Method for synthesizing diclofenac sodium

Patent metadata

Field	Value
Publication number	US-2023234911-A1
Application number	US-202318172414-A
Country	US
Kind code	A1
Filing date	Feb 22, 2023
Priority date	Feb 25, 2022
Publication date	Jul 27, 2023
Grant date	—

Abstract

A method of synthesizing diclofenac sodium, including: subjecting aniline and chloroacetic acid to amidation to obtain 2-chloro-N-phenylacetamide; subjecting 2-chloro-N-phenylacetamide and 2,6-dichlorophenol to condensation reaction to obtain 2-(2,6-dichlorophenoxy)-N-phenylacetamide; subjecting 2-(2,6-dichlorophenoxy)-N-phenylacetamide to Smiles rearrangement in the presence of an inorganic base to obtain N-(2,6-dichlorophenyl)-2-hydroxy-N-phenylacetamide; subjecting N-(2,6-dichlorophenyl)-2-hydroxy-N-phenylacetamide and thionyl chloride to chlorination to obtain N-(2,6-dichlorophenyl)-2-chloro-N-phenylacetamide; subjecting N-(2,6-dichlorophenyl)-2-chloro-N-phenylacetamide to Friedel-Crafts alkylation in the presence of a Lewis acid catalyst to obtain 1-(2,6-dichlorophenyl)-1,3-dihydro-2H-indol-2-one; and subjecting 1-(2,6-dichlorophenyl)-1,3-dihydro-2H-indol-2-one to hydrolysis in the presence of an inorganic base to obtain diclofenac sodium.

First claim

What is claimed is:

1 . A method for synthesizing diclofenac sodium, comprising:
(S1) subjecting aniline and chloroacetic acid to amidation in an organic solvent in the presence of a boric acid catalyst to obtain 2-chloro-N-phenylacetamide (II); (S2) subjecting 2-chloro-N-phenylacetamide (II) and 2,6-dichlorophenol to condensation reaction in the presence of potassium carbonate and a phase transfer catalyst to obtain 2-(2,6-dichlorophenoxy)-N-phenylacetamide (III); (S3) subjecting 2-(2,6-dichlorophenoxy)-N-phenylacetamide (III) to Smiles rearrangement in the presence of a basic catalyst to obtain N-(2,6-dichlorophenyl)-2-hydroxy-N-phenylacetamide (IV); (S4) subjecting N-(2,6-dichlorophenyl)-2-hydroxy-N-phenylacetamide (IV) and thionyl chloride to chlorination in the presence of a catalyst to obtain N-(2,6-dichlorophenyl)-2-chloro-N-phenylacetamide (V); (S5) subjecting N-(2,6-dichlorophenyl)-2-chloro-N-phenylacetamide (V) to Friedel-Crafts alkylation in the presence of a Lewis acid catalyst to obtain 1-(2,6-dichlorophenyl)-1,3-dihydro-2H-indol-2-one (VI); and (S6) subjecting 1-(2,6-dichlorophenyl)-1,3-dihydro-2H-indol-2-one (VI) to hydrolysis in the presence of an inorganic base to obtain diclofenac sodium (I).

2 . The method of claim 1 , wherein in step (S1), the boric acid catalyst is fluoro-substituted arylboronic acid, o-halogenated arylboronic acid, aminoboronic acid, boric acid or boronate ester.

3 . The method of claim 1 , wherein in step (S1), a molar ratio of aniline to chloroacetic acid to the boric acid catalyst is 1:(1-5):(0.001-0.5);
the organic solvent is chlorobenzene, toluene, xylene, dichlorobenzene, mesitylene, acetonitrile or 1-butanol; and the amidation is performed at 0-150° C. for 1-20 h.

