Method of synthesizing diclofenac sodium

Patent metadata

Field	Value
Publication number	US-10662145-B2
Application number	US-201916288031-A
Country	US
Kind code	B2
Filing date	Feb 27, 2019
Priority date	Aug 17, 2018
Publication date	May 26, 2020
Grant date	May 26, 2020

Abstract

The invention relates to the chemical synthesis of pharmaceutical API, and specifically to a method of synthesizing diclofenac sodium, which is a kind of nonsteroidal anti-inflammatory drug for relieving pain. The method includes: nitrating phenylacetate to prepare o-nitrophenylacetate (2); hydrogenating o-nitrophenylacetate (2) to prepare o-aminophenylacetate (3); amidating an amino group of o-aminophenylacetate (3) to obtain 2-(2-benzoylaminophenyl) acetate (4); 2-(2-benzoylaminophenyl) acetate (4) reacting with thionyl chloride to prepare a chloroimine intermediate, and then condensing the intermediate of chloroimine with 2,6-dichlorophenol using an inorganic base to prepare (E)-methyl-2-(2-((2,6-dichlorophenoxy)(phenyl)methyleneamino) phenyl ester (5); subjecting (E)-methyl-2-(2-((2,6-dichlorophenoxy)(phenyl)methyleneamino) phenyl ester (5) to Chapman rearrangement to afford methyl 2-(2-(N-(2,6-dichlorophenyl)benzoylamino)phenyl) ester (6); and hydrolyzing methyl 2-(2-(N-(2,6-dichlorophenyl)benzoylamino)phenyl) ester (6) to provide the target compound as of diclofenac sodium API. The overall yield is up to 67% based on methyl phenylacetate.

First claim

What is claimed is:

1. A method of synthesizing diclofenac sodium, comprising:
step (1) ortho-nitrating phenylacetate in a solution of dichloromethane containing a nitration agent to obtain o-nitrophenylacetate;
step (2) hydrogenating o-nitrophenylacetate in the presence of a palladium catalyst to obtain o-aminophenylacetate;
step (3) amidating the amino group of o-aminophenylacetate to obtain 2-(2-benzoylaminophenyl) acetate;
step (4) 2-(2-benzoylaminophenyl) acetate reacting with thionyl chloride to obtain a chloroimine intermediate, and then condensing the chloroimine intermediate with 2,6-dichlorophenol using an inorganic base to obtain (E)-methyl-2-(2-((2,6-dichloro phenoxy)(phenyl)methyleneamino)phenyl) ester;
step (5) subjecting (E)-methyl-2-(2-((2,6-dichlorophenoxy)(phenyl) methylene amino) phenyl) ester to Chapman rearrangement to obtain methyl 2-(2-(N-(2,6-dichlorophenyl)benzoylamino)phenyl) ester; and
step (6) hydrolyzing methyl 2-(2-(N-(2,6-dichlorophenyl)benzoylamino)phenyl) ester with an inorganic base to obtain the target product of diclofenac sodium.

2. The method of claim 1 , wherein in step (1), the nitration agent is selected from the group consisting of nitric acid, fuming nitric acid, a mixture of nitric acid and sulfuric acid, or a mixture of nitric acid and acetic acid; and an organic solvent is selected from the group consisting of dichloromethane, tetrahydrofuran, dioxane, or a mixture thereof; and a reaction temperature is −10˜25° C.

3. The method of claim 1 , wherein in step (1), the nitration agent is fuming nitric acid or a mixture of nitric acid and sulfuric acid; and an organic solvent is absent or dichloromethane; and a reaction temperature is from 0° C.˜25° C.

4. The method of claim 1 , wherein in step (2), the palladium catalyst is selected from the group consisting of Pd/C, D61-Pd, D72-Pd, D152-Pd, D261-Pd and D296-Pd; a hydrogenation pressure is from atmospheric pressure to 1.0 Mpa; an organic solvent is an alcohol of low molecular weight or an ester of low molecular weight; an organic solvent is a single solvent, or a mixed solvent; and a reaction temperature is 0˜50° C.

5. The method of claim 4 , wherein the palladium catalyst is Pd/C; the hydrogenation pressure is atmospheric pressure; the organic solvent is selected from the group consisting of methanol, ethanol and ethyl acetate; and the reaction temperature is 5˜25° C.

6. The method of claim 1 , wherein in step (3), an amidating agent is benzoyl chloride; an acid acceptor is selected from the group consisting of triethylamine, potassium carbonate and sodium carbonate; and a reaction temperature is 0˜30° C.

7. The method of claim 1 , wherein in step (4), the inorganic base is selected from the group consisting of sodium carbonate, potassium carbonate, sodium bicarbonate and sodium hydride; an organic solvent is selected from the group consisting of dichloromethane, dichloroethane, tetrahydrofuran, toluene and xylene; and a reaction temperature is 60˜130° C.

8. The method of claim 7 , wherein the inorganic base is selected from the group consisting of sodium carbonate and potassium carbonate; and the organic solvent is toluene.

9. The method of claim 1 , wherein in step (5), an organic solvent is absent or selected from the group consisting of toluene, xylene and diphenyl ether; and a reaction temperature is 110˜300° C.

10. The method of claim 1 , wherein in step (6), the inorganic base is sodium hydroxide; an organic solvent is selected from the group consisting of toluene and methanol; and a reaction temperature is 50˜150° C.

Assignees

• Univ Fudan

Inventors

• Chen Fener
• Wang Lingdong
• Meng Ge
• Huang Zedu
• Cheng Dang
• Peng Haihui
• Liang Guanfeng

Classifications

• C07C227/16

  by reactions not involving the amino or carboxyl groups · CPC title

• C07C227/18 Primary

  by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters · CPC title

• C07C257/08

  having carbon atoms of imino-carboxyl groups bound to carbon atoms of six-membered aromatic rings · CPC title

• C07C231/02

  from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines · CPC title

• C07C231/10

  from compounds not provided for in groups C07C231/02 - C07C231/08 · CPC title