阅读说明：本技术 一种盐酸苯海索精制方法 (Method for refining dipheny hydrochloride ) 是由 梁志祥 朱占元 刘文杰 刘文丽 孔凯丽 于 2020-04-25 设计创作，主要内容包括：本发明公开了一种盐酸苯海索精制方法,包括如下步骤：步骤一,将盐酸苯海索粗品加入纯化水中搅拌均匀,碱性溶液调节pH后,保温,过滤、洗涤,滤饼收集；步骤二,将步骤一所得滤饼再加到纯化水中搅拌均匀,盐酸溶液调节pH至2～3,活性炭脱色,过滤,盐酸溶液调节pH成盐,再升温并保温,再降温析晶,过滤、洗涤、减压干燥即得盐酸苯海索纯品。本发明采用碱洗酸调的方法,能高收率、高纯度的得到盐酸苯海索纯品,从而替代现有技术采用含有机溶剂重结晶精制盐酸苯海索的方法,不仅所得精品外观好,收率高,无有机溶剂残留,产品符合药用标准要求,而且工艺操作简便,节约成本,有利于盐酸苯海索工业化生产。(The invention discloses a method for refining diphenhydrazole hydrochloride, which comprises the following steps: adding a crude product of trihexyphenidyl hydrochloride into purified water, uniformly stirring, adjusting the pH value with an alkaline solution, preserving heat, filtering, washing, and collecting a filter cake; and step two, adding the filter cake obtained in the step one into purified water, uniformly stirring, adjusting the pH value to 2-3 by using a hydrochloric acid solution, decoloring by using activated carbon, filtering, adjusting the pH value by using the hydrochloric acid solution to form salt, heating and preserving heat, cooling and crystallizing, filtering, washing, and drying under reduced pressure to obtain the pure product of the trihexyphenidyl hydrochloride. The invention adopts the method of alkali washing and acid adjustment, can obtain the pure product of the benzhexol hydrochloride with high yield and high purity, thereby replacing the method of refining the benzhexol hydrochloride by recrystallization with organic solvent in the prior art, not only the obtained refined product has good appearance and high yield, has no organic solvent residue, and the product meets the requirement of medicinal standard, but also the process operation is simple and convenient, saves the cost, and is beneficial to the industrial production of the benzhexol hydrochloride.)

1. The method for refining the diphenhydrasol hydrochloride is characterized by comprising the following steps of:

adding a crude product of trihexyphenidyl hydrochloride into purified water, uniformly stirring, adjusting the pH value by using an alkaline solution, preserving heat, pulping, filtering, washing, and collecting a filter cake;

and step two, adding the filter cake obtained in the step one into purified water, uniformly stirring, adjusting the pH value of a hydrochloric acid solution to 2-3, decoloring with active carbon, filtering, adjusting the pH value of the filtrate with a hydrochloric acid solution to form salt, heating, preserving heat, cooling, crystallizing, filtering, washing, and drying under reduced pressure to obtain the pure product of the trihexyphenidyl hydrochloride.

2. The method for refining diphenhydrasol hydrochloride according to claim 1, characterized in that: in the first step, the weight of the purified water is 5-20 times of the weight of the crude product of the trihexyphenidyl hydrochloride.

3. The method for refining diphenhydrasol hydrochloride according to claim 1, characterized in that: in the first step, the alkaline solution is a sodium hydroxide solution, a potassium hydroxide solution, a sodium carbonate solution, a potassium carbonate solution or a sodium bicarbonate solution.

4. The method for refining diphenhydrasol hydrochloride according to claim 1, characterized in that: in the first step, the pH value of the alkaline solution is adjusted to 10-14.

5. The method for refining diphenhydrasol hydrochloride according to claim 1, characterized in that: in the step one, the temperature for heat preservation and pulping is 20-80 ℃, and the time is 1-3 h.

6. The method for refining diphenhydrasol hydrochloride according to claim 1, characterized in that: and in the second step, the weight of the purified water is 20-60 times of that of the filter cake.

