CN111100057A - Method for synthesizing diclofenac sodium intermediate 1- (2, 6-dichlorophenyl) indoline-2-ketone - Google Patents
Method for synthesizing diclofenac sodium intermediate 1- (2, 6-dichlorophenyl) indoline-2-ketone Download PDFInfo
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- CN111100057A CN111100057A CN201911227300.2A CN201911227300A CN111100057A CN 111100057 A CN111100057 A CN 111100057A CN 201911227300 A CN201911227300 A CN 201911227300A CN 111100057 A CN111100057 A CN 111100057A
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- dichlorophenyl
- polyethylene glycol
- diclofenac sodium
- indoline
- ketone
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- 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
Abstract
The invention discloses a method for synthesizing a diclofenac sodium intermediate 1- (2, 6-dichlorophenyl) indoline-2-ketone, which comprises the following steps: under the existence of phase transfer catalyst, the N-phenyl-N- (2, 6-dichlorophenyl) -chloroacetamide and Lewis acid are subjected to Friedel-crafts reaction to prepare the diclofenac sodium intermediate 1- (2, 6-dichlorophenyl) indoline-2-ketone. According to the invention, the phase transfer catalyst is added in the Friedel-crafts reaction, so that N-phenyl-N- (2, 6-dichlorophenyl) -chloroacetamide and Lewis acid can be better combined, the Friedel-crafts reaction can be carried out at a lower temperature, the temperature is reduced from 150-160 ℃ to about 60-80 ℃, the energy consumption is saved, the operation risk in the production is reduced, and the purity of 1- (2, 6-dichlorophenyl) indoline-2-ketone and diclofenac sodium is improved.
Description
Technical Field
The invention relates to a synthetic process of a non-steroidal anti-inflammatory drug, in particular to a synthetic method of a diclofenac sodium intermediate 1- (2, 6-dichlorophenyl) indoline-2-ketone.
Background
Diclofenac sodium, Diclofenac Sodium (DS), is a 3 rd generation non-steroidal anti-inflammatory drug with a chemical name: 2- [ (2, 6-dichlorophenyl) amino ] -sodium phenylacetate. Diclofenac sodium is first marketed in 1974 abroad, is synthesized in 1985 domestically, and is produced in a plurality of pharmaceutical factories in succession domestically, and is clinically used for diminishing inflammation, easing pain, relieving fever, resisting rheumatism and the like. Diclofenac sodium has 2-2.5 times stronger anti-inflammatory and antipyretic effects than indometacin and 26-50 times stronger than aspirin, has the advantages of good curative effect, small side effect, no accumulation after long-term application and the like in similar medicines, is applied to more than 120 countries and regions in 1995, and is one of world-friendly medicines.
Nevertheless, diclofenac sodium still has a gastrointestinal stimulation effect, and it is widely believed that its pharmacological effect is related to inhibition of prostaglandin synthesis, it is a strong inhibitor of cyclooxygenase, and can reduce synthesis of prostaglandin, prostacyclin and thromboxane products, while cyclooxygenase and prostaglandin help to form a gastric mucosal barrier by inhibiting gastric acid secretion, thereby having a protective effect on gastric mucosa.
At present, the synthetic route of diclofenac sodium is to use 2, 6-dichlorodiphenylamine as an initial raw material to generate N-phenyl-N- (2, 6-dichlorophenyl) chloroacetamide under the action of chloroacetyl chloride, perform Friedel-crafts reaction on the N-phenyl-N- (2, 6-dichlorophenyl) chloroacetamide under the action of anhydrous aluminum trichloride to generate 1- (2, 6-dichlorophenyl) indoline-2-ketone, and hydrolyze in the presence of sodium hydroxide to obtain the finished product of diclofenac sodium. However, in the existing process for synthesizing diclofenac sodium, the Friedel-crafts reaction temperature is too high, namely 150 ℃ and 160 ℃, reactants are not easy to disperse, and the obtained diclofenac sodium has low purity.
The information disclosed in this background section is only for enhancement of understanding of the general background of the invention and should not be taken as an acknowledgement or any form of suggestion that this information forms the prior art already known to a person skilled in the art.
Disclosure of Invention
The invention aims to provide a method for synthesizing a diclofenac sodium intermediate 1- (2, 6-dichlorophenyl) indoline-2-ketone, which can greatly reduce the Friedel-crafts reaction temperature and improve the purity of diclofenac sodium.
