Method for improving clarity and color of solution in oxybuprocaine hydrochloride

Abstract

The invention relates to the technical field of medicines, and discloses a method for improving the clarity and color of a solution in oxybutecaine hydrochloride, which comprises the following steps: S110: adding oxybutecaine into a reactor, adding an organic solvent, controlling the temperature of a reaction system at 0-10 DEG C while stirring, and adding an antioxidant; s120, slowly adding hydrochloric acid into the temperature-controlled reaction system in batches, controlling the temperature at 0-10 DEG C after the hydrochloric acid is added, reacting for 2-4 hours, heating to 40-50 DEG C, reacting for 2-4 hours, and adding activated carbon; and S130, carrying out suction filtration while the solution is hot, slowly dropwise adding a solvent into the filtrate until a product is separated out, pulping at 25-35 DEG C for 2 hours, carrying out suction filtration, and carrying out vacuum drying on a filter cake in a vacuum drying oven at 40-50 DEG C for 12-16 hours to obtain the olbucaine hydrochloride. According to the novel method for obtaining the olbucaine hydrochloride by adding the antioxidant and the activated carbon in the salifying step, the clarity and the color of the obtained product solution meet the requirements of pharmacopeia.

Description

Technical Field

[0001] The invention relates to the technical field of medicines, and in particular to a method for improving the clarity and color of a solution in oxybuprocaine hydrochloride. Background Art

[0002] Oxybuprocaine hydrochloride, chemical name is 2-(Diethylamino)ethyl 4-amino-3-butoxybenzoate hydrochloride, the structural formula is as follows

[0003]

[0004] In the reference patent: CN113185419, 3-hydroxy-4-nitrobenzoic acid methyl ester is used as a raw material to undergo an etherification reaction with 1-bromobutane to prepare compound 2, which is then subjected to an ester exchange and salt-forming reaction with 2-(diethylamino)ethanol in the presence of a catalyst to obtain compound 3, which is then subjected to a reduction reaction to obtain oxybuprocaine free base, which is then subjected to a salt-forming reaction and crystallization to obtain oxybuprocaine hydrochloride. This route directly uses hydrochloric acid to form a salt, and there is no special treatment in the intermediate process. Excessive iron powder is used in the process, and post-processing is difficult, which is not conducive to large-scale production. In addition, the clarity and color of the resulting material solution do not meet the pharmacopoeia standard requirements due to the residual iron ions, and multiple refinings have also failed to meet the requirements. The route is as follows

[0005]

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

[0007]

[0008] In this route, under alkaline conditions, 3-hydroxy-4-nitrobenzoic acid ethyl ester is substituted with bromobutyl to obtain 3-butoxy-4-nitrobenzoic acid ethyl ester; it is then hydrolyzed with sodium hydroxide to obtain 3-butoxy-4-nitrobenzoic acid; under alkaline conditions, it is substituted with diethylaminochloroethane to generate 4-nitro-2-butoxybenzoic acid-2-(diethylamino)ethyl ester, which is then reduced and salted with a small amount of iron and hydrazine hydrate to obtain oxybuprocaine hydrochloride. Although the clarity and color problems of the product were solved, hydrazine hydrate was used in the last step, which is a mutagenic impurity and increases the difficulty of impurity research.

[0009] To this end, the present invention provides a method for improving the clarity and color of oxybuprocaine hydrochloride solution. Summary of the invention

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

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

[0012]

[0013] It specifically includes the following steps:

[0014] S110: adding oxybuprocaine to a reactor, adding an organic solvent, controlling the reaction system at 0 to 10° C. under stirring, and adding an antioxidant;

[0015] S120: slowly adding hydrochloric acid in batches to the temperature-controlled reaction system, controlling the temperature at 0-10°C for reaction for 2-4 hours, raising the temperature to 40-50°C for reaction for 2-4 hours, and adding activated carbon;

[0016] S130: Filter while hot, slowly add solvent to the filtrate until the product precipitates, beat at 25-35°C for 2h, filter, and dry the filter cake in a vacuum drying oven at 40-50°C under vacuum (P≤-0.09Mpa) for 12-16h 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 pyrosulfite, sodium bisulfite, and sodium sulfite, preferably sodium sulfite.