7. The method for refining diphenhydrasol hydrochloride according to claim 1, characterized in that: and after the activated carbon is decolorized in the second step, adjusting the pH value of the hydrochloric acid solution to 1-4.

8. The method for refining diphenhydrasol hydrochloride according to claim 1, characterized in that: in the second step, the heat preservation temperature is 50-100 ℃, and the heat preservation time is 40-80 min; the temperature for cooling and crystallizing is 0-20 ℃, and the time is 1-3 h.

9. The method for refining diphenhydrasol hydrochloride according to claim 1, characterized in that: and the mass concentration of the hydrochloric acid solution in the second step is 8-25%.

10. The method for refining diphenhydrasol hydrochloride according to any one of claims 1 or 3, characterized in that: the mass concentration of the alkaline solution in the first step is 15-32%.

Technical Field

The invention belongs to the technical field of drug synthesis, relates to purification of drugs, and particularly relates to a refining method of diphenhydrasol hydrochloride.

Background

Diphenysol hydrochloride has emerged in 1949 as a clinical study in the treatment of parkinson's disease and has formally obtained us FDA approval in 2003 as 1-cyclohexyl-1-phenyl-3- (1-piperidinyl) -propanol hydrochloride, the structural formula of which is as follows:

the diphenhydrasol hydrochloride is a central anticholinergic drug for resisting Parkinson's disease, and the action mechanism is to selectively block the cholinergic nerve passage of striatum, thereby being beneficial to restoring the balance of dopamine and acetylcholine in brain and improving the Parkinson's disease of patients.

The synthetic route of the trihexyphenidyl hydrochloride of the company is approximately as follows: the 3- (1-piperidyl) propiophenone hydrochloride reacts with a format reagent for addition reaction, hydrochloric acid is added for hydrolysis reaction, and a crude product of trihexyphenidyl hydrochloride is generated, wherein the specific route is as follows, multiple batches of liquid phase detection shows that an unknown impurity exists at 1.6min, the content of the unknown impurity is about 1.0%, the impurity cannot reach a good clearing effect by recrystallization with a conventional solvent or a mixed solvent, and although the impurity can be removed by repeated recrystallization, the product yield is seriously reduced.

Disclosure of Invention

Aiming at the defects of the prior art, the invention aims to provide a method for refining the benzhexol hydrochloride, and the invention adopts a method of alkali washing and acid adjusting, can obtain the pure benzhexol hydrochloride with high yield and high purity, thereby replacing the method for refining the benzhexol hydrochloride by recrystallization with an organic solvent in the prior art, not only the obtained refined product has good appearance and high yield, has no organic solvent residue, and the product meets the requirements of medicinal standards, but also has simple and convenient process operation, saves the cost, and is beneficial to the industrial production of the benzhexol hydrochloride.

The invention is realized by the following technical scheme:

a refining method of trihexyphenidyl hydrochloride comprises the following steps:

adding a crude product of trihexyphenidyl hydrochloride into purified water, uniformly stirring, adjusting the pH value by using an alkaline solution, preserving heat, pulping, filtering, washing, and collecting a filter cake;

and step two, adding the filter cake obtained in the step one into purified water, uniformly stirring, adjusting the pH value of a hydrochloric acid solution to 2-3, decoloring with active carbon, filtering, adjusting the pH value of the filtrate with a hydrochloric acid solution to form salt, heating, preserving heat, cooling, crystallizing, filtering, washing, and drying under reduced pressure to obtain the pure product of the trihexyphenidyl hydrochloride.

The improvement scheme of the invention is as follows:

in the first step, the weight of the purified water is 5-20 times, preferably 8-12 times of the weight of the crude product of the trihexyphenidyl hydrochloride.

Further, in the step one, the alkaline solution is a sodium hydroxide solution, a potassium hydroxide solution, a sodium carbonate solution, a potassium carbonate solution or a sodium bicarbonate solution.

Further, the mass concentration of the alkaline solution in the first step is 15-32%.

