阅读说明：本技术 一种6-氟-3-（4-哌啶基）-1,2-苯并异噁唑盐酸盐的纯化方法 (Purification method of 6-fluoro-3- (4-piperidyl) -1, 2-benzisoxazole hydrochloride ) 是由 余文龙 赵祖 黄文锋 胡佳兴 于 2021-01-19 设计创作，主要内容包括：本发明公开一种利培酮中间体如式II所示的6-氟-3-(4-哌啶基)-1,2-苯并异噁唑盐酸盐的纯化方法,其特征在于,所述的纯化方法是将6-氟-3-(4-哌啶基)-1,2-苯并异噁唑盐酸盐加入到乙醇中,再加入一定量的水,加热回流至溶清,降温至一定温度进行养晶,然后再降温至-5～10℃,过滤,烘干得到。本发明提供的6-氟-3-(4-哌啶基)-1,2-苯并异噁唑盐酸盐的纯化方法,能有效地将式Ⅴ二聚体分离出去,纯化收率在85％以上,成品的化学纯度可达到99.9％以上,并且在大生产中不会产生放大效应,工艺稳定。(The invention discloses a method for purifying a risperidone intermediate 6-fluoro-3- (4-piperidyl) -1, 2-benzisoxazole hydrochloride shown as a formula II, which is characterized by adding 6-fluoro-3- (4-piperidyl) -1, 2-benzisoxazole hydrochloride into ethanol, adding a certain amount of water, heating and refluxing to be clear, cooling to a certain temperature for crystal growth, then cooling to-5-10 ℃, filtering and drying to obtain the risperidone intermediate. The purification method of 6-fluoro-3- (4-piperidyl) -1, 2-benzisoxazole hydrochloride provided by the invention can effectively separate out the dimer in the formula V, the purification yield is more than 85%, the chemical purity of a finished product can reach more than 99.9%, and the amplification effect can not be generated in large-scale production, and the process is stable.)

1. A method for purifying a risperidone intermediate 6-fluoro-3- (4-piperidyl) -1, 2-benzisoxazole hydrochloride shown as a formula II is characterized in that the risperidone intermediate is obtained by adding the 6-fluoro-3- (4-piperidyl) -1, 2-benzisoxazole hydrochloride into ethanol, adding a certain amount of water, heating and refluxing to be clear, cooling to a certain temperature for crystal growth, then cooling to-5-10 ℃, filtering and drying,

2. the method for purifying a risperidone intermediate according to claim 1, wherein the mass-to-volume ratio of 6-fluoro-3- (4-piperidinyl) -1, 2-benzisoxazole hydrochloride, ethanol, and water is 0.4-0.6: 2-3: 1.

3. The intermediate purification method of risperidone of claim 1 or 2, wherein the intermediate purification method comprises heating and refluxing to dissolve and clear, then cooling to 60-70 ℃ for crystal growth for 1-6 hours, then cooling to-5-10 ℃ for 1-6 hours.

4. The method for purifying the risperidone intermediate according to claim 1, wherein the 6-fluoro-3- (4-piperidinyl) -1, 2-benzisoxazole hydrochloride is obtained by performing cyclization reaction on 2, 4-difluorophenyl (4-piperidinyl) ketoxime represented by formula III or hydrochloride thereof in a mixed solvent containing solid potassium hydroxide, toluene and water, dissolving a product obtained after cyclization in ethanol, and adjusting pH to 2-3 with hydrochloric acid to form a salt,

5. the method for purifying risperidone intermediate according to claim 4, wherein the 6-fluoro-3- (4-piperidinyl) -1, 2-benzisoxazole hydrochloride obtained after salification can be directly subjected to the next purification step without separation from ethanol.

Technical Field

The invention relates to a purification method of 6-fluoro-3- (4-piperidyl) -1, 2-benzisoxazole hydrochloride, belonging to the field of organic chemical synthesis.

