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Preparation method of racecadotril

A technology of racecadotril and acetyl mercapto, which is applied in the field of preparation of racecadotril, can solve the problems of low yield and low purity, achieve less reagents, simple process and high atom economy Effect

Inactive Publication Date: 2014-04-30
陕西汉江药业集团股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] The invention provides a preparation method of racecadotril using 2-benzyl acrylic acid as a raw material, which solves the technical problems of low yield and low purity of the existing preparation method

Method used

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  • Preparation method of racecadotril
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  • Preparation method of racecadotril

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] 1] Preparation of intermediate 3-acetylmercapto-2-benzylpropionic acid

[0047] 1.1] Add 26.75g of 2-benzylacrylic acid to a 250ml reaction flask, then add 20.06g of thioacetic acid, stir to dissolve; slowly raise the temperature to 30°C; keep it warm for 8 hours, and generate the intermediate 3-acetylmercapto-2-benzyl A solution of propionic acid;

[0048] 1.2] After the reaction in step 1.1 is completed, distill under reduced pressure. The end point temperature of the distillation is about 78°C (75~80°C), and the vacuum degree is ≥-0.08MPa; Distill toluene, the distillation end point temperature is 78°C (75-80°C), and vacuum dry; after distillation, take a sample and check the purity of the liquid phase, the purity of the intermediate 3-acetylmercapto-2-benzylpropionic acid is ≥95.0%, thio Acetic acid≤0.1%.

[0049] In this step, thioacetic acid is both a reagent and a solvent, and the thioacetic acid is distilled off after the reaction of this step is completed.

...

Embodiment 2

[0059] 1] Preparation of intermediate 3-acetylmercapto-2-benzylpropionic acid

[0060] 1.1] Add 26.75g of 2-benzylacrylic acid to a 250ml reaction bottle, then add 20.06g of thioacetic acid, stir to dissolve; slowly raise the temperature to 60°C; keep it warm for 5 hours;

[0061] 1.2] After the reaction in step 1.1 is completed, distill under reduced pressure. The end point temperature of the distillation is about 78°C (75~80°C), and the vacuum degree is ≥-0.08MPa; Distill toluene, the distillation end point temperature is 78°C (75-80°C), and vacuum dry; after distillation, take a sample and check the purity of the liquid phase, the purity of the intermediate 3-acetylmercapto-2-benzylpropionic acid is ≥95.0%, thio Acetic acid≤0.1%.

[0062] In this step, thioacetic acid is both a reagent and a solvent, and the thioacetic acid is distilled off after the reaction.

[0063] 2) Preparation of racecadotril

[0064] 2.1] Put 55.65g of glycine benzyl ester p-toluenesulfonate into...

Embodiment 3

[0070] 1) Preparation of 3-acetylmercapto-2-benzylpropionic acid

[0071] 1.1] Add 26.75g of 2-benzylacrylic acid to a 250ml reaction flask, then add 25.11g of thioacetic acid, stir to dissolve; slowly raise the temperature to 90°C; keep the reaction for 2 hours.

[0072] 1.2] After the reaction in step 1.1 is completed, distill under reduced pressure. The end point temperature of the distillation is about 78°C (75~80°C), and the vacuum degree is ≥-0.08MPa; Distill toluene, the distillation end point temperature is 78°C (75-80°C), and vacuum dry; after distillation, take a sample and test the purity of the liquid phase, the purity is ≥95.0%, and the thioacetic acid is ≤0.1%.

[0073] 2) Preparation of racecadotril

[0074] 2.1] Put 55.65g of glycine benzyl ester p-toluenesulfonate in another reaction flask and dissolve it with 165ml of dichloromethane, add 26.3g of pyridine; stir to dissolve; cool the system to 2°C (-2~5°C), add 3- Acetylmercapto-2-benzylpropionic acid solut...

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Abstract

The invention relates to a preparation method of racecadotril. The method comprises the following steps: (1) enabling thioacetic acid to react with 2-benzylacrylic acid to prepare an intermediate 3-acetyl mercapto-2-benzyl propanoic acid; (2) carrying out amidation on the intermediate 3-acetyl thiol-2-glycin benzyl propionic acid and glycine benzyl ester p-toluenesulfonate salt under existence of a catalyst to generate the racecadotril. By adopting the method, the racecadotril with high yield and purity can be obtained, the defect of the original technology is compensated, pollution is reduced, and the cost is reduced. Thioacetic acid is used as a solvent and is also used as a reaction reagent, reaction process is simple and rapid, few reagents are used, and the purity and the yield are greater than or equal to 95%; EDCI or DCC is selected as a condensation reagent; a mixed solvent is used for crystallization, the influence on product yield is small, and impurity removal effect is good; the overall technology adopts a one-step to synthetize, simple, efficient, high in atom economy, more green and environment-friendly, and the racecadotril product which is high in yield, and accords with the EP quality standard can be obtained.

Description

technical field [0001] The invention relates to a preparation method of racecadotril. technical background [0002] Racecadotril (Racecadotril), chemical name: N-[(R,S)-3-acetylmercapto-2-benzylpropionyl)]glycine benzyl ester, belongs to antidiarrheal drug, developed and created by French Bioproject company. At present, the drug is one of the first-choice drugs for the treatment of acute diarrhea in children in many medical institutions. [0003] A method for the synthesis of amides [0004] Carboxylic acid and amine are subjected to azeotropic distillation in benzene or toluene to remove the generated water and move the reaction in the positive direction. [0005] example: [0006] The advantage of this method is that the reaction is more complete, the cost is lower, the post-treatment is simple, and no other additives or catalysts need to be added, and the disadvantage is that it is not universal. [0007] Amide Synthesis Method 2 [0008] The carboxylic acid is fir...

Claims

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Application Information

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IPC IPC(8): C07C327/32
Inventor 丁现帅陈峙张佳唐耀光燕国武
Owner 陕西汉江药业集团股份有限公司
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