Method for synthesizing and preparing metformin hydrochloride

Abstract

The invention belongs to the technical field of synthesis and preparation of chemical drugs, and particularly relates to a synthesis and preparation method of metformin hydrochloride. The method comprises the steps of mother liquor preparation, resin impurity removal treatment, reflux reaction, filtration, purification and the like. In the application, the mother liquor after the primary reaction is taken as a production raw material; on one hand, the problem of reaction liquid explosion boiling in a single solvent reaction process in the prior art is solved by adjusting and improving a reaction solvent; meanwhile, the technical operation of solvent recovery is also omitted; on the other hand, by combining with a resin adsorption treatment technology, the technical problems of dark mother liquor color and high crude product filtering difficulty in the prior art can be well solved. The reaction temperature in the related reaction process is controllable, and the related solvent recovery process can be omitted, so that the method has the technical advantages of simple process operation and high repeatability; meanwhile, the method has the advantages of being good in product quality, high in yield and the like, and therefore the technical scheme has good application and popularization significance.

Description

technical field

[0001] The application belongs to the technical field of synthesis and preparation of chemical drugs, in particular to a method for the synthesis and preparation of metformin hydrochloride. Background technique

[0002] Metformin hydrochloride, as a biguanide hypoglycemic drug, is a commonly used drug for mild diabetic patients in clinic. In the current industrial production, the main process of the drug is: use dicyandiamide and dimethylamine hydrochloride to react in a high-boiling solvent, and then obtain the crude product by hot filtration or distillation after high-temperature liquid separation. Since the process needs to react under high pressure conditions (to meet the requirements of the reaction temperature), the bumping phenomenon of the reaction liquid is relatively serious during the reaction process, which makes the safety of the production process relatively low. On the other hand, it is difficult to filter the crude product after the reaction. ...

Examples

Embodiment 1

[0033] The synthetic preparation method of metformin hydrochloride provided by the present embodiment specifically comprises the following steps:

[0034] (1) Prepare mother liquor

[0035] The reaction solution after reacting dicyandiamide and dimethylamine hydrochloride in cyclohexanol at 150°C for 5 hours is used as the mother liquor, and 80Kg is taken as the raw material for preparation;

[0036] (2) Resin removal treatment

[0037] Using 8% hydrogen chloride ethanol solution, adjust the pH of the mother liquor in step (1) to 6.0, add it to LX-22 macroporous adsorption resin, after the adsorption is completed, add 300Kg of absolute ethanol for elution, and collect the eluate;

[0038] (3) Reflux reaction

[0039] Add dicyandiamide and dimethylamine hydrochloride to the eluent in step (2), and reflux at 140°C for 5 hours to make full use of related materials;

[0040] The amount of dicyandiamide is 20Kg;

[0041] Dimethylamine hydrochloride consumption is 22Kg;

[0042...

Embodiment 2

[0047] The preparation method is the same as that of Example 1. In this example, only some process parameters are adjusted to investigate the influence of different process conditions on the quality of the final product. The details are as follows.

[0048] In step (1), raw material is identical with embodiment 1;

[0049] In step (2), the condition is pH=5.5, and LX-1500 macroporous adsorption resin is used for filtration and adsorption;

[0050] In step (3), material consumption and reaction conditions are identical with embodiment 1;

[0051] In step (4), in the cooling tank, cool down to about 50°C and filter while it is hot, and collect and obtain 160.3Kg of filter cake (that is, the crude product); in the decolorization tank, add 800Kg of 95% ethanol for recrystallization (the process parameters are the same as in Example 1) , after drying (the process parameters are the same as in Example 1), 35.1Kg of metformin hydrochloride was finally obtained, and the calculated w...

Embodiment 3

[0053] The preparation method is the same as that of Example 1. In this example, only some process parameters are adjusted to investigate the influence of different process conditions on the quality of the final product. The details are as follows.

