CN101701003A - Diclofenac sodium synthetic method - Google Patents
Diclofenac sodium synthetic method Download PDFInfo
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- CN101701003A CN101701003A CN 200910224071 CN200910224071A CN101701003A CN 101701003 A CN101701003 A CN 101701003A CN 200910224071 CN200910224071 CN 200910224071 CN 200910224071 A CN200910224071 A CN 200910224071A CN 101701003 A CN101701003 A CN 101701003A
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Abstract
The invention discloses a diclofenac sodium synthetic method; N,N- dimethyl o-bromophenylacetamide and 2,6-dichloroaniline carry out condensation reaction in organic solvent to prepare N,N-dimethyl-2-(2,6- dichloroaniline) phenylacetamide (compound II) under the existence of Fe catalytic agent and inorganic base; hydrolysis reaction is carried out to the compound II to obtain diclofenac sodium, by calculating the N,N- dimethyl o-bromophenylacetamide, the overall yield is about 80 percent. The synthetic method has high yield and low cost and is environmental friendly, therefore, the method has good industrial prospect.
Description
Technical field
The present invention relates to the pharmaceutical chemistry field, particularly relate to a kind of non-steroidal anti-inflammatory analgesics synthetic method of sodium diclofenac.
Background technology
Diclofenac sodium, its chemistry 2-(2,6-dichlorobenzene amido) sodium phenylacetate by name, molecular formula: C
14H
10C
12NNaO
2, molecular weight: 318.13.Be white or off-white color crystalline powder.Structural formula is shown below:
Diclofenac sodium is by Switzerland vapour Ba-Jia Ji company development, and in the potent anti-inflammatory analgesic of a kind of non-steroidal of listing in 1974, is widely used in the pain, inflammation of each rheumatoid arthritis, lupus erythematosus, neuritis and postoperative etc.Because its good effect, oral absorption is rapid, drains soon, takes no depot action for a long time, and individual difference is little, is one of world's situation of selling well medicine always.
It is that starting raw material makes key intermediate 2 through Ullmann condensation and decarboxylic reaction that English Patent 1132128, United States Patent (USP) 3558690 etc. have been narrated with adjacent chlorine (bromine, iodine) phenylformic acid; the 6-dichloro diphenylamine promptly gets diclofenac sodium through acidylate, pass ring, hydrolysis/salify then.Present method is that the pharmaceutical factory is used to the operational path produced the earliest, be characterized in that raw material is easy to get, but reactions steps is tediously long, total recovery lower (about 15%).Japanese Patent 55108845 has been described with adjacent halobenzene formic acid and 2, and the condensation of 6-dichlorphenamide bulk powder gets 2-(2,6-dichlorobenzene amido) phenylformic acid, is carbon source with diazomethane or sodium cyanide etc. again, increases a carbon atom and obtains product.Owing to have complicated operation and use problem such as dangerous hypertoxic raw material, do not have industrial production to be worth.(Chinese patent, publication number: CN 1580039A) described with the pimelinketone is starting raw material to Chen Fener etc., makes diclofenac sodium through chlorination, carboxylation, hydro-reduction, condensation, aromizing/salt-forming reaction.Though this method yield is higher, tediously long, used organophosphorus, the palladium catalyst of step is very big to the toxicity of environment.United States Patent (USP) 4978773, Qin Bingchang etc. (use chemical industry; 2008,3,275) and (Institutes Of Technology Of Taiyuan's journal such as Wei Wenlong; 2004; 6,710) narrated with 2,6-dichloro diphenylamine and chloroacetyl chloride are main raw material; pay-the Ke alkylation through acidylate, intramolecularly; obtain 1-(2, the 6-dichlorophenyl) Indolin-2-one, obtain product through the alkaline hydrolysis open loop.This method is the production method that generally adopts at present, but reactions steps is more, and total recovery is lower.1979, Japanese Patent 72152,87748,108844 grades have disclosed o-chlorobenzene acetic acid and 2, and the 6-dichlorphenamide bulk powder carries out Ullmann condensation reaction (Liv Ullmann condensation reaction) and goes on foot the simple and direct method of diclofenac sodium that makes under the catalysis of cuprous iodide.China Zhu Shui ploughs (Chinese Journal of Pharmaceuticals, 1991,22,387), (Jiangsu chemical industry, 1989 such as Gao Xueming, 3,19), (Guangdong chemical industry such as Huang Qipeng, 1992,3,36) and (Chinese Journal of Pharmaceuticals such as Fu Jianlong, 2000,31,296) all improved the method for Japanese Patent, but yield is generally lower, and catalyzer cuprous iodide cost is higher.
