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Preparation of glimepiride raw material

A glimepiride and raw material technology, applied in the field of preparation of glimepiride raw materials for the treatment of type II diabetes, can solve the problems of high content of organic solvent chloroform and difficult removal, etc., so as to be suitable for industrial production and reduce residues , the effect of simplifying the synthetic route

Active Publication Date: 2012-05-23
JIANGSU WANBANG BIOPHARMLS +1
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0005] At present, the glimepiride raw materials produced by most manufacturers are obtained according to the literature Drugs of the future 1992, 17 (9): 774-778, with 3-ethyl-4-methyl-2-oxo-3- Pyrroline-2-one as a raw material reacts with phenethyl isocyanate to obtain 3-ethyl-4-methyl-2-oxo-N-(2-phenylethyl)-3-pyrroline-1-methanol Amide, sulfonated with chlorosulfonic acid at 30°C to generate the corresponding sulfonyl chloride, and then react with concentrated ammonia to obtain amide (4-[2-(3-ethyl-4-methyl-2-oxo-3- Pyrroline-1-carboxamido)-ethyl]-benzenesulfonamide), finally condensed with trans-4-methylcyclohexyl isocyanate in acetone, and finally obtained by recrystallization with chloroform and acetone, this process The content of organic solvent chloroform in the final glimepiride product is high, which is not easy to remove

Method used

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  • Preparation of glimepiride raw material
  • Preparation of glimepiride raw material
  • Preparation of glimepiride raw material

Examples

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Embodiment 1

[0027] A kind of preparation method of glimepiride raw material, with compound A: 4-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-formylamino)-ethyl ]-benzenesulfonamide and compound B: trans-4-methyl-cyclohexyl isocyanate is raw material, comprises the following steps in order:

[0028] The first step: Add compound A: 4-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-formylamino) in the reaction kettle according to 1:0.81:20 -Ethyl]-benzenesulfonamide, anhydrous potassium carbonate and organic solvent acetone, heated to 56°C and refluxed for 5 hours under stirring, then stopped heating; when the temperature was lowered to 50°C, slowly added compound B: trans-4-methyl - cyclohexyl isocyanate, wherein, the ratio of benzenesulfonamide and trans-4-methyl-cyclohexyl isocyanate addition is 1: 0.43 (molar ratio is about 1: 1); Continue heating and stirring to reflux at this temperature for 5.5 hours, Stop heating and let it stand for more than 8 hours to obtain a synthetic liquid of a mixture ...

Embodiment 2

[0034] A kind of preparation method of glimepiride raw material, with compound A: 4-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-formylamino)-ethyl ]-benzenesulfonamide and compound B: trans-4-methyl-cyclohexyl isocyanate is raw material, comprises the following steps in order:

[0035] Step 1: Add compound A: 4-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) in the reaction kettle according to 1:0.81:22 -Ethyl]-benzenesulfonamide, anhydrous potassium carbonate and organic solvent acetone, heated to 60°C and refluxed for 5.5 hours under stirring, then stopped heating; when the temperature was lowered to 54°C, slowly added compound B: trans-4-methyl - Cyclohexyl isocyanate, wherein, the ratio of benzenesulfonamide and trans-4-methyl-cyclohexyl isocyanate addition is 1:0.43 (molar ratio is about 1:1); Continue to stir and reflux at this temperature for 5.5 hours, stop Heating and standing for more than 8 hours to obtain a synthetic liquid of a mixture of crude glimepiride and...

Embodiment 3

[0040] A kind of preparation method of glimepiride raw material, with compound A: 4-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-formylamino)-ethyl ]-benzenesulfonamide and compound B: trans-4-methyl-cyclohexyl isocyanate is raw material, comprises the following steps in order:

[0041] The first step: Add compound A: 4-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-formylamino) in the reaction kettle according to 1:0.81:20 -Ethyl]-benzenesulfonamide, anhydrous potassium carbonate and organic solvent acetone, heated to 56°C and refluxed for 6 hours under stirring, then stopped heating; when the temperature was lowered to 50°C, slowly added compound B: trans-4-methyl - Cyclohexyl isocyanate, wherein, the ratio of benzenesulfonamide and trans-4-methyl-cyclohexyl isocyanate is 1:0.43 (molar ratio is about 1:1); continue to stir and reflux at this temperature for 6 hours, stop Heating and standing for more than 8 hours to obtain a synthetic liquid of a mixture of crude glimepiride and potass...

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Abstract

The invention discloses a preparation method of Glimepiride raw material, which comprises the following steps in sequence: in the presence of K2CO3, a condensation reaction is carried out between a compound A: 4-[2-(3-ethyl-4-methyl-2-keto-3-pyrroline-1-formamido)-ethyl]-benzene sulfonamide and a compound B: trans-4-methyl-cyclohexyl isocyanate of the same molar weight in an organic solvent. The mass ratio of the compound A and K2CO3 is 1:0.8-0.9; the mixture synthetic fluid of a crude Glimepiride product and K2CO3 is filtered in a suction way, and then an extract is added into pure water anddissolved to form a solution. The solution is filtered for removing impurities to obtain the aqueous solution of Glimepiride; a hydrochloric acid solution is added into the aqueous solution of the Glimepiride for acidification and then a crude product is separated; acetone is added into the crude Glimepiride product and then refined, filtered in a suction manner, dried in a vacuum environment to obtain a pure Glimepiride product. The method has the advantages of simplifying the synthetic route, selecting mature intermediates as raw materials, adding K2CO3 for promoting the condensation reaction, avoiding the use of chloroform, reducing the residual organic solvent, and being applicable to industrialized production.

Description

technical field [0001] The invention relates to a method for preparing a raw material of glimepiride, a medicine for treating type II diabetes. Glimepiride is a hypoglycemic medicine of sulfonylureas. Background technique [0002] Glimepiride is a hypoglycemic drug of the sulfonylurea class. It was developed by the German company Hoechst Marion Roussel in the early 1980s. It was first launched in Germany, and later in Switzerland, Sweden, Denmark and other countries. In 1995, it was approved by the US Drug Administration (FDA), and in 2000, it was developed, produced and launched by many manufacturers in China. [0003] Commonly used oral hypoglycemic drugs include sulfonylureas and biguanides, and sulfonylurea oral hypoglycemic drugs are one of the main drugs for the treatment of non-insulin-dependent diabetes. These drugs are rapidly absorbed when taken orally, and are more combined with plasma proteins in the blood. The mechanism of action has been confirmed by pharmacol...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D207/38A61P3/10
Inventor 李孝成乔德水高雪芹
Owner JIANGSU WANBANG BIOPHARMLS
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