阅读说明：本技术 一种盐酸二甲双胍的合成制备方法 (Synthetic preparation method of metformin hydrochloride ) 是由 杨明 王俊臣 赖珅 徐文斌 吕伟 赵臻 王文华 刘学威 钱丹 年蓓蕾 殷恒亮 于 2021-09-13 设计创作，主要内容包括：本申请属于化学药物合成制备技术领域,具体涉及一种盐酸二甲双胍的合成制备方法。该方法包括：准备母液、树脂去杂处理、回流反应、过滤、提纯等步骤。本申请中,以初步反应后母液为生产原料,一方面通过对反应溶剂的调整和改进,从而解决现有技术中单一溶剂反应过程中的反应液爆沸的问题,同时也减免了溶剂回收的技术操作；另一方面,结合树脂的吸附处理技术,可以较好解决现有技术中母液颜色深、粗品过滤难度高的技术问题。由于相关反应过程中反应温度可控,且可以减免相关溶剂回收工序,具有工艺操作简单、重复性强的技术优点,同时由于具有制备产品质量好、收率高等优点,因此,使得本申请的技术方案具有较好的推广应用意义。(The application belongs to the technical field of chemical drug synthesis and preparation, and particularly relates to a synthetic preparation method of metformin hydrochloride. The method comprises the following steps: preparing mother liquor, removing impurities by resin, refluxing, reacting, filtering, purifying and the like. In the application, the mother liquor after the primary reaction is taken as a production raw material, and on one hand, the problem of bumping of reaction liquid in the reaction process of a single solvent in the prior art is solved by adjusting and improving the reaction solvent, and meanwhile, the technical operation of solvent recovery is also avoided; on the other hand, the technical problems of dark color of mother liquor and high difficulty in filtering crude products in the prior art can be better solved by combining the adsorption treatment technology of resin. The reaction temperature in the relevant reaction process is controllable, the recovery process of the relevant solvent can be omitted, the technical advantages of simple process operation and strong repeatability are achieved, and meanwhile, the technical scheme has good popularization and application significance due to the advantages of good quality of prepared products, high yield and the like.)

1. The synthetic preparation method of metformin hydrochloride is characterized by comprising the following steps:

(1) preparing mother liquor

Reacting dicyandiamide and dimethylamine hydrochloride in a solvent at 130-160 ℃ for 2-6h, and taking the reaction liquid as mother liquid;

(2) resin impurity removal treatment

Adjusting the pH = 5-6 of the mother liquor obtained in the step (1), adsorbing by using resin, and eluting by using absolute ethyl alcohol to obtain an eluent after adsorption is finished;

(3) reflux reaction

Adding dicyandiamide and dimethylamine hydrochloride into the eluent in the step (2), and carrying out reflux reaction at the temperature of 130-150 ℃ for 2-6h to fully utilize related materials;

(4) filtering and purifying

Cooling the reaction solution obtained in the step (2) to 50-100 ℃, and filtering while the reaction solution is hot to obtain a metformin hydrochloride crude product;

and dissolving the crude product by using 85-95% ethanol, decoloring, recrystallizing, and drying in vacuum to obtain the metformin hydrochloride.

2. The method for synthesizing metformin hydrochloride according to claim 1, wherein in the step (1), the solvent is cyclohexanol or isoamyl alcohol.

3. The method for synthesizing metformin hydrochloride according to claim 1, wherein in the step (2), when the pH value of the mother liquor is adjusted, an ethanol solution of 8% -10% hydrogen chloride is used;

the resin is macroporous adsorption resin, and the specific model is LX-22, LX-1500, ADX16N, PAD550, PAD990 or SD 2000;

when in elution, the volume ratio of absolute ethyl alcohol for elution is 2-10 times of the mother liquor.

4. The method for synthesizing metformin hydrochloride according to claim 1, wherein in the step (3), the amount of dicyandiamide used is 0.2 to 0.3 times of the weight of the mother liquor in the step (1);

the dosage of the dimethylamine hydrochloride is 0.2-0.35 time of the weight of the mother liquor in the step (1).

5. The method for synthesizing metformin hydrochloride according to claim 1, wherein in the step (4), the decoloring is performed by using activated carbon.

6. The method for synthesizing metformin hydrochloride according to claim 1, wherein in the step (4), when the crude product is dissolved and recrystallized, the amount of ethanol is 2 to 5 times of the mass of the crude metformin hydrochloride in terms of mass ratio;

and during vacuum drying, the temperature is 60-100 ℃, and the vacuum degree is more than or equal to-0.08 MPa.

Technical Field

The application belongs to the technical field of chemical drug synthesis and preparation, and particularly relates to a synthetic preparation method of metformin hydrochloride.