In order to achieve the above object, the present invention provides a method for synthesizing diclofenac sodium intermediate 1- (2, 6-dichlorophenyl) indolin-2-one, comprising the following steps: in the presence of a phase transfer catalyst, carrying out Friedel-crafts reaction on N-phenyl-N- (2, 6-dichlorophenyl) -chloroacetamide shown as the following formula (I) and Lewis acid to prepare a diclofenac sodium intermediate 1- (2, 6-dichlorophenyl) indoline-2-ketone shown as the following formula (II),
in one embodiment of the present invention, the phase transfer catalyst is one or more selected from the group consisting of N-alkyl ammonium halides and polyethylene glycols.
In an embodiment of the present invention, the N-alkyl ammonium halide is one or more selected from tetrabutylammonium bromide, tetrabutylammonium chloride and tetrabutylammonium fluoride.
In one embodiment of the present invention, the N-alkylammonium halide is tetrabutylammonium bromide.
In an embodiment of the present invention, the polyethylene glycol is selected from one or more of polyethylene glycol 200, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 800, polyethylene glycol 1000, polyethylene glycol 1500, and polyethylene glycol 2000.
In an embodiment of the present invention, the polyethylene glycol is polyethylene glycol 400.
In one embodiment of the present invention, the lewis acid is one or more selected from the group consisting of anhydrous aluminum trichloride, anhydrous ferric trichloride, and boron trifluoride; preferably, the lewis acid is aluminum trichloride.
In one embodiment of the present invention, the molar ratio of the phase transfer catalyst to N-phenyl-N- (2, 6-dichlorophenyl) -chloroacetamide is 0.06-0.12: 1; preferably, the mass ratio of the phase transfer catalyst to the N-phenyl-N- (2, 6-dichlorophenyl) -chloroacetamide is 0.07-0.10: 1.
In an embodiment of the present invention, the mass ratio of N-phenyl-N- (2, 6-dichlorophenyl) -chloroacetamide to lewis acid is 1:1.0 to 3.0; preferably, the molar ratio of N-phenyl-N- (2, 6-dichlorophenyl) -chloroacetamide to lewis acid is 1: 2.0.
In one embodiment of the present invention, the temperature of the friedel-crafts reaction is 60 ℃ to 80 ℃.
Compared with the prior art, the invention has the following beneficial effects:
(1) according to the invention, a phase transfer catalyst is added in the Friedel-crafts reaction, so that N-phenyl-N- (2, 6-dichlorophenyl) -chloroacetamide and Lewis acid can be better combined, the Friedel-crafts reaction can be carried out at a lower temperature, and the temperature is reduced to about 60-80 ℃ from the original 150-160 ℃; therefore, the addition of the phase transfer catalyst greatly reduces the temperature of the Friedel-crafts reaction, greatly saves energy consumption, and the reduction of the Friedel-crafts reaction temperature enables the reaction to be mild, thereby avoiding the related problems of safety and environmental protection caused by the generation of violent HCl in the large production process, simultaneously avoiding the production scald in the production due to the temperature reduction, and in short, the reduction of the Friedel-crafts reaction temperature further reduces the operation danger in the production.
(2) Because the Friedel-crafts reaction temperature is greatly reduced, the purity of the diclofenac sodium intermediate 1- (2, 6-dichlorophenyl) indoline-2-ketone is greatly improved, the purity of the diclofenac sodium is further improved, and the purity of the diclofenac sodium is improved from 99.7 percent to 99.9 percent; in addition, due to the reduction of the Friedel-crafts reaction temperature, the side reaction is greatly reduced, and the color of the finished product of the diclofenac sodium is greatly improved.
(3) The method adopts anhydrous aluminum trichloride, anhydrous ferric trichloride and boron trifluoride as Lewis acid, and enlarges the range of the Friedel-crafts reaction catalyst.
(4) The temperature of the Friedel-crafts reaction is greatly reduced because the phase transfer catalyst is added in the Friedel-crafts reaction, and the temperature is reduced, so that a reaction system is in a non-solid phase state and the phase transfer catalyst is not condensed, and therefore, a pipeline can not be blocked in the synthesis process; and because the phase transfer catalyst is added, the system has better fluidity, and the reaction product is easy to disperse.
Detailed Description
The following detailed description of specific embodiments of the invention is provided, but it should be understood that the scope of the invention is not limited to the specific embodiments.
Example 1: synthesis method of 1- (2, 6-dichlorophenyl) indoline-2-ketone
The synthesis method comprises the following steps: 30g (0.096mol) of N-phenyl-N- (2, 6-dichlorophenyl) -chloroacetamide and 2.5g (0.0096mol) of phase transfer catalyst tetrabutylammonium fluoride are added into a reaction bottle, the temperature is raised to 70 ℃, then 25.5g (0.19mol) of Lewis acid anhydrous aluminum trichloride (about 0.5h) is slowly added, Friedel-crafts reaction is carried out at 70 ℃, a point plate detection reaction is carried out, after the reaction is finished, the reactant is dripped into purified water to be dispersed and stirred for 5h, and 26g of diclofenac sodium intermediate 1- (2, 6-dichlorophenyl) indoline-2-ketone is prepared.
