A method for purifying 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride

Abstract

The application discloses a purification method of a risperidone intermediate, 6-fluoro-3-(4-piperidyl)-1,2-benzisoxazole hydrochloride shown in formula II, characterized in that the purification method comprises the following steps: adding 6-fluoro-3-(4-piperidyl)-1,2-benzisoxazole hydrochloride into ethanol, adding a certain amount of water, heating to reflux until the solution is clear, cooling to a certain temperature to perform crystal growing, then cooling to-5-10 DEG C, filtering and drying to obtain the product. The purification method of 6-fluoro-3-(4-piperidyl)-1,2-benzisoxazole hydrochloride provided by the application can effectively separate the formula V dimer, the purification yield is more than 85%, the chemical purity of the finished product can reach more than 99.9%, and the method will not produce amplification effect in mass production, and the process is stable.

Description

TECHNICAL FIELD

[0001] The present invention relates to a method for purifying 6-fluoro-3-(4-piperidyl)-1,2-benzisoxazole hydrochloride, belonging to the field of organic chemical synthesis. BACKGROUND

[0002] Risperidone is a potent serotonin antagonist for the treatment of psychotic disorders, especially for the treatment of schizophrenia.

[0003] The chemical name of risperidone is 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, and its structural formula is shown as formula I:

[0004]

[0005] At present, there are many reported methods for synthesizing risperidone, and the intermediate benzisoxazole derivative, i.e. 6-fluoro-3-(4-piperidyl)-1,2-benzisoxazole hydrochloride, is used in these methods for preparing risperidone, and its structural formula is shown as formula II:

[0006]

[0007] European patent EP-196132 discloses a method for preparing risperidone, which is obtained by reacting a compound of formula (III) with a compound of formula (II).

[0008]

[0009] In the patent, the compound of formula II, 6-fluoro-3-(4-piperidyl)-1,2-benzisoxazole hydrochloride, is prepared from the compound of formula (IV), 2,4-(difluorophenyl)-4-piperidyl ketoxime, by high-temperature reaction in aqueous potassium hydroxide solution, the reaction solution is extracted and dried with toluene, and the residue is crystallized with petroleum ether.

[0010]

[0011] During the reaction, the ortho F atom undergoes cyclization reaction with the hydroxyl group of the oxime to obtain the target compound, but the para F atom also participates in the reaction to generate 5% of a dimer, as shown in formula (V):

[0012]

[0013] After the crude product is extracted and dried with toluene, and then crystallized with petroleum ether, the content of the dimer of formula V in 6-fluoro-3-(4-piperidyl)-1,2-benzisoxazole is still about 5%, and the purification effect is not obvious.

[0014] Chinese patent CN101328173 discloses a method for preparing 6-fluoro-3-(4-piperidyl)-1,2-benzisoxazole hydrochloride, which comprises the following steps: mixing 2,4-(difluorophenyl)-4-piperidyl ketoxime with potassium hydroxide powder and acetone, heating to 55-60℃, refluxing for 2 hours; then adding appropriate amount of anhydrous sodium sulfate to dry, cooling to room temperature, stirring for 30 minutes, filtering; then passing HCl gas into the filtrate, crystallizing to precipitate; filtering and drying to obtain 6-fluoro-3-(4-piperidyl)-1,2-benzisoxazole hydrochloride, with a yield of 97.47% and a content of >99%; the method is complicated, and the product quality is low due to the explosion phenomenon and the wrapping of impurities.

[0015] PCT patent WO2010082110 example 2 first uses ammonia to free 6-fluoro-3-(4-piperidyl)-1,2-benzisoxazole hydrochloride, then adds tartaric acid to remove impurities, and finally generates hydrochloride, with a purity of 99.93% and an impurity (V) of 0.05%. However, the method is complicated and not suitable for industrial mass production.

[0016] Chinese Journal of Pharmaceuticals, 2018, 49(12), P1670-1672 discloses an improved synthesis process of 6-fluoro-3-(4-piperidyl)-1,2-benzisoxazole hydrochloride. The method uses a mixed solvent of toluene and water for cyclization, then adds hydrochloric acid-ethanol in ethanol to adjust the pH for salting out, and directly cools and crystallizes. In the finished product obtained in the pilot test, the content of the formula V dimer impurity is 0.68%, but when the kilogram-level amplification is carried out, the content of the formula V dimer impurity increases to 1.018%. In actual production, with the increase of the amount of reactants, the amplification effect is enhanced, and the content of the formula V dimer impurity continuously increases, and even some batches reach more than 2%.

[0017] Since the formula V dimer impurity has low water solubility and is difficult to remove, and the impurity can participate in the subsequent reaction to generate formula VI dimer impurity, leading to the exceeding of the single impurity in the final risperidone product, and the formula VI dimer impurity is difficult to remove, it is necessary to develop a purification method for a high-purity risperidone intermediate 6-fluoro-3-(4-piperidyl)-1,2-benzisoxazole hydrochloride.

