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CN-119735519-B - Method for improving clarity and color of solution in oxybuprocaine hydrochloride

CN119735519BCN 119735519 BCN119735519 BCN 119735519BCN-119735519-B

Abstract

The invention relates to the technical field of medicines and discloses a method for improving clarity and color of a solution in oxybuprocaine hydrochloride, which comprises the following steps of S110, adding oxybuprocaine into a reactor, adding an organic solvent, stirring, controlling a reaction system at 0-10 ℃, adding an antioxidant, S120, slowly adding hydrochloric acid in batches in a temperature-controlled reaction system, heating to 40-50 ℃ after the temperature control is finished for 2-4 hours of reaction at 0-10 ℃, adding active carbon, S130, performing hot suction filtration, slowly dripping a solvent into a filtrate until a product is separated out, pulping for 2 hours at 25-35 ℃, performing suction filtration, vacuum drying a filter cake in a vacuum drying box at 40-50 ℃ for 12-16 hours to obtain oxybuprocaine hydrochloride. According to the novel method for preparing the obucaine 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 pharmacopoeia requirements.

Inventors

  • HE ZUOPENG
  • SU RUIFEI
  • LI ZHONGJING
  • CHEN JIANG
  • SUN SHOUFEI

Assignees

  • 辰欣药业股份有限公司

Dates

Publication Date
20260505
Application Date
20241225

Claims (6)

  1. 1. A method for improving the clarity and color of a solution in oxybuprocaine hydrochloride, comprising the steps of: S110, adding oxybuprocaine into a reactor, adding an organic solvent, stirring, controlling the temperature of a reaction system to be 0-10 ℃, and adding an antioxidant; S120, slowly adding hydrochloric acid into the temperature-controlled reaction system in batches, after finishing the addition and reacting for 2-4 hours at the temperature of 0-10 ℃, heating to 40-50 ℃ and reacting for 2-4 hours, and adding active carbon; S130, performing suction filtration while the solution is hot, slowly dripping a solvent into the filtrate until a product is separated out, pulping for 2 hours at 25-35 ℃, performing suction filtration, and vacuum drying a filter cake in a vacuum drying oven at 40-50 ℃ for 12-16 hours to obtain oxybuprocaine hydrochloride; the activated carbon is oxidation modified activated carbon; the preparation of the oxidation modified activated carbon comprises the following steps: S210, firstly screening, washing, suction filtering and drying pretreatment are carried out on the activated carbon, wherein the screening mesh is 8-30 meshes, distilled water is used for washing to remove surface scum and impurities, and the drying temperature is 120 ℃ for 12 hours; S220, carrying out oxidation reaction, namely mixing the pretreated activated carbon with an oxidant solution, wherein the reaction time is 30-90min; s230, after the oxidation reaction is finished, filtering, washing until the total solid solubility of the supernatant is less than 10mg/l, and drying for 12 hours at 120 ℃ to obtain the oxidation modified activated carbon; The oxidant is hydrogen peroxide solution with volume concentration of 10-15%, and the mass ratio of the activated carbon to the oxidant is 100 (1-5).
  2. 2. The method for improving clarity and color of solution in oxybuprocaine hydrochloride according to claim 1, wherein in S110, the organic solvent is one of toluene, dichloromethane, methanol, and ethanol.
  3. 3. The method for improving clarity and color of solution in oxybuprocaine hydrochloride according to claim 2, wherein in S110, the antioxidant is one of sodium thiosulfate, sodium metabisulfite, sodium bisulfite and sodium sulfite.
  4. 4. The method for improving the clarity and color of the solution in oxybuprocaine hydrochloride according to claim 3, wherein in S120, after adding the antioxidant, the temperature of the dropwise adding hydrochloric acid is controlled to be 0-10 ℃.
  5. 5. The method for improving clarity and color of oxybuprocaine hydrochloride according to claim 4, wherein in S120, after adding antioxidant, the temperature of dropwise adding hydrochloric acid is controlled at 5 ℃.
  6. 6. The method for improving the clarity and color of an oxybuprocaine hydrochloride solution of claim 5, wherein the crystallization solvent is one of ethyl acetate, isopropyl acetate and n-butyl acetate.

