CN1580039A - Method for synthesizing dichlofenac sodium - Google Patents
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Abstract
The invention provides a synthetic method of sodium diclofenac. The method includes the following steps: 1. Make the 2, 2, 6, 6-tetrachloride cyclohexanone (II) from the cyclohexanone through chlorination. 2. The carboxylation reaction occurs to the close nitrotoluene and carbon dioxide after the phase-transfer catalysis to get the close nitrophenyl acetic acid (III). 3. The hydrogenation reaction happens to the compound (III) catalysed by the polymer catalyst Pd/D-296 to produce the close aminophenyl acetic acid (IV). 4. The condensation reaction occurs to the compound IV and compound II to produce the compound of N-(2-carboxymerhy1 phenyl)-2,2,6,6-hexamethylene imine (V). 5. After the aromatization reaction and salifying happen to the compound V, we get the sodium diclofenac (I). By the close nitrotoluene, the yield is 85%. The invention is featured by facility of the raw material, simple operation, mild reation condition and easy industrialization.
Description
Technical field
The invention belongs to the pharmaceutical chemistry field, is a kind of non-steroidal anti-inflammatory analgesics synthetic method of sodium diclofenac.
Background technology
Diclofenac sodium (I) is the potent non-steroidal anti inflammation and heat resolution anodyne of the third generation, is widely used in analgesia after chronic rheumatic arthritis, distortion vertebra disease, neurodynia, flu syndrome, pharyngitis, dysmenorrhoea, operation and the exodontia, anti-inflammatory etc.Its anti-inflammatory intensity and Ibuprofen BP/EP and Naproxen Base compare favourably.But GI reaction is little more than Naproxen Base and Ibuprofen BP/EP.Has determined curative effect, characteristics such as side effect is light.
(medicine industries such as English Patent 1132128, United States Patent (USP) 3558690 and Fei Shengqian; 1979; 10; 14) having narrated with the 0-chloro-benzoic acid is that starting raw material makes key intermediate 2 through Ullmann condensation and decarboxylic reaction; the 6-dichloro diphenylamine promptly gets I through acidylate, pass ring, hydrolysis/salify then.This method is that China is used for producing the synthetic route of (I) the earliest, and step is tediously long, and yield is low, by 0-chloro-benzoic acid to 2, and 6-dichloro diphenylamine yield only 44%, and decarboxylation temperature is high 280 ℃, severe reaction conditions, and the equipment requirements height, environmental pollution is serious.Total recovery only is 15%.It is acylating reagent that German Patent 1815802 has disclosed with the oxalyl chloride; by the Stoll method 2; introduce the method for carboxymethyl synthetic (I) on the 6-dichloro diphenylamine molecule; this method respectively goes on foot yield all more than 90%; but weak point oxalyl chloride valency is expensive; equipment corrosion is strong, and three-waste pollution is serious, and labour protection requires high.HOII P 6604752 and Japanese Patent 23418 have been described with bromobenzene and 2, the 6-dichlorphenamide bulk powder carries out Ullmann condensation reaction one step and has made 2, the 6-dichloro diphenylamine, yield nearly 50%, this method once had been Switzerland, Japan and domestic the employing, but find except that generating principal product, also still have and be difficult to isolating N-phenyl-by products such as 2-chloro-6-bromaniline generation on a small quantity, the back finds that the existence of fragrant bromide in (I) of these trace easily causes side effects such as stomach ulcer, needs chromatographic separation can get high purity (I).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 one and goes on foot (I) the simple and direct method that makes in the presence of the inferior ketone of iodate.China Zhu Shui ploughs (Chinese Journal of Pharmaceuticals, 1991,22,387), (Jiangsu chemical industry, 1989 such as Gao Xueming, 3,19) and (Chinese Journal of Pharmaceuticals, 2000 such as Fu Jianlong, 31,296) all improved the method for Japanese Patent, yield is about 40～45%, the preparation of o-chlorobenzene acetic acid difficulty in this method, three-waste pollution is more serious, the cost height.European patent 0380712, it is starting raw material that world patent 022522 has successively been described with aniline, resets the synthetic method of the preparation (I) of three step one pot reactions through acidylate, etherificate, Chapman.Chen Fener etc. (Chinese Journal of Pharmaceuticals, 1998,29,339) carry out significant improvement to this method, once be the universal method of domestic production (I), but this method three-waste pollution are serious, and labour protection requires high, and total recovery increases substantially.
