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Triphosgene method for synthesizing benzene sulphanilamide, intermediate of glimepiride, drug for Type ii Diabetes Mellitus

A diabetes drug, glimepiride technology, applied in the field of compound preparation, can solve the problems of inconvenient operation and complicated process steps, and achieve the effect of high product yield and simple process

Inactive Publication Date: 2013-12-04
姜树林
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Glimepiride intermediate N-4-[2-(3-ethyl-4-methyl-2-oxide-3-pyrroline-1- Formamido)ethyl]-benzenesulfonamide is a core intermediate of type Ⅱ diabetes drugs, and its synthesis methods have been reported a lot, Indian Pat. Appl., 2006MU00502, and Journal of China Pharmaceutical University 38(1), 1-5 ; 2007; Fine Chemical Intermediates 36 (3), 16-18; 2006, etc. reported that the synthesis of this intermediate is to make phenethylamine into phenethyl isocyanate first, and then combine it with 3-ethyl-4-methyl Base pyrrolinone reaction, further progressive sulfonation and amination, this method has complex process steps and is not easy to operate

Method used

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  • Triphosgene method for synthesizing benzene sulphanilamide, intermediate of glimepiride, drug for Type ii Diabetes Mellitus
  • Triphosgene method for synthesizing benzene sulphanilamide, intermediate of glimepiride, drug for Type ii Diabetes Mellitus

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Effect test

Embodiment 1

[0012] Add 1200 milliliters of dichloromethane, 170 grams of phenethylamine, 175 grams of 3-ethyl-4-methylpyrrolidinone in a 3000 milliliter three-necked flask, and add 132 grams of triphosgene and The mixed solution of 600 ml of dichloromethane, about 3 hours after the end of the dropwise addition, continued to react for 3 hours after the end of the dropwise addition, then warmed up to room temperature, stirred for 2 hours until the end of the reaction, added 800

[0013] Stir in milliliters of water, concentrate to remove the solvent dichloromethane, then add 1000 milliliters of water, stir and cool to 0 ° C, and stir at this temperature for 3 hours, filter, wash with 100 milliliters of ethanol, and dry to obtain 190 grams of intermediate N-[2 -(3-Ethyl-4-methyl-2-oxide-3-pyrroline-1-carboxamido)ethyl]-benzene.

[0014] Pump 640 grams of chlorosulfonic acid into a 2000 ml reactor, and then add 190 grams of N-[2-(3 -Ethyl-4-methyl-2-oxidation-3-pyrroline-1-carboxamido)...

Embodiment 2

[0016] Add 1200 milliliters of methylene chloride, 170 grams of phenethylamine, and 175 grams of 3-ethyl-4-methylpyrrolidone in a 2000 milliliter three-necked flask, and add 152 grams of triphosgene and The mixed solution of 800 ml of dichloromethane, the dropwise addition is completed in about 3 hours, continue to react for 3 hours after the dropwise addition, then warm up to room temperature, stir for 2 hours to the end of the reaction, add 800 ml of water and stir, concentrate and remove the solvent dichloromethane , then add 1000 ml of water, stir and cool to 0°C, and stir at this temperature for 3 hours, filter, wash with 100 ml of ethanol, and dry to obtain 193 g of intermediate 3.

[0017] Pump 640 grams of chlorosulfonic acid into a 2000 milliliter reactor, and then add 193 grams of N-[2-(3 -Ethyl-4-methyl-2-oxidation-3-pyrroline-1-carboxamido)ethyl]-benzene Stir for 15 minutes after adding the materials, slowly raise the temperature to room temperature, and keep the r...

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Abstract

The invention discloses a triphosgene method for synthesizing benzene sulphanilamide, the intermediate of glimepiride, a drug for Type ii Diabetes Mellitus. Triphosgene is slowly dropped into a solution which contains phenethylamine and 3-ethyl-4-methyl pyrroline ketone, at a controlled temperature, so that N-[2-(3-ethyl-4-methyl-2-oxidation-3-pyrroline-1-formylamino)ethyl]-benzene (3) is obtained; the product reacts with chlorosulfonic acid to generate sulfonated product; the sulfonated product reacts with ammonia water to generate crude product benzenesulfonamide; the crude product is refined through solvent treatment to generate fine product; the reaction formula is show in the specification. The triphosgene method is simple in technology, simple in operation and high in yield; compared with the conventional method of phosgene, the solid phosgene (triphosgene) method is safer and is convenient to operate.

Description

[0001] technical field [0002] The invention relates to a method for synthesizing benzsulfatriphosgene, an intermediate of glimepiride, a drug for type II diabetes, and belongs to the field of compound preparation. Background technique [0003] Glimepiride is the third-generation sulfonylurea oral hypoglycemic drug. The main mechanism of its hypoglycemic effect is to stimulate the secretion of insulin by pancreatic β cells, and partially increase the sensitivity of surrounding tissues to insulin. This product binds and dissociates faster than glibenclamide with the insulin receptor, and causes less severe hypoglycemia. After oral administration, glimepiride is 100% absorbed in the gastrointestinal tract, and the plasma concentration reaches the peak (Cmax) within 2 to 3 hours, and the protein binding rate is greater than 99.5%. Glimepiride is completely metabolized through oxidative biotransformation, the main metabolites are cyclohexyl hydroxymethyl derivatives (M1) and c...

Claims

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Application Information

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IPC IPC(8): C07D207/38
Inventor 王德峰王炳才朱小飞
Owner 姜树林
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