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Preparation method of glimepiride EP impurities D and I

A technology for glimepiride and impurities, which is applied in the field of medicine and can solve the problems that the preparation method of glimepiride has not been reported in the literature.

Inactive Publication Date: 2019-06-18
SHANDONG XINHUA PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] 1-[[3-[2-(3-Ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)ethyl]phenyl]sulfonyl]-3-(trans Formula - 4-methylcyclohexyl)urea and 1-[[2-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)ethyl] Phenyl]sulfonyl]-3-(trans-4-methylcyclohexyl)urea is Glimepiride European Pharmacopoeia EP impurity D and EP impurity I, these two impurities are the main impurities in the finished product of glimepiride , but the preparation methods of EP impurity D and impurity I of glimepiride have not been reported in the literature

Method used

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  • Preparation method of glimepiride EP impurities D and I
  • Preparation method of glimepiride EP impurities D and I
  • Preparation method of glimepiride EP impurities D and I

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Example 1 Preparation of sulfonamide analogue 1 and sulfonamide analogue 2

[0024] Add 180g of chlorosulfonic acid to a 250ml reaction flask, lower the temperature to below 20°C, slowly add 30g of the condensate under the conditions of 10-20°C, then heat up to 40°C, and react at 40±2°C for 7 hours. After the reaction, the reaction solution was slowly poured into 1000 ml of ice water. Then filter and wash with water to obtain a white solid.

[0025] Add the white solid to a 100ml reaction flask, add 800ml of concentrated ammonia, and react at 20-25°C for 4 hours, then increase the temperature to 40±2°C and continue the reaction for 4 hours. After the reaction, the temperature was lowered to 25° C., filtered and washed with water to obtain a white solid.

[0026] Finally, the white solid was applied to high performance liquid chromatography with chromatographic conditions: Column: C18, 300*50.0mm, particle size 10μm, pore size 120A, wavelength: 225nm, mobile phase A: methanol...

Embodiment 2

[0027] Example 2. Preparation of EP Impurity D

[0028] Add 1.0g compound 1, 0.51g anhydrous potassium carbonate, 16ml acetone into a 50ml reaction flask, raise the temperature to 50℃, and react at this temperature. After 0.5 hours, add 0.40g trans-4-methylcyclohexyl isocyanate dropwise With 4ml of acetone mixed solution, continue to react for 5 hours. After the reaction is completed, the temperature is lowered to room temperature, filtered and washed to obtain 1.10 g of EP impurity D.

Embodiment 3

[0029] Example 3 Preparation of EP Impurity D

[0030] Add 1.0g compound 1, 0.51g anhydrous potassium carbonate, 16ml acetone into a 50ml reaction flask, raise the temperature to 55℃, and react at this temperature. After 0.5 hours, add 0.60g trans-4-methylcyclohexyl isocyanate dropwise With 4ml of acetone mixed solution, continue to react for 8 hours. After the reaction is completed, it is cooled to room temperature, filtered and washed to obtain 1.35 g of EP impurity D.

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Abstract

The invention provides a preparation method of glimepiride EP impurities D and I, comprising allowing 3-ethyl-4-methyl-2-oxo-3-pyrrolin-N-(2-phenethyl)formamide to reaction with chlorosulfonic acid, allowing reaction with ammonia water, carrying out liquid preparative purification to obtain sulfamide analogues 1 and 2, and subjecting the sulfamide analogues to reaction separately with trans-4-methylcyclohexyl isocyanate to obtain the glimepiride EP impurities D and I. By preparing high-purity controls of glimepiride EP impurities D and I, it is possible to affiliate main impurities in crude glimepiride, control the purity of the crude glimepiride and optimize a production technique of the crude glimepiride; more importantly, the contents of EP impurities D and I in finished glimepiride arecontrolled in advance by controlling the purity of the crude glimepiride instead of by refining at the cost of yield loss; therefore, glimepiride quality is controllable, the yield is high, and the cost is low.

Description

Technical field [0001] The invention belongs to the field of medicine, and specifically relates to a preparation method of glimepiride EP impurity D and EP impurity I. Background technique [0002] Glimepiride tablets are the first third-generation sulfonyluria hypoglycemic agents to be marketed and are used in the treatment of non-insulin-dependent diabetes. It has the advantages of small dose, long action time, high bioavailability, etc. It is currently the best sulfonyl hypoglycemic agent in clinical evaluation. [0003] In the "Twelfth Five-Year Plan for National Drug Safety", the country requires generic drugs to be consistent with the quality and efficacy of the original drugs, including consistent impurity profiles, consistent stability, and consistent dissolution rules in vivo and in vitro. It can be seen that the study of impurities is an important part of the consistency study. In addition, the study of impurity profiles can also improve the controllability of drug prod...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/38
Inventor 商艳梅郑忠辉蒋涛
Owner SHANDONG XINHUA PHARMA CO LTD
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