Preparation method of glimepiride impurity

A technology for glimepiride and impurities, which is applied in the field of preparation of glimepiride impurities, can solve problems such as inseparability, and achieve the effects of mild reaction, controllable process parameters and high purity

Active Publication Date: 2020-10-30
SHANDONG XINHUA PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Impurity J is an impurity in glimepiride, but its amount is very small and cannot be separated

Method used

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  • Preparation method of glimepiride impurity
  • Preparation method of glimepiride impurity
  • Preparation method of glimepiride impurity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] (1) Preparation of N-acetylphenethylamine

[0039] Add 24.2 g of 2-phenylethylamine and 50 ml of dichloromethane into a four-necked flask, and stir to lower the temperature to below 10°C. 21.4 g of acetic anhydride was added dropwise while keeping the temperature below 10°C. After the addition, keep the reaction for 10 minutes, and add 200ml of purified water dropwise. After standing still, the organic layer was separated, and the aqueous layer was extracted once more with 25ml of dichloromethane. The organic layers were combined, washed twice with 25ml×2 saturated sodium bicarbonate solution, and then washed twice with 25ml×2 purified water. The organic layer was dried over an appropriate amount of anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure at 45°C to obtain 32.5 g of crude N-acetylphenethylamine, which was directly used in the next step without purification.

[0040] (2) Preparation of impurity J benzenesulfonamide (chemical ...

Embodiment 2

[0049] (1) Preparation of N-acetylphenethylamine

[0050]Add 24.2 g of 2-phenylethylamine and 50 ml of ethyl acetate into a four-necked flask, and stir to lower the temperature to below 10°C. 21.4 g of acetic anhydride was added dropwise while keeping the temperature below 10°C. After the addition, keep the reaction for 10 minutes, and add 200ml of purified water dropwise. After standing still, the organic layer was separated, and the aqueous layer was extracted once more with 25 ml of ethyl acetate. The organic layers were combined, washed twice with 25ml×2 saturated sodium bicarbonate solution, and then washed twice with 25ml×2 purified water. The organic layer was dried over an appropriate amount of anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure at 50°C to obtain 30.7 g of crude N-acetylphenethylamine. It was directly used in the next step without refining.

[0051] (2) Preparation of impurity J benzenesulfonamide (chemical name: 4-(N...

Embodiment 3

[0060] (1) Preparation of N-acetylphenethylamine

[0061] Add 24.2 g of 2-phenylethylamine and 50 ml of dichloromethane into a four-necked flask, and stir to lower the temperature to below 15°C. 21.4 g of acetic anhydride was added dropwise while keeping the temperature below 15°C. After the addition, keep the reaction for 10 minutes, and add 200ml of purified water dropwise. After standing still, the organic layer was separated, and the aqueous layer was extracted once more with 25ml of dichloromethane. The combined base layer was first washed twice with 25ml×2 saturated sodium bicarbonate solution, and then washed twice with 25ml×2 purified water. The organic layer was dried over an appropriate amount of anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure at 45°C to obtain 31.7 g of crude N-acetylphenethylamine. It was directly used in the next step without refining.

[0062] (2) Preparation of impurity J benzenesulfonamide (chemical name: ...

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Abstract

The invention belongs to the technical field of medicinal chemistry and particularly relates to a preparation method of a glimepiride impurity. The preparation method comprises the following steps: dropwise adding acetic anhydride into a solution of 2-phenethylamine and an organic solvent with a low boiling point to be subjected to reaction to generate N-acetyl phenethylamine; dropwise adding chlorosulfonic acid into the N-acetyl phenethylamine at the temperature of lower than 20 DEG C to be subjected to chlorosulfonation reaction, and performing hydrolysis after the reaction is completed to remove excess chlorosulfonic acid; performing filtration and washing to obtain an impurity J benzenesulfonyl chloride; performing ammonolysis on the impurity J benzenesulfonyl chloride to obtain an impurity J benzene sulfonamide; in acetone, enabling the impurity J benzene sulfonamide to firstly react with a catalyst and then react with trans-p-methylcyclohexyl isocyanate to obtain an impurity J acetyl substance; enabling the impurity J acetyl substance and ethanol to be subjected to alcoholysis under the condition of the catalyst to generate an impurity J and ethyl acetate; and performing refining to obtain a high-purity impurity J. The purity of the glimepiride impurity J prepared by the method is high, the liquid phase content of the glimepiride impurity J is greater than 98.5%, the rawmaterials used in the method are easily available, the process parameters are controllable, and the reaction is mild.

Description

technical field [0001] The invention relates to a preparation method of glimepiride impurities, belonging to the technical field of medicinal chemistry. Background technique [0002] Glimepiride is a second-class new drug jointly developed by our company and JC Corporation of the United States. Glimepiride was first developed by the German company Hoechst Marion Roussel (HMR). It was first launched in Sweden under the trade name Amaryl in September 1995. It was approved by the FDA to enter the U.S. market in 1996. It is used for the treatment of uncontrolled diet and exercise. It is the first sulfonylurea drug approved by the FDA for simultaneous use with insulin. [0003] Glimepiride is currently the most clinically evaluated sulfonylurea hypoglycemic drug and has a good market prospect. Compared with similar products, it has the following advantages: (1) Since the action time of glimepiride and the receptor is shorter, the time of insulin secretion is shortened, so it ha...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C303/40C07C311/49C07C303/38C07C309/46C07C303/08C07C309/88
CPCC07B2200/07C07C303/08C07C303/38C07C303/40C07C311/49C07C309/46C07C309/88
Inventor 刘胜高吴辉
Owner SHANDONG XINHUA PHARMA CO LTD
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