Further, in the step one, the pH value of the alkaline solution is adjusted to 10-14, preferably 11-13.

Further, in the step one, the heat preservation and pulping temperature is 20-80 ℃, preferably 30-60 ℃, and the time is 1-3 hours.

Further, the weight of the purified water in the second step is 20-60 times of that of the filter cake, and preferably 30-50 times.

Further, after the activated carbon is decolorized in the second step, the pH value of the hydrochloric acid solution is adjusted to 1-4, preferably 1-2.

Further, in the second step, the heat preservation temperature is 50-100 ℃, preferably 60-80 ℃, and the heat preservation time is 40-80 min; the temperature for cooling and crystallizing is 0-20 ℃, preferably 5-10 ℃, and the time is 1-3 hours.

Further, the mass concentration of the hydrochloric acid solution in the second step is 8-25%.

The invention has the beneficial effects that:

the fine product of the diphenhydrasol hydrochloride refined by the method has good appearance, high content and yield, and the product quality meets the requirements of pharmacopoeia. Particularly, the technical scheme of the invention can effectively remove unknown impurities which are difficult to remove at one time in the prior art within 1.6min by one-time refining, so that the content of the refined trihexyphenidyl hydrochloride can reach more than 99.5%, the impurities within 1.6min in the HPLC detection process of related substances are basically controlled to be about 0.05%, the rest single impurities are less than 0.01%, and the molar yield range reaches more than 90%.

The method avoids organic solvents, has high safety factor, is simple and convenient to operate, saves cost and is easier to realize industrial production.

Drawings

FIG. 1 is an HPLC chromatogram of crude diphenhydrasol hydrochloride of batch No. 201909022;

FIG. 2 is an HPLC chromatogram of a fine diphenhydramine hydrochloride prepared in example 1.

Detailed Description

Example 1

Stirring 20g of crude benzohexol hydrochloride with the batch number of 201909022 uniformly by using 200g of purified water, adjusting the pH value to 12 by using 15wt% of sodium hydroxide solution, pulping for 2 hours at the temperature of 50 ℃, filtering, washing filter cakes to be neutral by using the purified water, stirring uniformly by using 800g of the purified water, adjusting the pH value to about 2.5 by using 8wt% of hydrochloric acid solution, adding appropriate amount of activated carbon for decoloring for 30 minutes after solid is completely dissolved, filtering, adjusting the pH value of filtrate to 2 by using 15wt% of hydrochloric acid solution, heating to 70 ℃, keeping the temperature for 1 hour, cooling to 5 ℃, crystallizing for 2 hours, performing suction filtration, washing by using purified water, drying at the temperature of 75 ℃ under reduced pressure to constant weight to obtain 18.4g of refined white solid powder benzohexol hydrochloride, wherein the yield is 92.2%, sampling the refined benzohexol hydrochloride is determined by adopting an HPLC method of Chinese pharmacopoeia, and the determination method comprises the following steps:

chromatograph: shimadzu;

a detector: shimadzu PDA;

a chromatographic column: octadecylsilane chemically bonded silica gel column

Measuring wavelength: 210nm

Mobile phase: 0.1% Triethylamine solution (pH adjusted to 4.0 with phosphoric acid) -acetonitrile (70: 30)

Flow rate: 1.0 ml/min;

sample introduction amount: 20 mu L of the solution;

according to the method, the content of the fine diphenhydrasol hydrochloride product is 99.5 percent, the unknown single impurity content is 0.05 percent after about 1.6min, and the map is shown in figure 2.

