A method for improving the clarity and color of a solution of oxybuprocaine hydrochloride

Abstract

This invention relates to the field of pharmaceutical technology and discloses a method for improving the clarity and color of oxybuprocaine hydrochloride solution, comprising the following steps: S110: Oxoplasmin is added to a reactor, and an organic solvent is added while stirring to control the reaction system at 0-10°C; an antioxidant is added. S120: Hydrochloric acid is slowly added in batches to the temperature-controlled reaction system. After the addition is complete, the temperature is controlled at 0-10°C for 2-4 hours, then the temperature is raised to 40-50°C for 2-4 hours, and activated carbon is added. S130: The mixture is filtered while hot, and solvent is slowly added dropwise to the filtrate until the product precipitates. After slurrying at 25-35°C for 2 hours, the mixture is filtered, and the filter cake is vacuum dried in a vacuum drying oven at 40-50°C for 12-16 hours to obtain oxybuprocaine hydrochloride. This invention provides a novel method for obtaining oxybuprocaine hydrochloride by adding antioxidants and activated carbon in the salt formation step. The clarity and color of the resulting product solution meet pharmacopoeia requirements.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to a method for improving the clarity and color of oxybuprocaine hydrochloride solution. Background Technology

[0002] Obucaine hydrochloride, chemically named 2-(diethylamino)ethyl 4-amino-3-butoxybenzoate hydrochloride, has the following structural formula:

[0003]

[0004] In reference patent CN113185419, methyl 3-hydroxy-4-nitrobenzene is used as a raw material, and etherification with 1-bromobutane is carried out to prepare compound 2. Then, it undergoes transesterification and salt formation with 2-(diethylamino)ethanol under a catalyst to obtain compound 3. Compound 3 undergoes reduction to obtain oxybuprocaine free base, which is then subjected to salt formation and crystallization to obtain oxybuprocaine hydrochloride. This route directly uses hydrochloric acid for salt formation without any special treatment in the intermediate process. The process uses excessive iron powder, making post-processing difficult and unsuitable for scale-up production. Furthermore, the clarity and color of the resulting solution do not meet pharmacopoeia standards due to residual iron ions, and multiple purification processes have failed to achieve the required quality. The route is as follows:

[0005]

[0006] Patent CN106810463 reports another synthetic route as follows:

[0007]

[0008] In this route, under alkaline conditions, ethyl 3-hydroxy-4-nitrobenzoate is substituted with bromobutane to yield ethyl 3-butoxy-4-nitrobenzoate; this is then hydrolyzed with sodium hydroxide to give 3-butoxy-4-nitrobenzoic acid; under alkaline conditions, it is substituted with diethylaminochloroethane to generate 2-(diethylamino)ethyl 4-nitro-2-butoxybenzoate, which is then reduced and salted with a small amount of iron and hydrazine hydrate to give oxybuprocaine hydrochloride. Although this method solves the problems of product clarity and color, the final step uses hydrazine hydrate, a mutagenic impurity, increasing the difficulty of impurity research.

[0009] Therefore, this invention proposes a method to improve the clarity and color of oxybuprocaine hydrochloride solution. Summary of the Invention

[0010] The purpose of this invention is to fill the gap in existing technical solutions and propose a new method for obtaining oxybuprocaine hydrochloride by adding antioxidants and activated carbon in the salt formation step. This method has the advantages of high quality and good reproducibility, and meets the needs of laboratory research and large-scale chemical production in the pharmaceutical and chemical industries.

[0011] This application provides a method for improving the clarity and color of oxybuprocaine hydrochloride solution, and the reaction equation is as follows:

[0012]

[0013] Specifically, it includes the following steps:

[0014] S110: Add oxybuprocaine to the reactor, add organic solvent and stir to control the reaction system at 0-10℃, and add antioxidant;

[0015] S120: Add hydrochloric acid slowly in batches to the temperature-controlled reaction system. After the addition is complete, control the temperature at 0-10℃ and react for 2-4 hours. Then raise the temperature to 40-50℃ and react for 2-4 hours. Add activated carbon.

[0016] S130: Filter while hot, slowly add solvent to the filtrate until the product precipitates, pulverize at 25-35℃ for 2 hours, filter, and dry the filter cake in a vacuum drying oven at 40-50℃ under vacuum (P≤-0.09Mpa) for 12-16 hours to obtain oxybuprocaine hydrochloride.

[0017] Furthermore, in S110, the organic solvent is one of toluene, dichloromethane, methanol, and ethanol, preferably toluene.

[0018] Furthermore, in S110, the antioxidant is one of sodium thiosulfate, sodium metabisulfite, sodium bisulfite, and sodium sulfite, preferably sodium sulfite.

[0019] Furthermore, in S120, after adding the antioxidant, the temperature of adding hydrochloric acid is controlled at 0-10°C.

[0020] Furthermore, in S120, after adding the antioxidant, the temperature of adding hydrochloric acid needs to be controlled at 5°C.

