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CN-121991154-A - Method for purifying rocuronium bromide

CN121991154ACN 121991154 ACN121991154 ACN 121991154ACN-121991154-A

Abstract

The invention discloses a method for purifying rocuronium bromide. The method comprises the steps of reacting crude rocuronium bromide with alkali metal bromine in dichloromethane, filtering, mixing filtrate with methyl tertiary butyl ether, and separating out solid. The method can effectively control the residual of chloride ions in rocuronium bromide, and has good application prospect in industrial production of rocuronium bromide.

Inventors

  • CHEN XIAODONG
  • WU TENG
  • LIU XUEJUN

Assignees

  • 上海药坦药物研究开发有限公司

Dates

Publication Date
20260508
Application Date
20241107

Claims (10)

  1. 1. A method for purifying rocuronium bromide is characterized by comprising the following steps of reacting a crude rocuronium bromide with alkali metal bromide in methylene dichloride, filtering, mixing filtrate with methyl tertiary butyl ether, and separating out solids.
  2. 2. The method of purifying rocuronium bromide according to claim 1, characterized in that it satisfies one or more of the following conditions; (1) The alkali metal bromine is sodium bromide, lithium bromide and potassium bromide; (2) The mass ratio of the crude rocuronium bromide to the alkali metal bromine is 1 (0.01-0.5); (3) The mass volume ratio of the crude rocuronium bromide to the dichloromethane is 1g (1-6) ml; (4) The mass volume ratio of the crude rocuronium bromide to the methyl tertiary butyl ether is 1g (20-60 ml); (5) The reaction time of the reaction is 4-50h; (6) The reaction temperature of the reaction is 0-30 ℃; (7) The crude rocuronium bromide contains chloride ions and (8) The chloride ion content in the rocuronium bromide after purification is less than or equal to 0.1 percent.
  3. 3. A method of purifying rocuronium bromide according to claim 2, characterized in that it satisfies one or more of the following conditions; (1) The alkali metal bromine is sodium bromide; (2) The mass ratio of the crude rocuronium bromide to the alkali metal bromine is 1:0.1, 1:0.02 or 1:0.3; (3) The mass volume ratio of the crude rocuronium bromide to the dichloromethane is 1g to 5 ml, 1g to 2.5 ml or 1g to 2 ml; (4) The mass volume ratio of the crude rocuronium bromide to the methyl tertiary butyl ether is 1g to 50 ml or 1g to 25 ml; (5) The reaction time of the reaction is 18h-24h, 6h or 48h; (6) The reaction temperature of the reaction is 0-20 ℃; (7) The crude rocuronium bromide product contains more than 0.2 percent of chloridion and (8) The chloride ion content in the rocuronium bromide after purification is 0.03%, 0.02% or 0.01%.
  4. 4. A method of purifying rocuronium bromide according to claim 3, characterized in that it fulfils one or both of the following conditions; (1) The reaction temperature of the reaction is 0-10 ℃ or 20 ℃, and (2) The crude rocuronium bromide contains 0.38%, 0.37%, 0.33%, 0.47%, 0.35% or 0.26% of chloride ions.
  5. 5. The method for purifying rocuronium bromide according to claim 1, further comprising a post-treatment step of recrystallization.
  6. 6. The method of purifying rocuronium bromide according to claim 5, wherein the recrystallization is crystallization from acetone.
  7. 7. The method for purifying rocuronium bromide according to claim 1, wherein the crude rocuronium bromide is prepared by reacting compound 1 with allyl bromide in methylene chloride to obtain crude rocuronium bromide; 。
  8. 8. The method for purifying rocuronium bromide according to claim 7, wherein the process for producing crude rocuronium bromide satisfies one or more of the following conditions; (1) The molar ratio of the compound 1 to the allyl bromide is 1 (2-5); (2) The mass volume ratio of the compound 1 to the dichloromethane is 1g (1-3) ml; (3) In the preparation method of the crude rocuronium bromide, the reaction time of the reaction is 6-20h; (4) In the preparation method of the crude rocuronium bromide, the reaction temperature of the reaction is 0-20 ℃; (5) In the preparation method of the crude rocuronium bromide, the reaction is carried out under inert gas condition, and (6) In the preparation method of the crude rocuronium bromide, the reaction also comprises the following post-treatment steps of precipitation in a solvent, filtration and vacuum drying.
  9. 9. The method for purifying rocuronium bromide according to claim 8, wherein the process for preparing crude rocuronium bromide satisfies one or more of the following conditions; (1) The molar ratio of the compound 1 to the allyl bromide is 1:4.1; (2) The mass volume ratio of the compound 1 to the dichloromethane is 1g to 2.5 ml or 1g to 3.3 ml; (3) In the preparation method of the crude rocuronium bromide, the reaction time of the reaction is 8-16h; (4) In the preparation method of the crude rocuronium bromide, the reaction temperature of the reaction is 5-15 ℃ or 0-10 ℃, and (5) In the preparation method of the crude rocuronium bromide, the inert gas can be nitrogen.
  10. 10. The method for purifying rocuronium bromide according to claim 8, wherein in the preparation method of the crude rocuronium bromide, the precipitation in a solvent is performed after stirring in methyl tertiary butyl ether for 2 hours, the filtering further comprises leaching a filter cake with methyl tertiary butyl ether, and the vacuum drying is performed for 48 hours under the vacuum of 30-35 ℃.