4 . The method of claim 1 , wherein in step (S2), the phase transfer catalyst is polyethylene glycol 400 (PEG-400), polyethylene glycol 600 (PEG-600), benzyltriethylammonium chloride (TEBAC) or tetrabutylammonium bromide;
a molar ratio of 2-chloro-N-phenylacetamide (II) to 2,6-dichlorophenol to potassium carbonate to the phase transfer catalyst is 1:(0.5-2):(1-5):(0.001-0.5); the condensation reaction is performed in an organic solvent selected from the group consisting of chlorobenzene, toluene, xylene, dichlorobenzene, mesitylene, acetonitrile and 1-butanol; and the condensation reaction is performed at 80-160° C. for 2-15 h.

5 . The method of claim 1 , wherein in step (S3), the basic catalyst is an inorganic base or an organic base; the inorganic base is selected from the group consisting of sodium hydroxide, calcium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate and sodium hydride; and the organic base is selected from the group consisting of triethylamine, pyridine, sodium methoxide, lithium diisopropylamide and 1,8-diazabicyclo[5.4.0]undec-7-ene;
a molar ratio of 2-(2,6-dichlorophenoxy)-N-phenylacetamide (III) to the basic catalyst is 1:(0.001-20); the Smiles rearrangement is performed in an organic solvent selected from the group consisting of N,N-dimethylformamide, dimethyl sulfoxide, methanol, ethanol, toluene, acetonitrile, ethyl acetate and acetone; and the Smiles rearrangement is performed at 0-100° C. for 0.5-10 h.

6 . The method of claim 1 , wherein in step (S4), the catalyst is pyridine, N,N-dimethylaniline, triethylamine or N,N-dimethylformamide;
a molar ratio of N-(2,6-dichlorophenyl)-2-hydroxy-N-phenylacetamide (IV) to thionyl chloride to the catalyst is 1:(1-4):(0.001-0.5); the chlorination is performed in an organic solvent selected from the group consisting of N,N-dimethylformamide, dimethyl sulfoxide, thionyl chloride, toluene, acetonitrile, dichloromethane, 1,2-dichloroethane, ethyl acetate and acetone; and the chlorination is performed at 10-100° C. for 0.5-10 h.

7 . The method of claim 1 , wherein in step (S5), the Lewis acid catalyst is selected from the group consisting of aluminum chloride, ferric chloride, zinc chloride, zinc bromide and tin tetrachloride;
a molar ratio of N-(2,6-dichlorophenyl)-2-chloro-N-phenylacetamide (V) to the Lewis acid catalyst is 1:(0.5-5); the Friedel-Crafts alkylation is performed in a solvent-free manner or in the presence of an organic solvent selected from the group consisting of dichloromethane, 1,2-dichloroethane, chlorobenzene, toluene, xylene, dichlorobenzene, 1-butanol or diphenyl ether; and the Friedel-Crafts alkylation is performed at 50-200° C. for 1-10 h.

8 . The method of claim 1 , wherein in step (S6), the inorganic base is sodium carbonate, sodium bicarbonate or sodium hydroxide; and
the hydrolysis is performed in the presence of a phase transfer catalyst; a molar ratio of 1-(2,6-dichlorophenyl)-1,3-dihydro-2H-indol-2-one (VI) to the inorganic base to the phase transfer catalyst is 1:(0.1-10):(0-0.5); and the phase transfer catalyst is benzyltriethylammonium chloride or tetrabutylammonium bromide.

9 . The method of claim 1 , wherein in step (S6), the hydrolysis is performed in a solvent-free manner or in an organic solvent selected from the group consisting of toluene, xylene, diphenyl ether, methanol and ethanol.

10 . The method of claim 1 , wherein in step (S6), the hydrolysis is performed at 10-130° C. for 1-10 h.

Assignees

• Univ Fudan

Inventors

• Chen Fener
• Cheng Dang
• Wang Lulu
• Meng Ge
• Ning Yingtang
• Huang Zedu

Classifications

• C07C227/22 Primary

  from lactams, cyclic ketones or cyclic oximes, e.g. by reactions involving Beckmann rearrangement · CPC title

• C07C231/12

  by reactions not involving the formation of carboxamide groups · CPC title

• C07C231/02 Primary

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

• C07C231/08

  from amides by reaction at nitrogen atoms of carboxamide 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