[0021] Furthermore, the crystallization solvent is one of ethyl acetate, isopropyl acetate, and n-butyl acetate, preferably isopropyl acetate.

[0022] Furthermore, the activated carbon is oxidized modified activated carbon.

[0023] Furthermore, the preparation of the oxidized modified activated carbon includes the following steps:

[0024] S210. First, the activated carbon is screened, washed, filtered and dried. The screening mesh is 8-30 mesh. Distilled water is used for washing to remove surface scum and impurities. The drying temperature is 120℃ and the time is 12h.

[0025] S220, Oxidation reaction: Mix the pretreated activated carbon with the oxidant solution, and react for 30-90 minutes.

[0026] After the S230 oxidation reaction is completed, the mixture is filtered and washed until the total dissolved solids in the supernatant are less than 10 mg / L. Then it is dried at 120℃ for 12 h to obtain oxidized modified activated carbon.

[0027] Furthermore, the oxidant is a hydrogen peroxide solution with a volume concentration of 10%-15%, and the mass ratio of activated carbon to oxidant is 100:(1-5).

[0028] Compared with the prior art, the beneficial effects of the technical solution of this application are as follows:

[0029] This invention provides a novel method for obtaining oxybuprocaine hydrochloride by adding antioxidants and activated carbon during the salt formation step. The resulting product solution meets pharmacopoeia requirements in terms of clarity and color.

[0030] The process and post-processing of this invention are simple, reducing the costs of solvents, labor, and power required for complex refining, and thus have significant economic benefits.

[0031] This invention uses oxidized activated carbon, which has a good decolorization effect on polar drugs and can effectively filter and adsorb impurities in drugs, thereby improving the clarity of the oxybuprocaine hydrochloride solution. Attached Figure Description

[0032] Other features, objects, and advantages of the present invention will become more apparent from the following detailed description of non-limiting embodiments with reference to the accompanying drawings:

[0033] Figure 1 This is a comparison chart of the clarity and color of the oxybuprocaine hydrochloride solution prepared in the embodiments of the present invention. Detailed Implementation

[0034] The present invention will be further described below with reference to the accompanying drawings and embodiments, but this should not be construed as limiting the present invention.

[0035] Example 1:

[0036] Add 20.0g of oxybuprocaine and 100ml of toluene to a 250ml three-necked reaction flask. Stir with a thermostatic magnetic stirrer and cool to 0-10℃ in an ice-water bath. Add 2g of sodium sulfite and slowly add 5g of hydrochloric acid solution (concentration: 1mol / L) in batches. Control the temperature at 0-10℃ and react for 3h. Then raise the temperature to 40-50℃ and continue reacting for 3h. Add 0.5g of oxidized modified activated carbon, filter, add 100ml of isopropyl acetate to the filtrate to precipitate solid, slurry at 25-35℃ for 2h, filter, and dry the filter cake in a vacuum drying oven at 40℃ for 12h to obtain oxybuprocaine hydrochloride with a yield of 80.5%.

[0037] Example 2:

[0038] 20.0 g of oxybuprocaine and 100 ml of dichloromethane were added to a 250 ml three-necked reaction flask. The mixture was stirred using a thermostatic magnetic stirrer and cooled to 0–10 °C in an ice-water bath. 2 g of sodium thiosulfate was added, followed by 5 g of hydrochloric acid solution (concentration: 1 mol / L) in batches. The reaction was carried out at 0–10 °C for 3 h, then the temperature was raised to 40–50 °C and the reaction was continued for another 3 h. 0.5 g of oxidized activated carbon was added, and the mixture was filtered. 100 ml of ethyl acetate was added to the filtrate to precipitate a solid. The solid was then stirred at 25–35 °C for 2 h, filtered, and the filter cake was dried in a vacuum drying oven at 40–50 °C for 12 h to obtain oxybuprocaine hydrochloride with a yield of 75.4%.

[0039] Example 3:

[0040] 20.0 g of oxybuprocaine and 100 ml of methanol were added to a 250 ml three-necked reaction flask. The mixture was stirred using a thermostatic magnetic stirrer and cooled to 0–10 °C in an ice-water bath. 2 g of sodium metabisulfite was added, followed by 5 g of hydrochloric acid solution (concentration: 1 mol / L) in batches. The reaction was carried out at 0–10 °C for 3 h, then the temperature was raised to 40–50 °C and the reaction continued for another 3 h. 0.5 g of activated carbon was added, and the mixture was filtered. 100 ml of n-butyl acetate was added to the filtrate to precipitate a solid. The mixture was then stirred at 25–35 °C for 2 h, filtered, and the filter cake was dried in a vacuum drying oven at 40–50 °C for 12 h to obtain oxybuprocaine hydrochloride with a yield of 76.85%.