Summary of the invention
The object of the invention is to overcome the deficiencies in the prior art, provides a kind of yield height, adult low, the synthetic method of the diclofenac sodium that reaction environment is good (I).
The present invention is under the catalysis of organophosphorus, and pimelinketone and chlorine carry out chlorination reaction and makes 2,2,6 in organic solvent, 6-tetrachloro pimelinketone (II).Under the catalysis of phase-transfer catalyst, Ortho Nitro Toluene carries out carboxylation reaction with carbonic acid gas and makes o-Nitrophenylacetic acid (III) in organic solvent in the presence of mineral alkali.Disperse at polymer under the catalysis of palladium catalyst, compound III is carried out hydrogenation and is made o aminophenylacetic acid (IV).Under the catalysis of acid, Compound I I and compound IV are carried out condensation reaction and are made N-(2-carboxymethyl phenyl)-2,2,6,6-U-4527 (V) in organic solvent.Compound V and mineral alkali carry out aromatization in organic solvent and two step of salify one pot reaction promptly gets diclofenac sodium (I).Calculated by Ortho Nitro Toluene, total recovery is about 85%.Quality product meets USP, BP, Japanese officina and the every standard of Chinese Pharmacopoeia.Its synthetic route is as follows:
Under the catalysis of the present invention by organophosphorus, pimelinketone and chlorine carry out chlorination reaction and make 2,2,6 in organic solvent, 6-tetrachloro pimelinketone (II); Under the catalysis of phase-transfer catalyst, Ortho Nitro Toluene carries out carboxylation reaction with carbonic acid gas and makes o-Nitrophenylacetic acid (III) in organic solvent in the presence of mineral alkali; Disperse at polymer under the catalysis of palladium catalyst, compound III is carried out hydrogenation and is made o aminophenylacetic acid (IV); Under the catalysis of acid, compound (II) carries out condensation reaction with compound (IV) and makes N-(2-carboxymethyl phenyl)-2,2,6,6-U-4527 (V) in organic solvent; Compound (V) carries out aromatization with mineral alkali in organic solvent and two step of salify one pot reaction promptly gets diclofenac sodium (I).
The present invention prepares 2 by pimelinketone through chlorination, 6,6-tetrachloro pimelinketone (II), the used organophosphorus catalyzer of chlorination reaction are any of trimethyl phosphite, triethyl-phosphite, tricresyl phosphite propyl ester, tributyl phosphate, tricresyl phosphite pentyl ester, triphenyl phosphite.Pimelinketone and phosphorous acid ester mol ratio are 1: 0.01～0.3.Reaction can be finished.The organic solvent that reacts used can be hexanaphthene, tetracol phenixin, sherwood oil, can be single solvent, also can be mixed solvent.Its proportion of composing does not have special stipulation.Temperature of reaction is 40～80 ℃.The structure of phosphorous acid ester is as follows:
R is C in the formula
1-C
5Alkyl, aralkyl
The present invention is that triethyl-phosphite, pimelinketone and phosphorous acid mol ratio are 0.1～0.15 by the organophosphorus catalyzer, and organic solvent is a hexanaphthene, and temperature of reaction is 75～80 ℃.
The present invention prepares o-Nitrophenylacetic acid (III) by Ortho Nitro Toluene through the phase-transfer catalysis carboxylation reaction, and the mineral alkali that reacts used is sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, potassium hydride KH or lithium hydride.The mol ratio of Ortho Nitro Toluene and mineral alkali is 1: 1.2～3.5.The phase-transfer catalyst that is adopted is a polyethylene glycols.The weight ratio of Ortho Nitro Toluene and catalyzer is 1: 0.01～0.1.Organic solvent can be tetrahydrofuran (THF), 1,4-dioxane, N, dinethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide (DMSO) or arene.Temperature of reaction is 50～130 ℃.
The present invention is sodium hydroxide or potassium hydroxide by mineral alkali, consisting of phase-transferring agent polyethylene glycols molecular weight is 300～1500, consisting of phase-transferring agent is a polyoxyethylene glycol-600, the weight ratio of Ortho Nitro Toluene and catalyzer is 1: 0012～0.05, organic solvent is toluene or dimethylbenzene, and temperature of reaction is 100～110 ℃.