Summary of the invention
The object of the invention is to overcome the deficiencies in the prior art, and a kind of preparation method of environmentally friendly, yield is high, cost is low diclofenac sodium is provided.
Synthetic method of the present invention may further comprise the steps:
(1) in the presence of Fe catalyzer and mineral alkali, make N, the adjacent bromobenzene ethanamide and 2 of N-dimethyl, the 6-dichlorphenamide bulk powder carries out condensation reaction and makes N in organic solvent, N-dimethyl-2-(2,6-dichlorobenzene amido) phenylacetamide (Compound I I); Temperature of reaction is 100～200 ℃, and the reaction times is 30～90h.
(2) N that obtains of step (1), N-dimethyl-2-(2,6-dichlorobenzene amido) phenylacetamide and mineral alkali in solvent, be hydrolyzed react diclofenac sodium; Temperature of reaction is 50～150 ℃, and the reaction times is 2～50h.
By N, the adjacent bromobenzene ethanamide of N-dimethyl calculates, and total recovery is about 80%.Wherein adopt iron catalyst to replace traditional copper catalyst, iron catalyst is compared price with copper catalyst cheaper, friendly more to environment.Mineral alkali in the reaction mainly plays the auxiliary catalysis effect.
Product meets USP, BP, Japanese officina and the every standard of Chinese Pharmacopoeia, and its synthetic route is as follows:
Compound I I
Step of the present invention (1) is by N, the adjacent bromobenzene ethanamide and 2 of N-dimethyl, and the 6-dichlorphenamide bulk powder prepares Compound I I through condensation reaction, N, the adjacent bromobenzene ethanamide and 2 of N-dimethyl, the mol ratio of 6-dichlorphenamide bulk powder is 1: 2～5.The used Fe catalyzer of condensation reaction is Fe
2O
3, Fe
3O
4Or FeCl
3, be preferably Fe
2O
3, N, adjacent bromobenzene ethanamide of N-dimethyl and Fe
2O
3Mol ratio be 1: 0.1～0.3.The solvent that reacts used can be chlorobenzene, bromine benzene,toluene,xylene or N, and dinethylformamide (DMF) can be a single solvent, also can be mixed solvent.The mineral alkali that reacts used is potassium hydroxide, anhydrous sodium carbonate, Anhydrous potassium carbonate, potassiumphosphate, and preferred mineral alkali is an Anhydrous potassium carbonate.N, the mol ratio of adjacent bromobenzene ethanamide of N-dimethyl and mineral alkali is 1: 2～3.Temperature of reaction is 100～200 ℃.Reaction times is 30～90h.
The preferred reaction conditions of step (1) is: N, and the adjacent bromobenzene ethanamide and 2 of N-dimethyl, the mol ratio of 6-dichlorphenamide bulk powder is 1: 2～3, N, adjacent bromobenzene ethanamide of N-dimethyl and Fe
2O
3Mol ratio be 1: 0.15～0.25, reaction solvent is dimethylbenzene or N, dinethylformamide (DMF), mineral alkali are Anhydrous potassium carbonate, N, the mol ratio of adjacent bromobenzene ethanamide of N-dimethyl and mineral alkali is 1: 2.5～3, temperature of reaction is 100～160 ℃.Reaction times is 40～60h.