[0041] Example 4:

[0042] Add 20.0 g of oxybuprocaine and 100 ml of toluene to a 250 ml three-necked reaction flask. Stir with a thermostatic magnetic stirrer and cool to 0–10 °C in an ice-water bath. Add 2 g of sodium bisulfite and slowly add 5 g of hydrochloric acid solution (concentration: 1 mol / L) in batches. React at 0–10 °C for 3 h, then raise the temperature to 40–50 °C and continue the reaction for 3 h. Add 0.5 g of oxidized activated carbon, filter, add 100 ml of isopropyl acetate to the filtrate to precipitate solid, slurry at 25–35 °C for 2 h, filter, and dry the filter cake in a vacuum drying oven at 40–50 °C for 12 h to obtain oxybuprocaine hydrochloride with a yield of 79.6%.

[0043] Example 5:

[0044] 20.0 g of oxybuprocaine and 100 ml of ethanol were added to a 250 ml three-necked reaction flask. The mixture was stirred using a thermostatic magnetic stirrer and cooled to 0–10 °C in an ice-water bath. 2 g of sodium sulfite was added, followed by 5 g of hydrochloric acid solution (concentration: 1 mol / L) in batches. The reaction was carried out at 0–10 °C for 3 h, then the temperature was raised to 40–50 °C and the reaction was continued for another 3 h. 0.5 g of oxidized activated carbon was added, and the mixture was filtered. 100 ml of isopropyl acetate was added to the filtrate to precipitate a solid. The mixture was then stirred at 25–35 °C for 2 h, filtered, and the filter cake was dried in a vacuum drying oven at 40–50 °C for 12 h to obtain oxybuprocaine hydrochloride with a yield of 77.8%.

[0045] This application, while avoiding the introduction of mutagenic impurities, explores the salt formation step of oxybuprofen, adds antioxidants, and decolorizes again with activated carbon. By controlling various process parameters, a solution with the clarity and color required for the solution meets the standards outlined in the 2020 edition of the Chinese Pharmacopoeia, Part II. Figure 1 As shown.

[0046]

[0047] To control product quality, antioxidants with reducing and bleaching effects and activated carbon with decolorizing effects must be used simultaneously in the salt-forming process to ensure compliance with product standards.

[0048] This article uses specific examples to illustrate the inventive concept in detail. The description of the above embodiments is only for the purpose of helping to understand the core idea of ​​the present invention. It should be noted that any obvious modifications, equivalent substitutions or other improvements made by those skilled in the art without departing from the inventive concept should be included within the protection scope of the present invention.

Claims

1. A method for improving the clarity and color of a solution containing oxybuprofen hydrochloride, characterized in that, Includes the following steps: S110: Add oxybuprocaine to the reactor, add organic solvent and stir to control the reaction system at 0-10℃, and add antioxidant; S120: Add hydrochloric acid slowly in batches to the temperature-controlled reaction system. After the addition is complete, control the temperature at 0-10℃ and react for 2-4 hours. Then raise the temperature to 40-50℃ and react for 2-4 hours. Add activated carbon. S130: Filter while hot, slowly add solvent to the filtrate until the product precipitates, pulp at 25-35℃ for 2 hours, filter, and vacuum dry the filter cake at 40-50℃ for 12-16 hours to obtain oxybuprocaine hydrochloride. The activated carbon is an oxidized modified activated carbon; The preparation of the oxidized modified activated carbon includes the following steps: S210. First, the activated carbon is screened, washed, filtered and dried. The screening mesh is 8-30 mesh. Distilled water is used for washing to remove surface scum and impurities. The drying temperature is 120℃ and the time is 12h. S220, Oxidation reaction: Mix the pretreated activated carbon with the oxidant solution, and react for 30-90 minutes. After the S230 oxidation reaction is completed, the mixture is filtered and washed until the total dissolved solids in the supernatant are less than 10 mg / L. Then it is dried at 120℃ for 12 h to obtain oxidized modified activated carbon. The oxidant is a hydrogen peroxide solution with a volume concentration of 10%-15%, and the mass ratio of activated carbon to oxidant is 100:(1-5).

2. The method for improving the clarity and color of oxybuprofen hydrochloride solution according to claim 1, characterized in that, In S110, the organic solvent is one of toluene, dichloromethane, methanol, and ethanol.

3. The method for improving the clarity and color of oxybuprofen hydrochloride solution according to claim 2, characterized in that, In S110, the antioxidant is one of sodium thiosulfate, sodium metabisulfite, sodium bisulfite, and sodium sulfite.

4. The method for improving the clarity and color of oxybuprofen hydrochloride solution according to claim 3, characterized in that, In S120, after adding the antioxidant, the temperature of adding hydrochloric acid is controlled at 0-10℃.

5. The method for improving the clarity and color of oxybuprofen hydrochloride solution according to claim 4, characterized in that, In S120, after adding the antioxidant, the temperature of adding hydrochloric acid needs to be controlled at 5°C.

6. The method for improving the clarity and color of oxybuprofen hydrochloride solution according to claim 5, characterized in that, The crystallization solvent is one of ethyl acetate, isopropyl acetate, and n-butyl acetate.

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