Technical Field

Risperidone is a potent 5-hydroxytryptamine antagonist for the treatment of psychotic disorders, particularly for the treatment of schizophrenia.

The chemical name of risperidone is 3- [2- [4- (6-fluoro-1, 2-benzisoxazol-3-yl) -1-piperidinyl ] ethyl ] -6,7,8, 9-tetrahydro-2-methyl-4H-pyrido [1,2- α ] pyrimidin-4-one, the structural formula of which is shown in formula I:

at present, a plurality of synthesis methods of risperidone are reported, and an intermediate benzisoxazole derivative, namely 6-fluoro-3- (4-piperidyl) -1, 2-benzisoxazole hydrochloride, is used in the methods for preparing risperidone, and the structural formula of the benzisoxazole hydrochloride is shown as a formula II:

european patent EP-196132 discloses a process for the preparation of risperidone by reacting a compound of formula (III) with a compound of formula (II) to obtain risperidone.

In the patent, the compound 6-fluoro-3- (4-piperidyl) -1, 2-benzisoxazole hydrochloride of the formula II is prepared by reacting a compound 2,4- (difluorophenyl) -4-piperidyl ketoxime of the formula (IV) in an aqueous solution of potassium hydroxide at high temperature, extracting and drying reaction liquid by using toluene, and crystallizing residues by using petroleum ether.

In the reaction process, the ortho-position F atom and the oxime hydroxyl group are subjected to cyclization reaction to obtain the target compound, however, the para-position F atom also participates in the reaction to generate 5% of dimer, as shown in formula (V):

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

Chinese patent CN101328173 discloses a preparation method of 6-fluoro-3- (4-piperidyl) -1, 2-benzisoxazole hydrochloride, which comprises the steps of mixing 2,4- (difluorophenyl) -4-piperidyl ketoxime with acetone in potassium hydroxide powder, heating to 55-60 ℃, and carrying out reflux reaction for 2 hours; then adding a proper amount of anhydrous sodium sulfate, drying, cooling to room temperature, stirring for 30 minutes, and filtering; then introducing HCl gas into the filtrate, and crystallizing and separating out; filtering and drying to obtain 6-fluoro-3- (4-piperidyl) -1, 2-benzisoxazole hydrochloride, wherein the yield is 97.47 percent, and the content is more than 99 percent; the method is complex to operate, can generate an explosive precipitation phenomenon, is easy to wrap impurities, and leads to lower product quality.

PCT patent WO2010082110 example 2 firstly uses ammonia water to dissociate 6-fluoro-3- (4-piperidyl) -1, 2-benzisoxazole hydrochloride, and then adds tartaric acid to form salt and remove impurities, and finally generates the hydrochloride with the purity of 99.93 percent and the impurity (V) of 0.05 percent. However, the method is complicated and not suitable for industrial mass production.

The journal of Chinese medical industry, 2018,49(12), P1670-1672 discloses an improvement of a synthesis process of 6-fluoro-3- (4-piperidyl) -1, 2-benzisoxazole hydrochloride, which comprises the steps of cyclizing in a mixed solvent of toluene and water, adding hydrochloric acid-ethanol dropwise into ethanol to adjust PH to form salt, and directly cooling and crystallizing. The final product obtained at the pilot plant had a dimer impurity content of formula v of 0.68%, but at kg scale up the dimer impurity content of formula v increased to 1.018%. In actual production, the amplification effect is enhanced with increasing amounts of reactants, and the content of the dimer impurity of formula v is continuously increased, even to more than 2% for some batches.

Because the dimer impurity of formula V has low water solubility and is not easy to remove, and the impurity can participate in the subsequent reaction to generate the dimer impurity of formula VI, the single impurity in the final product of risperidone exceeds the standard, and the dimer impurity of formula VI is difficult to remove, the development of a purification method of the risperidone intermediate 6-fluoro-3- (4-piperidyl) -1, 2-benzisoxazole hydrochloride with high purity is necessary.

