CN109608351B - Preparation method of bromfenac sodium - Google Patents
Preparation method of bromfenac sodium Download PDFInfo
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- CN109608351B CN109608351B CN201811454333.6A CN201811454333A CN109608351B CN 109608351 B CN109608351 B CN 109608351B CN 201811454333 A CN201811454333 A CN 201811454333A CN 109608351 B CN109608351 B CN 109608351B
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- 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
Abstract
The invention discloses a preparation method of bromfenac sodium, relating to the technical field of pharmaceutical chemicals and comprising the following steps: adding 7- (4-bromobenzoyl) -1, 3-dihydro-2H-indole-2-one and sodium hydroxide into a monohydric alcohol-deionized water system, carrying out closed stirring reaction for 3-5H at 90-110 ℃, cooling, dropwise adding hydrochloric acid to adjust the pH, adding a decolorizing agent, carrying out reflux stirring and decolorizing at normal pressure, filtering while hot, crystallizing, and drying to obtain the sodium bromophenolate. The method uses a monohydric alcohol-deionized water system as a reaction solvent to replace a mixed solvent of water-soluble organic solvents/water-insoluble organic solvents such as toluene/ethanol, dichloromethane/ethanol and the like in the prior art, simplifies the process operation and improves the product yield by changing the solvent system in the bromfenac sodium synthesis reaction, and the decoloring process is integrated into the post-reaction treatment process, so that the product purity is improved while decoloring, the production cost is saved, the product purity can reach 100 percent by HPLC method, the reaction solvent can be recycled, and the harmless treatment cost of the solvent is low.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemicals, in particular to a preparation method of bromfenac sodium.
Background
Bromfenac sodium (bromfnac sodium sesquihydrate), chemical name 2-amino-3- (4-bromobenzoyl) phenylacetic acid sodium salt sesquihydrate, developed by Senju Pharmaceutical corporation of japan, and its formulation 0.1% Bromfenac sodium eye drops were first marketed in japan in 2000 (trade name:
specification: 5 ml/count), was marketed in the united states in 2005. Bromfenac sodium is a non-steroidal anti-inflammatory drug and is mainly used for the symptomatic treatment of inflammatory diseases of the outer eye and the anterior eye in clinic, such as: blepharitis, conjunctivitis, uveitis (including superior uveitis), postoperative inflammation, etc.
The synthetic route of bromfenac sodium is few, and a typical synthetic method is to hydrolyze 7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one (II) by sodium base to obtain the bromfenac sodium (I).
The 7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one is insoluble in water and has good solubility in water-insoluble organic solvents, while the product sodium bromfenac is soluble in water and is insoluble in water-insoluble organic solvents. Therefore, in order to complete the reaction, a mixture of a water-soluble organic solvent and a water-insoluble organic solvent is generally used as a reaction solvent in the literature, and a common solvent is toluene/ethanol, dichloromethane/ethanol, or the like. Such as: stephen a. dibase et al (j. heterocyclic chem.,1980,45(18)) hydrolyzed 7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one with 50% sodium hydroxide in toluene/95% ethanol as solvent, and precipitated with isopropyl ether to give crude bromfenac sodium in 86% yield; crude bromfenac sodium was also obtained in the same manner as Xiaju (proceedings of Chinese pharmaceutical university, 2003(34)), with a yield of 86.9%. And on horses or the like (improvement of partial synthesis process of bromfenac sodium, journal of scientific and technological economy, 2016(06)) by using dichloromethane/ethanol as a solvent, hydrolyzing 7- (4-bromobenzoyl) -1, 3-indolin-2-one with 50% sodium hydroxide, and then adding isopropyl ether for crystallization to obtain a crude bromfenac sodium product with a yield of 84%.
In conclusion, the 7- (4-bromobenzoyl) -1, 3-dihydro-2H-indole-2-ketone is adopted to prepare the bromfenac sodium through sodium-base hydrolysis, the existing process adopts a mixed solvent, the solvent cannot be recycled, and the environmental-friendly treatment cost is high.
Disclosure of Invention
Based on the technical problems in the background art, the invention provides the preparation method of the bromfenac sodium, which reduces the harmless treatment cost of a reaction solvent, improves the purity of the bromfenac sodium, and is simple and easy to produce.
