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Preparation method of cariprazine

A technology for preparing cariprazine and its preparation steps, which is applied in the field of preparation of cariprazine for treating psychosis, and can solve problems such as cumbersome steps, harsh reaction conditions, high temperature and pressure, and achieve environmentally friendly and economical process and easy-to-obtain raw materials , the effect of simple process

Active Publication Date: 2016-02-17
中科恩吉瑞特(烟台)科技发展有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are following deficiencies or defects in this synthetic route: the first, the reduction of nitrophenylacetic acid needs very high temperature and pressure, and needs to use precious metal catalysts such as palladium or platinum
It can be seen from this that the existing synthetic routes and method steps are relatively cumbersome, the reaction conditions are harsh and the cost is high, which is not conducive to industrial production.

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

[0032] Add 4-(2-hydroxyethyl)cyclohexanone (II) (1.42g, 10mmol), 1-(2,3-dichlorophenyl)piperazine (III) (2.30g, 10mmol) into the reaction flask , triphenylphosphine (3.14g, 12mmol) dry tetrahydrofuran 25mL, add dropwise a solution of diethyl azodicarboxylate (2.09g, 12mmol) in tetrahydrofuran 25mL under ice bath, dropwise, rise to room temperature, stir the reaction 3- After 4 hours, TLC detected that the reaction was complete. Distilled under reduced pressure, the residue was dissolved with ethyl acetate and n-hexane, the insoluble matter was filtered off, the filtrate was washed with water three times, and dried over anhydrous sodium sulfate. Concentrate, and recrystallize the crude product from n-hexane / ethyl acetate (2:1) to obtain off-white solid 4-[2-[4-(2,3-dichlorophenyl)piperazin)-1-yl]ethyl] Cyclohexanone (IV) 3.20g, yield 90.4%; 1 HNMR (CDCl 3 )δ7.19-7.21(m,2H),6.94-7.06(m,1H),3.63-3.67(m,2H),3.42-3.46(m,2H),3.01-3.30(m,4H),2.55- 2.58(m,4H),2.36-2..40(m,2H),1.85...

Embodiment 2

[0034] Add 4-[2-[4-(2,3-dichlorophenyl)piperazine)-1-yl]ethyl]cyclohexanone (IV) (1.77g, 5mmol), benzylamine ( 0.54g, 5mmol), 0.5g of 4A molecular sieve and 50mL of methanol, stirred at room temperature for 5-7 hours. After filtering, the filtrate was transferred to a hydrogenation reactor, 0.18 g of 10% palladium carbon was added, hydrogen gas was introduced, the pressure was kept at 2 atmospheres and the temperature was 35-40° C., and the reaction was carried out for 5-6 hours. TLC detects that the reaction is complete. Cool down to room temperature and recover the catalyst by filtration. Concentration and concentration under reduced pressure, the residue was slurried with n-hexane to obtain a yellow waxy solid trans-4-[2-[4-(2,3-dichlorophenyl)piperazin)-1-yl]ethyl]cyclo Hexylamine (V) 1.5g, yield 84.5%, 1 HNMR (CDCl 3 )δ7.11-7.20(m,2H),6.94-7.09(m,1H),3.09(m,4H),2.58-2.76(m,5H),2.38-2.49(m,2H),1.83-1.94( m,2H),1.74-1.82(m,2H),1.35-1.52(m,4H),1.18-1.32(m,1H),0.95-1.16(...

Embodiment 3

[0036]Add 4-[2-[4-(2,3-dichlorophenyl)piperazine)-1-yl]ethyl]cyclohexanone (IV) (1.77g, 5mmol), hydroxylamine hydrochloride ( 0.42g, 6mmol), sodium acetate (0.82g, 10mmol), 25mL each of ethanol and water, and stirred at room temperature for 12 hours. Concentrate, extract with dichloromethane, and dry over anhydrous sodium sulfate. The solvent was recovered under reduced pressure, 20 mL of acetic acid was added to the obtained solid, and zinc powder (2.6 g, 40 mmol) was added in portions at room temperature. The temperature was raised to 80-90° C., and the reaction was incubated for 2-3 hours. TLC detected that the reaction was complete. Filtrate, concentrate the filtrate under reduced pressure, adjust the residue to be alkaline with 10% sodium hydroxide solution, extract 3 times with ethyl acetate, combine the organic phases, concentrate under reduced pressure, and beat with n-hexane to obtain a yellow waxy solid trans-4 -[2-[4-(2,3-Dichlorophenyl)piperazin)-1-yl]ethyl]cyclo...

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Abstract

The invention discloses a preparation method of cariprazine (Cariprazine, RGH 188). The method includes the preparation steps of preparing 4-[2-[4-(2,3-dichlorophenyl)piperazine]-1-based]ethyl]cyclohexanone by making 4-(2-hydroxyethyl)cyclohexanone and 1-(2,3-dichlorophenyl)piperazine subjected to a condensation reaction, preparing trans-4-[[2-]4-(2,3-dichlorophenyl)piperazine]-1-based]ethyl]cyclohexylamine by making the obtained intermediate subjected to a reduction ammonolysis reaction, and preparing cariprazine by making the intermediate and N,N-dimethylcarbamyl chloride subjected to an acylation reaction. According to the preparation method, raw materials can be easily obtained, the process is simple, and the method is economical, environmentally friendly and suitable for industrialized production.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis route design and preparation of raw materials and intermediates, and particularly relates to a preparation method of cariprazine, a drug for treating psychosis. Background technique [0002] Cariprazine (RGH188) is an atypical antipsychotic drug developed by Forest Lab in the United States, which belongs to the partial agonist of dopamine D2 and D3 receptors. In September 2015, the U.S. FDA approved the drug, with the trade name Vraylar, for the treatment of adult patients with schizophrenia and bipolar disorder. Since there is no standard Chinese name for Cariprazine, the applicant transliterates it as "Cariprazine". [0003] The chemical name of Cariprazine (Cariprazine, I): N'-[trans-4-[2-[4-(2,3-dichlorophenyl)-1-piperazinyl]ethyl]cyclohexyl ]-N,N-dimethylurea (I), its structural formula is: [0004] [0005] Analyzing the structure of cariprazine, its compound is composed of "...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/135
CPCC07D295/135A61K31/495A61P25/18C07D241/04
Inventor 许学农
Owner 中科恩吉瑞特(烟台)科技发展有限公司
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