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Novel synthetic method for rebamipide intermediate

A technology for rebamipide and intermediates, which is applied in the field of synthesis of rebamipide intermediates, can solve the problems of complex and tedious splitting methods, and achieves the effects of avoiding many reaction steps, avoiding splitting steps, and simple and convenient operation.

Active Publication Date: 2018-07-31
CHONGQING CHANGJIE MEDICINE CHEM +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This resolution method is complicated and cumbersome, and the racemate (R,S)-2-amino-3-[2(1 H )-quinolone-4]propionic esterification, resolution, and hydrolysis in three steps to obtain its single isomer

Method used

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  • Novel synthetic method for rebamipide intermediate
  • Novel synthetic method for rebamipide intermediate
  • Novel synthetic method for rebamipide intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0017] Example 1 Rebamipide key intermediate 2-amino-3-[2(1 H )-quinolone-4] the preparation of propionic acid

[0018] Add 10g (75.1mmol) of aspartic acid L-aspartic acid, 13.1g (90.1mmol) of 2-hydroxyquinoline, and 1.3g (7.51mmol) of silver nitrate into a mixed solution of 400mL of acetonitrile and 100mL of water, and heat up to 300 mL of 0.13 g / mL potassium persulfate aqueous solution was slowly added dropwise at 70 ° C, and reacted at 70 ° C for 3 h after the drop was completed. Cool the reaction solution to room temperature, add 400 mL of purified water, extract with ethyl acetate 800 mL*3, combine the organic layers, wash with water 2000 mL*3, dry over anhydrous sodium sulfate, filter with suction, concentrate the filtrate under reduced pressure, and crystallize with acetone to obtain S- 2-Amino-3-[2(1 H )-quinolone-4]propionic acid 6.8g (29.3mmol), molar yield: 39%. HPLC content 99.60%; m.p.: 196-198 °C; [α] 20 =+21.5 。 (DMSO); 1 H-NMR (600 MHz, DMSO) δ: 11.7(bs, ...

Embodiment 2

[0019] Embodiment 2 rebamipide key intermediate 2-amino-3-[2(1 H )-quinolone-4] the preparation of propionic acid

[0020] Add 10g (75.1mmol) of aspartic acid D-aspartic acid, 12.0g (82.6mmol) of 2-hydroxyquinoline, and 1.7g (9.8mmol) of silver nitrate into a mixed solution of 400mL of acetonitrile and 100mL of water, and heat up to Slowly add 300 mL of 0.13 g / mL potassium persulfate aqueous solution dropwise at 60°C, and react at 60°C for 4 hours after the drop is completed. Cool the reaction solution to room temperature, add 400 mL of purified water, extract with 800 mL*3 of ethyl acetate, combine the organic layers, wash with 2000 mL*3 of water, dry over anhydrous sodium sulfate, filter with suction, concentrate the filtrate under reduced pressure, and crystallize with acetone to obtain R- 2-Amino-3-[2(1 H )-quinolone-4] propionic acid 6.6g (28.5mmol), molar yield: 38%. [α] 20 =-20.2 。 (DMSO); HPLC content 99.7%.

Embodiment 3

[0021] Embodiment 3 rebamipide key intermediate 2-amino-3-[2(1 H )-quinolone-4] the preparation of propionic acid

[0022] Add aspartic acid D, L-aspartic acid 10g (75.1mmol), 2-hydroxyquinoline 16.4g (112.6mmol), silver nitrate 1.3g (7.51mmol) into the mixed solution of acetonitrile 400mL and water 100mL, Raise the temperature to 80°C and slowly add 300mL of 0.13g / mL potassium persulfate aqueous solution dropwise, and react at 80°C for 3h after the dropwise completion. Cool the reaction solution to room temperature, add 400 mL of purified water, extract with 800 mL*3 of ethyl acetate, combine the organic layers, wash with 2000 mL*3 of water, dry over anhydrous sodium sulfate, filter with suction, concentrate the filtrate under reduced pressure, and crystallize with acetone to obtain racemization Body (R,S)-2-amino-3-[2(1 H )-quinolone-4]propionic acid 5.9g (25.5mmol), molar yield: 34%. HPLC content 99.53%.

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Abstract

The invention discloses a novel synthetic method for a rebamipide intermediate, i.e., 2-amino-3-[2(1H)-quinolone-4]propionic acid. The method comprises a step of reacting aspartic acid with 2-hydroxyquinoline to prepare the key rebamipide intermediate, i.e., 2-amino-3-[2(1H)-quinolone-4]propionic acid; and the key rebamipide intermediate and p-chlorobenzoyl chloride undergo a condensation reactionso as to prepare rebamipide. The synthetic method for the intermediate has the advantages of low cost and easy availability of raw materials, short reaction steps and good optical purity.

Description

technical field [0001] The present invention relates to the technical field of medical chemicals, and more specifically relates to a new method for synthesizing rebamipide intermediates. Background technique [0002] Rebamipide, the Chinese chemical name is 2-(4-chlorobenzamido)-3-(1,2-dihydro-2-oxide-4-quinolyl)propionic acid, which is a gastric mucosal protective Drugs and anti-ulcer drugs currently play an important role in the treatment of gastric ulcer and acute gastric mucosal injury. The structural formula of rebamipide is as follows: [0003] [0004] There is a chiral center in the structure of rebamipide, and there are two enantiomers. The activity of R-rebamipide is 1.8 times that of S-rebamipide, and its racemate is currently used in medicine. There are many synthetic routes of rebamipide, and the most classic synthetic route was reported by Uchida et al.: 4-bromomethylquinolone and diethyl acetamidomalonate synthetic intermediate (R,S)-2-amino-3 -[2(1 H )...

Claims

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Application Information

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IPC IPC(8): C07D215/227
CPCC07D215/227
Inventor 刘军杨波
Owner CHONGQING CHANGJIE MEDICINE CHEM
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