The invention provides a preparation method of bromfenac sodium, which comprises the following steps: adding 7- (4-bromobenzoyl) -1, 3-dihydro-2H-indole-2-one and sodium hydroxide into a monohydric alcohol-deionized water system, carrying out closed stirring reaction for 3-5H at 90-110 ℃, cooling, dropwise adding hydrochloric acid to adjust the pH, adding a decolorizing agent, carrying out reflux stirring and decolorizing at normal pressure, filtering while hot, crystallizing, and drying to obtain the sodium bromophenolate.
Preferably, the monohydric alcohol is any one of methanol, ethanol and isopropanol.
Preferably, the monohydric alcohol-deionized water system is a mixed solvent system composed of monohydric alcohol and deionized water, and the monohydric alcohol-deionized water system contains 60-80 vt% of monohydric alcohol by volume.
Preferably, the mass ratio of the 7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one to the sodium hydroxide is 316: 60-80.
Preferably, the mass-volume ratio g/mL of the 7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one to the monohydric alcohol-deionized water system is 1: 3-4.
Preferably, the temperature is reduced to 20-30 ℃, and hydrochloric acid is dripped to adjust the pH value to 11.
Preferably, the decolorizing agent is any one of activated carbon, diatomite and neutral alumina.
Preferably, the crystallization is to cool the filtrate to 15-20 ℃, add seed crystals, stand and crystallize for 2-3 h, and then stand and crystallize for 2-3 h at 0-10 ℃ and stand and crystallize for 3-4 h at-10-0 ℃.
The invention also provides the bromfenac sodium prepared by the method. The bromfenac sodium prepared by the invention is yellow to orange yellow crystals.
In the screening process of the synthesis process conditions of bromfenac sodium, the inventor finds that 7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one (II) firstly generates a sodium salt transition state of lactam in the hydrolysis process of sodium hydroxide, and then hydrolyzes and opens a ring to obtain bromfenac sodium, and the route is as follows:
the 7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one (II) is insoluble in water and has good solubility in a water-insoluble organic solvent, while the sodium salt transition state and the product sodium bromfenac are soluble in water and are insoluble in a water-insoluble organic solvent. Therefore, in order to promote the reaction, the reaction is carried out in a homogeneous system, in the prior art, a mixed solvent of a water-insoluble organic solvent (toluene, dichloromethane and the like) and a water-soluble organic solvent (ethanol, isopropanol and the like) is generally adopted to ensure the complete reaction, and the reaction phenomenon is that a large amount of sodium salt transient-state precipitate is immediately separated out after the materials are dissolved in alkali liquor, and then the sodium bromfenac is slowly dissolved and ring-opened, and finally the sodium bromfenac is separated out. If the amount of the solvent is too small, the transition state of the sodium salt included in the bromfenac sodium is separated out in the transition state dissolving process of the sodium salt in the reaction process, and the reaction is difficult to complete.
The inventor researches and finds that the existing time of the transition state of the sodium salt in the reaction process is closely related to the reaction temperature. The reaction is carried out for 2 hours, the hydrolysis ring opening speed is obviously accelerated, and the hydrolysis can be completed. And further replacing the mixed solvent with a single water-insoluble organic solvent (toluene, dichloromethane and the like) or a water-soluble organic solvent (ethanol, isopropanol and the like), so that the mixed solvent reacts only in lower alcohol (methanol, ethanol, isopropanol and the like), the mixture is sealed and heated to 90-120 ℃ for reaction, and the color of the product is obviously deepened along with the rise of the reaction temperature and pressure and gradually changed from yellow to orange red. The inventor finds that the colored impurities contained in the bromfenac sodium can be effectively removed after being adsorbed by the activated carbon, the diatomite and the neutral alumina through experiments. Therefore, the method comprises the processes of closed heating, decoloring and crystallizing.
Compared with the prior art, the invention has the following beneficial effects: according to the invention, a monohydric alcohol-deionized water system is used as a reaction solvent to replace a mixed solvent of water-soluble organic solvents/water-insoluble organic solvents such as toluene/ethanol, dichloromethane/ethanol and the like in the prior art, the solvent system in the bromfenac sodium synthesis reaction is changed, the process operation is simplified, the product yield is improved, the decoloring process is integrated into the post-reaction treatment process, the product purity is improved while decoloring, the production cost is saved, the product purity can reach 100% by HPLC (high performance liquid chromatography) method, the reaction solvent can be recycled, the harmless treatment cost of the solvent is low, and the method is suitable for industrial production.