Step of the present invention (2) is by Compound I I (N, N-dimethyl-2-(2,6-dichlorobenzene amido) phenylacetamide) with the mineral alkali prepared in reaction diclofenac sodium that in solvent, is hydrolyzed, the mineral alkali that reacts used is potassium hydroxide, Anhydrous potassium carbonate, sodium hydroxide, and preferred mineral alkali is potassium hydroxide, sodium hydroxide.The mol ratio of Compound I I and alkali is 1: 3～20.Solvent be water or inert organic solvents as: methyl alcohol, ethanol, propyl alcohol, dioxane can be single solvents, also can be mixed solvents.Temperature of reaction is 50～150 ℃, and the reaction times is 2～50h.
The preferred reaction conditions of step (2) is: alkali is potassium hydroxide, and the mol ratio of Compound I I and alkali is 1: 4～15, and solvent is an ethanol, and temperature of reaction is 60～70 ℃.Reaction times 4～20h.
The present invention has overcome many deficiencies of prior art, and yield height, low, the environmental friendliness of cost have excellent industrial application foreground.
Embodiment
Below in conjunction with embodiment, the specific embodiment of the present invention is described in further detail.Following examples are used to illustrate the present invention, but are not used for limiting the scope of the invention.
Embodiment 1
1) N, the preparation of N-dimethyl-2-(2,6-dichlorobenzene amido) phenylacetamide
With N, and the adjacent bromobenzene ethanamide of N-dimethyl (5.2g, 0.0215mol), 2, the 6-dichlorphenamide bulk powder (8.5g, 0.0525mol), Fe
2O
3(0.69g; 0.0043mol), Anhydrous potassium carbonate (7.4g; 0.0538mol) and dimethylbenzene (80mL, bp:138～141 ℃) place the exsiccant reaction flask, under nitrogen protection; back flow reaction is 48 hours under stirring; temperature of reaction is 135 ℃, after reaction finishes, adds activated carbon; suction filtration while hot, filtrate decompression is concentrated into dried.The residue dissolve with methanol, crystallisation by cooling in ice-water bath, suction filtration, dry incarnadine solid 5.7g (the Compound I I that gets; N, N-dimethyl-2-(2,6-dichlorobenzene amido) phenylacetamide), yield 82.1%.Mp:158～160 ℃, HPLC measures content greater than 98%.
2) diclofenac sodium is synthetic
Potassium hydroxide (2.0g), ethanol (15mL) are placed reaction flask, add Compound I I (1.0g) down in stirring, 65 ℃ of reaction 6h, after reaction finished, decompression steamed solvent, residue water (10mL) heating for dissolving, crystallisation by cooling in ice-water bath, suction filtration, the dry crude product that gets.Crude product deionized water recrystallization, decolorizing with activated carbon gets white crystalline powder 0.94g, yield 95.7%.Mp:284～285 ℃, HPLC measures content greater than 99%.
The total recovery of above-mentioned reaction is 78.6%.
Embodiment 2
1) N, the preparation of N-dimethyl-2-(2,6-dichlorobenzene amido) phenylacetamide
With N, and the adjacent bromobenzene ethanamide of N-dimethyl (5.2g, 0.0215mol), 2, the 6-dichlorphenamide bulk powder (10.5g, 0.0645mol), Fe
2O
3(0.86g; 0.0054mol), Anhydrous potassium carbonate (7.4g; 0.0538mol) and dimethylbenzene (100mL, bp:138～141 ℃) place the exsiccant reaction flask, under nitrogen protection; back flow reaction is 52 hours under stirring; temperature of reaction is 130 ℃, after reaction finishes, adds activated carbon; suction filtration while hot, filtrate decompression is concentrated into dried.The residue dissolve with methanol, crystallisation by cooling in ice-water bath, suction filtration, dry incarnadine solid 5.8g (the Compound I I that gets; N, N-dimethyl-2-(2,6-dichlorobenzene amido) phenylacetamide), yield 83.6%.Mp:158～160 ℃, HPLC measures content greater than 98%.
2) diclofenac sodium is synthetic
Potassium hydroxide (1.0g), ethanol (15mL) are placed reaction flask, add Compound I I (1.0g) down in stirring, 70 ℃ of reaction 8h, after reaction finished, decompression steamed solvent, residue water (10mL) heating for dissolving, crystallisation by cooling in ice-water bath, suction filtration, the dry crude product that gets.Crude product deionized water recrystallization, decolorizing with activated carbon gets white crystalline powder 0.93g, yield 94.7%.Mp:283～285 ℃, HPLC measures content greater than 98%.
