阅读说明：本技术 一种高纯度盐酸地芬尼多的制备方法 (Preparation method of high-purity difenidol hydrochloride ) 是由 周泽银 徐彬滨 陈雪兰 周元蓉 金秉德 朱维君 袁秀菊 王洪锋 于 2019-09-10 设计创作，主要内容包括：本发明公开了一种高纯度盐酸地芬尼多的制备方法。所述方法为当制备得到中间体α,α-二苯基-1-哌啶丁醇后,将其溶于丙酮、乙酸乙酯、四氢呋喃、丁酮、乙腈或二氯甲烷的一种；然后升温至40～45℃,加入活性炭混匀搅拌0.5～1h；趁热过滤,滤液保温在40～45℃,然后以2mL/min～8mL/min的速度滴加盐酸溶液,至溶液pH为4～6,然后继续保温反应1～2h；然后降温至20～25℃保温1～2h,再降温至5～10℃搅拌2～4h,即可析出盐酸地芬尼多。本发明所述制备方法不仅简单,对于仪器设备的要求低,生产成本低,而且制备的目标产物的杂质种类少,且含量低,产物成盐摩尔收率为90％以上,纯度为99.8％以上,杂质二苯甲醇控制在0.05％以下,同时烯化物杂质控制在0.05％以下,总杂质的含量在0.1％以下。(The invention discloses a preparation method of high-purity difenidol hydrochloride. After preparing an intermediate alpha, alpha-diphenyl-1-piperidine butanol, dissolving the intermediate alpha, alpha-diphenyl-1-piperidine butanol in one of acetone, ethyl acetate, tetrahydrofuran, butanone, acetonitrile or dichloromethane; then heating to 40-45 ℃, adding active carbon, uniformly mixing and stirring for 0.5-1 h; filtering while the solution is hot, keeping the temperature of the filtrate at 40-45 ℃, then dropwise adding a hydrochloric acid solution at the speed of 2-8mL/min until the pH of the solution is 4-6, and then continuing to keep the temperature and react for 1-2 hours; and then cooling to 20-25 ℃, preserving heat for 1-2h, cooling to 5-10 ℃, and stirring for 2-4h to separate out difenidol hydrochloride. The preparation method disclosed by the invention is simple, has low requirements on instruments and equipment and low production cost, and the prepared target product has few impurity types and low content, the salifying molar yield of the product is more than 90%, the purity is more than 99.8%, the impurity of diphenylmethanol is controlled to be less than 0.05%, meanwhile, the olefine impurity is controlled to be less than 0.05%, and the content of the total impurity is less than 0.1%.)

1. A preparation method of high-purity difenidol hydrochloride is characterized in that after an intermediate alpha, alpha-diphenyl-1-piperidine butanol is prepared, the intermediate alpha, alpha-diphenyl-1-piperidine butanol is dissolved in one of acetone, ethyl acetate, tetrahydrofuran, butanone, acetonitrile or dichloromethane; then heating to 40-50 ℃, adding active carbon, uniformly mixing and stirring for 0.5-1 h; filtering while the solution is hot, keeping the temperature of the filtrate at 40-45 ℃, then dropwise adding a hydrochloric acid solution at the speed of 2-8mL/min until the pH of the solution is 4-6, and then continuing to keep the temperature and react for 1-2 hours; and then cooling to 20-25 ℃, preserving heat for 1-2h, cooling to 5-10 ℃, and stirring for 2-4h to separate out difenidol hydrochloride.

2. The method for preparing high-purity difenidol hydrochloride according to claim 1, wherein the mass ratio of the addition volume of acetone, ethyl acetate, tetrahydrofuran, butanone, acetonitrile or dichloromethane to the mass of α, α -diphenyl-1-piperidinebutanol is 5-8 mL/g.

3. The method for preparing high-purity difenidol hydrochloride according to claim 2, wherein the mass ratio of the addition volume of acetone, ethyl acetate, tetrahydrofuran, butanone, acetonitrile or dichloromethane to α, α -diphenyl-1-piperidinebutanol is 6 mL/g.