Drawings
FIG. 1 is a bromfenac sodium impurity localization HPLC chromatogram;
FIG. 2 is an HPLC chromatogram of bromfenac sodium synthesized in a toluene/ethanol solvent in the method of reference 1;
FIG. 3 is an HPLC chromatogram of bromfenac sodium synthesized in the method of reference 2 using dichloromethane/ethanol as solvent;
FIG. 4 is a HPLC chromatogram of bromfenac sodium synthesized in methanol/water as a solvent in the present invention;
FIG. 5 is an HPLC chromatogram of bromfenac sodium synthesized in ethanol/water as a solvent in the present invention;
FIG. 6 is an HPLC chromatogram of bromfenac sodium synthesized in isopropanol/water as a solvent in the present invention.
Detailed Description
Examples
The invention provides a preparation method of bromfenac sodium, which comprises the following steps: and (2) putting 7- (4-bromobenzoyl) -1, 3-dihydro-2H-indole-2-ketone (II) and sodium hydroxide into a lower monohydric alcohol-deionized water system, carrying out closed stirring reaction at 90-110 ℃ for 3-5H, cooling, dropwise adding hydrochloric acid to adjust the pH value, adding a decolorizing agent, carrying out reflux stirring and decolorizing at normal pressure, filtering while hot, crystallizing and drying to obtain the sodium bromophenolate (I).
The technical solution of the present invention will be described in detail below with reference to specific examples.
Example 1
Adding 30L of 60% methanol, 2.5kg (62.5mol) of sodium hydroxide and 10kg (31.6mol) of 7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one into a pressurized reactor in sequence, carrying out closed stirring reaction for 5H at 90 ℃, cooling to 20-30 ℃, dropwise adding hydrochloric acid to adjust the pH to 11, adding 500g of activated carbon, refluxing and stirring at normal pressure for decoloring for 30min, filtering while hot, cooling the filtrate to 15-20 ℃, adding seed crystals, standing for crystallizing for 2H at 0-10 ℃ and standing for crystallizing for 3H at-10-0 ℃, filtering, and vacuum drying the solid for 6H at 40-50 ℃ to obtain 10kg of orange sodium bromophenol, wherein the yield is 88.9%, and the purity is 100% (HPLC method).
Example 2
Adding 36L of 70% methanol, 1.9kg (47.5mol) of sodium hydroxide and 10kg (31.6mol) of 7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one into a pressurized reactor in sequence, carrying out closed stirring reaction for 3H at 110 ℃, cooling to 20-30 ℃, dropwise adding hydrochloric acid to adjust the pH to 11, adding 500g of kieselguhr, carrying out reflux stirring and decoloration for 5min at normal pressure, filtering while hot, cooling the filtrate to 15-20 ℃, adding seed crystals, standing and crystallizing for 3H at 0-10 ℃ and 10-0 ℃ respectively, filtering, and carrying out vacuum drying on the solid for 8H at 40-50 ℃ to obtain 10.2kg of orange sodium bromophenolate with the yield of 90.6% and the purity of 100% (HPLC).
Example 3
Adding 40L of 80% methanol, 1.9kg (47.5mol) of sodium hydroxide and 10kg (31.6mol) of 7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one into a pressurized reactor in sequence, carrying out closed stirring reaction for 4H at 100 ℃, cooling to 20-30 ℃, dropwise adding hydrochloric acid to adjust the pH to 11, adding 500g of neutral alumina, carrying out reflux stirring and decoloration for 10min at normal pressure, filtering while hot, cooling the filtrate to 15-20 ℃, adding seed crystals, standing and crystallizing for 2H, standing and crystallizing for 3H at 0-10 ℃ and 10-0 ℃ respectively for 4H, filtering, and carrying out vacuum drying on the solid at 40-50 ℃ for 6H to obtain 9.9kg of orange-yellow sodium bromophenol, wherein the yield is 88.0%, and the purity is 100% (HPLC method).