The total recovery of above-mentioned reaction is 79.2%.
Embodiment 3
1) N, the preparation of N-dimethyl-2-(2,6-dichlorobenzene amido) phenylacetamide
With N, and the adjacent bromobenzene ethanamide of N-dimethyl (5.2g, 0.0215mol), 2, the 6-dichlorphenamide bulk powder (8.5g, 0.0525mol), Fe
2O
3(0.69g; 0.0043mol), Anhydrous potassium carbonate (8.9g; 0.0645mol) and DMF (100mL, bp:153 ℃) place the exsiccant reaction flask, under nitrogen protection; back flow reaction is 52 hours under stirring; temperature of reaction is 140 ℃, after reaction finishes, adds activated carbon; suction filtration while hot, filtrate decompression is concentrated into dried.The residue dissolve with methanol, crystallisation by cooling in ice-water bath, suction filtration, dry incarnadine solid 5.6g (the Compound I I that gets; N, N-dimethyl-2-(2,6-dichlorobenzene amido) phenylacetamide), yield 80.7%.Mp:159～160 ℃, HPLC measures content greater than 98%.
2) diclofenac sodium is synthetic
Potassium hydroxide (1.5g), ethanol (15mL) are placed reaction flask, add Compound I I (1.0g) down in stirring, 60 ℃ of reaction 10h, after reaction finished, decompression steamed solvent, residue water (10mL) heating for dissolving, crystallisation by cooling in ice-water bath, suction filtration, the dry crude product that gets.Crude product deionized water recrystallization, decolorizing with activated carbon gets white crystalline powder 0.95g, yield 96.7%.Mp:283～285 ℃, HPLC measures content greater than 98%.
The total recovery of above-mentioned reaction is 78.04%.
Embodiment 4
1) N, the preparation of N-dimethyl-2-(2,6-dichlorobenzene amido) phenylacetamide
With N, and the adjacent bromobenzene ethanamide of N-dimethyl (5.2g, 0.0215mol), 2, the 6-dichlorphenamide bulk powder (8.5g, 0.0525mol), Fe
2O
3(0.69g; 0.0043mol), anhydrous phosphoric acid potassium (13.67g; 0.0645mol) and DMF (80mL, bp:153 ℃) place the exsiccant reaction flask, under nitrogen protection; back flow reaction is 54 hours under stirring; temperature of reaction is 135 ℃, after reaction finishes, adds activated carbon; suction filtration while hot, filtrate decompression is concentrated into dried.The residue dissolve with methanol, crystallisation by cooling in ice-water bath, suction filtration, dry incarnadine solid 5.7g (the Compound I I that gets; N, N-dimethyl-2-(2,6-dichlorobenzene amido) phenylacetamide), yield 82.1%.Mp:158～160 ℃, HPLC measures content greater than 98%.
2) diclofenac sodium is synthetic
Sodium hydroxide (1.0g), ethanol (15mL) are placed reaction flask, add Compound I I (1.0g) down in stirring, 65 ℃ of reaction 7h, after reaction finished, decompression steamed solvent, residue water (10mL) heating for dissolving, crystallisation by cooling in ice-water bath, suction filtration, the dry crude product that gets.Crude product deionized water recrystallization, decolorizing with activated carbon gets white crystalline powder 0.95g, yield 96.7%.Mp:283～285 ℃, HPLC measures content greater than 98%.
The total recovery of above-mentioned reaction is 79.39%.
The above only is a preferred implementation of the present invention; should be pointed out that for those skilled in the art, under the prerequisite that does not break away from the technology of the present invention principle; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (10)
1. a synthetic method of sodium diclofenac is characterized in that, may further comprise the steps:
(1) in the presence of Fe catalyzer and mineral alkali, make N, the adjacent bromobenzene ethanamide and 2 of N-dimethyl, the 6-dichlorphenamide bulk powder carries out condensation reaction and makes N in organic solvent, N-dimethyl-2-(2,6-dichlorobenzene amido) phenylacetamide; Temperature of reaction is 100～200 ℃, and the reaction times is 30～90h.
