CN111116391A - Preparation method of sodium 2- [ (2, 6-dichlorophenyl) amino ] phenylacetate - Google Patents

Preparation method of sodium 2- [ (2, 6-dichlorophenyl) amino ] phenylacetate Download PDF

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CN111116391A
CN111116391A CN201911299773.3A CN201911299773A CN111116391A CN 111116391 A CN111116391 A CN 111116391A CN 201911299773 A CN201911299773 A CN 201911299773A CN 111116391 A CN111116391 A CN 111116391A
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reaction
dichlorophenyl
amino
phenylacetate
sodium
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罗书平
徐丹丹
任晨超
王天琦
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Zhejiang University of Technology ZJUT
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
    • C07C227/20—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters by hydrolysis of N-acylated amino-acids or derivatives thereof, e.g. hydrolysis of carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/54—Improvements relating to the production of bulk chemicals using solvents, e.g. supercritical solvents or ionic liquids

Abstract

The invention belongs to the field of chemical pharmacy, relates to a production process of a chemical raw material medicament, and particularly relates to a preparation method of 2- [ (2, 6-dichlorophenyl) amino ] sodium phenylacetate, which comprises the following steps: 2, 6-dichlorodiphenylamine and chloroacetyl chloride are used as initial raw materials, and an acylation reaction, a Lewis acidic ionic liquid catalyzed Friedel-crafts alkylation reaction and a hydrolysis reaction are completed through a one-pot method, so that the 2- [ (2, 6-dichlorophenyl) amino ] -sodium phenylacetate is finally obtained. The method adopts a one-pot preparation scheme to synthesize the 2- [ (2, 6-dichlorophenyl) amino ] -sodium phenylacetate, has the advantages of short reaction time, simple operation, mild condition, high yield, good catalytic effect, high selectivity, recycling and the like, and is favorable for industrial production.