Example 4
Adding 30L of 60% ethanol, 2.5kg (62.5mol) of sodium hydroxide and 10kg (31.6mol) of 7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one into a pressurized reactor in sequence, carrying out closed stirring reaction for 5H at 90 ℃, cooling to 20-30 ℃, dropwise adding hydrochloric acid to adjust the pH to 11, adding 500g of activated carbon, refluxing and stirring at normal pressure for decoloring for 30min, filtering while hot, cooling the filtrate to 15-20 ℃, adding seed crystals, standing for crystallizing for 2H at 0-10 ℃ and standing for crystallizing for 3H at-10-0 ℃, filtering, and vacuum drying the solid for 8H at 40-50 ℃ to obtain 10.3kg of orange sodium bromophenolate, wherein the yield is 91.5%, and the purity is 100% (HPLC).
Example 5
Adding 38L of 65% ethanol, 1.9kg (47.5mol) of sodium hydroxide and 10kg (31.6mol) of 7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one into a pressurized reactor in sequence, carrying out closed stirring reaction for 4H at 100 ℃, cooling to 20-30 ℃, dropwise adding hydrochloric acid to adjust the pH to 11, adding 500g of kieselguhr, carrying out reflux stirring and decoloration for 5min at normal pressure, filtering while hot, cooling the filtrate to 15-20 ℃, adding seed crystals, standing and crystallizing for 3H at 0-10 ℃ and 10-0 ℃ respectively, filtering, and carrying out vacuum drying on the solid for 8H at 40-50 ℃ to obtain 10.2kg of orange sodium bromophenolate with the yield of 90.6% and the purity of 100% (HPLC).
Example 6
Adding 40L of 80% ethanol, 1.9kg (47.5mol) of sodium hydroxide and 10kg (31.6mol) of 7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one into a pressurized reactor in sequence, carrying out closed stirring reaction for 3H at 110 ℃, cooling to 20-30 ℃, dropwise adding hydrochloric acid to adjust the pH to 11, adding 500g of neutral alumina, refluxing and stirring for decoloration for 10min at normal pressure, filtering while hot, cooling the filtrate to 15-20 ℃, adding seed crystals, standing for crystallization for 3H at 0-10 ℃ and 10-0 ℃ respectively, standing for crystallization for 4H, filtering, and vacuum drying the solid for 10H at 40-50 ℃ to obtain 10.4kg of orange-yellow sodium bromophenolate, wherein the yield is 92.4%, and the purity is 100% (HPLC method).
Example 7
Adding 33L of 60% isopropanol, 2.5kg (62.5mol) of sodium hydroxide and 10kg (31.6mol) of 7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one into a pressurized reactor in sequence, carrying out closed stirring reaction at 90 ℃ for 4H, cooling to 20-30 ℃, dropwise adding hydrochloric acid to adjust the pH to 11, adding 500g of activated carbon, carrying out reflux stirring and decoloration at normal pressure for 30min, filtering while hot, cooling the filtrate to 15-20 ℃, adding seed crystals, standing and crystallizing for 2H at 0-10 ℃ and 10-0 ℃ respectively for 3H, filtering, and carrying out vacuum drying on the solid at 40-50 ℃ for 10H to obtain 10.6kg of yellow sodium bromophenolate, wherein the yield is 94.2%, and the purity is 100% (HPLC).
Example 8
Adding 39L of 70% isopropanol, 1.9kg (47.5mol) of sodium hydroxide and 10kg (31.6mol) of 7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one into a pressurized reactor in sequence, carrying out closed stirring reaction for 3H at 100 ℃, cooling to 20-30 ℃, dropwise adding hydrochloric acid to adjust the pH to 11, adding 500g of kieselguhr, carrying out reflux stirring decoloration for 5min under normal pressure, filtering while hot, cooling the filtrate to 15-20 ℃, adding seed crystals, standing for crystallization for 3H at 0-10 ℃ and 10-0 ℃ respectively, standing for crystallization for 4H, filtering, and vacuum drying the solid for 9H at 40-50 ℃ to obtain 10.3kg of yellow sodium bromophenolate, wherein the yield is 91.5%, and the purity is 100% (HPLC).
