0047] NMR: 1 H NMR(300MHz,d-DMSO):δ=8.1370(s,3H),7.1239-7.0817(d,2H),6.9022-6.8705(t.1H),3.68401(s,2H),3.5653(s,2H) ,2.9258-2.8468(m,5H),2.1947-2.1728(d,2H),2.0095-1.9679(d,2H,),1.8355-1.7916(d,3H),1.4355-1.3200(m,2H),1.0471-0.9174 (m,2H).

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Abstract

The invention relates to a preparation method of cariprazine. The invention provides a novel intermediate of cariprazine and a method for preparing cariprazine from the intermediate. According to the method, use of a genotoxic impurity dimethyl carbamoyl chloride is avoided, so that the safety is good, the product yield and purity are ideal, and the method is suitable for industrial production.

Description

technical field [0001] The invention relates to the field of chemical medicine, in particular to a preparation method of cariprazine. Background technique [0002] Cariprazine is an atypical antipsychotic drug jointly developed by Forest Laboratories of the United States and Gedeon Richter Ltd. It is a partial agonist of dopamine D2 and D3 receptors. It was approved for marketing by the US Food Administration on September 17, 2015. Its chemical name is: trans-4-{2-[4-(2,3-dichlorophenyl)-piperazin-1-yl] -Ethyl}-N, N-dimethylformyl-cyclohexylamine, the structural formula is as follows: [0003] [0004] WO2005012266A discloses the compound of cariprazine. For the reaction schemes A and C given in the specification, method A uses trans-1-4-{2-[4-(2,3-dichlorophenyl)- Piperazin-1-yl]-ethyl}--cyclohexyl-amine hydrochloride Preparation of cariprazine under the conditions of triethylamine and N,N-dimethylcarbamoyl chloride. Its defects are: N,N-dimethylcarbamoyl chloride is ...

Claims

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Application Information

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IPC IPC(8): C07D295/135
CPCC07D295/135
Inventor 柯潇胡川朱安云
Owner 四川弘远药业有限公司
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