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Preparation method of cariprazine

A technology of cariprazine and piperazine, which is applied in the field of preparation of cariprazine, can solve the problems of complex post-processing, low yield, and many by-products, and achieve simple post-processing, high yield, and low reaction by-products little effect

Active Publication Date: 2020-06-12
ZHEJIANG JINGXIN PHARMA +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] The technical problem that the present invention solves is that synthetic route 1) by-product is many in the prior art, 2) aftertreatment is complicated, 3) the defect such as low yield, provides a kind of preparation method of new cariprazine

Method used

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  • Preparation method of cariprazine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] The preparation method of trans-1-(BOC-amino)-4-(2-hydroxyethyl)cyclohexane preparation formula compound 3 is: add trans-1-(BOC-amino)-4 to a 500ml single-necked bottle -(2-Hydroxyethyl)cyclohexane 20g (0.082mol), add 200ml dichloromethane to dissolve, add triethylamine 12.5g (0.123mol), add p-toluenesulfonyl chloride 18.76g (0.0984mol) under stirring, room temperature Stir the reaction for 20 hours, TLC (ratio of developing agent: dichloromethane: methanol = 10:1) to confirm the completion of the reaction, add 200ml of water to the reaction system, stir to dissolve, separate the layers, separate the water phase, and concentrate the organic phase Until there is almost no flow, add 200ml of n-hexane to the concentrate, stir for 2 hours, filter, rinse the filter cake with n-hexane, bake under reduced pressure at 50-60°C for 8-10 hours, and obtain 26.5g of white solid, with a yield of 81.3%;

[0062] Wherein the formula compound 3 1 H NMR data are:

[0063] δ7.76-7.78(d,...

Embodiment 2

[0065] Preparation of formula compound 2 trans N-tert-butoxycarbonyl-4-(2-(4-(2,3-dichlorophenyl)-piperazin-1-yl)-ethyl)-cyclohexylamine

[0066]

[0067] Add 33.7g 1-(2,3-dichlorophenyl)piperazine hydrochloride (formula compound 4), 400g ethanol, 27.2g potassium carbonate, 50g trans 2-(1-(4- (N-tert-butoxycarbonyl)-amino)-cyclohexyl)-ethyl-4-methylbenzenesulfonate (formula compound 3), reacted at 75°C for 12-18h, cooled to room temperature after the reaction, and added to the reaction Add 400g of water to the system and stir for 2h, filter, rinse the filter cake with ethanol, and dry at 50°C to constant weight to obtain 63g of trans-N-tert-butoxycarbonyl-4-(2-(4-(2,3-dichloro Phenyl)-piperazin-1-yl)-ethyl)-cyclohexylamine;

[0068] Wherein the 1H NMR data of formula compound 2 is:

[0069] δ10.7(s, 1 H),7.33-7.38(m,2H),7.18-7.21(m,1H),6.67-6.69(d,1H),3.40-3.57(m,2H),3.15-3.33(m9H),1.70-1.77( t,4H), 1.61-1.62(t,2H), 1.37(s,9H), 1.21-1.23(d,4H), 1.14-1.18(d,2H).

Embodiment 3

[0071] The preparation of formula compound 2

[0072]

[0073] Add 21g (0.052mol) of compound 6 crude product to the reaction flask, add 12.6g (0.052mol) of compound 5, potassium carbonate 14.4g (0.104mol), acetonitrile 200ml, reflux and stir to react for 12h, the central control reaction is completed, and add to the reaction system Add 200ml of water, stir for 1 hour, filter, rinse the filter cake with water and acetonitrile respectively, bake the solid at 50-60°C for 6 hours, and obtain 18.8g of compound 2 as a white solid, with a yield of 79.3%;

[0074] Wherein the 1H NMR data of formula compound 2 is:

[0075] δ10.7(s, 1 H),7.33-7.38(m,2H),7.18-7.21(m,1H),6.67-6.69(d,1H),3.40-3.57(m,2H),3.15-3.33(m9H),1.70-1.77( t,4H), 1.61-1.62(t,2H), 1.37(s,9H), 1.21-1.23(d,4H), 1.14-1.18(d,2H).

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Abstract

The invention provides a preparation method of cariprazine, which comprises the following steps: reacting trans-N-tert-butyloxycarbonyl-4-(2-(4-(2,3-dichlorophenyl)-piperazine-1-yl)-ethyl)-cyclohexylamine with dimethylamine under the conditions of an organic solvent, an acid-binding agent and an additive to obtain the cariprazine. The preparation method of cariprazine provided by the invention hasthe advantages of short reaction time, high reaction yield, few byproducts, simple post-treatment and suitability for industrial production, and overcomes the problems of difficult solvent recovery,environmental pollution, complex operation and the like in the prior art.

Description

technical field [0001] The invention relates to the technical field of organic synthesis, in particular, the invention relates to a preparation method of cariprazine. Background technique [0002] Cariprazine (Cariprazine, CAS No.: 839712-12-8), is a D drug jointly developed by Gedeon Richter Ltd of Hungary and Forest Laboratories of the United States. 3 / D 2 Receptor partial agonist, used for the treatment of schizophrenia (before registration), mania (before registration), severe depression (phase III); it was approved for marketing by the US Food and Drug Administration on September 17, 2015. 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] Antipsychotic drugs are mainly divided into typical antipsychotic drugs and atypical antipsychotic drugs. At present, atypical antipsychotic drugs (such as D 2 / 5-HT 2a dual antagonists), cariprazine is the...

Claims

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Application Information

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IPC IPC(8): C07D295/135
CPCC07D295/135
Inventor 张敏郑飞
Owner ZHEJIANG JINGXIN PHARMA
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