Background

Metformin hydrochloride is used as a biguanide hypoglycemic drug and is a common drug for mild diabetes patients in clinic. In the current industrial production, the main process of the medicine is as follows: dicyandiamide reacts with dimethylamine hydrochloride in a high-boiling point solvent, and a crude product is obtained by a hot filtration mode or a high-temperature liquid separation and distillation mode. The process needs to react under a high pressure condition (to meet the requirement of reaction temperature), so that the bumping phenomenon of reaction liquid in the reaction process is serious, the safety of the production process is relatively low, and on the other hand, the technical defects of high crude product filtering difficulty and high energy consumption for recovery after the reaction is finished exist. A brief description of the prior art for the production of metformin hydrochloride is given below.

Chinese patent CN105968032A provides a method for synthesizing metformin hydrochloride, in which dimethylamine, dicyandiamide and hydrochloric acid solution are added in a high-pressure closed environment, and a catalyst organic acid is heated to react with the solution to obtain a crude metformin hydrochloride product, and the crude metformin hydrochloride product is refined with ethanol to obtain a finished product; the process requires high-temperature and high-pressure reaction conditions, so that the equipment requirement is high (the safety requirement can be met), and the process is not beneficial to application and popularization of large-scale industrial production.

In chinese patent CN106278953A (a method for producing high-purity metformin hydrochloride), N-methylpyrrolidone is used as a solvent, dicyandiamide and dimethylamine hydrochloride are used as solutes, and the metformin hydrochloride is prepared by stirring, cooling, spin-drying, washing, crystallizing and drying in a synthesis kettle. Although the purity of the metformin hydrochloride prepared by the method reaches 99.3 percent, the product and the quality produced by the method can not meet the medical quality requirements from the medical standard requirements.

In world patent WO2010/146604 (Processes for preparing methyl for min hydrochloride), the process flow is as follows: adding dicyandiamide and xylene into a reaction kettle, heating to 80 ℃, adding dimethylamine hydrochloride in batches, stirring for 3 hours, heating to 100-105 ℃, finally heating to 140 ℃, stirring for 4 hours, cooling to 95 ℃, adding purified water, separating liquid, back-extracting an organic phase by using the purified water, merging aqueous phases, adding activated carbon for decolorization, and refining by using methanol to obtain a product. It can be seen that the method has long reaction time, needs repeated water distillation and has large energy consumption, thus being not beneficial to industrialized production popularization and application.

Disclosure of Invention

Based on the relevant defects of the existing metformin hydrochloride production process, the application aims to further improve the relevant production process so as to be beneficial to further industrial production, popularization and application.

The technical solution adopted in the present application is detailed as follows.

A synthetic preparation method of metformin hydrochloride specifically comprises the following steps:

(1) preparing mother liquor

Reacting dicyandiamide and dimethylamine hydrochloride in a solvent at 130-160 ℃ for 2-6h, and taking the reaction liquid as mother liquid;

in the preferable operation of the mother liquor, after the reaction of the reaction system is finished, the reaction liquid is cooled to 50-100 ℃, filtered while hot, and after precipitates are washed by absolute ethyl alcohol, the filtrate and an ethanol washing liquid are combined to fully recycle related raw materials as much as possible;

the solvent is cyclohexanol or isoamyl alcohol;

(2) resin impurity removal treatment

Adjusting the pH = 5-6 of the mother liquor obtained in the step (1), adsorbing by using resin, and eluting by using absolute ethyl alcohol to obtain an eluent after adsorption is finished;

in the step, the pH adjustment is combined, and resin adsorption is matched to remove impurities which are difficult to filter as far as possible;

when the pH value of the mother liquor is adjusted, 8-10% of hydrogen chloride ethanol solution (hydrochloric acid ethanol solution) is adopted;

the resin is macroporous adsorption resin, and the specific models are LX-22, LX-1500, ADX16N, PAD550, PAD990 or SD2000 and the like; the resin adsorption has the advantages that substances which are difficult to filter or easy to influence the filtering speed in the reaction product in a conventional filtering mode can be effectively removed, and the purity of a crude product can be effectively improved;

when in elution, the volume ratio of absolute ethyl alcohol for elution is 2-10 times of the mother liquor;

(3) reflux reaction

Adding dicyandiamide and dimethylamine hydrochloride into the eluent in the step (2), and carrying out reflux reaction at the temperature of 130-150 ℃ for 2-6h to fully utilize related materials;

before reflux reaction, a certain amount of solvent can be distilled off by adopting a heating mode so as to improve the reaction rate;

the amount of dicyandiamide is 0.2-0.3 times of the weight of the mother liquor in the step (1);

the dosage of dimethylamine hydrochloride is 0.2-0.35 times of the weight of the mother liquor in the step (1);

(4) filtering and purifying

Cooling the reaction solution obtained in the step (2) to 50-100 ℃, and filtering while the reaction solution is hot to obtain a metformin hydrochloride crude product;

dissolving the crude product with 85-95% ethanol, decolorizing, recrystallizing, and vacuum drying to obtain pure metformin hydrochloride;

when the crude product is dissolved and recrystallized, the using amount of ethanol is 2-5 times of the mass of the crude product of the metformin hydrochloride in terms of mass ratio;

and during vacuum drying, the temperature is 60-100 ℃, and the vacuum degree is more than or equal to-0.08 MPa.

