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Synthesis process of hypoglycemic drug repaglinide

A synthesis process and hypoglycemic technology, which is applied to the synthetic process field of the hypoglycemic drug repaglinide, can solve the problems of complicated post-processing operations, poor solubility, low extraction efficiency, etc., and achieve stable and large quality of intermediates and finished products. Socio-economic and environmental benefits, high solvent recovery rate

Pending Publication Date: 2020-09-08
江西博雅欣和制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] Although the reaction routes of the above-mentioned several methods are reasonable, there are disadvantages such as low product yield and purity, complicated post-treatment operations, flammable, explosive and volatile solvents, increased production costs, and low production safety factor.
[0012] For example, in the dissociation step of CN108047163A, petroleum ether is used as the reaction solvent and extraction agent. Due to the poor solubility of compound III in petroleum ether, there is a problem that the extraction efficiency is low and the yield of the later product is low. In addition, petroleum ether has a low flash point and a low boiling point. , it is extremely dangerous to use; the crude repaglinide, the final product, is refined with acetone, and there are similar shortcomings
[0013] In the dissociation step of CN105175361A, ammonia water with a pungent smell is used as an acid-binding agent, which has a certain impact on the workshop environment and the health of workers; because compound V has a large solubility in toluene, toluene is used as a refining solvent in the condensation step, and there is The disadvantage of low yield

Method used

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  • Synthesis process of hypoglycemic drug repaglinide
  • Synthesis process of hypoglycemic drug repaglinide
  • Synthesis process of hypoglycemic drug repaglinide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0077] The first step: dissociation

[0078] Add 60g of 10% aqueous sodium hydroxide solution and 180g of toluene successively in the 500L reaction flask, add 33g of wrigamine glutamate (compound II) powdery solid at 5~10°C, add and keep warm for 0.5 hours; After standing and stratifying, the organic phase was collected, washed once with 35 g of drinking water, and the obtained toluene solution of Regigamid (Compound III) directly entered the next step of condensation reaction.

[0079] Step 2: Condensation

[0080] Add 180g of toluene, 19g of Regalic acid (compound IV) and 17g of triethylamine in sequence to a 1000ml reaction flask, and dropwise add a mixed solution of 10g of pivaloyl chloride and 35g of toluene at 10-15°C. The reaction was incubated at ℃ for 1 hour.

[0081] At 10-15°C, add the toluene solution of Regigamid (compound III) obtained in the first step dropwise, and raise the temperature to 40-45°C for 1 hour after the dropping; take a sample and control it. ...

Embodiment 2

[0088] The first step: dissociation

[0089] Add 2.4kg of 10% sodium hydroxide aqueous solution and 6.65kg of toluene successively in the 20L reaction kettle, add 1.33kg of wrigamine glutamate (compound II) powdery solid at 5~10 ℃, add and keep warm and react at 0.5 hour; after the reaction, the reaction was left to stand for stratification, and the organic phase was collected, washed once with 1.35kg of drinking water, and the toluene solution of gained Regigamide (Compound III) directly entered the next step of condensation reaction.

[0090] Step 2: Condensation

[0091] Add 6.65kg of toluene, 0.79kg of Regalic acid (Compound IV), 0.67kg of triethylamine in sequence to a 50L reactor, and dropwise add a mixed solution of 0.40kg of pivaloyl chloride and 1.35kg of toluene at 10 to 15°C. , keep the reaction at 10-15°C for 1 hour.

[0092] At 10-15°C, add the toluene solution of Regigamid (compound III) obtained in the first step dropwise, and raise the temperature to 40-45°C ...

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Abstract

The invention discloses a synthesis process of a hypoglycemic drug repaglinide. The process comprises the following steps: a) by using a compound II (S,S')-3-methyl-1-(2-piperidinophenyl)butylamine asa raw material, dissociating with an alkali, and directly condensing the obtained organic phase containing a compound III repigine with a compound IV 3-ethoxy-4-ethoxycarbonyl phenylacetic acid in the presence of an acylation reagent and an alkali without concentration; b) refining the compound V repaglinide ester crude product obtained after condensation by using an alkane solvent; and c) hydrolyzing in the presence of an alcohol solvent and an inorganic alkali, carrying out acidifying of post-treatment at a proper temperature, and purifying the obtained compound I repaglinide crude productby using an alcohol-water mixed solvent to obtain a repaglinide fine product. The synthesis process provided by the invention simplifies the synthesis steps, has the advantages of environmental protection, simple operation, high yield, low cost and the like, and is a repaglinide synthesis process suitable for industrial large-scale production.

Description

technical field [0001] The invention relates to a synthesis process of repaglinide, a hypoglycemic drug, and belongs to the technical field of drug synthesis. Background technique [0002] Repaglinide, trade name Prandin (Chinese name: Nuohelong). The prodrug of repaglinide was developed by German scientist Dr. Karl Thomae GmbH at the end of 1983, and was acquired by German Boehringer Ingelheim (Chinese name: Boehringer Ingelheim) in 1990. After the successful development of repaglinide, it was authorized to Boehringer Ingelheim (Chinese name: Novo Nordisk) headquartered in Denmark. Novo Nordisk is the world's leading biopharmaceutical company in the development and production of insulin for diabetes treatment In 1992, Novo Nordisk submitted an IND application for repaglinide to the US FDA. In July 1997, it submitted an NDA application. It was approved in December 1997 and was first listed in the US in 1998. [0003] The chemical name of repaglinide is S(+)-2-ethoxy-4-[N-{...

Claims

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Application Information

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IPC IPC(8): C07D295/135A61K31/451A61P3/10
CPCC07D295/135A61K31/451A61P3/10
Inventor 王建朱向宏谢西平黄鹿叶刚刘毅
Owner 江西博雅欣和制药有限公司