The present invention prepares o aminophenylacetic acid (IV) by compound (III) through reduction reaction, the polymer catalyst that reacts used is that polymer disperses palladium catalyst, as D61-Pd, D72-Pd, D152-Pd, D261-Pd, D296-Pd, D290-Pd, D370-Pd, D401-Pd.Hydrogenation pressure is normal pressure～1.0Mpa, and temperature of reaction is 15～110 ℃.Organic solvent be low-molecular-weight alcohol as: methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, isopropylcarbinol or low-molecular-weight ester class as: methyl acetate, ethyl acetate, propyl acetate and butylacetate can be single solvents, also both mixed solvents.Temperature of reaction is 15～100 ℃.
It is D296-Pd that the present invention disperses palladium catalyst by polymer, and hydrogenation pressure is a normal pressure, and reaction solvent is methyl alcohol or ethyl acetate, and temperature of reaction is 25～35 ℃.
The present invention prepares N-(2-carboxymethyl phenyl)-2,2,6 by compound (IV) through condensation reaction, 6-U-4527 (V), and the acid of reacting used is the vitriol oil, Glacial acetic acid or p-methyl benzenesulfonic acid.Compound (IV) is 1: 0.001～0.05 with the mol ratio of acid.Organic solvent is an arene as benzene,toluene,xylene and hexanaphthene.Temperature of reaction can make reaction carry out in 15～80 ℃ of scopes.
The present invention is 1: 0.01～0.02 by the mol ratio of compound (IV) and acid, and organic solvent is a toluene, and temperature of reaction is 25～35 ℃.
The present invention carries out aromatization by compound (V) and mineral alkali in organic solvent and two step of salify one pot reaction prepares diclofenac sodium (I), the mineral alkali that reacts used is sodium hydroxide, yellow soda ash, sodium bicarbonate, sodium hydride, and preferred mineral alkali is sodium hydroxide or sodium bicarbonate.Compound (V) with the mol ratio of alkali is: 1: 2～4.5, and optimum mol ratio is 1: 2.5～3.5.Organic solvent is an arene as benzene,toluene,xylene and hexanaphthene.Temperature of reaction is 15～110 ℃.
The present invention is sodium hydroxide or sodium bicarbonate by the used mineral alkali of reaction, and compound (V) is 1: 2.5～3.5 with the mol ratio of alkali, and organic solvent is a toluene, and temperature of reaction is 100～110 ℃
The present invention has overcome many deficiencies of prior art, the yield height, and cost is low, and especially reaction conditions gentleness and environmental friendliness have excellent industrial application foreground.
Embodiment
One, 2,2,6, the preparation of 6-tetrachloro pimelinketone (II)
Example 1 with pimelinketone (50g, 0.51mol), (12g 0.072mol) puts in the dry reaction bottle, after heated and stirred refluxes, slowly feeds chlorine and shows that until GLC pimelinketone raw material peak all disappears for hexanaphthene (200mL) and triethyl-phosphite.The content of II reaches at 98% o'clock, stops logical chlorine (consuming chlorine 185g approximately), continues stirring and refluxing 40min.Reaction is finished, and is cooled to 10 ℃, separates out solid, filters.With a small amount of hexanaphthene washing,, get white crystalline powder II (118g, 98%), 81～82 ℃ of mp in 50 ℃ of dryings.
Example 2 is with pimelinketone (50g, 0.51mol), sherwood oil (350mL) and triphenyl phosphite (1.58g, 0.0051mol) put in the dry reaction bottle, after heated and stirred refluxes, slowly feed chlorine and show that until GLC pimelinketone raw material peak all disappears, when the content of compound (II) reaches 98.5%, stop to feed chlorine, continue stirring and refluxing 30min.Reaction is finished, and is cooled to 5～10 ℃, separates out solid, filters.Use a small amount of petroleum ether,, get white crystalline powder II (111.9g, 94%), 79～81 ℃ of mp in 50 ℃ of dryings.