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

[0020] Furthermore, in S120, after adding the antioxidant, the temperature of the hydrochloric acid dropwise addition 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 oxidatively modified activated carbon.

[0023] Furthermore, the preparation of the oxidatively modified activated carbon comprises the following steps:

[0024] S210, firstly screen, wash, filter and dry the activated carbon for pretreatment, the screening mesh size is 8-30 mesh, distilled water is used for washing to remove surface scum and impurities, the drying temperature is 120°C, and the drying time is 12h;

[0025] S220, oxidation reaction: mixing the pretreated activated carbon with the oxidant solution, with a reaction time of 30-90 minutes;

[0026] S230, after the oxidation reaction is completed, filtering and washing are performed until the total dissolved solids in the supernatant are less than 10 mg / l, and then drying at 120° C. for 12 hours to obtain oxidatively 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 technical solution of this application has the following beneficial effects:

[0029] The invention discloses a new method for obtaining oxybuprocaine hydrochloride by adding an antioxidant and activated carbon in the salt-forming step, and the clarity and color of the obtained product solution meet the requirements of the pharmacopoeia.

[0030] The process operation and post-processing of the invention are simple, and the costs of solvent, labor and power required for complex refining are reduced, thus having significant economic benefits.

[0031] The invention adopts oxidatively modified activated carbon, has a good decolorization effect on polar drugs, can effectively filter and adsorb impurities in the drugs, and improves the clarity of the solution in oxybuprocaine hydrochloride. BRIEF DESCRIPTION OF THE DRAWINGS

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

[0033] Figure 1 This is a comparison chart of the clarity and color of the oxybuprocaine hydrochloride solution prepared in the examples of the present invention. DETAILED DESCRIPTION

[0034] The present invention is further described below in conjunction with the accompanying drawings and embodiments, but they are not intended to limit the present invention.

[0035] Embodiment 1:

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

[0037] Embodiment 2:

[0038] Add 20.0 g of oxybuprocaine and 100 ml of dichloromethane into a 250 ml three-necked reaction flask, stir with a heat-collecting constant temperature magnetic stirrer and cool to 0-10°C with an ice-water bath, add 2 g of sodium thiosulfate, slowly add 5 g (concentration: 1 mol / L) of hydrochloric acid solution in batches, control the temperature at 0-10°C for reaction for 3 h, then raise the temperature to 40-50°C and continue to react for 3 h, add 0.5 g of oxidized modified activated carbon, filter with suction, add 100 ml of ethyl acetate to the filtrate to precipitate solids, beat at 25-35°C for 2 h, filter with suction, 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 75.4%.

[0039] Embodiment 3:

[0040] Add 20.0 g of oxybuprocaine and 100 ml of methanol into a 250 ml three-necked reaction flask, stir with a heat-collecting constant temperature magnetic stirrer and cool to 0-10°C with an ice-water bath, add 2 g of sodium metabisulfite, slowly add 5 g (concentration: 1 mol / L) of hydrochloric acid solution in batches, control the temperature at 0-10°C for reaction for 3 h, then raise the temperature to 40-50°C and continue to react for 3 h, add 0.5 g of activated carbon, filter with suction, add 100 ml of n-butyl acetate to the filtrate to precipitate solid, beat at 25-35°C for 2 h, filter with suction, 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 76.8.5%.