Example 2

Stirring 20g of crude benzohexol hydrochloride with the lot number of 201909022 uniformly by using 240g of purified water, adjusting the pH value to 13 by using a potassium hydroxide solution, pulping for 2 hours at the temperature of 40 ℃, filtering, washing a filter cake to be neutral by using purified water, stirring uniformly by using 1000g of purified water, adjusting the pH value to about 2.5 by using a hydrochloric acid solution, adding a proper amount of activated carbon for decoloring for 30 minutes after the solid is completely dissolved, filtering, adjusting the pH value of a filtrate to 1 by using a hydrochloric acid solution, heating to 80 ℃, keeping the temperature for 1 hour, cooling to 10 ℃, crystallizing for 2 hours, performing suction filtration, washing by using purified water, drying at the temperature of 75 ℃ under reduced pressure to a constant weight to obtain a white solid refined product of the benzohexol hydrochloride, wherein the yield is 93.4%, the content is 99.6% by detecting according to the detection method of the embodiment 1, and the single impurity content is 0.07% by about 1.6 min.

Example 3

50g of crude benzohexol hydrochloride with the batch number of 201909022 is uniformly stirred by 450g of purified water, the pH value of a sodium hydroxide solution is adjusted to 11, the mixture is pulped for 2 hours at the temperature of 30 ℃, filtered, the filter cake is washed by the purified water to be neutral, then 2000g of purified water is uniformly stirred, the pH value of a hydrochloric acid solution is adjusted to about 2.5, after the solid is completely dissolved, a proper amount of activated carbon is added for decolorization for 30 minutes, the mixture is filtered, the pH value of the filtrate is adjusted to 2 by the hydrochloric acid solution, the temperature is raised to 65 ℃, the temperature is kept for 1 hour, then the filtrate is cooled to 8 ℃ for crystallization for 2 hours, the filtrate is filtered, the purified water is washed, and the filtrate is dried under the reduced pressure at the temperature of 75 ℃ until the constant weight is obtained, the refined product of the white solid benzohexol hydrochloride is obtained, the yield is 90.3%, the content is 99.7% according to the detection method of the embodiment 1, and the content of the single impurity content is 0.06% in about 1.6 min.

Example 4

30g of crude benzohexol hydrochloride with the batch number of 201909022 is uniformly stirred by using 330g of purified water, the pH value of potassium hydroxide solution is adjusted to 11, the mixture is pulped for 2 hours at the temperature of 60 ℃, filtered, the filter cake is washed by the purified water to be neutral, then 900g of purified water is uniformly stirred, the pH value of hydrochloric acid solution is adjusted to about 2.5, after the solid is completely dissolved, proper amount of active carbon is added for decolorization for 30 minutes, the mixture is filtered, the pH value of the filtrate is adjusted to 2 by using hydrochloric acid solution, the temperature is raised to 60 ℃, the temperature is kept for 1 hour, then the filtrate is cooled to 7 ℃ for crystallization for 2 hours, the filtrate is filtered, the purified water is washed, and the filtrate is dried under reduced pressure at the temperature of 75 ℃ until the constant weight is obtained, so that fine product of the white solid benzohexol hydrochloride is obtained, the yield is 94.3%, the content is 99.7% according to the detection method of the embodiment 1, and the single impurity content is 0.04% in about 1.6 min.

Example 5

100g of crude benzhexol hydrochloride product is uniformly stirred by 1200g of purified water, the pH value of the crude benzhexol hydrochloride product is adjusted to 12 by potassium hydroxide solution, the mixture is pulped for 2 hours at the temperature of 45 ℃, the mixture is filtered, the filter cake is washed by purified water to be neutral, then 4000g of purified water is uniformly stirred, the pH value of the hydrochloric acid solution is adjusted to about 2.5, after the solid is completely dissolved, an appropriate amount of active carbon is added for decolorization for 30 minutes, the mixture is filtered, the pH value of the filtrate is adjusted to 1 by hydrochloric acid solution, the temperature is raised to 75 ℃ and is kept for 1 hour, then the temperature is lowered to 6 ℃ for crystallization for 2 hours, the filtrate is filtered, the purified water is washed, and the concentrated solution is dried under the reduced pressure at the temperature of 75 ℃ until the constant weight to obtain refined benzhexol hydrochloride white solid powder, the yield is 93.5%, the content is detected by the detection method of the embodiment 1, the content is 99.8%, and the single impurity content is about 1.6min and is 0.03%.