In the application, the mother liquor after the primary reaction is taken as a production raw material, and on one hand, the problem of bumping of reaction liquid in the reaction process of a single solvent in the prior art is solved by adjusting and improving the reaction solvent, and meanwhile, the technical operation of solvent recovery is also avoided; on the other hand, the technical problems of dark color of mother liquor and high difficulty in filtering crude products in the prior art can be better solved by combining the adsorption treatment technology of resin.

Generally, the reaction temperature is controllable in the relevant reaction process, the recovery process of the relevant solvent can be omitted, the technical advantages of simple process operation and strong repeatability are achieved, and meanwhile, the technical scheme has good popularization and application significance due to the advantages of good quality of prepared products, high yield and the like.

Detailed Description

The present application is further illustrated by the following examples.

Example 1

The synthetic preparation method of metformin hydrochloride provided in this embodiment specifically includes the following steps:

(1) preparing mother liquor

Reacting dicyandiamide and dimethylamine hydrochloride in cyclohexanol at 150 ℃ for 5 hours, and taking 80Kg as a mother solution as a preparation raw material;

(2) resin impurity removal treatment

Adopting 8% ethanol solution of hydrogen chloride, adjusting the pH =6.0 of the mother liquor in the step (1), adding into LX-22 type macroporous adsorption resin, after adsorption is finished, adding 300Kg of absolute ethyl alcohol for elution, and collecting eluent;

(3) reflux reaction

Adding dicyandiamide and dimethylamine hydrochloride into the eluent in the step (2), and carrying out reflux reaction at 140 ℃ for 5 hours to fully utilize related materials;

the dosage of dicyandiamide is 20 Kg;

the dosage of dimethylamine hydrochloride is 22 Kg;

(4) filtering and purifying

Transferring the reaction solution in the step (2) into a cooling tank, cooling to about 90 ℃, and filtering while the solution is hot to obtain a metformin hydrochloride crude product (in the form of a filter cake);

the filter cake was washed with absolute ethanol (the filtrate and the washing solution were combined and used further), and finally weighed and collected to obtain 158.9Kg of filter cake (i.e., crude product).

Transferring the filter cake into a decolorizing tank, adding 350Kg of 80% ethanol, heating properly under stirring to ensure full dissolution until the solution is clear, and adding 0.8Kg of activated carbon for full decolorization. Then, the heat filtration is carried out, the filtrate is transferred into a crystallizing tank, the temperature is reduced to about 4 ℃ for recrystallization, the wet metformin hydrochloride product is obtained by centrifugation, the wet metformin hydrochloride product is dried under the conditions of vacuum degree (vacuum degree of minus 0.08 MPa) and 80 ℃, and finally the metformin hydrochloride is weighed to obtain 34.3Kg, and the calculated weight yield is 171.5%.

Example 2

As with the preparation method of example 1, this example only adjusts some process parameters to examine the influence of different process conditions on the quality of the final product. The specific case is briefly described as follows.

In the step (1), the raw materials are the same as in example 1;

in the step (2), under the condition that the pH is =5.5, filtering and adsorbing by adopting LX-1500 type macroporous adsorption resin;

in the step (3), the material consumption and the reaction conditions are the same as those in the example 1;

in the step (4), in a cooling tank, the temperature is reduced by about 50 ℃ and the hot filter cake is collected to obtain 160.3Kg of filter cake (namely a crude product); in the decolorizer, 800Kg of 95% ethanol was added to carry out recrystallization (the same process parameters as in example 1) and oven-drying (the same process parameters as in example 1) to obtain 35.1Kg of metformin hydrochloride with a calculated weight yield of 175.5%.

Example 3

As with the preparation method of example 1, this example only adjusts some process parameters to examine the influence of different process conditions on the quality of the final product. The specific case is briefly described as follows.

In the step (1), the raw materials are the same as in example 1;

in the step (2), under the condition that the pH is =5.8, PAD990 type macroporous adsorption resin is adopted for filtration and adsorption;

in the step (3), the material consumption and the reaction conditions are the same as those in the example 1;

in the step (4), in a cooling tank, the temperature is reduced to about 80 ℃, and the hot filter cake is collected to obtain 160.0Kg of filter cake (namely a crude product); 400Kg of 95% ethanol was added to the decolorizer for recrystallization (same process parameters as in example 1), and then dried (same process parameters as in example 1) to obtain 34.9Kg of metformin hydrochloride, with a calculated weight yield of 174.5%.

The quality of the metformin hydrochloride products prepared in the above examples 1 to 3 is respectively detected according to the method specified in the current pharmacopoeia, and the results are as follows:

。

from the results in the table above, compared with the standard requirements of the prior pharmacopoeia, the metformin hydrochloride product prepared by the preparation process has lower impurity content and higher purity, and the related process operation is relatively simple, safe and controllable, so that the technical scheme of the application has better practical value.