Description

Method for purifying rocuronium bromide Technical Field The invention relates to the field of pharmaceutical chemistry, in particular to a method for purifying rocuronium bromide. Background Rocuronium bromide (Rocuronium Bromide) is a novel mono-quaternary ammonium muscle relaxant, is a clinically widely used muscle relaxant, and is characterized by quick response, quick recovery, weak inhibition effect on cardiovascular system and no anaphylactic reaction. Rocuronium bromide has the chemical structural formula: The synthesis of rocuronium bromide is described in a number of patents and literature, and as is known from the literature references presently disclosed, the starting materials and intermediates used are all of varying sizes, and the final step is the quaternization of rocuronium bromide intermediate (CAS No. 119302-24-8) with 3-bromopropene to effect the synthesis of rocuronium bromide, the specific reactions being as follows: Many documents report on the reaction process and purification of rocuronium bromide through document retrieval and reading of rocuronium bromide, but the documents reporting the final quality of rocuronium bromide are less, and the documents reporting the residual result of chloride ions in rocuronium bromide are more absent. When the literature schemes reported by the publications are repeatedly studied, the chloride ion residue in the obtained rocuronium bromide sample is usually 0.3% -0.5%. Among pharmacopoeia standards of rocuronium bromide, USP, CP, JP, etc. are not mentioned as control standards of chloride ions, only the residual of chloride ions is controlled in EP (≤0.1%). Therefore, in order to meet the quality standard of rocuronium bromide in Eupopean Pharmacopoeia 10.0.0, the development of a preparation method for removing and controlling chloride ions in rocuronium bromide has important significance. Disclosure of Invention The invention aims to overcome the defect of high chloride ion content in rocuronium bromide preparation in the prior art. The invention provides a method for purifying rocuronium bromide. The method can effectively control the residual of chloride ions in rocuronium bromide, and has good application prospect in industrial production of rocuronium bromide. The invention provides a method for purifying rocuronium bromide, which comprises the following steps of reacting a crude rocuronium bromide product with alkali metal bromide in methylene dichloride, filtering, mixing filtrate with methyl tertiary butyl ether, and separating out solids. In one embodiment of the invention, the alkali metal bromine is sodium bromide, lithium bromide, or potassium bromide, e.g., sodium bromide. In one embodiment of the invention, the mass ratio of the crude rocuronium bromide to the alkali metal bromine is 1 (0.01-0.5), preferably 1:0.1, 1:0.02 or 1:0.3. In one embodiment of the invention, the mass volume ratio of the crude rocuronium bromide to the dichloromethane is 1g (1-6) ml, preferably 1g:5 ml, 1g:2.5 ml or 1g:2 ml. In one embodiment of the invention, the mass volume ratio of the crude rocuronium bromide to the methyl tertiary butyl ether is 1g (20-60 ml), preferably 1g:50 ml or 1g:25 ml. In one embodiment of the invention, the reaction time of the reaction is 4 to 50 hours, preferably 18 to 24 hours, 6 hours or 48 hours. In one embodiment of the invention, the reaction temperature of the reaction is 0 to 30 ℃, preferably 0 to 20 ℃, and more preferably 0 to 10 ℃ or 20 ℃. In one embodiment of the invention, the method for purifying rocuronium bromide further comprises a post-treatment step of recrystallization, e.g., the recrystallization is crystallization in acetone. In one embodiment of the present invention, the crude rocuronium bromide contains chloride ions, preferably, the chloride ion content is more than 0.2%, such as 0.38%, 0.37%, 0.33%, 0.47%, 0.35% or 0.26%. In one embodiment of the invention, the chloride ion content of the purified rocuronium bromide is less than or equal to 0.1%, for example 0.03%, 0.02% or 0.01%. In one scheme of the invention, the crude rocuronium bromide is prepared by reacting a compound 1 with allyl bromide in dichloromethane to prepare the crude rocuronium bromide; 。 In one embodiment of the invention, the molar ratio of compound 1 to allyl bromide is 1 (2-5), preferably 1:4.1. In one embodiment of the invention, the mass to volume ratio of the compound 1 to the dichloromethane is 1g (1-3) ml, preferably 1g:2.5 ml or 1g:3.3 ml. In a certain scheme of the invention, in the preparation method of the crude rocuronium bromide, the reaction time of the reaction is 6-20h, preferably 8-16h. In one embodiment of the invention, the reaction temperature of the crude rocuronium bromide is 0-20 ℃, preferably 5-15 ℃ or 0-10 ℃. In one scheme of the invention, in the preparation method of the crude rocuronium bromide, the reaction is carried out under the condition of inert gas, and the inert gas can be nitrogen. In the prepara