4. The method for preparing high-purity difenidol hydrochloride according to claim 3, wherein the α, α -diphenyl-1-piperidinebutanol is dissolved in acetone or ethyl acetate.

5. The method for preparing high-purity difenidol hydrochloride according to claim 1, wherein the dropping speed of the hydrochloric acid solution is 5 mL/min.

6. the method for preparing high-purity difenidol hydrochloride according to claim 1, wherein the concentration of the hydrochloric acid solution is 3-6 mol/L.

7. The method for preparing high-purity difenidol hydrochloride according to claim 1, wherein the intermediate α, α -diphenyl-1-piperidinebutanol is prepared by the following steps: reacting 1, 3-bromochloropropane and piperidine at room temperature, and separating to obtain an intermediate 1- (3-chloropropyl) piperidine after the reaction is finished; then the intermediate 1- (3-chloropropyl) piperidine reacts with magnesium, iodine and ethyl bromide in an organic solvent in a Grignard reaction mode, then benzophenone is dripped to continue the reaction, and after the reaction is finished, the alpha, alpha-diphenyl-1-piperidine butanol can be prepared by separation.

8. The method for preparing high-purity difenidol hydrochloride according to claim 7, wherein the reaction mass ratio of the 1, 3-bromochloropropane to the piperidine is as follows: 1.8-2: 1; the separation process of the 1- (3-chloropropyl) piperidine comprises the following steps: and adding the reaction liquid into alkali liquor, uniformly mixing, standing for layering, collecting an upper-layer oily matter, and drying to obtain the intermediate 1- (3-chloropropyl) piperidine.

9. The method for preparing high-purity difenidol hydrochloride according to claim 7, wherein the intermediate 1- (3-chloropropyl) piperidine is subjected to Grignard reaction at a reaction temperature of 70 ℃; the separation process of the alpha, alpha-diphenyl-1-piperidine butanol comprises the following steps: adding the reaction solution into an ammonium chloride solution for hydrolysis, filtering the solid, and drying to obtain the alpha, alpha-diphenyl-1-piperidinebutanol.

Technical Field

The invention relates to the technical field of medicines, and particularly relates to a preparation method of high-purity difenidol hydrochloride.

Background

The difenidol hydrochloride is chemically named as 1, 1-diphenyl-4- (1-piperidyl) -1-butanol hydrochloride, is a main component of vertigo curing, can improve vertebrobasilar artery blood supply insufficiency, dilate spasm blood vessels, regulate vestibular nervous system, inhibit abnormal impulse of vestibular nervous system, inhibit vomiting center and brain-extending emetic chemosensory area, has peripheral weak anticholinergic effect, is widely applied to vertigo resistance and antiemetic, can be used for treating Meniere's disease, ear postoperative (labyrinthitis) and motion sickness, improving nystagmus, preventing and treating vertigo, nausea and emesis caused by various diseases and medicines, and in recent years, the application of difenidol hydrochloride is continuously expanded, for example, the compound salvia miltiorrhiza dripping pill is combined with the difenidol hydrochloride tablet to treat cervical vertigo, the bupleurum decoction is combined with the difenidol hydrochloride tablet to treat vertigo after stroke, and the like.

The publication No. CN106749101A patent application discloses a method for preparing difenidol hydrochloride, wherein, the S3 salifying step mainly adopts the steps of adding buffer salt, decoloring by active carbon, filtering, adding hydrochloric acid to control the pH value to be 5-6, stirring for 25-35min at 50-60 ℃, filtering and drying to obtain the difenidol hydrochloride. The buffer salt is added in the preparation method of the technology, so that the inorganic salt in the product is possibly overproof, the impurity content is higher, the product purity is reduced, the solvent is not beneficial to cyclic utilization, and meanwhile, the adopted alcohol-water system is crystallized, so that the removal of the grignard reaction byproduct, namely the benzhydryl alcohol is not beneficial; secondly, the yield of the difenidol hydrochloride prepared by the method is low, and the production cost is increased.

