Novel synthesis route of glipizide

The technology of a kind of glipizide and synthetic method is applied in the field of preparation of hypoglycemic drug glipizide, which can solve the problems of unfavorable industrialized production, high cost, and difficulty in obtaining starting materials, and achieves environmental friendliness, mild reaction conditions, Post-processing simple effects

Active Publication Date: 2013-03-27
WUHAN WUYAO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] The above two reactions adopt one-step reaction to obtain glipizide, which The raw materials are difficult to obtain and the cost...

Method used

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  • Novel synthesis route of glipizide
  • Novel synthesis route of glipizide
  • Novel synthesis route of glipizide

Examples

Experimental program
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Effect test

Embodiment 1

[0026] Embodiment 1: the preparation of compound III

[0027] Add 3.96 g (0.020 mol) of 4-(2-aminoethyl) ammonium benzenesulfonate (compound II) into a 100 ml single-necked bottle, then add 75 ml of DMF, cool to 10°C in an ice-water bath, and stir to dissolve. After dissolving, add 4.8g of Boc anhydride (0.022mol) dropwise into the reaction system at 0-5°C, raise the temperature to room temperature and react for 1.5-2h. After the reaction, the reaction solution was poured into 300ml of purified water, and a white solid was precipitated, which was filtered and dried to obtain 5.58g of compound III as a solid, with a yield of 93%.

Embodiment 2

[0028] Embodiment 2: Preparation method 1 of compound IV

[0029] Add 5.54g (0.018mol) of compound III, 5.1g (0.037mol) of potassium carbonate, and 200ml of acetone into a 250ml three-necked flask, set up a condenser, stir and heat to reflux, and react for 6-7 hours. After the reaction, add 2.78g (0.022mol) cyclohexyl isocyanate to the reaction system, and continue the reflux reaction for 6-7h. After the reaction again, filter with suction, take out the solid and transfer it to a beaker, add a small amount of purified water, adjust the pH to 5-6 with 10% HCl solution, filter with suction again, wash the solid with purified water, take out and dry to obtain the compound IV solid 7.81g, yield 99.36%.

[0030]

Embodiment 3

[0031] Embodiment 3: The preparation method 2 of compound IV

[0032] Add 5.54g (0.018mol) of compound III, 3.9g (0.037mol) of sodium carbonate, and 200ml of acetone into a 250ml three-neck flask, set up a condenser, stir and heat to reflux, and react for 6-7 hours. After the reaction, add 2.78g (0.022mol) cyclohexyl isocyanate to the reaction system, and continue the reflux reaction for 6-7h. After the reaction again, filter with suction, take out the solid and transfer it to a beaker, add a small amount of purified water, adjust the pH to 5-6 with 10% HCl solution, filter with suction again, wash the solid with purified water, take out and dry to obtain the compound IV solid 7.81g, yield 99.36%

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Abstract

The invention relates to a novel synthesis route of glipizide, which is characterized by comprising the following steps of protecting 4-(2-amino ethyl)benzenesulfonic acid ammonia (II) by Boc anhydride to obtain a compound (III); reacting the compound (III) with cyclohexyl isocyanate to obtain a compound (IV); carrying out deprotection on the compound (IV) to obtain a compound (V); and reacting the compound (V) with 2-methyl-5-pyrazine carboxylic acid to obtain the glipizide (I) with the single impurity which is less than or equal to 0.5% and the high purity which is more than or equal to 99%. The process is simple, the yield is high, the purity is high and the single impurity is low; and the process is environment-friendly and industrial production is easy to realize.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of the hypoglycemic drug glipizide. Background technique [0002] Glipizide: The chemical name is 1-cyclohexyl-3-{4-[2-(5-methylpyrazine-2-amide)-ethyl]benzenesulfonyl}urea, and the chemical structure is as follows: [0003] [0004] Glipizide is a hypoglycemic drug for non-insulin-dependent (type II) diabetes, and it is used for mild and moderate non-insulin-dependent patients who have failed to achieve good results with diet control alone. [0005] The synthetic routes that have been publicly reported mainly include the following types: [0006] Compound (Ⅵ) and compound (Ⅶ) in anhydrous alkaline condition in EP(8585109.2) [0007] (where R1=NH2, R2=NHCOCl3) reaction, using N.N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), N,N-dimethylaniline (DMA) as solvent, the synthesis route is as follows: [0008] In WO / 01 05354 A2, compoun...

Claims

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Application Information

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IPC IPC(8): C07D241/24
Inventor 皮金红丁友友尹冬魏金维潘文清谢国范
Owner WUHAN WUYAO PHARMA
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