Example 3 with pimelinketone (50g, 0.51mol), (1.9g 0.015mol) puts in the dry reaction bottle for sherwood oil (350mL) and trimethyl phosphite, after heated and stirred refluxes, slowly feed chlorine and show that until GLC pimelinketone raw material peak all disappears, stop to feed chlorine, continue stirring and refluxing 30min.Reaction is finished, and is cooled to 5 ℃, separates out solid, filters.Use a small amount of petroleum ether,, get white crystalline powder II (110.7g, 92%), 80～82 ℃ of mp in 50 ℃ of dryings.
Two, the preparation of o-Nitrophenylacetic acid (III)
Example 1 is with Ortho Nitro Toluene (41.2g, 0.30mol), sodium hydroxide (30g, 0.75mol), polyoxyethylene glycol-600 (0.5g) and toluene (200mL) puts in the dry reaction bottle, heated and stirred backflow 1h, feed carbon dioxide again, till absorbing carbon dioxide not (about 6h approximately consumes 23.15g).Reaction is finished, and is cooled to room temperature, adds entry (150mL) again, in 60 ℃ of stirring 1h, is cooled to room temperature, leaves standstill, and tells organic layer.Water layer transfers to pH 1～2 with concentrated hydrochloric acid, separates out solid, filters, and drying gets white powder III (53.3g, 98%), 135～137 ℃ of mp.
Example 2 is with Ortho Nitro Toluene (41.2g, 0.30mol), potassium hydroxide (50.4g, 0.9mol), polyoxyethylene glycol-400 (1.5g) and N, dinethylformamide (180mL) is put in the dry reaction bottle, stir 40min in 130 ℃, feed carbon dioxide again, till absorbing carbon dioxide not.Reaction is finished, and is cooled to 10 ℃, adds entry (200mL) again, in 70 ℃ of stirring 1h, is cooled to room temperature, leaves standstill, and tells organic layer.Water layer transfers to pH 1～2 with concentrated hydrochloric acid, separates out solid, filters, and drying gets white powder III (52.6g, 96.8%), 134～136 ℃ of mp.
Example 3 is with Ortho Nitro Toluene (41.2g, 0.30mol), lithium hydride (2.9g, 0.36mol), polyoxyethylene glycol-1500 (1.5g) and dimethyl sulfoxide (DMSO) (200mL) put in the dry reaction bottle, stirs 1.5h in 120 ℃, feed carbon dioxide again, till absorbing carbon dioxide not.Reaction is finished, and is cooled to 10 ℃, adds entry (200mL) again, in 50 ℃ of stirring 0.5h, is cooled to room temperature, leaves standstill, and tells organic layer.Water layer transfers to pH 1～2 with concentrated hydrochloric acid, separates out solid, filters, and drying gets white powder III (51.62g, 95%), 135～137 ℃ of mp.
The preparation of o aminophenylacetic acid (IV)
Example 1 with III (90.6g, 0.50mol), D296-Pd (1.0g) and methyl alcohol (200mL) puts in the reaction flask, in the logical hydrogen hydrogenation 3h of normal temperature and pressure.Reaction is complete, filters, and with the small amount of methanol washing, merging filtrate and washing lotion reclaim methyl alcohol, and solid is separated out in cooling, and vacuum-drying gets white powder IV (74g, 98%), 116～118 ℃ of mp.
Example 2 with III (90.6g, 0.50mol), D261-Pd (1.5g) and ethyl acetate (220mL) put in the reaction flask, in 30 ℃, logical hydrogen hydrogenation 1h under the 0.3Mpa hydrogen pressure.Reaction is complete, filters, and with the amount of ethyl acetate washing, merging filtrate and washing lotion reclaim ethyl acetate, and solid is separated out in cooling, and vacuum-drying gets white powder IV (11.8g, 95%), 117～119 ℃ of mp.
N-(2-carboxymethyl phenyl)-2,2,6, the preparation of 6-U-4527 (V)
Example 1 with IV (30.2g, 0.2mol), II (47.2g, 0.2mol) and toluene (200mL) put in the dry reaction bottle, in room temperature, stir and to drip the vitriol oil (2.5g) down, in 0.5h, drip and finish, in stirring at room 6h.Reaction is finished, and drips water (100mL) in reactant, stirs 10min, leaves standstill, and tells organic layer, and water layer extracts with toluene (40mL * 3), merges organic layer, is washed to pH 6～7.Decompression and solvent recovery, solid is separated out in cooling, filters, and drying gets white powder V (70.1g, 95%), 120～123 ℃ of mp.