Disclosure of Invention

The technical problem to be solved by the invention is to overcome the defects of the prior art and provide a method for purifying a risperidone intermediate 6-fluoro-3- (4-piperidyl) -1, 2-benzisoxazole hydrochloride, and the method has the characteristics of simple operation, high purification efficiency and the like.

The purpose of the invention is realized by the following technical scheme:

a method for purifying a risperidone intermediate 6-fluoro-3- (4-piperidyl) -1, 2-benzisoxazole hydrochloride comprises the steps of adding the 6-fluoro-3- (4-piperidyl) -1, 2-benzisoxazole hydrochloride into ethanol, adding a certain amount of water, heating and refluxing to be clear, cooling to a certain temperature for crystal growth, and then cooling to-5-10 ℃. Filtering and drying to obtain the product.

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

preferably, after heating and refluxing to be dissolved and clear, cooling to 60-70 ℃ for crystal growth for 1-6 hours, then cooling to-5-10 ℃ for 1-6 hours;

preferably, the 6-fluoro-3- (4-piperidyl) -1, 2-benzisoxazole hydrochloride is obtained by performing cyclization reaction on 2, 4-difluorophenyl (4-piperidyl) ketoxime shown in a formula III or hydrochloride thereof in a mixed solvent containing solid potassium hydroxide, toluene and water, dissolving a product obtained after cyclization with ethanol, adjusting pH to 2-3 with hydrochloric acid, and salifying,

preferably, the 6-fluoro-3- (4-piperidinyl) -1, 2-benzisoxazole hydrochloride obtained after salification can be directly subjected to the next purification step without isolation from ethanol.

The purification method of 6-fluoro-3- (4-piperidyl) -1, 2-benzisoxazole hydrochloride provided by the invention can effectively separate out the dimer in the formula V, the purification yield is more than 85%, the chemical purity of a finished product can reach more than 99.9%, and the amplification effect can not be generated in large-scale production, and the process is stable.

Detailed Description

The invention will be further illustrated with reference to specific embodiments:

example 1:

preparation of 6-fluoro-3- (4-piperidinyl) -1, 2-benzisoxazole hydrochloride (preparation by the process of reference patent EP-196132)

To a mixture containing 65 parts of 1, 3-difluorobenzene, 130 parts of aluminum chloride and 195 parts of dichloromethane, a solution of 95 parts of 1-acetyl-4-piperidine-carbonyl chloride in 65 parts of dichloromethane was added dropwise with cooling and stirring, after all of them were added dropwise, stirring was continued at room temperature for 3 hours, and the reaction mixture was poured into a mixture of crushed ice and hydrochloric acid to extract the product with dichloromethane. The organic layer was dried, filtered and evaporated to give 48 parts of 1-acetyl-4- (2, 4-difluorobenzoyl) piperidine as a residue in 36% yield.

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 is evaporated, the solution of the residue in 2-propanol is stirred, the product is filtered and dried to yield 39 parts of (2, 4-difluorophenyl) (4-piperidinyl) ketonate with a yield of 83% of hydrochloric acid.

A mixture containing 12 parts of (2, 4-difluorophenyl) (4-piperidyl) ketoxime, 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 obtain 11 parts of (2, 4-difluorophenyl) (4-piperidyl) ketoxime in a yield of 100%.

Stirring a mixture containing 11 parts of (2, 4-difluorophenyl) (4-piperidyl) ketoxime, 25 parts of potassium hydroxide and 25 parts of water, heating and refluxing for 2 hours, cooling the reaction mixture, extracting and drying with toluene, filtering and evaporating the extract to obtain a residue;

detecting the content of V dimer impurity in the residue to be 5%; crystallizing the residue with petroleum ether to obtain 6-fluoro-3- (4-piperidyl) -1, 2-benzisoxazole; the purity of the obtained 6-fluoro-3- (4-piperidyl) -1, 2-benzisoxazole is 94.90 percent, the content of the dimer impurity of the formula V is still 5 percent, the yield is 70.34 percent, and experiments show that the technique cannot effectively remove the dimer impurity of the formula V.

