Preparation method of cariprazine and intermediate thereof

An intermediate, volumetric technology, applied in the direction of organic chemistry, bulk chemical production, etc., can solve the problems of unsuitable for industrial production, strong equipment corrosion, cumbersome reaction steps, etc., to achieve safe and controllable drug quality and high reaction yield. , the effect of easy availability of raw materials

Pending Publication Date: 2022-05-27
上海新礼泰药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The present invention provides a cariprazine

Method used

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  • Preparation method of cariprazine and intermediate thereof
  • Preparation method of cariprazine and intermediate thereof
  • Preparation method of cariprazine and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0079] Example 1 Preparation of trans-2-{1-[4-(N-tert-butoxycarbonyl)-amino]-cyclohexyl}-ethyl acetate (cariprazine intermediate 2)

[0080] In a 50mL there-necked flask, add 4g (0.018mol) of trans-2-[1-(4-amino]-cyclohexyl)-ethyl acetate hydrochloride 1 and 16mL of dichloromethane, then add 1.8g (0.018mol) of Triethylamine, the mixture was cooled to 5-10 ℃, and then under nitrogen protection, 4.0 g (0.018 mol) of di(tert-butyl) dicarbonate solution in 10 mL of dichloromethane was added dropwise, and stirred at 20 ℃ after the dropwise addition. , After 10h, the reaction was completed, 20mL of saturated sodium bicarbonate solution was added, and the phases were separated. The organic layer was washed with 10 mL of water, and the phases were separated with anhydrous Na 2 SO 4 The organic phase was dried, the solvent was removed under reduced pressure, and dried under reduced pressure at 30° C. to obtain 4.64 g of the target compound with a yield of 90.0%. HPLC purity 98.5%. ...

Embodiment 2

[0081] Example 2 Preparation of trans-2-{1-[4-(N-tert-butoxycarbonyl)-amino]-cyclohexyl}-acetic acid (cariprazine intermediate 3)

[0082] In a 50mL three-necked flask, add 4.0g (0.014mol) of trans-2-{1-[4-(N-tert-butoxycarbonyl)-amino]-cyclohexyl}-ethyl acetate (cariprazine intermediate 2 ), 40 mL of tetrahydrofuran, 10 mL of distilled water and 1.18 g (0.028 mol) of lithium hydroxide monohydrate, and the reaction was stirred at 40 °C for 6 h. After the reaction was completed, the tetrahydrofuran was removed under reduced pressure, 14 mL (6 M) of hydrochloric acid was added for acidification, and after stirring in an ice bath for 1 h, Filtration, washing with 10 mL of distilled water, drying under reduced pressure at 50° C. to obtain 1.8 g of the target compound with a yield of 90.0% and HPLC purity of 99.0%.

Embodiment 3

[0083] Example 3 tert-butyl (1R,4R-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)-2-oxoethyl)cyclohexyl)carbamate Preparation of (Cariprazine Intermediate 5)

[0084] Method a: In a 50mL three-necked flask, add 3.86g (0.015mol) of trans-2-{1-[4-(N-tert-butoxycarbonyl)-amino]-cyclohexyl}-acetic acid (cariprazine intermediate body 3), 20 mL of acetone and 2.9 g (0.018 mol) of N,N-carbonyldiimidazole, stirred at 25 °C for 4 h, added 2 mL of isopropanol, stirred at 25 °C for 1 h, then added 2.1 mL of triethylamine and 3.47 g (0.015 mol of ) 1-(2,3-dichlorophenyl)-piperazine 4, stirred at room temperature for 12 hours, after the reaction was completed, added 80 mL of distilled water, stirred for 1 hour, filtered, and washed with 40 mL of distilled water. Drying under reduced pressure at 45° C. obtained 6.4 g of the target compound with a yield of 90.0% and HPLC purity of 99.5%.

[0085] Method b: add 5 g (0.019 mol) of trans-2-{1-[4-(N-tert-butoxycarbonyl)-amino]-cyclohexyl}-acetic ...

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Abstract

The invention provides a preparation method of cariprazine and an intermediate thereof. The invention discloses a preparation method of a cariprazine intermediate 5, which comprises the following steps: a) carrying out condensation reaction on 2-[1-(4-amino]-cyclohexyl)-ethyl acetate hydrochloride 1 and an amino protection reagent in a solvent in the presence of alkali to obtain a cariprazine intermediate 2; b) in a solvent, hydrolyzing the cariprazine intermediate 2 under an alkaline condition, and then acidifying to obtain a cariprazine intermediate 3; and c) carrying out condensation reaction on the cariprazine intermediate 3 and 1-(2, 3-dichlorophenyl)-piperazine 4 in an organic solvent in the presence of a catalyst and alkali to obtain the cariprazine intermediate 5. The preparation method has the advantages of easily available raw materials, simple operation and high reaction yield, and is suitable for industrial production.

Description

technical field [0001] The present invention relates to the preparation method of cariprazine and its intermediate. Background technique [0002] In 2015, the US FDA approved cariprazine (Cariprazine; brand name: Vraylar) capsules for the treatment of adults with schizophrenia and bipolar disorder. Criprazine, a partial agonist of dopamine D3 / D2 receptors, is an investigational atypical antipsychotic drug for patients with schizophrenia and bipolar I disorder-related manic or mixed episodes. [0003] [0004] Patent WO2005012266 first reported the synthesis of cariprazine. First, 1-(2,3-dichlorophenyl)piperazine and trans-2-{1-[4-(N-tert-butoxycarbonyl)-amino ]-Cyclohexyl}-acetaldehyde reaction reductive amination to give trans N-{4-{2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl}-ring Hexyl}-tert-butyl carbamate. After de-tert-butoxycarbonyl protection, it reacts with dimethyl-carbamoyl chloride to obtain cariprazine. Preparation of starting material trans 2-{1-[4-(...

Claims

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Application Information

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IPC IPC(8): C07D295/182C07D295/135
CPCC07D295/182C07D295/135Y02P20/55
Inventor 郝群陈修雷唐超王婷婷应述欢
Owner 上海新礼泰药业有限公司
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