Preparation method of rebamipide intermediate

Abstract

The invention discloses a preparation method of a compound disclosed as a structural formula 1. The compound is a key intermediate for synthesizing rebamipide. The method comprises the following steps: I. in the presence of alkali, reacting a compound disclosed as a structural formula 2 with a compound disclosed as a structural formula 3 in C1-C4 fatty alcohol; after the reaction finishes, regulating the pH value to higher than or equal to 8 with acid, adding water, and filtering to obtain a compound disclosed as a structural formula 4; and II. in an organic solvent, reacting the compound disclosed as the structural formula 4 in step I with acid at 30-130 DEG C, after the reaction finishes, cooling to crystallize, and filtering to obtain the compound disclosed as the structural formula 1, wherein the acid is composed of organic acid and inorganic acid in any ratio, the organic acid is one or more of formic acid, acetic acid, propanoic acid and oxalic acid, and the inorganic acid is one or more of hydrochloric acid, sulfuric acid, phosphoric acid and hydrobromic acid. The invention solves the problems of high material wash-away tendency and low yield in the prior art.

Description

technical field

[0001] The invention belongs to the field of organic chemistry, and in particular relates to a preparation method of 2-amino-3-[2(1hydrogen)-quinolone-4-yl]propionate, a key intermediate of rebamipide. Background technique

[0002] Rebamipide can improve gastric motility and treat gastric mucosal damage caused by gastric ulcer, acute gastritis, and acute exacerbation of chronic gastritis. Its systematic name is: 2-(4-chlorobenzamido)-3-[2(1hydrogen)-quinolone-4-yl]propionic acid, and its CAS registration number is 111911-87-6. The key intermediate in the synthesis of rebamipide is 2-amino-3-[2(1hydrogen)-quinolone-4-yl] propionate hydrochloride, except for hydrochloride, the 2-amino-3-[2 (1H)-quinolone-4-yl] propionic acid sulfate, phosphate, hydrobromide, etc., can also be used as intermediates of rebamipide, and the general structural formula of the above-mentioned various salts is shown in 1 .

[0003]

[0004] For the preparation method of 2-amino-3...

Examples

Embodiment 1

[0028] Example 1: Preparation of ethyl 2-acetylamino-2-carboxylate-3-(2-quinolinone-4 base)-propionic acid ethyl ester (compound of structural formula 4) in a 10000ml three-necked bottle, first put into 6000ml of water and ethanol, then 900 grams of 4-bromomethylbenzene-1 hydrogen-2-quinolinone (the compound of structural formula 2), 900 grams of diethyl acetamidomalonate (the compound of structural formula 3), 425 grams of sodium ethoxide gram, heat up to 75°C, keep warm for 10 hours, adjust pH=6 with acetic acid, add water equivalent to ethanol, cool to 0°C to crystallize for 8 hours, filter, and dry the filter cake under reduced pressure at 60°C for 8 hours to obtain 2 -Acetamido-2-formic acid ethyl ester-3-(2-quinolinone-4 base)-propionic acid ethyl ester (compound of structural formula 4) 1360 grams, yield 96.2%. The purity of ethyl 2-acetamido-2-carboxylate-3-(2-quinolinone-4yl)-propionate was determined by HPLC to be 98.3%.

Embodiment 2

[0029] Example 2: Preparation of 2-amino-3-[2(1hydrogen)-quinolone-4-yl] propionate hydrochloride In a 1000ml three-necked flask, 280g of formic acid, 280g of concentrated hydrochloric acid, 2 -Acetamido-2-ethyl carboxylate-3-(2-quinolinone-4 base)-propionate ethyl ester 250g, heat up to 85°C for 2 hours, then heat up to reflux, keep the reaction under reflux conditions 24 hours, cooled to below 20°C, and filtered. The filter cake was dried at 60°C to obtain 163.6 g of 2-amino-3-[2(1hydrogen)-quinolon-4-yl]propionate hydrochloride with a yield of 91% and a purity of over 99.5% as determined by HPLC.

[0030] 1 H-NMR (DMSO- d6 , 400MHz): δ11.69(1H, HCl), δ8.55(3H, NH 2 , NH), δ7.81(1H, 8-Hor11-H), δ7.52(1H, 9-Hor10-H), δ7.36(1H, 8-Hor11-H ), δ7.22(1H, 9 -Hor10-H ), δ6.49(1H, 5-H ), δ4.14(1H, 2-H ), δ3.30-3.40(2H, 3-H ).

[0031] 13 C-NMR (DMSO- d6 , 400MHz): δ170(1C, 1-Cor6-C), δ161.36(1C, 1-Cor6-C), δ144.7(1C, 7-C), δ139.29(1C, 12-C), δ130.54(1C, 8-Cor9-Cor10-Cor11-C),...

Embodiment 3

[0033] Embodiment 3: Preparation of 2-amino-3-[2(1 hydrogen)-quinolone-4-yl] propionate hydrochloride In a 1000ml three-necked flask, 280g of acetic acid, 280g of concentrated hydrochloric acid, 2 -Acetamido-2-formic acid ethyl ester-3-(2-quinolinone-4 base)-propionic acid ethyl ester 250g, heat up to 87°C for 2 hours, then heat up to reflux, and keep the temperature under reflux for reaction 24 hours, cooled to below 20°C, and filtered. The filter cake was dried at 60°C to obtain 172.6 g of 2-amino-3-[2(1hydrogen)-quinolon-4-yl]propionate hydrochloride with a yield of 96% and a purity of over 99.5% as determined by HPLC.