Example 2:

adding the 6-fluoro-3- (4-piperidyl) -1, 2-benzisoxazole hydrochloride (22g) obtained in example 1 into 105ml of absolute ethyl alcohol, then adding 40ml of water, heating to 70-80 ℃, refluxing to clear, cooling to 60-70 ℃, keeping the temperature and stirring for 60 minutes, then continuously cooling to-5 ℃, keeping the temperature and stirring for 60 minutes, performing suction filtration, drying, and purifying to obtain the 6-fluoro-3- (4-piperidyl) -1, 2-benzisoxazole hydrochloride with the purity of 99.90%, wherein the content of the dimer impurity of the formula V is N.D (not detected), the yield is 90.27%.

Example 3:

150ml of toluene, 150ml of drinking water, 45g of solid potassium hydroxide powder and 35g of ketoxime wet material are added into a 1L three-neck flask, reflux reaction is carried out for 6 hours at 80 ℃, the material is cooled to room temperature, and standing and layering are carried out. The lower aqueous layer was extracted with toluene, the toluene phases were combined and distilled under reduced pressure. After the distillation is finished, adding 175ml of absolute ethyl alcohol into a flask to dissolve the materials, adding 10-13 ml of hydrochloric acid into the flask until the pH value is 2.0-3.0, adding 67ml of drinking water, heating to 80 ℃ until the materials are dissolved clearly, cooling to 70-80 ℃, keeping the temperature and stirring for 1 hour, continuously cooling to 20-40 ℃, further cooling to-5-0 ℃, keeping the temperature and stirring for 1 hour, performing suction filtration, leaching with 50ml of absolute ethyl alcohol, and drying. The white powder solid 6-fluoro-3- (4-piperidinyl) -1, 2-benzisoxazole hydrochloride is obtained, the pure content is 99.90%, the yield is 85.27%, and the impurity content of the dimer of the formula V is n.d (not detected).

Example 4:

under nitrogen atmosphere, wet methyl ketoxime (152kg), potassium hydroxide (120kg, 2142.5mol), water (600L) and toluene (600L) were added to a 2000L reactor, stirring was turned on, and heating was started until reflux reaction was carried out for 6 h. The reaction solution was cooled to room temperature and allowed to stand for delamination. The lower aqueous layer was extracted with toluene (600L), the toluene phases combined and concentrated to dryness under reduced pressure to give a brown solid. Dissolving the solid with absolute ethyl alcohol (600L), adjusting the pH value to 2-3 with hydrochloric acid, adding 267L of drinking water, heating to 70-80 ℃, refluxing to clear solution, cooling to 60-70 ℃, keeping the temperature and stirring for 1h, continuously cooling to-5 ℃, keeping the temperature and stirring for 1h, performing suction filtration and drying to obtain the 6-fluoro-3- (4-piperidyl) -1, 2-benzisoxazole hydrochloride with the purity of 99.91% and the yield of 86.33%; dimer impurity content of formula V n.d (not detected).

Comparative example 1:

under nitrogen atmosphere, wet methyl ketoxime (304kg), potassium hydroxide (240kg, 4285mol), water (1200L) and toluene (1200L) were added to a 3000L reactor, stirring was started, and heating was started until reflux reaction was carried out for 6 hours. The reaction solution was cooled to room temperature and allowed to stand for delamination. The lower aqueous layer was extracted with toluene (1200L), the toluene phases combined and concentrated to dryness under reduced pressure to give a brown solid. Dissolving the solid with absolute ethyl alcohol (1200L), adjusting the pH value to 2-3 with hydrochloric acid-ethanol, and controlling the temperature to 10-20 ℃. Cooling the feed liquid to 0 ℃, and carrying out heat preservation and crystallization l h. Finally, white powdery solid l (218kg) was obtained with a two-step yield of 75.6%, a purity of 97.8% and a dimeric impurity content of 4 of 2.018%.