Description

Preparation method of sodium 2- [ (2, 6-dichlorophenyl) amino ] phenylacetate
Technical Field
The invention belongs to the field of chemical pharmacy, relates to a production process of a chemical raw material medicament, and particularly relates to a preparation method of 2- [ (2, 6-dichlorophenyl) amino ] sodium phenylacetate.
Background
The 2- [ (2, 6-dichlorophenyl) amino ] sodium phenylacetate, its chemical name is 2- (2, 6-dichloro phenylamino) sodium phenylacetate, also known as diclofenac sodium, it is a non-steroidal potent anti-inflammatory analgesic, developed by Ciba-Jiaji of Switzerland, and marketed in 1974, it is used for the treatment of various rheumatic arthritis, lupus erythematosus, neuritis and cancer, postoperative pain and fever caused by various reasons, etc. The aceclofenac hydrochloride tablet has no accumulation effect after long-term use, good curative effect, quick oral absorption, quick excretion and small individual difference, is one of the world-popular medicaments, and is also a key intermediate for synthesizing other medicaments such as aceclofenac and the like.
Regarding the chemical synthesis method of diclofenac, the following 6 routes are mainly reported in the literature:
1) the product is obtained by condensation, N-acylation, cyclization and hydrolysis of o-chlorobenzoic acid and 2, 6-dichloroaniline.
2) The halogenated benzene and 2, 6-dichloroaniline are directly condensed to obtain N-phenyl-2, 6-dichloroaniline, and then the product is obtained through N-chloroacetylation, Fridle-Crafts intramolecular cyclization and hydrolysis.
3) And 1- (2, 6-dichlorophenyl) -indole-2, 3-diketone is used as a raw material for ring opening to obtain a product.
4) Preparing 1- (2, 6-dichlorophenyl) -2-indolinone from 2, 6-dichloro-N-phenyl aniline, and performing alkaline hydrolysis and ring opening to obtain the product.
5) And 2- (2, 6-dichloroanilino) benzoyl chloride and diethoxyethyl magnesium malonate are condensed and then acidified to obtain 2- (2, 6-dichloroanilino) -acetophenone, and then the 2- (2, 6-dichloroanilino) -acetophenone is subjected to Willgestrom-Kindler reaction with sulfur and morpholine and then hydrolyzed to obtain a product.
6) And condensing o-iodophenylacetic acid and 2, 6-dichloroaniline in the presence of copper powder and potassium carbonate to obtain the product.
7) 2, 6-dichlorodiphenylamine and chloroacetyl chloride are used as main raw materials, and are subjected to acylation and intramolecular Friedel-crafts alkylation to obtain 1- (2, 6-dichlorophenyl) indoline-2-ketone (II), and a product is obtained through alkaline hydrolysis ring opening, so that the post-treatment is complicated and the operation is complex.
The synthetic route has the defects of multiple steps, complex operation, expensive raw materials, low yield and the like, and has the problems of dangerous use, extremely toxic raw materials and the like.
Disclosure of Invention
The invention aims to solve the defects of the prior art and provides a method for synthesizing sodium 2- [ (2, 6-dichlorophenyl) amino ] phenylacetate by using 2, 6-dichlorodiphenylamine as a raw material.
In order to achieve the above object, the present invention provides the following technical solutions:
a preparation method of sodium 2- [ (2, 6-dichlorophenyl) amino ] phenylacetate comprises the following steps:
(a) performing acylation reaction on chloroacetyl chloride and 2, 6-dichlorodiphenylamine (IV) in an organic solvent, and heating for reaction for a certain time to obtain N-phenyl-N- (2, 6-dichlorophenyl) chloroacetamide (III);
(b) adding a certain amount of Lewis acid ionic liquid catalyst to carry out Friedel-crafts alkylation reaction, and heating the mixture to react for a certain time to obtain 1- (2, 6-dichlorophenyl) -2-indolinone (II);
(c) separating out Lewis acid ionic liquid catalyst layer from the reaction liquid, adding a certain amount of inorganic alkali solution into the residual organic layer for hydrolysis reaction, separating to obtain a water phase, and dehydrating and crystallizing under reduced pressure to obtain the sodium 2- [ (2, 6-dichlorophenyl) amino ] phenylacetate (I).
Preferably, the organic solvent in the present invention is chlorobenzene, toluene, xylene, dichlorobenzene, n-butanol or diphenyl ether, more preferably toluene.
Preferably, the feeding molar ratio of the 2, 6-dichlorodiphenylamine to the chloroacetyl chloride in the acylation reaction in the step (a) is 1: (0.8-5), more preferably 1: 1.1.