Example 2 with IV (30.2g, 0.2mol), II (47.2g, 0.2mol) and hexanaphthene (250mL) put in the dry reaction bottle, in room temperature, stir dropping Glacial acetic acid (1.5g) down, stir 5h in 35 ℃.Drip water (200mL) in reactant, stir 10min, leave standstill, tell organic layer, water layer extracts with toluene (50mL * 4), merges organic layer, is washed to pH 6～7.Decompression and solvent recovery, solid is separated out in cooling, filters, and drying gets white powder V (69g, 93.5%), 121～124 ℃ of mp.
Example 3 with IV (30.2g, 0.2mol), II (47.2g, 0.2mol) and dimethylbenzene (250mL) put in the dry reaction bottle, in room temperature, stir and to drip p-methyl benzenesulfonic acid (1.9g) down, stir 10h in 80 ℃.Drip water (250mL) in reactant, stir 10min, leave standstill, tell organic layer, water layer extracts with toluene (50mL * 4), merges organic layer, is washed to pH 6～7.Decompression and solvent recovery, solid is separated out in cooling, filters, and drying gets white powder V (66.4g, 90%), 121～124 ℃ of mp.
Synthesizing of diclofenac sodium (I)
Example 1 with sodium hydroxide (18.5g, 0.462mol) and water (18.5mL) put in the reaction flask, in stir add down V (50g, 0.14mol) and toluene (200mL), heated and stirred backflow 3h.Reaction is finished, and is cooled to room temperature, adds entry (100mL) in reactant, stirs 10min, placement 2h in 5～10 ℃.Separate out solid, filter, get crude product.Use the deionized water recrystallization, activated carbon decolorizing, white crystalline powder I (43.2g, 97%), mp284～285 ℃.
Example 2 with yellow soda ash (51.9g, 0.49mol) and water (100mL) put in the reaction flask, in stir add down V (50g, 0.14mol) and hexanaphthene (250mL), heated and stirred backflow 3.5h.Reaction is finished, and is cooled to room temperature, adds entry (100mL) in reactant, stirs 10min, placement 2h in 5～10 ℃.Separate out solid, filter, get crude product.Use the deionized water recrystallization, activated carbon decolorizing, white crystalline powder I (40g, 90%), mp285～286 ℃.
Above-mentioned example only is used to illustrate embodiments of the present invention, but the present invention not only is confined to above-mentioned example.
Claims (11)
1, a kind of synthetic method of sodium diclofenac is characterized in that taking following chemical process synthetic, and concrete steps are:
(1) under the catalysis of organophosphorus, pimelinketone and chlorine carry out chlorination reaction and make 2,2,6 in organic solvent, 6-tetrachloro pimelinketone (II);
(2) under the catalysis of phase-transfer catalyst, Ortho Nitro Toluene carries out carboxylation reaction with carbonic acid gas and makes o-Nitrophenylacetic acid (III) in organic solvent in the presence of mineral alkali;
(3) disperse under the catalysis of palladium catalyst at polymer, compound III is carried out hydrogenation and is made o aminophenylacetic acid (IV);
(4) under the catalysis of acid, compound (II) carries out condensation reaction with compound (IV) and makes N-(2-carboxymethyl phenyl)-2,2,6,6-U-4527 (V) in organic solvent;
(5) compound (V) and mineral alkali carry out aromatization and two step of salify one pot reaction promptly gets diclofenac sodium (I) in organic solvent.
2, as the synthetic method of right 1 described diclofenac sodium (I), it is characterized in that in the reactions steps (1), used organophosphorus catalyzer is phosphorous acid esters, the mol ratio of pimelinketone and phosphorous acid esters catalyzer is 1: 0.01～0.3, organic solvent is hexanaphthene or tetracol phenixin or sherwood oil, or single solvent, or mixed solvent, temperature of reaction is 40～80 ℃.
3, as the synthetic method of right 2 described diclofenac sodium (I), it is characterized in that the organophosphorus catalyzer is that triethyl-phosphite, pimelinketone and phosphorous acid mol ratio are 0.1～0.15, organic solvent is a hexanaphthene, temperature of reaction is 75～80 ℃.