Description

Method for improving clarity and color of solution in oxybuprocaine hydrochloride Technical Field The invention relates to the technical field of medicines, in particular to a method for improving the clarity and color of a solution in oxybuprocaine hydrochloride. Background Oxybuprocaine hydrochloride, chemical name 2- (diethylamino) ethyl 4-amino-3-butoxybenzoate hydrochloride (2- (Diethylamino) ethyl 4-amino-3-butoxybenzoate hydrochloride), has the following structural formula In the reference patent CN113185419, 3-hydroxy-4-nitrobenzoic acid methyl ester is taken as a raw material, etherification reaction is carried out with 1-bromobutane to prepare a compound 2, then transesterification and salifying reaction are carried out with 2- (diethylamino) ethanol under the action of a catalyst to obtain a compound 3, the compound 3 is subjected to reduction reaction to obtain oxybuprocaine free alkali, and then salifying reaction and crystallization are carried out to obtain oxybuprocaine hydrochloride. The method directly uses hydrochloric acid to form salt, the intermediate process has no special treatment, excessive iron powder is used in the process, the post-treatment difficulty is high, the amplified production is not facilitated, the clarity and the color of the obtained material solution do not meet the pharmacopoeia standard requirements due to the residual effect of iron ions, the repeated refining is not qualified, and the method is as follows The CN106810463 reports another synthetic route as follows: Under alkaline condition, 3-hydroxy-4-ethyl nitrobenzoate is substituted with bromobutane to obtain 3-butoxy-4-ethyl nitrobenzoate, which is hydrolyzed with sodium hydroxide to obtain 3-butoxy-4-nitrobenzoic acid, under alkaline condition, the 3-butoxy-4-ethyl nitrobenzoate is substituted with diethylamino chloroethane to generate 4-nitro-2-butoxybenzoic acid-2- (diethylamino) ethyl ester, and then the 2-ethyl nitrobucaine is reduced under the action of a small amount of iron and hydrazine hydrate to form salt to obtain the obucaine hydrochloride. Although the problems of clarity and color of the product are solved, hydrazine hydrate is used in the last step, so that impurity mutation is caused, and the research difficulty of the impurities is increased. Therefore, the invention provides a method for improving the clarity and the color of the solution in the oxybuprocaine hydrochloride. Disclosure of Invention The invention aims to make up the blank of the prior art scheme, and provides a novel method for obtaining the obucaine hydrochloride by adding the antioxidant and the activated carbon in the salifying step, which has the advantages of good quality, good reproducibility and the like, and meets the requirements of laboratory researches and large-scale chemical production in the pharmaceutical chemical industry. The embodiment of the application provides a method for improving the clarity and color of a solution in oxybuprocaine hydrochloride, which comprises the following reaction equation: The method specifically comprises the following steps: S110, adding oxybuprocaine into a reactor, adding an organic solvent, stirring, controlling the temperature of a reaction system to be 0-10 ℃, and adding an antioxidant; S120, slowly adding hydrochloric acid into the temperature-controlled reaction system in batches, after finishing the addition and reacting for 2-4 hours at the temperature of 0-10 ℃, heating to 40-50 ℃ and reacting for 2-4 hours, and adding active carbon; S130, filtering while the solution is hot, slowly dripping a solvent into the filtrate until a product is separated out, pulping for 2 hours at 25-35 ℃, filtering, placing the filter cake in a vacuum drying oven at 40-50 ℃, and drying for 12-16 hours under vacuum (P is less than or equal to minus 0.09 Mpa) to obtain the obucaine hydrochloride. Further, in S110, the organic solvent is one of toluene, dichloromethane, methanol, and ethanol, and toluene is preferred. Further, in S110, the antioxidant is one of sodium thiosulfate, sodium metabisulfite, sodium bisulphite and sodium sulfite, preferably sodium sulfite. Further, in the step S120, after the antioxidant is added, the temperature of dropwise adding hydrochloric acid is controlled to be 0-10 ℃. Further, in the step S120, after the antioxidant is added, the temperature of the hydrochloric acid is controlled to be 5 ℃. Further, the crystallization solvent is one of ethyl acetate, isopropyl acetate and n-butyl acetate, preferably isopropyl acetate. Further, the activated carbon is an oxidation modified activated carbon. Further, the preparation of the oxidation modified activated carbon comprises the following steps: S210, firstly screening, washing, suction filtering and drying pretreatment are carried out on the activated carbon, wherein the screening mesh is 8-30 meshes, distilled water is used for washing to remove surface scum and impurities, and the drying temperature is 120 ℃ fo