Preferably, the acylation reaction temperature in step (a) is 20-220 ℃, more preferably 120 ℃.
Preferably, the acylation reaction time in the step (a) is 1 to 24 hours, more preferably 3 hours
Preferably, the Lewis acid ionic liquid in the Friedel-crafts alkylation reaction of the step (b) is [ Et3NH]Cl-AlCl3、[Et3NH]Cl-FeCl3Or [ Et3NH]Cl-ZnCl2More preferably [ Et ]3NH]Cl-AlCl3。
Preferably, the feeding molar ratio of the 2, 6-dichlorodiphenylamine and the Lewis acid ionic liquid catalyst in the Friedel-crafts alkylation reaction in the step (b) is 1: (1-5), more preferably 1: 2.
Preferably, the friedel-crafts alkylation reaction temperature of step (b) is from 30 to 160 ℃, more preferably 60 ℃.
Preferably, the time for the friedel-crafts alkylation reaction of step (b) is 2 to 10 hours, more preferably 4 hours.
Preferably, the feeding molar ratio of the 2, 6-dichlorodiphenylamine and the inorganic base in the hydrolysis reaction in the step (c) is 1: (1-5), more preferably 1: 2.
Preferably, the inorganic base used in the hydrolysis reaction of step (c) is sodium hydroxide.
Preferably, the hydrolysis reaction temperature in the step (c) is 30-200 ℃, and the boiling point of the system solvent is more preferable.
Preferably, the hydrolysis reaction time in step (c) is 1 to 10 hours, more preferably 2 hours.
Preferably, the reaction formula of the present invention is as follows:
Figure BDA0002321562770000031
compared with the prior art, the invention has the following beneficial effects: the preparation method adopts a one-pot preparation scheme to obtain the 2- [ (2, 6-dichlorophenyl) amino ] -sodium phenylacetate, has the advantages of short reaction time, simple operation, mild conditions, high yield, ionic liquid catalyst used in Friedel-crafts alkylation reaction, good catalytic effect, high selectivity, recycling and the like, and is favorable for industrial production.
Detailed Description
The technical solution of the present invention is further specifically described below by specific examples, but the scope of the present invention is not limited thereto.
Example 1:
dissolving material 2, 6-dichlorodiphenylamine (IV) (15mmol,3.572g) in 50ml of toluene solvent, adding the solution into a three-neck flask, dropwise adding chloroacetyl chloride (16.5mmol,1.8637g), heating to 120 ℃, stirring for reaction for 3 hours, detecting by TLC that the 2, 6-dichlorodiphenylamine (IV) is completely reacted, and cooling to room temperature. Slowly dropwise adding [ Et ] into the reaction solution3NH]Cl-AlCl3(30mmol, 8.129g), stirring at room temperature for 30min, heating in oil bath to 60 ℃, stirring for reaction for 4h, monitoring by TLC until the intermediate of N-phenyl-N- (2, 6-dichlorophenyl) chloroacetamide (III) disappears, slowly pouring the reaction solution into a separating funnel, standing for layering, separating out ionic liquid, recycling, and applyingThe effect is shown in table 1, 10% NaOH (30mmol,1.2g) is dripped into the organic layer, the mixture is heated and refluxed for 2h, TLC monitors that the 1- (2, 6-dichlorophenyl) -2-indolinone (II) intermediate is completely reacted, the organic layer is separated and removed, the water layer is decompressed and distilled to remove part of water, and the mixture is cooled, crystallized and filtered, and recrystallized by water, 4.035g of white solid is obtained, the yield is 84.56%, and the HPLC content is 99.85%.1HNMR(600MHz,DMSO)δ10.30(s,1H),7.44(d,J＝8.0Hz,2H),7.06(dd,J＝11.2,4.9Hz,2H),6.92(td,J＝7.7,1.5Hz,1H),6.73(td,J＝7.4,1.0Hz,1H),6.24(d,J＝7.9Hz,1H),3.39(s,2H).
TABLE 1 Ionic liquid application results
Number of times of application Conversion ratio (%) -of 1- (2, 6-dichlorophenyl) -2-indolinone Yield of diclofenac sodium (%)
0 98.2353 84.56
1 97.9012 83.75
2 97.6559 82.39
3 97.2268 80.64
4 96.2108 78.62
5 88.6469 70.58
Example 2
Dissolving 2, 6-dichlorodiphenylamine (IV) (15mmol,3.572g) in dichlorobenzene solvent, adding into a three-neck flask, dropwise adding chloroacetyl chloride (16.5mmol,1.8637g), heating to 105 ℃, stirring for reaction for 12h, detecting by TLC that the 2, 6-dichlorodiphenylamine (IV) is reacted completely, and cooling to room temperature. Slowly dropwise adding the mixture into the reaction solution and pouring the mixture into [ Et3NH]Cl-FeCl3(30mmol,8.995g), stirring at room temperature for 30min, heating in an oil bath to 160 ℃, stirring for reaction for 2h, monitoring by TLC until the N-phenyl-N- (2, 6-dichlorophenyl) chloroacetamide (III) intermediate disappears, slowly pouring the reaction solution into a separating funnel, standing for layering, recovering ionic liquid, dropwise adding 10% NaOH (30mmol,1.2g) into an organic layer, heating for refluxing for 2h, monitoring by TLC that the 1- (2, 6-dichlorophenyl) -2-indolinone (II) intermediate completely reacts, separating to remove the organic layer, evaporating a part of water from an aqueous layer under reduced pressure, cooling for crystallization and filtering, recrystallizing with water to obtain 3.8309g of a white solid, wherein the yield is 80.28%.
