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Preparation method of metformin hydrochloride

A technology of metformin hydrochloride and dimethylamine hydrochloride, which is applied in the field of preparation of metformin hydrochloride, can solve the problems of low solubility of metformin hydrochloride, potential safety hazards, flushing phenomenon, etc., and achieve mild conditions, high safety, and avoid flushing phenomenon Effect

Active Publication Date: 2015-02-18
QINGDAO HUANGHAI PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In addition, due to the low solubility of metformin hydrochloride in organic solvents, when the reaction reaches a certain level, metformin hydrochloride will be precipitated from the reaction solution in an instant, and the heat will be released violently.
Therefore, when using a solvent whose boiling point is close to the reaction temperature, it is easy to appear the flushing phenomenon, and there is a potential safety hazard

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] Add 200kg of N,N-dimethylacetamide (DMAc) into a 300L reaction tank, add 50kg of dicyandiamide and 50kg of dimethylamine hydrochloride under stirring, and heat to 140±5℃ to react for 4h. After the reaction is over, the temperature is lowered to 20~30°C to crystallize, and centrifuged to dry. The filtrate recovers N,N-dimethylacetamide, which can be reused after passing the inspection. The obtained solid was dried under reduced pressure to obtain 83.3 kg of crude metformin hydrochloride with a yield of 84.6% and a dicyandiamide content of 0.11%.

[0020] Refining: Add 250kg of 80% ethanol into a 500L reaction tank, add 83.3kg of the above crude metformin hydrochloride under stirring, and heat to reflux. After the crude product is completely dissolved, adjust the pH value to 5-6 with hydrochloric acid. Then add 1kg of activated carbon and continue to reflux for 30 minutes. The reaction liquid is pumped into the crystallizing tank through the activated carbon filter, and t...

Embodiment 2

[0022] Add 150kg of N,N-dimethylacetamide into a 300L reaction tank, add 50kg of dicyandiamide and 58kg of dimethylamine hydrochloride under stirring, heat to 140±5℃, and react for 6h. After the reaction is over, the temperature is lowered to 20~30°C to crystallize, and centrifuged to dry. The filtrate recovers N,N-dimethylacetamide, which can be reused after passing the inspection. The solid obtained by centrifugation was dried under reduced pressure to obtain 87.8 kg of crude metformin hydrochloride. The yield was 89.1%, and the dicyandiamide content was 0.011%.

[0023] The purification was the same as in Example 1, and 79.3 kg of metformin hydrochloride was obtained, with a yield of 90.3%. The content is 99.81%, dicyandiamide is not detected.

Embodiment 3

[0025] Add 100kg of N,N-dimethylacetamide into a 300L reaction tank, add 50kg of dicyandiamide and 50kg of dimethylamine hydrochloride under stirring, heat to 140±5°C, and react for 6h. After the reaction is over, the temperature is lowered to 20~30°C to crystallize, and centrifuged to dry. The filtrate recovers N,N-dimethylacetamide. The solid obtained by centrifugation was dried under reduced pressure to obtain 91.0 kg of crude metformin hydrochloride. The yield was 92.4%, and the dicyandiamide content was 0.021%.

[0026] The purification was the same as in Example 1, to obtain 82.6 kg of metformin hydrochloride, with a yield of 90.8%. The content of 99.70%, the content of dicyandiamide: 0.0026%.

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Abstract

The invention discloses a method for preparing metformin hydrochloride. Dicyandiamide and dimethylamine hydrochloride are used as raw materials, and the molar ratio of dicyandiamide and dimethylamine hydrochloride is 1:1~1:1.2. 2~4 times the amount of N,N-dimethylacetamide or dimethyl sulfoxide as a solvent, react at 140±5°C for 4~8h, and prepare the crude metformin hydrochloride; recrystallize the crude product with ethanol, and adjust the pH value to 5 ~6, decolorize, stir and cool down to -10~0°C to crystallize, filter and dry to obtain the fine metformin hydrochloride, and recover the solvent from the filtrate. The qualified product yield of the invention is 80-85%, and the purity is high. Due to the high boiling point of the selected reaction solvent, the recovery rate of the solvent is high; the flushing phenomenon can also be effectively avoided, so the reaction conditions are mild, the operation is simple, and the safety is high.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a preparation method of metformin hydrochloride. Background technique [0002] Metformin Hydrochloride is a biguanide antihypertensive drug. More than 50 years of clinical use have proved that Metformin has a good hypoglycemic effect and safety. [0003] Metformin hydrochloride can effectively control the weight of patients while lowering blood sugar, and reduce cardiovascular complications such as myocardial infarction in patients with type 2 diabetes. In addition, the price of metformin hydrochloride is low; it can be used in combination with sulfonylureas, glitazones and insulins; it is administered orally and is convenient and quick to take. [0004] At present, the synthetic methods of metformin hydrochloride mainly contain dry method and wet method. The dry method is the melting method, which is widely used. However, the initial and later stages...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C279/26C07C277/08
Inventor 黄清华刘晓华高永吉胡杰李延顺
Owner QINGDAO HUANGHAI PHARM CO LTD
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