[0018] SUMMARY

[0019] The technical problem to be solved by the present application is to overcome the shortcomings of the prior art and provide a purification method for a risperidone intermediate 6-fluoro-3-(4-piperidyl)-1,2-benzisoxazole hydrochloride, which has the characteristics of simple operation and high purification efficiency.

[0020] The object of the present application is achieved by the following technical solutions.

[0021] A purification method of a risperidone intermediate 6-fluoro-3-(4-piperidyl)-1,2-benzisoxazole hydrochloride, which comprises adding 6-fluoro-3-(4-piperidyl)-1,2-benzisoxazole hydrochloride into ethanol, adding a certain amount of water, heating to reflux until clear, cooling to a certain temperature for crystallization, and then cooling to-5-10℃. Filtration and drying are performed to obtain the product.

[0022] Preferably, the mass-volume ratio of 6-fluoro-3-(4-piperidyl)-1,2-benzisoxazole hydrochloride, ethanol and water is 0.4-0.6:2-3:1.

[0023] Preferably, after heating to reflux until clear, cooling to 60-70℃ for crystallization for 1-6 hours, and then cooling to-5-10℃ for 1-6 hours;

[0024] Preferably, the 6-fluoro-3-(4-piperidyl)-1,2-benzisoxazole hydrochloride is prepared by cyclization reaction of 2,4-difluorophenyl(4-piperidyl)methanone oxime or its hydrochloride in a mixed solvent containing solid potassium hydroxide, toluene and water, and the product obtained after cyclization is dissolved in ethanol, and then salified by adjusting pH to 2-3 with hydrochloric acid,

[0025]

[0026] Preferably, the 6-fluoro-3-(4-piperidyl)-1,2-benzisoxazole hydrochloride obtained after salification can be directly subjected to the next purification step without separation from ethanol.

[0027] The purification method of 6-fluoro-3-(4-piperidyl)-1,2-benzisoxazole hydrochloride provided by the present application can effectively separate the dimer of formula V, and the purification yield is above 85%, the chemical purity of the finished product can reach above 99.9%, and the process is stable without magnification effect in mass production. DETAILED DESCRIPTION

[0028] The present application is further described below in combination with specific embodiments.

[0029] Example 1

[0030] Preparation of 6-fluoro-3-(4-piperidyl)-1,2-benzisoxazole hydrochloride (prepared according to the method of patent EP-196132)

[0031] In a mixture containing 65 parts of 1,3-difluorobenzene, 130 parts of aluminum chloride, and 195 parts of dichloromethane, 95 parts of a solution of 1-acetyl-4-piperidine-carbonyl chloride in 65 parts of dichloromethane were added dropwise under cooling and stirring. After the addition was complete, stirring was continued at room temperature for 3 hours. The reaction mixture was then injected into a mixture of crushed ice and hydrochloric acid, and the product was extracted with dichloromethane. The organic layer was dried, filtered, and evaporated to give a residue of 48 parts of 1-acetyl-4-(2,4-difluorobenzoyl)piperidine, in a yield of 36%.

[0032] A mixture containing 48 parts of 1-acetyl-4-(2,4-difluorobenzoyl)piperidine and 180 parts of 6N hydrochloric acid solution was stirred and heated under reflux for 5 hours. The reaction mixture was evaporated, and the residue was stirred in a solution of 2-propanol. The product was filtered and dried to give 39 parts of (2,4-difluorophenyl)(4-piperidinyl) methyl ketone salt, with a hydrochloric acid yield of 83%.

[0033] A mixture containing 12 parts of (2,4-difluorophenyl)(4-piperidinyl) ketone salt, 12 parts of hydroxylamine hydrochloride and 120 parts of ethanol was stirred at room temperature and heated under reflux for 3 hours. After cooling, the precipitate was filtered and dried to give 11 parts of (2,4-difluorophenyl)(4-piperidinyl) ketone oxime, with a yield of 100%.

[0034] Stir a mixture containing 11 parts (2,4-difluorophenyl)(4-piperidinyl) methyl ketone oxime, 25 parts potassium hydroxide and 25 parts water, heat under reflux for 2 hours, cool the reaction mixture, extract with toluene, dry, filter and evaporate the extract to obtain the residue;

[0035] The content of V-dimer impurity in the residue was found to be 5%. The residue was then crystallized with petroleum ether to obtain 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole. The purity of the obtained 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole was found to be 94.90%, with the content of V-dimer impurity still being 5%, and the yield being 70.34%. The experiment showed that this technique cannot effectively remove V-dimer impurity.

[0036] Example 2:

[0037] The 6-fluoro-3-(4-piperidyl)-1,2-benzisoxazole hydrochloride obtained in Example 1 (22 g) was added to 105 ml of anhydrous ethanol, then 40 ml of water was added, and heated to 70-80°C to reflux until the solution was clear, cooled to 60-70°C, and stirred for 60 minutes, then continued to cool to -5-5°C, and stirred for 60 minutes, filtered, and dried to obtain 6-fluoro-3-(4-piperidyl)-1,2-benzisoxazole hydrochloride with a purity of 99.90%, and the content of the dimer impurity of formula V was N.D (not detected), and the yield was 90.27%. Experiments showed that the technical scheme can effectively remove the dimer impurity of formula V, and the yield is high.

