Method for preparing 6-fluoro-3-(4- piperidyl)-1,2-benzo isoxazole hydrochlorate
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A technology of benzisoxazole hydrochloride and piperidinyl, which is applied in the field of chemical synthesis and can solve problems such as low water solubility, difficult separation, and affecting the yield of risperidone
Active Publication Date: 2008-12-24
CSPC OUYI PHARM CO LTD
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[0015] Due to the low water solubility of the dimer (VI), it is very difficult to separate the dimer (VI) from risperidone, which directly affects the yield of risperidone
In addition, the existence of the dimer (VI) makes the use of risperidone increase indefinite risk factors, which affects the efficacy of risperidone.
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Embodiment 1
[0027] Under stirring at room temperature, mix 13.6 g (0.049 mol) of 2,4-difluorophenyl (4-piperidinyl) ketone oxime hydrochloride, 6.9 g (0.123 mol) of solid KOH powder and 109 ml of acetone, and heat up to 55 ~60°C, reflux reaction for 2 hours; after the reaction, add an appropriate amount of anhydrous sodium sulfate to dry, cool to room temperature, stir for 30 minutes, and filter; pass HCl gas into the filtrate, and crystallize; filter and dry to obtain 6-fluoro - 3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride 12.25g, yield 97.47%, content>99%.
Embodiment 2
[0029] Under stirring at room temperature, 13.6 g (0.049 mol) of 2,4-difluorophenyl (4-piperidinyl) ketone oxime hydrochloride, 8.23 g (0.147 mol) of solid KOH powder and N, N-dimethyl Mix 136ml of formamide, heat up to 40-45°C, and reflux for 3 hours; after the reaction, add an appropriate amount of anhydrous sodium sulfate, cool down to room temperature, stir for 30 minutes, and filter; pass HCl gas into the filtrate, and crystallize; filter , and dried to obtain 11.69 g of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride, with a yield of 93.01% and a content of >99%.
Embodiment 3
[0031] Under stirring at room temperature, mix 24 g (0.1 mol) of 2,4-difluorophenyl (4-piperidinyl) ketone oxime, 11.2 g (0.2 mol) of solid KOH powder and 120 ml of N, N-dimethylacetamide , heated up to 45-50°C, and refluxed for 1 hour; after the reaction, add an appropriate amount of anhydrous sodium sulfate, cool down to room temperature, stir for 30 minutes, and filter; pass HCl gas into the filtrate, and crystallize; filter, dry, and get 24.55 g of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride, yield 95.7%, content>99%.
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Abstract
The invention relates to a method for preparing a hydrochloride of 6-Fluoro-3-(4-piperidinyl)-1,2-benzisoxazole. The method is to subject 2,4-difluorophenyl(4-piperidinyl) ketoxime or a hydrochloride thereof to cyclopropanation and salifying in an aprotic solvent containing an alkali metal hydroxdide, wherein the molar ratio of the 2,4-difluorophenyl(4-piperidinyl) ketoxime or a hydrochloride thereof to the alkali metal hydroxide is 1 to between 1 and 3. The method can effectively prevent F atoms on para positions from participating in the reaction and avoid the production of a dipolymer (V), thereby avoiding the production of a dipolymer (VI) during the following preparation of risperidone. The method crystallizes crystals of a target substance directly by salifying, thereby solving the problems of use of a plurality of kinds of organic solvents, complex operation and low yield due to the extraction by toluene, condensation, and crystallization of petroleum ether. The yield rate of the target substance is more than 80 percent, and the purity of target substance is more than 99 percent.
Description
technical field [0001] The invention relates to a preparation method of a compound, in particular to 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride, which belongs to the technical field of chemical synthesis. Background technique [0002] Risperidone is the general name of the compound of structural formula (I), and its chemical name is 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidine Base]ethyl]-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one, a potent A serotonin antagonist, especially for the treatment of schizophrenia. [0003] [0004] At present, a variety of methods for the synthesis of risperidone have been reported. In these methods for preparing risperidone, the intermediate benzisoxazole derivatives, namely 6-fluoro-3-(4-piperidinyl)-1 , 2-benzisoxazole hydrochloride, its structure is as formula (II). [0005] [0006] Hungarian patent HU-195,793 and the corresponding European patent EP-196132 disclose a method for preparing r...
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