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Preparation method of metformin hydrochloride

A technology of metformin hydrochloride and dimethylamine hydrochloride, which is applied in the field of easy-to-operate metformin hydrochloride production, high purity, and low cost, can solve the problems of high production cost, high market price, and difficulty in removal, and achieve simple and easy production operation, low solvent Cheap and easy to obtain, the effect of high utilization rate of raw materials

Inactive Publication Date: 2012-06-27
赤峰万泽药业股份有限公司
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  • Claims
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Problems solved by technology

In the above-mentioned second step synthesis reaction, several alcohols such as isoamyl alcohol, n-pentanol, n-hexanol, cyclohexanol, ethylene glycol, and glycerin are used as solvents, and the physical and chemical properties of these alcohols are as follows Disadvantages: Low-carbon alcohols such as methanol and ethanol have low viscosity at room temperature, but their boiling points are less than 85°C and cannot meet the temperature requirements of the reaction. High-carbon alcohols such as: isoamyl alcohol, n-pentanol, n-hexanol, Cyclohexanol, ethylene glycol, and glycerol are more viscous at room temperature or low temperature. When using it as a solvent to cool and crystallize after the reaction is completed, the solvent isoamyl alcohol, n-amyl alcohol, n-hexanol, Cyclohexanol, ethylene glycol, and glycerol have the problems of difficult operation and difficult cleaning of products with strong viscosity at low temperature and solvent separation.
In the above-mentioned second-step reaction, the reactant dicyandiamide is incompletely reacted, and the incompletely reacted dicyandiamide is difficult to dissolve in the above-mentioned alcohols, causing the product to be separated from the product when it is separated from the solvent.
Even when the product is refined, it is difficult to remove, and it is difficult to control the content of dicyandiamide, a related substance required by the quality standard, to less than 2 / 10,000
Moreover, the market prices of several solvents such as isoamyl alcohol, n-pentanol, n-hexanol, cyclohexanol, ethylene glycol, and glycerin are relatively expensive, resulting in very high production costs

Method used

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  • Preparation method of metformin hydrochloride
  • Preparation method of metformin hydrochloride
  • Preparation method of metformin hydrochloride

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preparation example Construction

[0024] A preparation method of metformin hydrochloride, comprising the steps of:

[0025] (1) Salt-forming reaction:

[0026] With 40% dimethylamine as the starting material, dimethylamine hydrochloride is generated through a salt-forming reaction with hydrochloric acid;

[0027] The reaction formula is as follows:

[0028]

[0029] (2) Addition reaction:

[0030] Addition reaction with dicyandiamide in solvent N,N-dimethylformamide generates metformin hydrochloride crude product, and obtains metformin hydrochloride through 80% ethanol refining;

[0031] The reaction formula is as follows:

[0032]

[0033] (3) Refined:

[0034] Metformin hydrochloride is obtained through refining with 80% ethanol; the total yield is 75%-78% based on dimethylamine;

[0035] in:

[0036] Step (1) Salt-forming reaction Add 40% dimethylamine solution into the reaction kettle, lower the temperature to below 20°C, then add concentrated hydrochloric acid solution dropwise for salt-formin...

Embodiment 1

[0040] Salt formation reaction: Use a vacuum pump to pump 520Kg of dimethylamine aqueous solution into the reaction tank, start stirring, pass cold brine through the jacket, cool down to below 20°C, and control the temperature below 20°C, start adding 500Kg of hydrochloric acid dropwise, then measure the pH value, If pH=1-2, stop adding hydrochloric acid dropwise, if pH≥2, continue to add hydrochloric acid dropwise until pH=1-2. After the dropwise addition, keep the reaction at 20-25°C for 12h. After the heat preservation is completed, heat up and distill under reduced pressure. After 590Kg of water is distilled, the mother liquor of the previous batch is pumped into the reaction tank with a vacuum pump, and the temperature is lowered to below 40°C by cooling water, and the temperature is lowered to 10°C by passing cold brine. After the crystallization is completely precipitated, put the material into the centrifuge, filter it, and remove the liquid by centrifugal filter until...

Embodiment 2

[0044] Salt-forming reaction and refining are the same as in Example 1.

[0045] Addition reaction: Use a vacuum pump to pump 520.0Kg of N,N-dimethylformamide into the reaction tank, start stirring, and evenly add 260Kg of dimethylamine hydrochloride and 375Kg of dicyandiamide from the feeding port. After the feeding is completed, the tank is sealed, and the interlayer starts to heat up with steam; the temperature is raised to 135-140°C, and the temperature is kept for 12 hours; After the crystallization is completely precipitated, put the material into the centrifuge, filter it, and remove the liquid by centrifugal filter until no liquid flows out, spread the wet material evenly on the baking tray with a thickness of 2-4cm, and dry it at 90-100°C for 10- After 12 hours, 456.0 kg of metformin hydrochloride was obtained, with a yield of 86.3%.

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Abstract

The invention discloses a preparation method of metformin hydrochloride. The method comprises: taking 40% dimethylamine as a starting material, which is subjected to a salification reaction with hydrochloric acid salt forming reaction of dimethylamine hydrochloride, subjecting the dimethylamine hydrochloride and dicyandiamide to an addition reaction in solvent N, N-dimethylformamide so as to generate a metformin hydrochloride crude product, then conducting refining, thus obtaining metformin hydrochloride. The solvent of the invention has viscosity insusceptible to temperature, and is easy to be separated from the product. Besides, the solvent can dissolve the reactant dicyandiamide, and even if dicyandiamide is not fully reacted, it cannot be separated out during separation of the product and the solvent, so that the production operation can be easier, and the purity of the final product can be very high. The method of the invention has the advantages of simple and easy production operation, high raw materialutilization rate, and cheap as well as easily available solvent, the market price of which is 2-3 times lower than prices of solvents in prior, and the synthesis cost is reduced by about 30%, so that the preparation method of the invention is very suitable for industrial production of metformin hydrochloride.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemical synthesis, and in particular relates to a method for producing metformin hydrochloride with high purity, low cost and easy operation. Background technique [0002] Metformin Hydrochloride (Metformin Hydrochloride) is a commonly used drug for lowering blood sugar. It is used for non-insulin-dependent diabetes mellitus. The mechanism of action of metformin hydrochloride is different from other types of oral hypoglycemic drugs. It can reduce the production of glycogen, reduce the absorption of glucose in the small intestine, and improve insulin sensitivity by increasing the uptake and utilization of glucose in peripheral tissues. Unlike sulfonylureas, metformin hydrochloride does not produce hypoglycemia in patients with type 2 diabetes or in patients with normoglycemia. After metformin hydrochloride treatment, insulin secretion remains unchanged, while reducing fasting insulin levels and...

Claims

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Application Information

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IPC IPC(8): C07C279/26C07C277/08
Inventor 臧晓明夏波张海立
Owner 赤峰万泽药业股份有限公司
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