Example 3
The material 2, 6-dichlorodiphenylamine (IV) (15mmol,3.572g) was dissolved in a xylene solvent and added to a three-necked flask, chloroacetyl chloride (75mmol,8.471g) was added dropwise, heated to 20 deg.C, stirred for 24h, TLC monitored for completion of the reaction of 2, 6-dichlorodiphenylamine (IV), and cooled to room temperature. Slowly dropwise adding the mixture into the reaction solution and pouring the mixture into [ Et3NH]Cl-FeCl3(75mmol,22.4875g), stirring at room temperature for 30min, heating in oil bath to 30 ℃, stirring for reaction for 10h, monitoring by TLC until the intermediate of N-phenyl-N- (2, 6-dichlorophenyl) chloroacetamide (III) disappears, slowly pouring the reaction solution into a separating funnel, standing for layering, recovering ionic liquid, dropwise adding 10% NaOH (75mmol,3.0g) into an organic layer, heating to 200 ℃ for reflux for 1h, monitoring by TLC 1- (2, 6-dichlorophenyl) ionThe intermediate of 2-indolinone (II) reacts completely, an organic layer is separated, a water layer is decompressed and distilled to remove part of water, cooling, crystallization and filtration are carried out, recrystallization is carried out by water, 3.8734g of white solid is obtained, and the yield is 81.17%.
Example 4
Dissolving 2, 6-dichlorodiphenylamine (IV) (15mmol,3.572g) in a xylene solvent, adding the mixture into a three-neck flask, dropwise adding chloroacetyl chloride (12mmol,1.3554g), heating to 110 ℃, stirring for 5 hours, monitoring by TLC that the 2, 6-dichlorodiphenylamine (IV) is completely reacted, and cooling to room temperature. Slowly dropwise adding the mixture into the reaction solution and pouring the mixture into [ Et3NH]Cl-AlCl3(15mmol,4.0645g), stirring at room temperature for 30min, heating in oil bath to 60 ℃, stirring for reaction for 4h, monitoring by TLC until the intermediate of N-phenyl-N- (2, 6-dichlorophenyl) chloroacetamide (III) disappears, slowly pouring the reaction solution into a separating funnel, standing for layering, recovering ionic liquid, dropwise adding 10% NaOH (15mmol,0.6g) into an organic layer, heating to 30 ℃ for reaction for 10h, monitoring by TLC that the intermediate of 1- (2, 6-dichlorophenyl) -2-indolinone (II) is completely reacted, separating the organic layer, evaporating part of water from the aqueous layer under reduced pressure, cooling for crystallization and filtering, recrystallizing with water to obtain 3.7660g of white solid, wherein the yield is 78.92%.
Example 5
Dissolving material 2, 6-dichlorodiphenylamine (IV) (15mmol,3.572g) in diphenyl ether solvent, adding the mixture into a three-neck flask, dropwise adding chloroacetyl chloride (18mmol,2.033g), heating to 220 ℃, stirring for reaction for 1h, completing the reaction of the 2, 6-dichlorodiphenylamine (IV), cooling to room temperature, adding 50ml of diphenyl ether, and slowly dropwise adding [ Et (ethyl acetate) ] into the reaction solution3NH]Cl-ZnCl2(22.5mmol,6.164g), stirring at room temperature for 30min, heating in oil bath to 40 ℃, stirring for reaction for 6h, monitoring by TLC until the intermediate of N-phenyl-N- (2, 6-dichlorophenyl) chloroacetamide (III) disappears, slowly pouring the reaction solution into a separating funnel, standing for layering, recovering ionic liquid, dropwise adding 10% NaOH (45mmol,1.8g) into an organic layer, heating and refluxing for 4h, monitoring by TLC that the intermediate of 1- (2, 6-dichlorophenyl) -2-indolinone (II) is completely reacted, separating the organic layer, evaporating part of water from the aqueous layer under reduced pressure, cooling, crystallizing, filtering, recrystallizing with water to obtain 3.9779g of white solid, wherein the yield is 83.36%.
The above-described embodiments are merely preferred embodiments of the present invention, which is not intended to be limiting in any way, and other variations and modifications are possible without departing from the scope of the invention as set forth in the appended claims.