[0041] Embodiment 4:

[0042] Add 20.0 g of oxybuprocaine and 100 ml of toluene into a 250 ml three-necked reaction flask, stir with a heat-collecting constant temperature magnetic stirrer and cool to 0-10°C with an ice-water bath, add 2 g of sodium bisulfite, slowly add 5 g (concentration: 1 mol / L) of hydrochloric acid solution in batches, control the temperature at 0-10°C for reaction for 3 h, then raise the temperature to 40-50°C and continue to react for 3 h, add 0.5 g of oxidized modified activated carbon, filter with suction, add 100 ml of isopropyl acetate to the filtrate to precipitate solid, beat at 25-35°C for 2 h, filter with suction, 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] Embodiment 5:

[0044] Add 20.0 g of oxybuprocaine and 100 ml of ethanol into a 250 ml three-necked reaction flask, stir with a heat-collecting constant temperature magnetic stirrer and cool to 0-10°C with an ice-water bath, add 2 g of sodium sulfite, slowly add 5 g (concentration: 1 mol / L) of hydrochloric acid solution in batches, control the temperature at 0-10°C for reaction for 3 h, then raise the temperature to 40-50°C and continue to react for 3 h, add 0.5 g of oxidized modified activated carbon, filter with suction, add 100 ml of isopropyl acetate to the filtrate to precipitate solid, beat at 25-35°C for 2 h, filter with suction, 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 77.8%.

[0045] In the present application, under the condition of avoiding the introduction of mutagenic impurities, the salt-forming step of oxybuprocaine is explored and studied, an antioxidant is added, and activated carbon is used for decolorization again, and various process parameters are controlled in the middle, so that the clarity and color of the solution in accordance with the Chinese Pharmacopoeia 2020 Edition Part II can be obtained. Figure 1 shown.

[0046]

[0047] In order to control product quality, in the salt-forming step, antioxidants with reducing and bleaching effects and activated carbon with decolorizing effects must be used simultaneously to meet product standard requirements.

[0048] The invention concept is described in detail using specific examples herein, and the description of the above embodiments is only used to help understand the core idea of ​​the invention. It should be pointed out that any obvious modification, equivalent substitution or other improvement made by a person of ordinary skill in the art without departing from the invention concept should be included in the protection scope of the present invention.

Claims

1. A method for improving the clarity and color of a solution of oxybuprocaine hydrochloride, characterized in that: The following steps are involved: S110: adding oxybuprocaine to a reactor, adding an organic solvent, controlling the reaction system at 0 to 10° C. under stirring, and adding an antioxidant; S120: slowly adding hydrochloric acid in batches to the temperature-controlled reaction system, controlling the temperature at 0-10°C for reaction for 2-4 hours, raising the temperature to 40-50°C for reaction for 2-4 hours, and adding activated carbon; S130: Filter while hot, slowly add solvent to the filtrate until the product precipitates, beat at 25-35°C for 2h, filter, and vacuum dry the filter cake in a vacuum drying oven at 40-50°C for 12-16h to obtain oxybuprocaine hydrochloride.

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

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

4. A method for improving the clarity and color of oxybuprocaine hydrochloride solution according to claim 3, characterized in that: In the S120, after the antioxidant is added, the temperature of the hydrochloric acid is controlled at 0-10°C.

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

7. A method for improving the clarity and color of oxybuprocaine hydrochloride solution according to claim 5, characterized in that: The activated carbon is oxidized modified activated carbon.

8. A method for improving the clarity and color of oxybuprocaine hydrochloride solution according to claim 7, characterized in that: The preparation of the oxidatively modified activated carbon comprises the following steps: S210, firstly screen, wash, filter and dry the activated carbon for pretreatment, the screening mesh size is 8-30 mesh, distilled water is used for washing to remove surface scum and impurities, the drying temperature is 120°C, and the drying time is 12h; S220, oxidation reaction: mixing the pretreated activated carbon with an oxidant solution, with a reaction time of 30-90 minutes; S230, after the oxidation reaction is completed, filtering and washing are performed until the total dissolved solids in the supernatant are less than 10 mg / l, and then drying at 120° C. for 12 hours to obtain oxidatively modified activated carbon.

9. A method for improving the clarity and color of oxybuprocaine hydrochloride solution according to claim 8, characterized in that: The oxidant is a hydrogen peroxide solution with a volume concentration of 10%-15%, and the mass ratio of activated carbon to the oxidant is 100:(1-5).

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