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New synthesis method of paliperidone

A technology of paliperidone and compounds, applied in the field of drug synthesis, to achieve high purity, be conducive to industrial production, and avoid the effects of column chromatography purification of finished products

Inactive Publication Date: 2018-07-06
JIANGSU HANSOH PHARMA CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0016] Aiming at the problems of low purity of crude product, long reaction time and difficulty in product purification in the preparation of paliperidone in the prior art, the present invention provides a synthetic high-purity paliperidone with simple production process, low cost and little pollution. The method is aimed at overcoming the relatively large shortcoming of impurity A existing in the above paliperidone synthesis method, improving the refining yield, and being suitable for industrial production requirements

Method used

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  • New synthesis method of paliperidone
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  • New synthesis method of paliperidone

Examples

Experimental program
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Effect test

Embodiment 1

[0026] Add 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (10.0g, 39mmol), 10ml of diisopropylamine, 3-(2-chloro Ethyl)-6,7,8,9-tetrahydro-9-hydroxyl-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (9.5g, 39mmol), under nitrogen protection Quickly add 50ml of anhydrous and oxygen-free methanol, stir the reaction solution for 10min, raise the temperature to 60°C and keep it warm for 22-24h. Take an appropriate amount of the reaction solution and send it to HPLC. The content of compound I is 88.79%, and the content of impurity A is 0.16%. The reaction solution is cooled to 5-15°C, filtered, and the obtained filter cake is added to 100ml of water and stirred for 1 hour, filtered, washed with a little ethanol, and dried to obtain Compound I: 14.9 g (35 mmol), molar yield 90%. The sample was sent to HPLC, and the detected compound I content was 98.92%, and the impurity A content was 0.15%.

Embodiment 2

[0028] Add 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (10.0g, 39mmol), 50ml of methanol, 1.0g of sodium sulfite, and 10ml of diisopropylamine into a 250ml three-necked flask in sequence , the reaction solution was stirred for 10min, and 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidine- 4-ketone (9.5g, 39mmol), the temperature of the reaction solution was raised to 60°C and the reaction was kept for 22-24h. Take an appropriate amount of the reaction solution and send it to HPLC. The content of compound I is 85.72%, and the content of impurity A is 0.03%. The reaction solution is cooled to 0-10°C, filtered, and the obtained filter cake is added to 100ml of water and stirred for 1 hour, filtered, washed with a little ethanol, and dried to obtain Compound I: 14.1 g (33 mmol), molar yield 85%. The sample was sent to HPLC, and the detected compound I content was 98.76%, the impurity A content was 0.03%, and the residue on ignition: ...

Embodiment 3

[0030] Add 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (10.0g, 39mmol), 50ml of methanol, 0.1g of sodium sulfite, and 10ml of diisopropylamine into a 250ml three-necked flask in sequence , the reaction solution was stirred for 10min, and 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidine- 4-ketone (9.5g, 39mmol), the temperature of the reaction solution was raised to 60°C and the reaction was kept for 22-24h. Take an appropriate amount of the reaction solution and send it to HPLC. The content of compound I is 82.27%, and the content of impurity A is 0.05%. The reaction solution is cooled to 0-10°C, filtered, and the obtained filter cake is added to 100ml of water and stirred for 1 hour, filtered, washed with a little ethanol, and dried to obtain Compound I: 14.2 g (33 mmol), molar yield 85%. The sample was sent to HPLC, and the compound I content was detected as 98.76%, the impurity A content was 0.04%, and the residue on ignitio...

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Abstract

The invention relates to a new synthesis method of paliperidone. 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride and 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one which are used as starting materials are reacted in the presence of a reducing reagent and an acid binding agent to obtain the paliperidone. The reducing agent is added in the reaction, so side reactions are reduced, the content of every impurity in the obtained finished product is significantly reduced, especially the content of the key impurity A is significantly reduced, the product has a high purity, and the method is simple to operate, and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of drug synthesis, in particular to a method for synthesizing paliperidone. Background technique [0002] Paliperidone, chemical name (±)-3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl ]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one is a new type of SARS Type antipsychotic drugs, which belong to benzisoxazole derivatives, were approved by the FDA in December 2006 for the treatment of schizophrenia. Janssen was approved by SFDA for import in October 2008, and the trade name was Invega. This product acts as dopamine type 2 (D 2 ) and 5-hydroxytryptamine type 2 (5HT 2A ) receptor antagonist, which is superior to the traditional drug olanzapine in terms of safety and drug resistance, and has fewer metabolic disorders, so it has good development prospects. [0003] There are many synthetic methods for preparing paliperidone, but all of them will produce impurity A, which will affec...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 杨勇盛志辉宋志刚陈安丰周炳城
Owner JIANGSU HANSOH PHARMA CO LTD
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