4, synthetic method as right 1 described diclofenac sodium (I), it is characterized in that in the reactions steps (2), used mineral alkali is a sodium hydroxide, or potassium hydroxide, or lithium hydroxide, or sodium hydride, or potassium hydride KH or lithium hydride, the mol ratio of Ortho Nitro Toluene and mineral alkali is 1: 1.2～3.5, phase-transfer catalyst is a polyethylene glycols, the weight ratio of Ortho Nitro Toluene and catalyzer is 1: 0.01～0.1, organic solvent is tetrahydrofuran (THF) or 1, the 4-dioxane, or N, dinethylformamide, or N, the N-N,N-DIMETHYLACETAMIDE, or dimethyl sulfoxide (DMSO) or arene, temperature of reaction is 50-130 ℃.
5, as the synthetic method of right 4 described diclofenac sodium (I), it is characterized in that mineral alkali is sodium hydroxide or potassium hydroxide, consisting of phase-transferring agent polyethylene glycols molecular weight is 300～1500, consisting of phase-transferring agent is a polyoxyethylene glycol-600, the weight ratio of Ortho Nitro Toluene and catalyzer is 1: 0.012～0.05, organic solvent is toluene or dimethylbenzene, and temperature of reaction is 100～110 ℃.
6,, it is characterized in that polymer catalyst used in the reactions steps (3) is that polymer disperses palladium catalyst as the synthetic method of right 1 described diclofenac sodium (I).Hydrogenation pressure is normal pressure～1.0Mpa, and temperature of reaction is 15～100 ℃, and organic solvent is low-molecular-weight alcohol or low-molecular-weight ester class, and solvent is a single solvent, or mixed solvent, and temperature of reaction is 15～110 ℃.
7, as the synthetic method of right 6 described diclofenac sodium (I), it is characterized in that it is D296-Pd that polymer disperses palladium catalyst, hydrogenation pressure is a normal pressure, and reaction solvent is methyl alcohol or ethyl acetate, and temperature of reaction is 25～35 ℃.
8, as the synthetic method of right 6 described diclofenac sodium (I), it is characterized in that acid used in the reactions steps (4) is the vitriol oil or Glacial acetic acid or p-methyl benzenesulfonic acid, compound (IV) with the mol ratio of acid is: 1: 0.001～0.05, organic solvent is the arene organic solvent, and temperature of reaction is 15～80 ℃.
9, as the synthetic method of right 8 described diclofenac sodium (I), it is characterized in that the compound (IV) and the mol ratio of acid are 1: 0.01～0.02, organic solvent is a toluene, temperature of reaction is 25～35 ℃.
10, as the synthetic method of right 1 described diclofenac sodium (I), it is characterized in that dehydrochlorination and salify one pot reaction in the reactions steps (5), used mineral alkali is sodium hydroxide or yellow soda ash or sodium bicarbonate or sodium hydride, compound (V) with the mol ratio of alkali is: 1: 2～4.5, organic solvent is the arene organic solvent, and temperature of reaction is 15～110 ℃.
11, as the synthetic method of right 10 described diclofenac sodium (I), it is characterized in that the mineral alkali that reacts used is sodium hydroxide or sodium bicarbonate, compound (V) is 1: 2.5～3.5 with the mol ratio of alkali, and organic solvent is a toluene, and temperature of reaction is 100～110 ℃.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108947861A (en) * | 2018-08-17 | 2018-12-07 | 复旦大学 | The synthetic method of C14H10Cl2NNaO2 |
| 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 |
| CN114539086A (en) * | 2022-02-25 | 2022-05-27 | 复旦大学 | Method for synthesizing diclofenac sodium |
| US11834388B2 (en) | 2022-02-25 | 2023-12-05 | Fudan University | Continuous-flow preparation method of diclofenac sodium |
-
2004
- 2004-05-20 CN CN 200410018505 patent/CN1242984C/en not_active Expired - Fee Related
Cited By (7)
| 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 |
| CN108947861A (en) * | 2018-08-17 | 2018-12-07 | 复旦大学 | The synthetic method of C14H10Cl2NNaO2 |
| 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 |
| US11834388B2 (en) | 2022-02-25 | 2023-12-05 | Fudan University | Continuous-flow preparation method of diclofenac sodium |
| US11905229B2 (en) | 2022-02-25 | 2024-02-20 | Fudan University | Method for synthesizing diclofenac sodium |
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