The patent publication No. CN108467372A discloses a preparation method of difenidol hydrochloride, wherein in the S3 salification step, alpha-diphenyl-1-piperidine butanol is mainly added into isopropanol, the mixture is heated and refluxed, cooled to 37 ℃, 16 wt% hydrochloric acid solution is dripped to adjust the pH value to be 3, and then cooling crystallization and centrifugal drying are carried out to obtain difenidol hydrochloride.

Therefore, there is a need to provide a method for preparing difenidol hydrochloride, which can simultaneously ensure high purity of target products, less impurity types, low content, simple operation and convenient production.

Disclosure of Invention

The invention aims to provide a preparation method of high-purity difenidol hydrochloride. The preparation method of the invention adopts a specific solvent to control the pH value of the whole system and the dropping speed of the hydrochloric acid solution, thereby effectively reducing the content of the impurity benzhydryl alcohol; finally, through the process of gradient cooling, the process of explosive precipitation is avoided, and the crystal of the precipitated target product is ensured to have good crystal form and less impurities; the whole method is simple and convenient to operate, the requirement on instruments and equipment is low, the prepared target product has few impurity types and low content, the salification molar yield is more than 90%, the purity is more than 99.9%, the by-product benzhydryl alcohol of the Grignard reaction is controlled to be less than 0.03%, and meanwhile, the olefination impurity is controlled to be less than 0.03%.

The above object of the present invention is achieved by the following scheme:

A preparation method of high-purity difenidol hydrochloride comprises the steps of dissolving an intermediate alpha, alpha-diphenyl-1-piperidine butanol in one of acetone, ethyl acetate, tetrahydrofuran, butanone, acetonitrile or dichloromethane after the intermediate is prepared; then heating to 40-50 ℃, adding active carbon, uniformly mixing and stirring for 0.5-1 h; filtering while the solution is hot, keeping the temperature of the filtrate at 40-45 ℃, then dropwise adding a hydrochloric acid solution at the speed of 2-8mL/min until the pH of the solution is 4-6, and then continuing to keep the temperature and react for 1-2 hours; and then cooling to 20-25 ℃, preserving heat for 1-2h, cooling to 5-10 ℃, and stirring for 2-4h to separate out difenidol hydrochloride.

In order to effectively remove the impurity, the invention selects a specific solvent for dissolving the intermediate alpha, alpha-diphenyl-1-piperidine butanol, and when one of acetone, ethyl acetate, tetrahydrofuran, butanone, acetonitrile or dichloromethane is adopted for dissolving, the impurity benzhydryl alcohol in the intermediate alpha, alpha-diphenyl-1-piperidine butanol can be effectively removed, thereby ensuring that the prepared difenidol hydrochloride contains no or very little impurity benzhydryl alcohol. Meanwhile, a single solvent is adopted, so that the solvent is convenient to recycle, the salifying yield is improved, and the production cost is reduced.

The pH value of the whole solution system is controlled to be 4-6, and the dripping speed of the hydrochloric acid solution is controlled to be 2-8mL/min, so that the grignard impurities in the target product are effectively removed, and the olefination reaction is avoided due to the over-low pH value of the system. When the dropping rate of the hydrochloric acid is too fast, the pH of a local region in the solution system is easily too low, so that the olefination reaction is easily generated, and impurities of the olefination reaction exist in the product. When the dripping speed of the hydrochloric acid solution is 2mL/min to 8mL/min, the occurrence of olefination reaction can be avoided, and the impurities of the olefination reaction are reduced.

In order to better separate out difenidol hydrochloride and avoid explosive separation, so that a target product contains higher impurities, the invention adopts a method of gradient cooling to separate out the target product, namely, the system is cooled to 20-25 ℃ from 40-45 ℃ and is kept warm for 1-2h, then the system is cooled to 5-10 ℃ and is stirred for 2-4h, the target product can be well separated out, the separated crystal form is good, and the content of benzhydryl alcohol is low.

Preferably, the mass ratio of the addition volume of acetone, ethyl acetate, tetrahydrofuran, butanone, acetonitrile or dichloromethane to the mass of alpha, alpha-diphenyl-1-piperidinebutanol is 5-8 mL/g. When the addition amount of the solvent is within the range, the impurity benzhydrol can be well removed, and meanwhile, the use amount of the solvent is kept to be the minimum use amount, so that the impurity removal effect is ensured, the cost is reduced, and the economical efficiency is good.