[0054] In step (1), raw material is identical with embodiment 1;

[0055] In step (2), the condition is pH=5.8, and the PAD990 macroporous adsorption resin is used for filtration and adsorption;

[0056] In step (3), material consumption and reaction conditions are identical with embodiment 1;

[0057] In step (4), in the cooling tank, cool down to about 80°C and filter while it is hot, collect and obtain 160.0Kg of filter cake (that is, the crude product); in the decolorization tank, add 400Kg of 95% ethanol for recrystallization (process parameters are the same as in Example 1) , after drying (the process parameters are the same as in Example 1), 34.9Kg of metformin hydrochloride was finally obtained, and the calculated weight...

technical field

[0001] The application belongs to the technical field of synthesis and preparation of chemical drugs, in particular to a method for the synthesis and preparation of metformin hydrochloride. Background technique

[0002] Metformin hydrochloride, as a biguanide hypoglycemic drug, is a commonly used drug for mild diabetic patients in clinic. In the current industrial production, the main process of the drug is: use dicyandiamide and dimethylamine hydrochloride to react in a high-boiling solvent, and then obtain the crude product by hot filtration or distillation after high-temperature liquid separation. Since the process needs to react under high pressure conditions (to meet the requirements of the reaction temperature), the bumping phenomenon of the reaction liquid is relatively serious during the reaction process, which makes the safety of the production process relatively low. On the other hand, it is difficult to filter the crude product after the reaction. ...

Examples

Embodiment 1

[0033] The synthetic preparation method of metformin hydrochloride provided by the present embodiment specifically comprises the following steps:

[0034] (1) Prepare mother liquor

[0035] The reaction solution after reacting dicyandiamide and dimethylamine hydrochloride in cyclohexanol at 150°C for 5 hours is used as the mother liquor, and 80Kg is taken as the raw material for preparation;

[0036] (2) Resin removal treatment

[0037] Using 8% hydrogen chloride ethanol solution, adjust the pH of the mother liquor in step (1) to 6.0, add it to LX-22 macroporous adsorption resin, after the adsorption is completed, add 300Kg of absolute ethanol for elution, and collect the eluate;

[0038] (3) Reflux reaction

[0039] Add dicyandiamide and dimethylamine hydrochloride to the eluent in step (2), and reflux at 140°C for 5 hours to make full use of related materials;

[0040] The amount of dicyandiamide is 20Kg;

[0041] Dimethylamine hydrochloride consumption is 22Kg;

[0042...

Embodiment 2

[0047] The preparation method is the same as that of Example 1. In this example, only some process parameters are adjusted to investigate the influence of different process conditions on the quality of the final product. The details are as follows.

[0048] In step (1), raw material is identical with embodiment 1;

[0049] In step (2), the condition is pH=5.5, and LX-1500 macroporous adsorption resin is used for filtration and adsorption;

[0050] In step (3), material consumption and reaction conditions are identical with embodiment 1;

[0051] In step (4), in the cooling tank, cool down to about 50°C and filter while it is hot, and collect and obtain 160.3Kg of filter cake (that is, the crude product); in the decolorization tank, add 800Kg of 95% ethanol for recrystallization (the process parameters are the same as in Example 1) , after drying (the process parameters are the same as in Example 1), 35.1Kg of metformin hydrochloride was finally obtained, and the calculated w...

Embodiment 3

[0053] The preparation method is the same as that of Example 1. In this example, only some process parameters are adjusted to investigate the influence of different process conditions on the quality of the final product. The details are as follows.

[0054] In step (1), raw material is identical with embodiment 1;

[0055] In step (2), the condition is pH=5.8, and the PAD990 macroporous adsorption resin is used for filtration and adsorption;

[0056] In step (3), material consumption and reaction conditions are identical with embodiment 1;

[0057] In step (4), in the cooling tank, cool down to about 80°C and filter while it is hot, collect and obtain 160.0Kg of filter cake (that is, the crude product); in the decolorization tank, add 400Kg of 95% ethanol for recrystallization (process parameters are the same as in Example 1) , after drying (the process parameters are the same as in Example 1), 34.9Kg of metformin hydrochloride was finally obtained, and the calculated weight...