The yield of the diclofenac sodium intermediate 1- (2, 6-dichlorophenyl) indoline-2-ketone prepared by the method is 86.6%, and the purity is 99.6%.
Example 2: synthesis method of 1- (2, 6-dichlorophenyl) indoline-2-ketone
The synthesis method comprises the following steps: 30g (0.096mol) of N-phenyl-N- (2, 6-dichlorophenyl) -chloroacetamide and 2.5g (0.0096mol) of phase transfer catalyst tetrabutylammonium fluoride are added into a reaction bottle, the temperature is raised to 60 ℃, then 25.5g (0.19mol) of Lewis acid anhydrous aluminum trichloride (about 0.5h) is slowly added, Friedel-crafts reaction is carried out at the temperature of 60 ℃, a plate counting detection reaction is carried out, after the reaction is finished, the reactant is dripped into purified water to be dispersed and stirred for 5h, and 27g of diclofenac sodium intermediate 1- (2, 6-dichlorophenyl) indoline-2-ketone is prepared, the yield is 90%, and the purity is 99.5%.
Example 3: synthesis method of 1- (2, 6-dichlorophenyl) indoline-2-ketone
The synthesis method comprises the following steps: 30g (0.096mol) of N-phenyl-N- (2, 6-dichlorophenyl) -chloroacetamide and 2.5g (0.0096mol) of phase transfer catalyst tetrabutylammonium fluoride are added into a reaction bottle, the temperature is raised to 60 ℃, then 25.5g (0.19mol) of Lewis acid anhydrous aluminum trichloride (about 0.5h) is slowly added, Friedel-crafts reaction is carried out at the temperature of 60 ℃, a plate spotting detection reaction is carried out, after the reaction is finished, the reactant is dripped into purified water to be dispersed and stirred for 5h, and 26.1g of diclofenac sodium intermediate 1- (2, 6-dichlorophenyl) indoline-2-ketone is prepared, the yield is 87%, and the purity is 99.3%.
Example 4: synthesis method of 1- (2, 6-dichlorophenyl) indoline-2-ketone
The synthesis method comprises the following steps: adding 30g of N-phenyl-N- (2, 6-dichlorophenyl) -chloroacetamide and 3g of polyethylene glycol 400 serving as a phase transfer catalyst into a reaction bottle, heating to 60 ℃, then slowly adding 25.5g (0.19mol) of Lewis acid anhydrous aluminum trichloride (about 0.5h), carrying out Friedel-crafts reaction at 60 ℃, carrying out point-plate detection reaction, dropwise adding the reactant into purified water after the reaction is finished, and carrying out dispersion stirring for 5h to prepare 26.3g of diclofenac sodium intermediate 1- (2, 6-dichlorophenyl) indoline-2-one, wherein the yield is 87.6%, and the purity is 99.3%.
Example 5: synthesis method of 1- (2, 6-dichlorophenyl) indoline-2-ketone
The synthesis method comprises the following steps: 30g (0.096mol) of N-phenyl-N- (2, 6-dichlorophenyl) -chloroacetamide and 2.5g (0.0096mol) of phase transfer catalyst tetrabutylammonium fluoride are added into a reaction bottle, the temperature is raised to 80 ℃, then 25.5g (0.19mol) of Lewis acid anhydrous aluminum trichloride (about 0.5h) is slowly added, Friedel-crafts reaction is carried out at 80 ℃, a point plate detection reaction is carried out, after the reaction is finished, the reactant is dripped into purified water to be dispersed and stirred for 5h, and 26.2g of diclofenac sodium intermediate 1- (2, 6-dichlorophenyl) indoline-2-ketone is prepared, the yield is 87.3%, and the purity is 99.2%.
Example 6: method for synthesizing diclofenac sodium
Carrying out hydrolysis reaction on the 1- (2, 6-dichlorophenyl) indoline-2-ketone obtained in the example 1 in a sodium hydroxide solution to obtain 26.5g of diclofenac sodium with the purity of 99.9%; the reaction formula is as follows:
comparative example:
exactly the same reactants, amounts and reaction conditions were used as in example 1, with the only difference that: in the Friedel-crafts reaction, tetrabutyl ammonium fluoride and polyvinyl alcohol are not added as phase transfer catalysts.