Preferably, the mass ratio of the added volume of acetone, ethyl acetate, tetrahydrofuran, butanone, acetonitrile or dichloromethane to α, α -diphenyl-1-piperidinebutanol is 6 mL/g.

Preferably, the α, α -diphenyl-1-piperidinebutanol is dissolved in acetone or ethyl acetate.

Preferably, the dropping speed of the hydrochloric acid solution is 5 mL/min.

preferably, the concentration of the hydrochloric acid solution is 3-6 mol/L. The concentration of hydrochloric acid is controlled to effectively avoid the occurrence of the olefination reaction.

Preferably, the intermediate α, α -diphenyl-1-piperidinebutanol is prepared by the following steps: reacting 1, 3-bromochloropropane and piperidine at room temperature, and separating to obtain an intermediate 1- (3-chloropropyl) piperidine after the reaction is finished; then the intermediate 1- (3-chloropropyl) piperidine reacts with magnesium, iodine and ethyl bromide in an organic solvent in a Grignard reaction mode, then benzophenone is dripped to continue the reaction, and after the reaction is finished, the alpha, alpha-diphenyl-1-piperidine butanol can be prepared by separation.

Preferably, the reaction mass ratio of the 1, 3-bromochloropropane to the piperidine is as follows: 1.8-2: 1; the separation process of the 1- (3-chloropropyl) piperidine comprises the following steps: and adding the reaction liquid into alkali liquor, uniformly mixing, standing for layering, collecting an upper-layer oily matter, and drying to obtain the intermediate 1- (3-chloropropyl) piperidine.

Preferably, the reaction temperature of the Grignard reaction of the intermediate 1- (3-chloropropyl) piperidine is 70 ℃; the separation process of the alpha, alpha-diphenyl-1-piperidine butanol comprises the following steps: adding the reaction solution into an ammonium chloride solution for hydrolysis, filtering the solid, and drying to obtain the alpha, alpha-diphenyl-1-piperidinebutanol.

Compared with the prior art, the invention has the following beneficial effects:

The preparation method of the invention adopts a specific solvent to control the pH value of the whole system and the dropping speed of the hydrochloric acid solution, thereby effectively reducing the content of the impurity benzhydryl alcohol; finally, through the process of gradient cooling, the process of explosive precipitation is avoided, and the crystal of the precipitated target product is ensured to have good crystal form and less impurities;

The whole method is simple and convenient to operate, the requirement on instruments and equipment is low, the single solvent is adopted, the solvent is convenient to recycle, the salt forming yield is improved, the production cost is reduced, the prepared target product has few impurity types and low content, the salt forming molar yield of the product is more than 90%, the purity is more than 99.9%, a by-product benzhydryl alcohol of the Grignard reaction is controlled below 0.03%, meanwhile, the olefinating impurity is controlled below 0.03%, and the total impurity is controlled below 0.1%.

Drawings

FIG. 1 HLPC spectrum of difenidol hydrochloride finished product prepared in example 1

FIG. 2 HLPC spectrum of difenidol hydrochloride finished product prepared in example 2

FIG. 3 HLPC spectrum of difenidol hydrochloride finished product prepared in example 3

FIG. 4 HLPC spectrum of difenidol hydrochloride finished product prepared in example 4

FIG. 5 HLPC spectrum of difenidol hydrochloride finished product prepared in example 5

FIG. 6 example 6 HLPC profile of difenidol hydrochloride finished product prepared in test group 5

FIG. 7 HLPC spectrum of difenidol hydrochloride finished product prepared in comparative example 1

FIG. 8 HLPC spectrum of difenidol hydrochloride finished product prepared by comparative example 3

Detailed Description

The present invention is further described in detail below with reference to specific examples, which are provided for illustration only and are not intended to limit the scope of the present invention. The test methods used in the following examples are all conventional methods unless otherwise specified; the materials, reagents and the like used are, unless otherwise specified, commercially available reagents and materials.