[0034] 1 H-NMR (DMSO- d6 , 400MHz): δ11.72(1H, HCl), δ8.69(3H, NH 2 , NH), δ7.83(1H, 8-Hor11-H), δ7.48(1H, 9-Hor10-H), δ7.30(1H, 8-Hor11-H ), δ7.19(1H, 9 -Hor10-H ), δ6.52(1H, 5-H ), δ4.10(1H, 2-H ), δ3.25-3.34(2H, 3-H ).

[0035] ESI-MS: m / z267[M-H] + , m / z231[M-HCl-H] + .

technical field

[0001] The invention belongs to the field of organic chemistry, and in particular relates to a preparation method of 2-amino-3-[2(1hydrogen)-quinolone-4-yl]propionate, a key intermediate of rebamipide. Background technique

[0002] Rebamipide can improve gastric motility and treat gastric mucosal damage caused by gastric ulcer, acute gastritis, and acute exacerbation of chronic gastritis. Its systematic name is: 2-(4-chlorobenzamido)-3-[2(1hydrogen)-quinolone-4-yl]propionic acid, and its CAS registration number is 111911-87-6. The key intermediate in the synthesis of rebamipide is 2-amino-3-[2(1hydrogen)-quinolone-4-yl] propionate hydrochloride, except for hydrochloride, the 2-amino-3-[2 (1H)-quinolone-4-yl] propionic acid sulfate, phosphate, hydrobromide, etc., can also be used as intermediates of rebamipide, and the general structural formula of the above-mentioned various salts is shown in 1 .

[0003]

[0004] For the preparation method of 2-amino-3...

Examples

Embodiment 1

[0028] Example 1: Preparation of ethyl 2-acetylamino-2-carboxylate-3-(2-quinolinone-4 base)-propionic acid ethyl ester (compound of structural formula 4) in a 10000ml three-necked bottle, first put into 6000ml of water and ethanol, then 900 grams of 4-bromomethylbenzene-1 hydrogen-2-quinolinone (the compound of structural formula 2), 900 grams of diethyl acetamidomalonate (the compound of structural formula 3), 425 grams of sodium ethoxide gram, heat up to 75°C, keep warm for 10 hours, adjust pH=6 with acetic acid, add water equivalent to ethanol, cool to 0°C to crystallize for 8 hours, filter, and dry the filter cake under reduced pressure at 60°C for 8 hours to obtain 2 -Acetamido-2-formic acid ethyl ester-3-(2-quinolinone-4 base)-propionic acid ethyl ester (compound of structural formula 4) 1360 grams, yield 96.2%. The purity of ethyl 2-acetamido-2-carboxylate-3-(2-quinolinone-4yl)-propionate was determined by HPLC to be 98.3%.

Embodiment 2

[0029] Example 2: Preparation of 2-amino-3-[2(1hydrogen)-quinolone-4-yl] propionate hydrochloride In a 1000ml three-necked flask, 280g of formic acid, 280g of concentrated hydrochloric acid, 2 -Acetamido-2-ethyl carboxylate-3-(2-quinolinone-4 base)-propionate ethyl ester 250g, heat up to 85°C for 2 hours, then heat up to reflux, keep the reaction under reflux conditions 24 hours, cooled to below 20°C, and filtered. The filter cake was dried at 60°C to obtain 163.6 g of 2-amino-3-[2(1hydrogen)-quinolon-4-yl]propionate hydrochloride with a yield of 91% and a purity of over 99.5% as determined by HPLC.

[0030] 1 H-NMR (DMSO- d6 , 400MHz): δ11.69(1H, HCl), δ8.55(3H, NH 2 , NH), δ7.81(1H, 8-Hor11-H), δ7.52(1H, 9-Hor10-H), δ7.36(1H, 8-Hor11-H ), δ7.22(1H, 9 -Hor10-H ), δ6.49(1H, 5-H ), δ4.14(1H, 2-H ), δ3.30-3.40(2H, 3-H ).

[0031] 13 C-NMR (DMSO- d6 , 400MHz): δ170(1C, 1-Cor6-C), δ161.36(1C, 1-Cor6-C), δ144.7(1C, 7-C), δ139.29(1C, 12-C), δ130.54(1C, 8-Cor9-Cor10-Cor11-C),...

Embodiment 3

[0033] Embodiment 3: Preparation of 2-amino-3-[2(1 hydrogen)-quinolone-4-yl] propionate hydrochloride In a 1000ml three-necked flask, 280g of acetic acid, 280g of concentrated hydrochloric acid, 2 -Acetamido-2-formic acid ethyl ester-3-(2-quinolinone-4 base)-propionic acid ethyl ester 250g, heat up to 87°C for 2 hours, then heat up to reflux, and keep the temperature under reflux for reaction 24 hours, cooled to below 20°C, and filtered. The filter cake was dried at 60°C to obtain 172.6 g of 2-amino-3-[2(1hydrogen)-quinolon-4-yl]propionate hydrochloride with a yield of 96% and a purity of over 99.5% as determined by HPLC.

[0034] 1 H-NMR (DMSO- d6 , 400MHz): δ11.72(1H, HCl), δ8.69(3H, NH 2 , NH), δ7.83(1H, 8-Hor11-H), δ7.48(1H, 9-Hor10-H), δ7.30(1H, 8-Hor11-H ), δ7.19(1H, 9 -Hor10-H ), δ6.52(1H, 5-H ), δ4.10(1H, 2-H ), δ3.25-3.34(2H, 3-H ).

[0035] ESI-MS: m / z267[M-H] + , m / z231[M-HCl-H] + .

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