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Preparation method of cariprazine

A technology of cariprazine and system, which is applied in the direction of organic chemistry, can solve the problems of unstable temperature, only 75-80%, process impurities, etc., achieve less route steps, increase yield and reaction speed, and simple process Effect

Active Publication Date: 2019-10-11
SHANGYU JINGXIN PHARMA +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] As can be seen from the above synthetic route, in the process of synthesizing cariprazine, the classic synthesis process has the following problems: it uses p-toluenesulfonyl chloride to produce genotoxic impurities (p-toluenesulfonate); intermediate SM01 p-piperazine The docking temperature needs to be above 80°C, otherwise the reaction is incomplete, and SM01 is unstable to temperature, and it begins to degrade at 60°C, so that the yield of docking SM01 and piperazine is always only about 75-80%, and the reaction time needs 10-12h Left and right; There is the generation of process impurity; Therefore this area needs urgently a kind of preparation method of the new cariprazine that solves above-mentioned technical problem

Method used

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Examples

Experimental program
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Embodiment

[0044] Reagents: The reactants and catalysts used in the examples of the present invention are all chemically pure and can be used directly or simply purified as needed; the organic solvents are all analytically pure and can be used directly. Reagents were purchased from China Pharmaceutical (Group) Shanghai Chemical Reagent Company.

[0045] Detection instrument: high performance liquid chromatography Agilent HPLC-1260

[0046] Nuclear magnetic resonance instrument model: Bruker avance III 400

[0047] Embodiment 1 Preparation of formula III compound trans 2-(trans-4-(3,3-dimethylureido) cyclohexyl) acetyl chloride

[0048] Preparation of trans 2-(trans-4-(3,3-dimethylureido) cyclohexyl) ethyl acetate of compound of formula I

[0049] Take compound trans 2-(4-aminocyclohexyl) ethyl acetate 5.0g (0.032mol), add 50ml of dichloromethane, 30% sodium hydroxide solution 8.5g (2eq), add N,N-di Methylformyl chloride 6.9g (0.064mol), heat preservation at 30°C and stir for 5h, point...

Embodiment 5

[0059] Example 5 Formula V compound N'-[trans-4-[2-[4-(2,3-dichlorophenyl)-1-piperazinyl]ethyl]cyclohexyl]-N,N-di Preparation of methylurea

[0060] Formula IV compound 3-((trans-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)-2-oxoethyl)cyclohexyl)-1,1 - Preparation of dimethylurea

[0061] Take 8.15g (0.03mol) of 1-(2,3-dichlorophenyl)piperazine hydrochloride, add 50ml of dichloromethane, add 8.3g (3eq) of potassium carbonate, cool to 0°C in an ice bath, and slowly drop into A solution composed of 5.0 g of compound III (0.02 mol) and 20 ml of dichloromethane was controlled at 0-10°C, and after 0.5 h of dripping, the plate was spotted to confirm that the reaction was complete. Add 100 ml of water to the reaction system, add hydrochloric acid, and adjust The pH value of the aqueous phase was 3-4, stirred for 10 minutes, the organic phase was separated, dried, filtered, and spin-dried to obtain 8.2 g of the compound of formula IV, with a yield of 93.1%;

[0062] Take 5g (0.011mo...

Embodiment 6

[0063] The preparation of embodiment 6 formula V compound

[0064] The preparation of formula IV compound

[0065] Take 8.15g (0.03mol) of 1-(2,3-dichlorophenyl)piperazine hydrochloride, add 50ml of dichloromethane, add 6.1g (3eq) of triethylamine, cool to 0°C in an ice bath, slowly drop Add 5.0 g of compound III (0.02 mol) and 20 ml of dichloromethane solution, control the internal temperature at 0-10 ° C, spot the plate after 0.5 h after the drop, confirm that the reaction is complete, add 100 ml of water to the reaction system, add hydrochloric acid, Adjust the pH value of the water phase to 3-4, stir for 10 minutes, separate the organic phase, dry, filter, and spin dry to obtain 8.2 g of the compound of formula IV, with a yield of 93.1%;

[0066] Take 5g (0.011mol) of the compound of formula IV, add 50ml of diethyl ether, cool the system to about 0°C, slowly drop in 28ml of DIBAL-H (1M n-hexane), keep the reaction at 0°C for 5h, and control the reaction in TLC (developing...

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Abstract

The invention provides a preparation method of cariprazine. The preparation method of the cariprazine includes that a trans-2-(trans-4-(3, 3-dimethylureido) cyclohexyl) derivative is enabled to reactwith 1-(2, 3-dichlorophenyl) piperazine or salt thereof in an acid-binding agent reaction condition, and then the cariprazine is generated in a reducing agent reaction condition. The preparation method of the cariprazine is few in a synthetic route, simple in technology and conformable to production requirements.

Description

technical field [0001] The invention relates to medicinal chemistry, in particular to a preparation method of cariprazine. Background technique [0002] The structural formula of Cariprazine is shown as the compound of formula A. It was jointly developed by Gedeon Richter Ltd and Forest Laboratories. It was first reported that it has a dopamine D3 / D2 partial agonist, and it has both preferential binding to D3R and DA partial agonists. It is used for the treatment of schizophrenia, mania, and severe depression. Its hydrochloride was listed in the United States as an anti-schizophrenia drug in 2015. The chemical name is trans-1-{4-[2-[ 4-(2,3-Dichlorophenyl)-piperazin-1-yl]ethyl]cyclohexyl}-3,3-dimethylurea hydrochloride. [0003] [0004] There are documents to disclose the cariprazine synthesis process route as follows: [0005] [0006] As can be seen from the above synthetic route, in the process of synthesizing cariprazine, the classic synthesis process has the fo...

Claims

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Application Information

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