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Pharmaceutical intermediate, preparation method thereof and method for preparing iloperidone by pharmaceutical intermediate

A technology for medicinal salts and compounds, which is applied in the field of preparing iloperidone, iloperidone intermediates and their preparation, can solve the problems of being unsuitable for large-scale production, low coupling reaction yield, difficult to remove impurities, and the like, Achieve the effect of suitable for large-scale industrial production, convenient post-processing and outstanding yield

Active Publication Date: 2010-07-21
天津泰普制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] But the defect of above-mentioned method is that the productive rate of last step coupling reaction is low, about 58% (total productive rate is about 46%), this is due to the side reaction that took place, as benzisoxazole derivative (formula 5 compound) self-polymerization
Moreover, the impurities produced by the side reactions are difficult to remove, and the post-treatment is difficult, so it is not suitable for large-scale production.

Method used

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  • Pharmaceutical intermediate, preparation method thereof and method for preparing iloperidone by pharmaceutical intermediate
  • Pharmaceutical intermediate, preparation method thereof and method for preparing iloperidone by pharmaceutical intermediate
  • Pharmaceutical intermediate, preparation method thereof and method for preparing iloperidone by pharmaceutical intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0043] 4-[3-[4-(2,4-difluorophenyl)-(hydroxyimino)methyl]-1-piperidinyl]propoxy]-3-methoxyacetophenone (formula 1 Compound) preparation:

[0044] a) raw material compound: 2, the preparation of 4-difluorophenyl (4-piperidinyl) ketone oxime (compound of formula 2):

[0045] Mix 30g of 2,4-difluorobenzene-(4-piperidinyl)methanone hydrochloride (purchased by Beijing Gaobo Pharmaceutical Chemical Technology Development Co., Ltd.), 30g of hydroxylamine hydrochloride and 300ml of absolute ethanol, and heat to 80°C for reflux , stirring, the rotating speed is 120~130 rpm, and the reaction is 5 hours. Cool to room temperature, filter, mix the filter cake with 90ml of water, adjust the pH value to ≥11 with 30% potassium hydroxide aqueous solution, filter, and vacuum dry below 60°C to obtain 25g of white solid. The obtained white solid was tested by a YRT-3 melting point apparatus, and the melting point of the white solid was 214-218° C. after testing. Therefore, it can be seen that ...

Embodiment 2

[0051] 4-[3-[4-(2,4-difluorophenyl)-(hydroxyimino)methyl]-1-piperidinyl]propoxy]-3-methoxyacetophenone (formula 1 The preparation of the shown compound):

[0052] 4.8g 2,4-difluorophenyl (4-piperidinyl) ketone oxime, 5g 4-chloropropoxy-3-methoxyacetophenone, 3.5g potassium carbonate, 0.1g sodium iodide and 60ml of N,N-dimethylformamide was mixed, heated and stirred, and reacted at 80°C for 8 hours. Cool to room temperature, add 200ml of water and 80ml of dichloromethane for liquid separation, wherein the water layer in the reaction system is extracted twice with dichloromethane, 50ml each time, the organic layer is combined, washed with water, and dried with anhydrous magnesium sulfate , and concentrated to dryness to obtain 7.7 g of the product with a yield of 86.5%. The product is tested by a YRT-3 melting point apparatus, and the melting point of the product is 138-142° C. after testing. Therefore, it can be seen that the resulting product is a compound 4-[3-[4-(2,4-difl...

Embodiment 3

[0054] 4-[3-[4-(2,4-difluorophenyl)-(hydroxyimino)methyl]-1-piperidinyl]propoxy]-3-methoxyacetophenone (formula 1 Shown compound) the preparation of hydrochloride:

[0055] With 6g 4-[3-[4-(2,4-difluorophenyl)-(hydroxyimino)methyl]-1-piperidinyl]propoxy]-3-methoxyacetophenone and Mix and stir with 24ml of ethanol, the stirring speed is 120-130 rpm, add hydrochloric acid ethanol solution dropwise to the reaction system, so that the pH of the reaction system is ≤2, after the white solid is precipitated, filter and vacuum dry below 60°C, 6 g of product were obtained in a yield of 93.7%. The product is tested by a YRT-3 melting point apparatus, and the melting point of the product obtained through testing is 190-193°C. Therefore, the obtained product is 4-[3-[4-(2,4-difluorophenyl)-(hydroxyimino)methyl]-1-piperidinyl]propoxy]-3-methoxy Acetophenone (compound shown in formula 1) hydrochloride.

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Abstract

The invention provides a novel pharmaceutical intermediate compound in a formula (1), medicinal salt and a preparation method thereof. In the presence or absence of catalyst, the pharmaceutical intermediate compound of the invention is obtained by mixing, heating and stirring the compounds in formulas (2) and (3) with organic solvent in the presence of alkali. The medicinal salt of the pharmaceutical intermediate compound is obtained by mixing the compound in the formula (1) with another organic solvent, adding corresponding acid into the mixture and adjusting the pH value of the system. The preparation method is simple, has higher yield, and is very applicable to industrial production. The invention further provides a method for preparing iloperidone by the pharmaceutical intermediate compound or the medicinal salt thereof, which comprises the steps of mixing the compound in the formula (1) or the medicinal salt thereof with the solvent, cyclization reacting in the presence of alkali, and then obtaining the iloperidone in a formula (4). The invention overcomes the defect of the existing iloperidone synthesizing method, has higher yield compared with the existing method, and is applicable to large-scale industrial production.

Description

technical field [0001] The invention belongs to the field of medicine. Specifically, the present invention relates to a pharmaceutical intermediate, more specifically, the present invention relates to an iloperidone intermediate and a preparation method thereof. The present invention also relates to a method for preparing iloperidone using the iloperidone intermediate of the present invention. Background technique [0002] The chemical name of iloperidone is 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy Base]-3-methoxyphenyl]ethanone, its chemical structural formula is as follows: [0003] [0004] iloperidone [0005] Iloperidone has anti-schizophrenia activity, and the clinical phase III shows better tolerance and safety than existing anti-psychotic drugs, and it is expected to become a good anti-schizophrenia drug. [0006] U.S. Patent US5776963 and its family patent EP402644 disclose the preparation method of iloperidone, and its synthetic rout...

Claims

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Application Information

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IPC IPC(8): C07D211/28C07D413/04
Inventor 陈蔚潘毅靳朝东薛津陶勇
Owner 天津泰普制药有限公司
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