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Method for preparing cariprazine and intermediate thereof

A cariprazine and intermediate technology, which is applied in the field of pharmaceutical compound preparation, can solve the problems of low industrialized production efficiency, unsuitable for industrialized production, harsh synthesis conditions, etc., and achieves the advantages of long reaction time, low equipment requirements and simplified post-processing. Effect

Pending Publication Date: 2022-04-01
SUZHOU VIGONVITA LIFE SCIENCES CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] In this route, the raw material trans-2-{1-[4-(N-tert-butoxycarbonyl)amino]cyclohexyl}-acetaldehyde has harsh synthesis conditions and is not easily commercially available. It needs to be used at a low temperature of -78°C. Reduction of trans-2-{1-[4-(N-tert-butoxycarbonyl)amino]cyclohexyl}-acetate with diisobutylaluminum hydride produced only 53% yield (Stemp et al., J .Med.Chem.2000,43,1878-1885), while diisobutyl aluminum hydride is highly flammable and requires low temperature equipment, which is not suitable for industrial production
Another compound trans-4-{2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl}-cyclohexylamine hydrochloride and dimethylcarbamoyl chloride was amide When compound cariprazine is prepared by compound reaction, triethylamine is used as acid binding agent, dichloromethane is used as reaction solvent, and reaction is 48 hours, and yield is only 65%, and industrial production efficiency is low

Method used

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  • Method for preparing cariprazine and intermediate thereof
  • Method for preparing cariprazine and intermediate thereof
  • Method for preparing cariprazine and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0103] Preparation of trans 2-{1-[4-(N-tert-butoxycarbonyl)-amino]-cyclohexyl}-ethyl acetate

[0104] In a 250ml three-necked flask, add 105g of dichloromethane, 15g (67.65mmol) trans-4-aminocyclohexane acetate hydrochloride, 7.8g (77.08mmol) triethylamine, stir and cool down to 5-10 °C, a solution consisting of 17.3 g (79.27 mmol) of di-tert-butyl dicarbonate and 45 g of dichloromethane was added dropwise thereto, and the temperature was controlled at 5-10 °C during the dropwise addition. After the dropwise addition was completed, the temperature was raised to 20-30° C., and the mixture was kept stirring for 2 hours. After HPLC detection, the reaction of the raw materials was complete (trans-4-aminocyclohexane acetate hydrochloride was not detected). Add 40g of 5% sodium carbonate dropwise thereto, stir for 15min after addition, separate layers, wash the organic layer with 15g of water, dry the organic layer with 10g of anhydrous sodium sulfate, filter with suction, concentra...

Embodiment 2

[0106] Preparation of trans 2-{1-[4-(N-tert-butoxycarbonyl)-amino]-cyclohexyl}ethanol

[0107] In a 500ml three-necked flask, add 17.28g (0.06mol) trans 2-{1-[4-(N-tert-butoxycarbonyl)-amino]-cyclohexyl}-ethyl acetate prepared in Example 1, 104g tetrahydrofuran, 5.04g (0.13mol) sodium borohydride; temperature control at 18-25°C, dropwise add a solution consisting of 8.07g (0.06mol) aluminum chloride and 60g tetrahydrofuran, dropwise, keep stirring for 3 hours, HPLC detection showed that the reaction of raw materials was complete (trans 2-{1-[4-(N-tert-butoxycarbonyl)-amino]-cyclohexyl}-ethyl acetate was not detected). After the reaction is complete, transfer the reaction solution to a 1L three-necked flask, lower the temperature of the system to 5-10°C, add 172g of toluene to dilute the reaction solution, control the temperature at 5-10°C, and slowly add 207g of water dropwise to it. About 12g concentrated hydrochloric acid to adjust the pH of the system to 2-4. After the adj...

Embodiment 3

[0109] Preparation of trans 2-{1-[4-(N-tert-butoxycarbonyl)-amino]-cyclohexyl}bromoethane

[0110] In a 250ml three-necked flask, add 6g (24.65mmol) trans 2-{1-[4-(N-tert-butoxycarbonyl)-amino]-cyclohexyl}ethanol, 120g dichloromethane, stir to dissolve, Lower the temperature of the system to 0-5° C., and add 7.8 g (29.75 mmol) of triphenylphosphine and 9.8 g (29.55 mmol) of carbon tetrabromide to it in sequence. After the addition, stir at 0-5°C for 1h, then raise the temperature to 20-30°C and stir for 1h, perform HPLC detection, the raw material reaction is complete (trans 2-{1-[4-(N-tert-butoxycarbonyl)-amino ]-cyclohexyl}ethanol was not detected). The reaction solution was concentrated and dried, then separated on a silica gel column, and eluted with n-heptane-ethyl acetate (volume ratio 5:1) to obtain 7.4 g of a white solid, which was the compound trans 2-{1-[4-(N- tert-butoxycarbonyl)-amino]-cyclohexyl}bromoethane, the purity is 100% (ELSD detector detection), and the ...

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Abstract

The invention relates to a method for preparing cariprazine and an intermediate thereof, and the method comprises the following steps: taking trans-4-aminocyclohexane acetate hydrochloride as a starting material, and carrying out Boc protection, reduction, halogenation, nucleophilic substitution, Boc protection removal and amidation reaction to prepare the cariprazine. The alcoholic hydroxyl group of the trans-2-{1-[4-(N-tert-butoxycarbonyl)-amino]-cyclohexyl} ethanol is activated and converted into a group easy to leave, the alcoholic hydroxyl group is creatively converted into the halogen atom, the reaction condition is mild, the yield is high, the raw material medicine which is high in purity and low in impurity content and meets the medicinal requirement can be obtained, and the method is suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of preparation of pharmaceutical compounds, in particular to a method for preparing cariprazine and its intermediates. Background technique [0002] Cariprazine, English name: Cariprazine, chemical name: trans-1-{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]ethyl]cyclohexyl }-3,3-Dimethylurea, the chemical structural formula is: [0003] [0004] Cariprazine is a typical antipsychotic drug. It is a dopamine D2 / D3 receptor agonist and an 5-HT2A receptor agonist. It preferentially binds to dopamine D2 receptors, thereby exerting anti-schizophrenia and treating bipolar disorder. The role of mania in type I affective disorder. Its hydrochloride was approved by the FDA in 2015 for the treatment of adult patients with schizophrenia and bipolar depression. [0005] In the existing patented technology, the Chinese patent CN102256953B uses trans 2-{1-[4-(N-tert-butoxycarbonyl)amino]cyclohexyl}-acetate as raw mate...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C271/24C07C269/04C07C269/06C07D295/135
CPCY02P20/55
Inventor 张利军邢兴龙田广辉
Owner SUZHOU VIGONVITA LIFE SCIENCES CO LTD
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