[0038] Example 3:

[0039] Into a 1L three-necked flask was added 150 ml of toluene, 150 ml of drinking water, 45 g of solid potassium hydroxide powder, and 35 g of acetone oxime wet material, and refluxed at 80°C for 6 hours. The material was cooled to room temperature, and allowed to stand and separate into layers. The lower aqueous layer was extracted with toluene, and the toluene phases were combined and distilled under reduced pressure. After distillation, 175 ml of anhydrous ethanol was added to the flask to dissolve the material, then 10-13 ml of hydrochloric acid was added until the pH was 2.0-3.0, then 67 ml of drinking water was added, heated to 80°C to reflux until the solution was clear, then cooled to 70-80°C, and stirred for 1 hour, then continued to cool to 20-40°C, then continued to cool to -5-0°C, and stirred for 1 hour, filtered, and washed with 50 ml of anhydrous ethanol, and dried to obtain white powder solid 6-fluoro-3-(4-piperidyl)-1,2-benzisoxazole hydrochloride with a purity of 99.90%, and the yield was 85.27%, and the content of the dimer impurity of formula V was N.D (not detected).

[0040] Example 4:

[0041] Under a nitrogen atmosphere, acetone oxime wet product (152 kg), potassium hydroxide (120 kg, 2142.5 mol), water (600 L), and toluene (600 L) were added to a 2000 L reaction kettle, stirring was started, and heating was started to reflux for 6 h. The reaction liquid was cooled to room temperature, and allowed to stand and separate into layers. The lower aqueous layer was extracted with toluene (600 L), and the toluene phases were combined and concentrated to dryness under reduced pressure to obtain brown solid. The solid was dissolved with anhydrous ethanol (600 L), then hydrochloric acid was added to adjust the pH to 2-3, then 267 L of drinking water was added, then heated to 70-80°C to reflux until the solution was clear, then cooled to 60-70°C, and stirred for 1 h, then continued to cool to -5-5°C, and stirred for 1 h, filtered, and dried. The final obtained 6-fluoro-3-(4-piperidyl)-1,2-benzisoxazole hydrochloride had a purity of 99.91%, and the yield was 86.33%; and the content of the dimer impurity of formula V was N.D (not detected).

[0042] Comparative Example 1:

[0043] Ketoxime wet product (304 kg), potassium hydroxide (240 kg, 4285 mol), water (1200 L) and toluene (1200 L) were added into a 3000 L reactor under nitrogen atmosphere. The reaction was heated to reflux for 6 h with stirring. The reaction was cooled to room temperature and allowed to separate into layers. The lower aqueous layer was extracted with toluene (1200 L) and the toluene phases were combined. The toluene phase was concentrated to dryness under reduced pressure to give a brown solid. The solid was dissolved in anhydrous ethanol (1200 L) and the pH was adjusted to 2-3 with hydrochloric acid-ethanol while controlling the temperature at 10-20 °C. The solution was cooled to 0 °C and allowed to crystallize for 1 h. Finally, a white powdery solid (218 kg) was obtained with a yield of 75.6% and a purity of 97.8% and a 4-dimer impurity content of 2.018%.

Claims

1. A method for purifying a risperidone intermediate, such as 6-fluoro-3-(4- piperidinyl)-l,2-benzisoxazole hydrochloride, shown as Formula II, characterized by, ###00001### Formula II, wherein the method comprises the steps of: a) dissolving the risperidone intermediate in a solvent; b) adding a base to the solution; c) adding a salt to the solution; d) filtering the solution; and e) drying the filtered solution. The purification method is that 6-fluoro-3-(4-piperidyl)-1,2-benzisoxazole hydrochloride is added into ethanol, a certain amount of water is added, heated to reflux until dissolved, cooled to a certain temperature for crystallization, then cooled to-5-10℃, filtered, and dried to obtain; The mass-volume ratio g:ml:ml of 6-fluoro-3-(4-piperidyl)-1,2-benzisoxazole hydrochloride, ethanol and water is 0.4-0.6:2-3:

1. After heated to reflux until dissolved, cooled to 60-70℃ for crystallization for 1-6 hours, then cooled to-5-10℃, and the cooling time is 1-6 hours.

2. The method of purifying a risperidone intermediate according to claim 1, wherein, The 6-fluoro-3-(4-piperidyl)-1,2-benzisoxazole hydrochloride is obtained by cyclization reaction of 2,4-difluorophenyl(4-piperidyl)methanone oxime or its hydrochloride of formula III in a mixed solvent containing solid potassium hydroxide, toluene and water, the obtained product after cyclization is dissolved in ethanol, and then hydrochloric acid is used to adjust the pH to 2-3 to form a salt, 3. The method of purifying a risperidone intermediate according to claim 2, wherein, The obtained 6-fluoro-3-(4-piperidyl)-1,2-benzisoxazole hydrochloride after salt formation can be directly used for the next purification step without separation from ethanol.

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