Claims (10)

1. A preparation method of sodium 2- [ (2, 6-dichlorophenyl) amino ] phenylacetate is characterized by comprising the following steps:
(a) performing acylation reaction on chloroacetyl chloride and 2, 6-dichlorodiphenylamine in an organic solvent to obtain N-phenyl-N- (2, 6-dichlorophenyl) chloroacetamide;
(b) adding a certain amount of Lewis acid ionic liquid catalyst to carry out Friedel-crafts alkylation reaction to obtain 1- (2, 6-dichlorophenyl) -2-indolinone;
(c) separating out Lewis acid ionic liquid catalyst layer from the reaction liquid, adding a certain amount of inorganic alkali solution into the residual organic layer for hydrolysis reaction, separating to obtain a water phase, and dehydrating and crystallizing under reduced pressure to obtain the sodium 2- [ (2, 6-dichlorophenyl) amino ] phenylacetate.
2. The method for preparing sodium 2- [ (2, 6-dichlorophenyl) amino ] phenylacetate according to claim 1, wherein the organic solvent is chlorobenzene, toluene, xylene, dichlorobenzene, n-butanol or diphenyl ether.
3. The method for preparing sodium 2- [ (2, 6-dichlorophenyl) amino ] phenylacetate according to claim 1, wherein the feeding molar ratio of 2, 6-dichlorodiphenylamine to chloroacetyl chloride in the acylation reaction of the step (a) is 1: (0.8-5), the reaction temperature is 20-220 ℃, and the reaction time is 1-24 hours.
4. The preparation method of sodium 2- [ (2, 6-dichlorophenyl) amino ] phenylacetate according to claim 3, wherein in the acylation reaction in the step (a), the organic solvent is toluene, the feeding molar ratio of 2, 6-dichlorodiphenylamine to chloroacetyl chloride is 1:1.1, the reaction temperature is 120 ℃, and the reaction time is 3 hours.
5. A process according to claim 12- [ (2, 6-dichlorophenyl) amino group]The preparation method of the sodium phenylacetate is characterized in that the Lewis acid ionic liquid in the Friedel-crafts alkylation reaction in the step (b) is [ Et3NH]Cl-AlCl3、[Et3NH]Cl-FeCl3Or [ Et3NH]Cl-ZnCl2。
6. The method for preparing sodium 2- [ (2, 6-dichlorophenyl) amino ] phenylacetate according to claim 1, wherein the feeding molar ratio of 2, 6-dichlorodiphenylamine to Lewis acid ionic liquid catalyst in the Friedel-crafts alkylation reaction of the step (b) is 1: (1-5), the reaction temperature is 30-160 ℃, and the reaction time is 2-10 hours.
7. The method for preparing sodium 2- [ (2, 6-dichlorophenyl) amino ] phenylacetate according to claim 6, wherein the feeding molar ratio of 2, 6-dichlorodiphenylamine to Lewis acid ionic liquid catalyst in the Friedel-crafts alkylation reaction of the step (b) is 1:2, the reaction temperature is 60 ℃, and the reaction time is 4 hours.
8. The method for preparing sodium 2- [ (2, 6-dichlorophenyl) amino ] phenylacetate according to claim 1, wherein the molar ratio of 2, 6-dichlorodiphenylamine to inorganic base fed in the hydrolysis reaction of step (c) is 1: (1-5), the reaction temperature is 30-200 ℃, and the reaction time is 1-10 hours.
9. The method for preparing sodium 2- [ (2, 6-dichlorophenyl) amino ] phenylacetate according to claim 8, wherein the molar ratio of 2, 6-dichlorodiphenylamine to inorganic base fed in the hydrolysis reaction of step (c) is 1:2, the reaction temperature is the boiling point of the system solvent, and the reaction time is 2 hours.
10. The process according to claim 1, wherein the inorganic base used in the hydrolysis reaction in step (c) is sodium hydroxide.
CN201911299773.3A 2019-12-17 2019-12-17 Preparation method of sodium 2- [ (2, 6-dichlorophenyl) amino ] phenylacetate Pending CN111116391A (en)

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CN114539086A (en) * 2022-02-25 2022-05-27 复旦大学 Method for synthesizing diclofenac sodium

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Publication number Priority date Publication date Assignee Title
CN113402408A (en) * 2021-05-31 2021-09-17 河南康达制药有限公司 Method for synthesizing diclofenac sodium
CN114539086A (en) * 2022-02-25 2022-05-27 复旦大学 Method for synthesizing diclofenac sodium
CN114539086B (en) * 2022-02-25 2023-10-03 复旦大学 Synthesis method of diclofenac sodium

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Application publication date: 20200508