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Preparation method of cariprazine and intermediate compound

A cariprazine and compound technology, which is applied to the preparation method of cariprazine and the field of intermediate compounds, can solve the problems of long reaction time, long reaction steps and high temperature, and achieves shortening of process steps, improvement of total yield, The effect of ensuring purity

Pending Publication Date: 2022-03-22
四川奥邦古得药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But, the method total reaction step of the method for preparing cariprazine that this technology provides is longer, finally with 1-(2,3-dichlorophenyl) piperazine condensation obtains cariprazine reaction time is long, temperature is high, in long-term Cariprazine is easy to decompose under high temperature and alkaline conditions for a long time

Method used

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  • Preparation method of cariprazine and intermediate compound
  • Preparation method of cariprazine and intermediate compound
  • Preparation method of cariprazine and intermediate compound

Examples

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preparation example Construction

[0046] The first aspect of the present invention provides a kind of preparation method of cariprazine, it comprises:

[0047] (1) React with trans-(N-Boc-4-aminocyclohexyl)acetic acid and 1-(2,3-dichlorophenyl)piperazine as raw materials to obtain trans-N-tert-butoxycarbonyl-4 -{2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-2-oxo-ethyl}-cyclohexylamine (compound shown in formula 1);

[0048](2) Make the resulting trans N-tert-butoxycarbonyl-4-{2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-2-oxo-ethyl}- Cyclohexylamine was deprotected by acid to give trans N-{4-{2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-2-oxo-ethyl}-cyclo Hexylamine (compound shown in II);

[0049] (3) The resulting trans N-{4-{2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-2-oxo-ethyl}-cyclohexylamine The reduction reaction obtains the trans N-{4-{2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl}-cyclohexylamine (compound shown in III) ;

[0050] (4) Make the resulting trans N-{4-{2-[4-(2,3-dichlorophenyl)-piperazin-1-...

Embodiment approach

[0052] According to some embodiments of the present invention, the activation is to react trans-(N-Boc-4-aminocyclohexyl)acetic acid with the activator to generate acid halide, acid anhydride or carbonylimidazole intermediate compound.

[0053] According to some preferred embodiments of the present invention, the activator is thionyl chloride, oxalyl chloride, isobutyl chloroformate or carbonyldiimidazole.

[0054] According to some preferred embodiments of the present invention, trans-(N-Boc-4-aminocyclohexyl)acetic acid and 1-(2,3-dichlorophenyl)piperazine are present in the presence of a condensing agent in step (1). Condensation reaction can be carried out directly to obtain the compound shown in formula 1.

[0055] According to some preferred embodiments of the present invention, the condensing agent is selected from 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, dicyclohexylcarbodiimide and 2 -at least one of (7-benzotriazole oxide)-N,N,N',N'-tetramethylur...

Embodiment 1

[0143] Synthesis of trans N-tert-butoxycarbonyl-4-{2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-2-oxo-ethyl}-cyclohexylamine

[0144]

[0145] Suspend trans-(N-Boc-4-aminocyclohexyl)acetic acid (100g, 0.39mol) in dichloromethane (500ml) and slowly add thionyl chloride (69.5g, 0.59mol) at 7-8°C After the addition, the system was heated to 25° C. and stirred for 4 h to obtain a reaction solution. The reaction solution was concentrated to dryness under reduced pressure, and 300 ml of dichloromethane was added to obtain an acid chloride solution, which was set aside.

[0146] Weigh 1-(2,3-dichlorophenyl)piperazine hydrochloride (125.7g, 0.47mol), add 1.2L water to dissolve, adjust the pH to 7~8 with sodium carbonate, and extract with dichloromethane (500mL *2 times), dried over anhydrous sodium sulfate to obtain a dichloromethane extract, added triethylamine (78.8 g, 0.78 mol) to the dichloromethane extract, and cooled in an ice-water bath. Control the temperature at 15°C and add ...

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Abstract

The invention provides a preparation method of cariprazine and an intermediate compound. The preparation method disclosed by the invention is simple in process, high-temperature and high-pressure conditions are not needed, a precious catalyst is not used, the cost is saved, and the prepared cariprazine is high in yield and purity.

Description

technical field [0001] The invention relates to a preparation method and an intermediate compound of cariprazine. Background technique [0002] Schizophrenia is a disease that seriously affects human health. It has affected the normal life of about 1% of the world's population and brought serious consequences to patients and their families. It is the seventh largest disease in social burden. [0003] Antipsychotic drugs are mainly divided into typical antipsychotic drugs and atypical antipsychotic drugs. At present, atypical antipsychotic drugs (such as D2 / 5-HT2a dual antagonists) are the main first-line clinical drugs. Schizophrenia drugs such as risperidone, aripiprazole, ziprasidone, and quetiapine can improve negative symptoms while treating positive symptoms, but they all have their own side effects, such as extrapyramidal side effects (EPS) probability is high, akathisia, insomnia, anxiety, cardiotoxicity, etc. There is no drug that can effectively reduce the above-me...

Claims

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Application Information

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IPC IPC(8): C07D295/135C07D295/182
CPCC07D295/135C07D295/182
Inventor 蒋忠君刘波王科杨仁明罗晓勇蒋伟
Owner 四川奥邦古得药业有限公司
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