Continuous-flow preparation method of diclofenac sodium

Patent metadata

Field	Value
Publication number	US-11834388-B2
Application number	US-202318172865-A
Country	US
Kind code	B2
Filing date	Feb 22, 2023
Priority date	Feb 25, 2022
Publication date	Dec 5, 2023
Grant date	Dec 5, 2023

Abstract

This application relates to pharmaceutical engineering, and more particularly to a continuous-flow preparation method of diclofenac sodium. The continuous-flow preparation method includes: subjecting aniline and chloroacetic acid to amidation to obtain 2-chloro-N-phenylacetamide (3); subjecting 2-chloro-N-phenylacetamide (3) and 2,6-dichlorophenol to continuous condensation to obtain N-(2,6-dichlorophenyl)-2-hydroxy-N-phenylacetamide (5); subjecting N-(2,6-dichlorophenyl)-2-hydroxy-N-phenylacetamide (5) and thionyl chloride to chlorination to obtain N-(2,6-dichlorophenyl)-2-chloro-N-phenylacetamide (6); subjecting N-(2,6-dichlorophenyl)-2-chloro-N-phenylacetamide (6) to Friedel-Crafts alkylation in the presence of aluminum chloride to obtain 1-(2,6-dichlorophenyl)-1,3-dihydro-2H-indol-2-one (7); and subjecting 1-(2,6-dichlorophenyl)-1,3-dihydro-2H-indol-2-one (7) to hydrolysis to obtain the diclofenac sodium.

First claim

What is claimed is:

1. A method for preparing diclofenac sodium using a continuous-flow reaction system, the continuous-flow reaction system comprising a first unit, a second unit, a third unit, a fourth unit and a fifth unit successively connected in series; the first unit comprising a first mixer, a first microchannel reactor and a first storage tank connected in sequence; the second unit comprising a second mixer, a second microchannel reactor, a third microchannel reactor, a filter and a second storage tank; the third unit comprising a third mixer, a fourth microchannel reactor and a third storage tank connected in sequence; the fourth unit comprising a fourth mixer, a fifth microchannel reactor, and a fourth storage tank connected in sequence; the fifth unit comprising a fifth mixer and a sixth microchannel reactor; and the method comprising:
(S1) respectively feeding a mixed solution of chloroacetic acid and a first catalyst, and an organic solution of aniline to the first mixer for mixing to obtain a first mixture; and allowing the first mixture to flow out of the first mixer and enter the first microchannel reactor for amidation reaction;
(S2) subjecting a reaction mixture flowing out of the first microchannel reactor to continuous quenching, liquid-liquid extraction and separation to collect an organic phase;
(S3) concentrating the organic phase obtained in step (S2) to obtain 2-chloro-N-phenylacetamide (3) followed by dissolving with a first organic solvent to obtain a 2-chloro-N-phenylacetamide (3) solution; and transporting the 2-chloro-N-phenylacetamide (3) solution to the first storage tank;
(S4) respectively transporting the 2-chloro-N-phenylacetamide (3) solution in the first storage tank, and a mixed solution of 2,6-dichlorophenol and a phase transfer catalyst to the second mixer to for mixing to obtain a second mixture; and allowing the second mixture to flow out of the second mixer and enter the second microchannel reactor and the third microchannel reactor in sequence for continuous condensation and Smiles rearrangement; wherein the second microchannel reactor and the third microchannel reactor are both filled with a basic catalyst;
(S5) concentrating a reaction mixture flowing out of the third microchannel reactor followed by dissolving with a second organic solvent obtain a suspension; and transporting the suspension to the filter for filtration to collect a filtrate and a filter cake; wherein the filter cake is N-(2,6-dichlorophenyl)-2-hydroxyl-N-phenylacetamide (5);
(S6) concentrating the filtrate followed by dissolution with a third organic solvent and transportation to the third microchannel reactor for Smiles rearrangement to allow 2-(2,6 dichlorophenoxy)-N-phenylacetamide (4) in the filtrate to be converted into N-(2,6-dichlorophenyl)-2-hydroxyl-N-phenylacetamide (5); and repeating step (S5) to obtain another filter cake;
(S7) combining filter cakes followed by dissolving with a fourth organic solvent to obtain a N-(2,6-dichlorophenyl)-2-hydroxyl-N-phenylacetamide (5) solution; and transporting the N-(2,6-dichlorophenyl)-2-hydroxyl-N-phenylacetamide (5) solution to the second storage tank;
(S8) respectively transporting the N-(2,6-dichlorophenyl)-2-hydroxyl-N-phenylacetamide (5) solution in the second storage tank and a mixed solution of thionyl chloride and a second catalyst to the third mixer for mixing to obtain a third mixture; allowing the third mixture to flow out of the third mixer and enter the fourth microchannel reactor for chlorination;
(S9) subjecting a reaction mixture flowing out from the fourth microchannel reactor to continuous quenching, liquid-liquid extraction and separation to collect an organic phase;
(S10) concentrating the organic phase obtained in step (S9) followed by dissolution with a fifth organic solvent to obtain a N-(2,6-dichlorophenyl)-2-chloro-N-phenylacetamide (6) solution; transporting the N-(2,6-dichlorophenyl)-2-chloro-N-phenylacetamide (6) solution to the third storage tank;
(S11) respectively transporting the N-(2,6-dichlorophenyl)-2-chloro-N-phenylacetamide (6) solution and an organic solution of aluminum chloride to the fourth mixer for mixing and preheating to obtain a fourth mixture; allowing the fourth mixture to flow out of the fourth mixer and enter the fifth microchannel reactor for Friedel-Crafts alkylation;
(S12) subjecting a reaction mixture flowing out of the fifth microchannel reactor to continuous quenching, liquid-liquid extraction and separation to collect an organic phase;
(S13) concentrating the organic phase obtained in step (S12) followed by dissolving with a sixth organic solvent to obtain a 1-(2,6-dichlorophenyl)-1,3-dihydro-2H-indol-2-one (7) solution; transporting the 1-(2,6-dichlorophenyl)-1,3-dihydro-2H-indol-2-one (7) solution to the fourth storage tank;
(S14) respectively transporting the 1-(2,6-dichlorophenyl)-1,3-dihydro-2H-indol-2-one (7) solution in the fourth storage tank and a solution of an inorganic base to the fifth mixer for mixing to obtain a fifth mixture; and allowing the fifth mixture to flow out of the fifth mixer and enter the sixth microchannel reactor for hydrolysis to obtain the diclofenac sodium (1);
as shown in the following reaction scheme:

2. The method of claim 1 , wherein in step (S1), the first catalyst is a boronic acid catalyst selected from the group consisting of o-halogenated arylboronic acid, aminoboronic acid, boric acid and boronate ester; a molar ratio of the aniline to the chloroacetic acid to the first catalyst is 1:(1-5):(0.001-0.5); the amidation reaction is performed in an organic solvent selected from the group consisting of toluene, xylene, mesitylene, chlorobenzene, dichlorobenzene, N,N-dimethylacetamide, ethyl acetate and acetonitrile; the first microchannel reactor is controlled at 70˜170° C.; and a residence time of the reaction mixture in the first microchannel reactor is 5˜100 min; and
in step (S2), the reaction mixture flowing out from the first microchannel reactor is subjected to quenching with an aqueous solution of an inorganic base, liquid-liquid extraction with a non-polar organic solvent, and separation to collect the organic phase; the aqueous solution of the inorganic base contains 1˜50% by weight of the inorganic base; the inorganic base is selected from the group consisting of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide and potassium hydroxide; a pH of the reaction mixture after quenched is 6-8; the non-polar organic solvent is an acetate solvent, a substituted benzene solvent or a halogenated hydrocarbon solvent; the liquid-liquid extraction is performed at 10-60° C.; the continuous quenching, liquid-liquid extraction and separation are performed in a first liquid-liquid extraction separator; a residence time of the reaction mixture in the first liquid-liquid extraction separator is 0.1-20 min; and in step (S3), the first organic solvent is selected from the group consisting of toluene, xylene, acetonitrile, N,N-dimethylformamide, ethyl acetate, acetone and n-butanol.

3. The method of claim 2 , wherein in step (S4), the phase transfer catalyst is selected from the group consisting of polyethylene glycol 400 (PEG-400), polyethylene glycol 600 (PEG-600), benzyltriethylammonium chloride and tetrabutylammonium bromide; a molar ratio of the 2-chloro-N-phenylacetamide (3) to the 2,6-dichlorophenol to the phase transfer catalyst is 1:(0.5-2):(1-5); the basic catalyst is an inorganic base or an organic base; wherein the inorganic base is selected from the group consisting of sodium hydroxide, calcium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate and sodium hydrogen; and the organic base is selected from the group

Assignees

• Univ Fudan

Inventors

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

Classifications

• 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

• C07C227/40

  Separation; Purification · CPC title

• C07C227/22 Primary

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

• C07C231/02 Primary

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

• C07D209/34

  in position 2 · CPC title