The synthesis method comprises the following steps: 30g (0.096mol) of 0.1mol of N-phenyl-N- (2, 6-dichlorophenyl) -chloroacetamide are added slowly with 25.5g (0.19mol) of Lewis acid anhydrous aluminum trichloride (approx. 0.5h) at a reaction temperature of 150 ℃; and then, detecting reaction by a point plate, dropwise adding the reactant into purified water after the reaction is finished, and carrying out dispersion stirring for 5 hours to prepare 24.5g of diclofenac sodium intermediate 1- (2, 6-dichlorophenyl) indoline-2-ketone, wherein the yield is 81.6%, and the purity is 98.7%.
From the experimental results of this comparative example, it can be seen that the friedel-crafts reaction of N-phenyl-N- (2, 6-dichlorophenyl) -chloroacetamide with lewis acid without the addition of a phase transfer catalyst has a relatively high temperature of 150 ℃, and that the yield and purity of the diclofenac sodium intermediate 1- (2, 6-dichlorophenyl) indolin-2-one are lower than those of the case of the addition of a phase transfer catalyst; under the same condition, under the condition of adding a phase transfer catalyst, the Friedel-crafts reaction temperature is only 60-80 ℃, the reaction temperature is greatly reduced, and the yield and the purity of the diclofenac sodium intermediate 1- (2, 6-dichlorophenyl) indoline-2-ketone are improved.
The foregoing descriptions of specific exemplary embodiments of the present invention have been presented for purposes of illustration and description. It is not intended to limit the invention to the precise form disclosed, and obviously many modifications and variations are possible in light of the above teaching. The exemplary embodiments were chosen and described in order to explain certain principles of the invention and its practical application to enable one skilled in the art to make and use various exemplary embodiments of the invention and various alternatives and modifications as are suited to the particular use contemplated. It is intended that the scope of the invention be defined by the claims and their equivalents.
Claims (10)
1. A synthetic method of a diclofenac sodium intermediate 1- (2, 6-dichlorophenyl) indoline-2-ketone is characterized by comprising the following steps:
in the presence of a phase transfer catalyst, carrying out Friedel-crafts reaction on N-phenyl-N- (2, 6-dichlorophenyl) -chloroacetamide shown as the following formula (I) and Lewis acid to prepare a diclofenac sodium intermediate 1- (2, 6-dichlorophenyl) indoline-2-ketone shown as the following formula (II),
2. the synthesis method of claim 1, wherein the phase transfer catalyst is selected from one or more of N-alkyl ammonium halide and polyethylene glycol.
3. The method of synthesis according to claim 1, wherein the N-alkyl ammonium halide is selected from one or more of tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium fluoride.
4. The method of synthesis of claim 1, wherein the N-alkyl ammonium halide is tetrabutylammonium bromide.
5. The method of claim 1, wherein the polyethylene glycol is selected from one or more of polyethylene glycol 200, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 800, polyethylene glycol 1000, polyethylene glycol 1500, and polyethylene glycol 2000.
6. The method of synthesis of claim 1, wherein the polyethylene glycol is polyethylene glycol 400.
7. The synthetic method of claim 1 wherein the lewis acid is selected from one or more of anhydrous aluminum trichloride, anhydrous ferric trichloride, and boron trifluoride; preferably, the lewis acid is aluminum trichloride.
8. The synthesis method according to claim 1, wherein the molar ratio of the phase transfer catalyst to N-phenyl-N- (2, 6-dichlorophenyl) -chloroacetamide is 0.06-0.12: 1; preferably, the molar ratio of the phase transfer catalyst to the N-phenyl-N- (2, 6-dichlorophenyl) -chloroacetamide is 0.07-0.10: 1.
9. The synthesis method according to claim 1, wherein the molar ratio of N-phenyl-N- (2, 6-dichlorophenyl) -chloroacetamide to lewis acid is 1:1.0 to 3.0; preferably, the molar ratio of N-phenyl-N- (2, 6-dichlorophenyl) -chloroacetamide to lewis acid is 1: 2.0.
10. A synthesis process according to claim 1, characterized in that the friedel-crafts reaction temperature is 60 ℃ to 80 ℃.
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| CN103145574A (en) * | 2013-04-02 | 2013-06-12 | 中国人民解放军防化学院 | Method for preparing diclofenac sodium |
| CN103288708A (en) * | 2013-04-02 | 2013-09-11 | 中国人民解放军防化学院 | Preparation method for 1-aryl-2-indolinone derivatives |
| CN106588612A (en) * | 2016-11-30 | 2017-04-26 | 江南大学 | Acidic ionic liquid catalysis method for synthesis of 5-chloro-1-indanone |
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