A process for the preparation of a rocuronium bromide intermediate

CN117801048BActive Publication Date: 2026-10-16CHENGDU SINO STRONG PHARMA
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Patent Information

Application Number
CN202311835573.1
Authority / Receiving Office
CN · China
Patent Type
Patents(China)
Current Assignee / Owner
Filing Date
2023-12-28
Publication Date
2026-10-16
Estimated Expiration
2043-12-28

AI Technical Summary

Technical Problem

[0016]为了解决罗库溴铵中间体收率低、杂质含量高，重结晶除去该杂质将损失大量产物，致使生产成本偏高、生产效率低、罗库溴铵成品质量差的缺陷，本发明提供一种罗库溴铵中间体LK-8的制备方法,其特征在于包含以下步骤：

Benefits of technology

[0028]This invention incorporates Novozymes N435 lipase and/or immobilized lipase Chiralzyme IM-100 as catalysts into the acetylation reaction system of rocuronium bromide intermediate LK-7. This enhances the regioselectivity of acetylation of acetic anhydride and reduces the generation of 3-acetylated, diacetylated, and their extended impurities during the reaction. The content of diacetylated impurities is reduced from 20% to 3%, and the content of 3-acetylated impurities remains below 0.3%. Simultaneously, the impact of diacetylated and 3-acetylated impurity derivatization on the quality of the finished product is reduced, decreasing the recrystallization times of rocuronium bromide intermediate LK-8 and increasing the product yield. The yield of rocuronium bromide intermediate LK-8 is increased from 55.2% to over 87%, making it more suitable for large-scale industrial production. Furthermore, it incorporates Novozymes N435 lipase, which is highly reactive with liquid substrates and organic cosolvents, reacts well with anhydrous and moisture-sensitive substrates, and can be used over a wide temperature range (20-110℃). Depending on the reaction conditions, it can be reused 5-10 times without inactivation and can be used for large-scale industrial production. The final product contains no protein residues.

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Abstract

The present application relates to a preparation method of a rocuronium bromide intermediate, which comprises three steps: in the first step, rocuronium bromide intermediate LK-7 (formula II: (2b, 3a, 5a, 16b, 17b)-2-(4-morpholinyl)-16-(1-pyrrolidinyl) androstan-3, 17-diol) is added and mixed with a reaction solvent, an acid binding agent and a catalyst in a reactor; in the second step, acetylation reagent is added dropwise into the reactor to perform acetylation reaction; and in the third step, rocuronium bromide intermediate LK-8 (formula I: 3A, 17B-(dihydroxy)-2B-(morpholine-1-yl)-16-(pyrrolidine-1-yl)-5A-androstan-17-acetic acid) is obtained through crystallization and filtration. The present application adds lipase, improves the regioselectivity of acetic anhydride in acetylation, reduces the content of diacetylation impurities and 3-acetylation impurities, simultaneously reduces the influence of impurity derivatives on the quality of the finished product, reduces the recrystallization times of rocuronium bromide intermediate LK-8, improves the yield of rocuronium bromide intermediate LK-8, and is more suitable for industrial large-scale production.
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