(2) N that obtains of step (1), N-dimethyl-2-(2,6-dichlorobenzene amido) phenylacetamide and mineral alkali in solvent, be hydrolyzed react diclofenac sodium; Temperature of reaction is 50～150 ℃, and the reaction times is 2～50h.
2. synthetic method as claimed in claim 1 is characterized in that, N in the described step (1), and the adjacent bromobenzene ethanamide and 2 of N-dimethyl, the mol ratio of 6-dichlorphenamide bulk powder is 1: 2～5.
3. synthetic method as claimed in claim 2 is characterized in that, N in the described step (1), and the adjacent bromobenzene ethanamide and 2 of N-dimethyl, the mol ratio of 6-dichlorphenamide bulk powder is 1: 2～3.
4. as each described synthetic method of claim 1-3, it is characterized in that the Fe catalyzer in the described step (1) is Fe
2O
3, Fe
3O
4Or FeCl
3
5. synthetic method as claimed in claim 4 is characterized in that, N in the described step (1), adjacent bromobenzene ethanamide of N-dimethyl and Fe
2O
3Mol ratio be 1: 0.1～0.3.
6. as each described synthetic method of claim 1-5, it is characterized in that the mineral alkali that adopts in the described step (1) is potassium hydroxide, anhydrous sodium carbonate, Anhydrous potassium carbonate or potassiumphosphate.
7. synthetic method as claimed in claim 6 is characterized in that, N in the described step (1), and the mol ratio of adjacent bromobenzene ethanamide of N-dimethyl and mineral alkali is 1: 2～3.
8. as each described synthetic method of claim 1-7, it is characterized in that the organic solvent in the described step (1) is selected from chlorobenzene, bromine benzene,toluene,xylene or N, one or more in the dinethylformamide.
9. as each described synthetic method of claim 1-8, it is characterized in that the mineral alkali that adopts in the described step (2) is potassium hydroxide, Anhydrous potassium carbonate or sodium hydroxide; N, the mol ratio of N-dimethyl-2-(2,6-dichlorobenzene amido) phenylacetamide and mineral alkali is 1: 3～20.
10. as each described synthetic method of claim 1-9, it is characterized in that the solvent in the described step (2) is selected from one or more in water, methyl alcohol, ethanol, propyl alcohol, the dioxane.
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|---|---|---|---|
| CN 200910224071 CN101701003B (en) | 2009-12-04 | 2009-12-04 | Diclofenac sodium synthetic method |
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|---|---|---|---|
| CN 200910224071 CN101701003B (en) | 2009-12-04 | 2009-12-04 | Diclofenac sodium synthetic method |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109553544A (en) * | 2017-09-27 | 2019-04-02 | 浙江普利药业有限公司 | A kind of synthetic method of C14H10Cl2NNaO2 |
| CN110156619A (en) * | 2019-06-26 | 2019-08-23 | 郸城县盛斐生物科技有限公司 | A kind of preparation method of Diclofenac |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5524116A (en) * | 1978-08-08 | 1980-02-21 | Ikeda Mohandou:Kk | Preparation of o-(2, 6-dichloroanilino)-phenylacetic acid |
-
2009
- 2009-12-04 CN CN 200910224071 patent/CN101701003B/en active Active
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109553544A (en) * | 2017-09-27 | 2019-04-02 | 浙江普利药业有限公司 | A kind of synthetic method of C14H10Cl2NNaO2 |
| CN109553544B (en) * | 2017-09-27 | 2022-02-08 | 浙江普利药业有限公司 | Method for synthesizing diclofenac sodium |
| CN110156619A (en) * | 2019-06-26 | 2019-08-23 | 郸城县盛斐生物科技有限公司 | A kind of preparation method of Diclofenac |
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|---|---|
| CN101701003B (en) | 2012-12-26 |
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