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A method suitable for industrialized production of high-purity 9-hydroxyrisperidone

A technology of hydroxyrisperidone and technical solutions, which is applied in the field of preparation and purification of the anti-schizophrenia drug 9-hydroxyrisperidone, which can solve the problems of using a large amount of solvents, difficult purification, and low reaction yield

Active Publication Date: 2016-06-15
JIANGSU QINGJIANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method is relatively simple to operate, but the reaction yield is low, the product purity is not high, and it needs multiple refining to meet the requirements
[0009] To sum up, the preparation and purification of (I) reported in the literature currently have disadvantages such as cumbersome operation, use of a large amount of solvents, and difficulty in purification. Therefore, it is necessary to develop a method for the production of (I) that is easy to operate and easy to purify.

Method used

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  • A method suitable for industrialized production of high-purity 9-hydroxyrisperidone
  • A method suitable for industrialized production of high-purity 9-hydroxyrisperidone
  • A method suitable for industrialized production of high-purity 9-hydroxyrisperidone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Accurately weigh (II) hydrochloride (48.77g, 0.195mol), (III) (48.54g, 0.2mol), sodium bicarbonate (50.40g, 0.6mol), potassium iodide (3.3g, 0.02mol), acetonitrile 400mL Put 100mL of water in a 1000mL three-necked bottle, heat up to 65 oC , After 16h of reaction, stop the reaction. cool down to 25 oC, slowly added 1000mL of water to the system, a large amount of solid matter was precipitated, after stirring for 30min, the crude product was obtained by filtration, the filter cake was washed with acetonitrile and water respectively, and the dried crude product was 72.0g.

[0037] Put 72.0g of (I) crude product in 720mL water, control the temperature at 20-25 oC , add 16.8mL of concentrated hydrochloric acid, stir to form (I) hydrochloride, wash the aqueous solution of (I) twice with 500mL of dichloromethane, take the aqueous solution layer, add 7.2g of activated carbon for decolorization, and heat up to 50 oC , after stirring for 30 min, filtered to obtain (I) hydrochl...

Embodiment 2

[0041] Accurately weigh (II) hydrochloride (170.5g, 0.665mol), (III) (169.9g, 0.7mol), sodium bicarbonate (176.4g, 2.1mol), potassium iodide (11.5g, 0.07mol), DMF850mL and Put 350mL of methanol in a 2500mL three-necked bottle and heat up to 65 oC , After 20h of reaction, stop the reaction. cool down to 40 oC , slowly added 1500mL of water to the system, a large amount of solid matter was precipitated, after stirring for 30min, the crude product was obtained by filtration, the filter cake was washed with acetonitrile and water respectively, and the dried crude product was 280.0g.

[0042] Put 280.0g of (I) crude product in 1400mL water, control the temperature at 20-25 oC , add 58.8mL of concentrated hydrochloric acid, stir to form (I) hydrochloride, wash the aqueous solution of (I) twice with 1000mL of dichloromethane, take the aqueous solution layer, add 28.0g of activated carbon for decolorization, and heat up to 50 oC , after stirring for 30 min, filtered to obtain (I) h...

Embodiment 3

[0046] Accurately weigh (II) hydrochloride (48.77g, 0.195mol), (III) (48.54g, 0.2mol), triethylamine (60.6g, 0.6mol), potassium iodide (3.3g, 0.02mol), methanol 250mL In a 1000mL three-necked bottle, heat up to 60 oC , After 24h of reaction, stop the reaction. cool down to 25 oC , slowly add 1000mL of water to the system, a large amount of solid matter is precipitated, after stirring for 30min, the crude product is obtained by filtration, the filter cake is washed with methanol and water respectively, and the dried crude product is 75.0g.

[0047] Put 75.0g of (I) crude product in 400mL water, control the temperature at 20-25 oC , add 17.8mL of concentrated hydrochloric acid, stir to form (I) hydrochloride, the aqueous solution of (I) is washed twice with 500mL of ethyl acetate, take the aqueous solution layer, add 10.0g of activated carbon for decolorization, stir at room temperature for 30min, and filter to obtain (I ) in aqueous solution of hydrochloride.

[0048] Cool ...

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PUM

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Abstract

The invention discloses a method suitable for industrial production of high-purity 9-hydroxy-risperidone. According to the method, the 9-hydroxy-risperidone is prepared by carrying out condensation on 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole and 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]-pyrimidin-4-one in a polar solvent system; by optimizing post-treatment operation and improving a refining method, the high-yield and high-purity 9-hydroxy-risperidone can be prepared by utilizing the steps of sedimentation, salifying, alkali regulation, crystallization and the like; the post-treatment and the refining method disclosed by the invention has the advantages of simplicity and convenience in operation, low production cost and high product purity and are suitable for use in the industrial production.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a method for preparing and purifying anti-schizophrenia drug 9-hydroxyrisperidone. Background technique [0002] Paliperidone, 9-hydroxyrisperidone (I), chemical name 3-[2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-1-piperidinyl]ethyl Base]-7-hydroxy-4-methyl-1,5-diazabicyclo[4.4.0]dec-3,5-dien-2-one, a new drug for the treatment of schizophrenia, belongs to benzene 5-HT antagonists of the class of isoxazole derivatives, which are themselves active metabolites of risperidone. Its structural formula is [0003] [0004] There are many reports on the preparation method of (I), and the most researched and used method for industrial preparation is the use of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (II) and 3- (2-Chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy 2-methyl-4H-pyrido[1,2-a]-pyrimidin-4-one (III) as starting material, The two undergo condensation reaction under certain cond...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04
Inventor 汪武卫陈洁吴廷照顾海成何佳
Owner JIANGSU QINGJIANG PHARMA