Purification method of 6-fluoro-3-(4-piperidyl)-1,2-benzoisoxazole hydrochloride

Abstract

The invention discloses a purification method of a risperidone intermediate 6-fluoro-3-(4-piperidyl)-1,2-benzoisoxazole hydrochloride as shown in a formula II, which is characterized by comprising the following steps: adding 6-fluoro-3-(4-piperidyl)-1,2-benzoisoxazole hydrochloride into ethanol, adding a certain amount of water, and carrying out heating reflux until the solution is clear to obtain the risperidone intermediate 6-fluoro-3-(4-piperidyl)-1,2-benzoisoxazole hydrochloride; and cooling the compound to a certain temperature for crystal growing, then cooling the mixture to -5 to 10 DEG C, and filtering and drying the mixture to obtain the crystal. According to the purification method of the 6-fluoro-3-(4-piperidyl)-1,2-benzoisoxazole hydrochloride, the dimer shown as the formula V can be effectively separated out, the purification yield is 85% or above, the chemical purity of a finished product can reach 99.9% or above, an amplification effect cannot be generated in large-scale production, and the process is stable.

Description

Technical field[0001]The present invention relates to a purification method of 6-fluorine-3- (4-piperidinyl) -1,2-benzoxazole hydrochloride, belonging to the field of organic chemical synthesis.[0002]technical background[0003]Ryperidone is a potent 5-hydroxine antagonist for the treatment of psychiatric disorders, particularly for the treatment of schizophrenia.[0004]The chemical name of risperketone is 3- [2- [4- (6-fluoro-1,2-benzoisoxazole-3-yl)-1-piperidyl] ethyl] -6, 7, 8 , 9-tetrahydro-2-methyl-4H-pyridine and [1,2-α] pyrimidine-4-ketone, its structural formula is shown in Formula I:[0005][0006]At present, there are many synthesis methods of risperketone, and these methods for preparing limenone are used in the process of intermediate benzozozole derivatives, 6-fluoro-3- (4-piperidinyl) -1, 2. - Benzoxazole hydrochloride, its structural formula, as shown in the formula II:[0007][0008]European Patent EP-196132 discloses a method of preparing a limenone, which is to react with t...

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Problems solved by technology

[0014] After the crude product was extracted and dried with toluene, and then crystallized with petroleum ether, the content of the dimer of formula V in 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole was still 5% left and right, the purification effect is not obvious

[0015] Chinese patent CN101328173 discloses a preparation method of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride, which comprises 2,4-(difluorophenyl)- 4-piperidinyl ketoxime is mixed with potassium hydroxide powder and acetone, heated to 55-60°C, and refluxed for 2 hours; then added an appropriate amount of anhydrous sodium sulfate to dry, cooled to room temperature, stirred for 30 minutes, and filtered; then Pass HCl gas into the filtrate, and crystallize out; filter and dry to obtain 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride, the yield is 97.47%, and the content is >99% %; This method is cumbersome to operate, there will be detonation phenomenon, and it is easy to wrap impurities, resulting in low product quality

[0018] Because the water solubility of the dimer impurity of formula V is low and difficult to remove, and this impurity will participate in the follow-up reaction to generate the dimer impurity of formula VI, resulting in single impurity exceeding the standard in the final product of risperidone, and the dimer impurity of formula VI is very It is difficult to remove, so it is necessary to develop a purification method for high-purity risperidone intermediate 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride

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