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Compound for preparation of cariprazine and preparation method thereof

A compound and a technology for sodium hydride, applied in the field of compounds for the preparation of cariprazine, can solve problems such as rare raw materials, unsuitable for industrial production, environmental pollution, etc., and achieve the effects of good yield, short reaction time, and less three wastes

Inactive Publication Date: 2017-03-29
NHWA PHARMA CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] The object of the present invention is to provide a kind of compound and preparation method thereof for preparing cariprazine, this method can overcome the defect that raw material is rare in the prior art, pollutes environment, is not suitable for industrialized production

Method used

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  • Compound for preparation of cariprazine and preparation method thereof
  • Compound for preparation of cariprazine and preparation method thereof
  • Compound for preparation of cariprazine and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0053] Preparation of ethyl 2-{4-[(N-tert-butoxycarbonyl)amino]cyclohexylylidene}acetate

[0054]

[0055] Add sodium hydrogen (60 g) and 200 ml of dry tetrahydrofuran to a 2 l four-necked flask. Cool down to 5°C, add dropwise a mixture of triethyl phosphonoacetate (69g, 0.31mol) and THF (400ml) under stirring; dropwise, react at the same temperature for 30 minutes; dropwise add tert-butyl (4-oxocyclohexyl ) carbamate (60 g, 0.28 mol) and dry THF (500 ml) mixture. After dropping, slowly warm up to room temperature and react for 3 hours.

[0056] After the reaction was completed, 430ml of water was added dropwise, followed by ethyl acetate (500mlX2) for extraction; the organic phases were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtering and concentrating until most solids are precipitated, add 150ml of n-hexane and stir at room temperature for 1 hour. After filtration and vacuum drying at 40°C to constant weight, 72.2 g of...

example 2

[0058] Preparation of ethyl 2-{4-[(N-tert-butoxycarbonyl)amino]cyclohexylylidene}acetate

[0059] Sodium hydrogen (50 g) and 170 ml of dry tetrahydrofuran were added to a 2 l four-necked flask. Cool down to 5°C, add dropwise a mixture of triethyl phosphonoacetate (79g, 0.35mol) and THF (450ml) under stirring; dropwise, react at the same temperature for 30 minutes; dropwise add tert-butyl (4-oxocyclohexyl ) carbamate (50 g, 0.23 mol) and dry THF (400 ml). After dropping, slowly warm up to room temperature and react for 3 hours.

[0060] After the reaction was completed, 430ml of water was added dropwise, followed by ethyl acetate (500mlX2) for extraction; the organic phases were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. Filter and concentrate until most solids are precipitated, add 125ml of n-hexane, and stir at room temperature for 1 hour. After filtering and vacuum drying at 40°C to constant weight, 60 g of white solid was obtained ...

example 3

[0062] Preparation of methyl 2-{4-[(N-tert-butoxycarbonyl)amino]cyclohexylylidene}acetate

[0063]

[0064] Add sodium hydrogen (30 g) and 100 ml of dry tetrahydrofuran to a 1 l four-necked flask. Cool down to 5°C, add dropwise a mixture of trimethyl phosphonoacetate (51.2g, 0.28mol) and THF (300ml) under stirring; Hexyl) carbamate (30 g, 0.14 mol) and dry THF (260 ml). After dropping, slowly warm up to room temperature and react for 3 hours.

[0065] After the reaction was completed, 220ml of water was added dropwise, followed by ethyl acetate (260mlX2) for extraction; the organic phases were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. Filter and concentrate until most solids are precipitated, add 100ml of n-hexane, and stir at room temperature for 1 hour. After filtration and vacuum drying at 40° C. to constant weight, 34.9 g of white solid was obtained, yield 93%.

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Abstract

The invention relates to a compound for preparation of cariprazine and a preparation method thereof. The method can overcome the defects in the prior art, the used raw materials and reagents are low toxic, cheap and easily available, the reaction conditions are mild, fewer three wastes are generated, at the same time, the operation is simple and safe, and the yield is good, therefore the method is suitable for industrialized production.

Description

technical field [0001] The invention relates to a compound used for preparing cariprazine and a preparation method thereof. Background technique [0002] Cariprazine hydrochloride, chemical name trans-1-{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}- 3,3-Dimethylurea hydrochloride, a D 2 and D 3 Receptor partial agonists, especially for D 3 Receptors have high selectivity for 5-HT 1A Also has partial agonism, co-developed by Gedeon Richter and Forest Laboratories. On September 17, 2015, the FDA approved it for the treatment of schizophrenia and bipolar disorder; it is currently in phase III clinical trials for the treatment of severe depression. The structure of cariprazine is shown below: [0003] [0004] The preparation method of the disclosed cariprazine at home and abroad mainly contains three classes at present: [0005] (1) Patent CN1829703 reports 2,3-dichlorophenylpiperazine (VII) and trans-tert-butyl (4-(2-oxoethyl)cyclohexyl)ammonium fo...

Claims

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Application Information

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IPC IPC(8): C07C269/06C07C271/24C07C303/28C07C309/73C07D295/135
CPCC07C269/06C07C271/24C07C303/28C07C309/73C07D295/135
Inventor 曹龙吉孙立杨相平司崇静张桂森
Owner NHWA PHARMA CORPORATION
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