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Method for producing 6-fluoro-3-(4-piperidine)-1,2-benzoisoxazole hydrochloride

A technology of benzisoxazole hydrochloride and production method, applied in the field of 6-fluoro-3--1, can solve problems such as low yield, difficulty in mass transfer in the system, and difficulty in industrialized production

Active Publication Date: 2014-07-02
CHANGZHOU NO 4 PHARMA FACTORY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

If the intramolecular dehydrofluorination ring-closure reaction is carried out with water-miscible aprotic solvents (such as acetone, DMF, DMSO, N-methylpyrrolidone), the mass transfer of the system is difficult, and it is difficult to industrialize production
If the aprotic solvent (such as ethylene glycol dimethyl ether, toluene) that is insoluble in water is used to carry out intramolecular dehydrofluorination ring closure reaction, then the yield of reaction is very low, is not suitable for suitability for suitability for industrialized production

Method used

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  • Method for producing 6-fluoro-3-(4-piperidine)-1,2-benzoisoxazole hydrochloride
  • Method for producing 6-fluoro-3-(4-piperidine)-1,2-benzoisoxazole hydrochloride
  • Method for producing 6-fluoro-3-(4-piperidine)-1,2-benzoisoxazole hydrochloride

Examples

Experimental program
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Effect test

Embodiment 1

[0029] In a 300-liter reactor, add 18 kilograms of water and 7.8 kilograms (195mol) of sodium hydroxide solid, stirring and dissolving. Add 180 kg of tert-butanol and 18 kg (65 mol) of 2,4-difluorophenyl (4-piperidinyl) ketone oxime hydrochloride. Heat and stir the reaction at 50°C for 3 hours. Cooling, standing at 30° C. for stratification, discarding the water phase, washing the organic phase with 30 kg of 20% by weight aqueous sodium chloride solution, and repeating the washing operation once. Add 6 liters (71mol) of concentrated hydrochloric acid dropwise to the organic phase after washing, stir and crystallize at 30°C for 3 hours, centrifuge, rinse with 2 kg of tert-butanol, and dry at 60°C until no weight loss is obtained to obtain 6-fluoro-3-(4 -Piperidinyl)-1,2-benzisoxazole hydrochloride 15.4 kg (60 mol), HPLC purity 99.3%, yield 92.3%.

Embodiment 2

[0031] In a 300-liter reactor, add 18 kg of water and 7.8 kg (195 mol) of sodium hydroxide solid, and stir to dissolve. Add 180 kg of the mother liquor in Example 1 and 18 kg (65 mol) of 2,4-difluorophenyl (4-piperidinyl) ketone oxime hydrochloride. Heat and stir the reaction at 50°C for 3 hours. Cooling, standing at 30° C. for stratification, discarding the water phase, washing the organic phase with 30 kg of 20% by weight aqueous sodium chloride solution, and repeating the washing operation once. Add 6 liters (71 mol) of concentrated hydrochloric acid dropwise to the organic phase after washing, stir and crystallize at 30°C for 3 hours, centrifuge, rinse with 2 kg of tert-butanol, and dry at 60°C until no weight loss is obtained to obtain 6-fluoro-3- (4-piperidinyl)-1,2-benzisoxazole hydrochloride 16.2 kg (63 mol), HPLC purity 99.0%, yield 97.2%.

Embodiment 3

[0033]In a 500-liter reactor, add 30 kg of water and 16.8 kg (300 mol) of potassium hydroxide solid, and stir to dissolve. Add 250 kg of tert-butanol and 25.65 kg (100 mol) of 2,4-difluorophenyl (4-piperidinyl) ketone oxime hydrochloride. Heat and stir the reaction at 50°C for 2 hours. Cooling, standing at 30°C for stratification, discarding the water phase, adding 40 kg of 25% by weight potassium chloride aqueous solution to the organic phase for washing, and repeating the washing operation once. Add 10 liters (120 mol) of concentrated hydrochloric acid dropwise to the organic phase after washing, stir and crystallize at 30°C for 3 hours, centrifuge, rinse with 3 kg of tert-butanol, and dry at 60°C until no weight loss is obtained to obtain 6-fluoro-3- (4-piperidinyl)-1,2-benzisoxazole hydrochloride 23.4 kg (91.20 mol), HPLC purity 99.4%, yield 91.2%.

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Abstract

The invention discloses a method for industrially producing 6-fluoro-3-(4-piperidine)-1,2-benzoisoxazole hydrochloride. The method comprises, subjecting 2,4-difluorophenyl-(4-piperidinyl)methanone oxime or hydrochloride thereof to intramolecular dehydrofluorination cyclization in mixed solvent of tertiary butanol and water in the presence of an alkali metal hydroxide; after the reaction, standing, demixing, discarding a water phase, washing an organic phase with aqueous solution of an inorganic salt with high water solubility, adding concentrated hydrochloric acid to form a salt, and performing centrifugal separation to obtain a product. In the invention, the cyclization and the post-treatment are performed in the same reaction kettle, the required equipment is simple, the on-site preparation of hydrogen chloride is not required in a production process, the mother liquor can be reduced in next cyclization without treatment, the production operation is simple and convenient, environment protection requirements are met, and the large-scale industrial production is easy.

Description

technical field [0001] The invention relates to a production method of a compound, in particular to a production method of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride. Background technique [0002] The chemical structural formula of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride is as I. [0003] [0004] The compound of formula I is an important intermediate for preparing anti-schizophrenia drugs risperidone and paliperidone. Oral formulations of risperidone are marketed under the trade name of Risperdal in the United States, and oral formulations of Paliperidone controlled release are listed under the trade name of Invega in the United States. They are anti-schizophrenia drugs widely used in clinical practice and belong to benzisoxazole derivatives class of 5-HT antagonists. It can be prepared by the following methods: [0005] Formula I compound and 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxyl 2-methyl-4H-pyrido[1,2-a]-pyrimidin-4-one ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D413/02
Inventor 董秀忠朱霞沈征葛纪龙屠永锐
Owner CHANGZHOU NO 4 PHARMA FACTORY