Preparation method of glimepiride intermediate sulfonamides analogue 1 and the sulfonamide analogue 2

A technology for sulfonamides and analogs, which is applied in the field of preparation of sulfonamide analog 1 and sulfonamide analog 2, the key intermediates of glimepiride, can solve problems such as no literature reports

Inactive Publication Date: 2019-06-11
SHANDONG XINHUA PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] At present, there are no literature reports at home and abroad on the re

Method used

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  • Preparation method of glimepiride intermediate sulfonamides analogue 1 and the sulfonamide analogue 2
  • Preparation method of glimepiride intermediate sulfonamides analogue 1 and the sulfonamide analogue 2
  • Preparation method of glimepiride intermediate sulfonamides analogue 1 and the sulfonamide analogue 2

Examples

Experimental program
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Effect test

Embodiment 1

[0032] Add 150g of chlorosulfonic acid to a 250ml reaction bottle, cool down to below 20°C, slowly add 30g of condensate at 10-20°C, then raise the temperature to 35°C, and react at 35±2°C for 5 hours. After the reaction was completed, the reaction solution was slowly poured into 1000 ml of ice water. Then filter and wash with water to obtain a white solid.

[0033] Add the white solid to a 100ml reaction flask, add 800ml of concentrated ammonia water, react at 20-25°C for 4 hours, then raise the temperature to 40±2°C, and continue the reaction for 4 hours. After the reaction, the temperature was lowered to below 25°C, filtered and washed with water to obtain a white solid.

[0034] Finally, the white solid was preparatively chromatographed by HPLC, chromatographic conditions: chromatographic column: C18, 300*50.0mm, particle size 10μm, pore size 120A, wavelength: 225nm, mobile phase A: methanol, mobile phase B: water, isocratic washing A 80% and B 20% (V / V) were separated t...

Embodiment 2

[0036] Add 180g of chlorosulfonic acid into a 250ml reaction bottle, cool down to below 20°C, slowly add 30g of condensate at 10-20°C, then raise the temperature to 40°C, and react at 40±2°C for 7 hours. After the reaction was completed, the reaction solution was slowly poured into 1000 ml of ice water. Then filter and wash with water to obtain a white solid.

[0037] Add the white solid to a 100ml reaction flask, add 800ml of concentrated ammonia water, react at 20-25°C for 4 hours, then raise the temperature to 40±2°C, and continue the reaction for 4 hours. After the reaction, the temperature was lowered to below 25°C, filtered and washed with water to obtain a white solid.

[0038] Finally, the white solid was preparatively chromatographed by HPLC, chromatographic conditions: chromatographic column: C18, 300*50.0mm, particle size 10μm, pore size 120A, wavelength: 225nm, mobile phase A: methanol, mobile phase B: water, isocratic washing A 80% and B 20% (V / V) were separated...

Embodiment 3

[0040] Add 300g of chlorosulfonic acid into a 250ml reaction bottle, cool down to below 20°C, slowly add 30g of condensate at 10-20°C, then raise the temperature to 50°C, and react at 50±2°C for 8 hours. After the reaction was completed, the reaction solution was slowly poured into 1000 ml of ice water. Then filter and wash with water to obtain a white solid.

[0041] Add the white solid to a 100ml reaction flask, add 800ml of concentrated ammonia water, react at 20-25°C for 4 hours, then raise the temperature to 40±2°C, and continue the reaction for 4 hours. After the reaction, the temperature was lowered to below 25°C, filtered and washed with water to obtain a white solid.

[0042] Finally, the white solid was preparatively chromatographed by HPLC, chromatographic conditions: chromatographic column: C18, 300*50.0mm, particle size 10μm, pore size 120A, wavelength: 225nm, mobile phase A: methanol, mobile phase B: water, isocratic washing A 80% and B 20% (V / V) were separated...

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Abstract

The invention provides a preparation method of glimepiride intermediates sulfonamide analogue 1 and sulfonamide analogue 2. The glimepiride intermediates sulfonamide analogue 1 and sulfonamide analogue 2 are produced by reacting 3-ethyl-4-methyl-2-oxo-3-pyrrolin-N-(2-phenethyl) formamide with chlorosulfonic acid and ammonia water. The preparation method of glimepiride intermediates sulfonamide analogue 1 and sulfonamide analogue 2 has the advantages that the purity of the key intermediate sulfonamide can be controlled better and the production process of the sulfonamide can be optimized; and more importantly, the purpose of controlling the contents of glimepiride EP impurity D and EP impurity I in advance is achieved by controlling the purity of the key intermediate amide rather than by merely depending on refining at the expense of yield loss, so that the glimepiride is controllable in quality, high in yield, and low in cost.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to a preparation method of sulfonamide analog 1 and sulfonamide analog 2, key intermediates of glimepiride. Background technique [0002] Glimepiride Tablets were developed by Sanofi-Aventis and are used for type Ⅱ diabetes mellitus whose blood sugar cannot be satisfactorily controlled by diet, physical exercise and weight loss. Glimepiride is the first of a new generation of sulfonylurea antidiabetic drugs. It has the advantages of small dosage, long action time and high bioavailability. [0003] 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 impurity D and impurity I of glimepiride European Pharmacopoeia EP, and is the main impurity in the finished product of glimepiride, and b...

Claims

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Application Information

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IPC IPC(8): C07D207/38
Inventor 商艳梅郑忠辉蒋涛
Owner SHANDONG XINHUA PHARMA CO LTD
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