Example 9
Adding 40L of 75% isopropanol, 1.9kg (47.5mol) of sodium hydroxide and 10kg (31.6mol) of 7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one into a pressurized reactor in sequence, carrying out closed stirring reaction at 110 ℃ for 3H, cooling to 20-30 ℃, dropwise adding hydrochloric acid to adjust the pH to 11, adding 500g of neutral alumina, carrying out reflux stirring and decoloration at normal pressure for 10min, filtering while hot, cooling the filtrate to 15-20 ℃, adding seed crystals, standing and crystallizing for 3H at 0-10 ℃ and 10-0 ℃ respectively, filtering, and carrying out vacuum drying on the solid at 40-50 ℃ for 8H to obtain 10.4kg of yellow sodium bromophenolate, wherein the yield is 92.4%, and the purity is 100% (HPLC method).
Aiming at the problems that the prior art adopts a mixed solvent to synthesize bromfenac sodium and the solvent has high environmental protection treatment cost, a synthetic scheme of the invention is formulated according to a reaction mechanism of bromfenac sodium, and compared with impurity levels of bromfenac sodium prepared by a reference 1 method (Xiaju (synthesis of bromfenac sodium, Chinese university of pharmacy, 2003(34)) and a reference 2 method (horse galloping and the like (improvement of a partial synthesis process of bromfenac sodium, scientific and economic headings, 2016(06)), HPLC is adopted for analysis, and the specific analysis method is as follows:
a chromatographic column: hypersil C18(250 mm. times.4.6 mm, 5.0 μm)
Mobile phase: a: 0.05mol/L ammonium acetate solution-methanol-tetrahydrofuran (65: 25: 15);
b: methanol
Gradient elution, procedure was as follows:
| time (minutes) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 100 | 0 |
| 20 | 100 | 0 |
| 40 | 50 | 50 |
| 90 | 50 | 50 |
| 91 | 100 | 0 |
| 100 | 100 | 0 |
Detection wavelength: 265 nm; diluent agent: 60% methanol; sample concentration: 1 mg/ml; flow rate: 1.0 ml/min; sample introduction amount: 10 μ L.
The impurities of the currently reported bromfenac sodium are as follows:
the bromfenac sodium prepared in the embodiments 1 to 9 of the invention and the bromfenac sodium sample prepared according to the method disclosed in the reference literature are detected by adopting an impurity comparison method, the chromatogram is shown in the figures 1 to 6, and the analysis result is shown in the table 1.
As can be seen from table 1, the bromfenac sodium sample prepared in the example of the present invention was not detected for known impurities a, B, C, D, E and F, and the purity was significantly improved (HPLC method) compared to the samples prepared by reference method 1 (toluene/ethanol as reaction solvent) and reference method 2 (dichloromethane/ethanol as reaction solvent).
TABLE 1 detection results of sodium bromfenac-related substances
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be considered to be within the technical scope of the present invention, and the technical solutions and the inventive concepts thereof according to the present invention should be equivalent or changed within the scope of the present invention.
Claims (4)
1. A preparation method of bromfenac sodium is characterized by comprising the following steps: adding 7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one and sodium hydroxide into a monohydric alcohol-deionized water system, carrying out closed stirring reaction for 3-5H at 90-110 ℃, cooling, dropwise adding hydrochloric acid to adjust the pH, adding a decolorizing agent, carrying out reflux stirring and decolorizing at normal pressure, filtering while hot, crystallizing, and drying to obtain sodium bromophenolate;
wherein, the monohydric alcohol is any one of methanol, ethanol and isopropanol;
the monohydric alcohol-deionized water system is a mixed solvent system formed by monohydric alcohol and deionized water, and the monohydric alcohol in the monohydric alcohol-deionized water system accounts for 60-80% by volume;
wherein the mass-volume ratio g/mL of the 7- (4-bromobenzoyl) -1, 3-dihydro-2H-indole-2-ketone to the monohydric alcohol-deionized water system is 1: 3-4;
wherein the crystallization is to cool the filtrate to 15-20 ℃, add seed crystals, stand and crystallize for 2-3 h, and then stand and crystallize for 2-3 h at 0-10 ℃ and stand and crystallize for 3-4 h at-10-0 ℃.
2. The preparation method of bromfenac sodium according to claim 1, wherein the mass ratio of 7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one to sodium hydroxide is 316: 60-80.
3. The method for preparing bromfenac sodium according to claim 1 or 2, wherein the temperature is reduced to 20-30 ℃, and hydrochloric acid is added dropwise to adjust the pH to 11.
4. The method for preparing bromfenac sodium according to claim 1 or 2, wherein the decolorizing agent is any one of activated carbon, diatomaceous earth and neutral alumina.
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