Resolution method of clomastine fumarate intermediate

By using a specific chiral resolving agent to react with racemic N-methyl-2-(2-chloroethyl)pyrrolidine, combined with crystallization and acid-adjusting substitution, the problems of low yield and unstable purity in the preparation of chlormastine fumarate were solved, achieving efficient and low-cost high-purity preparation.

CN122145364APending Publication Date: 2026-06-05HEZE BRANCH QILU UNIV OF TECH(SHANDONG ACAD OF SCI
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Patent Information

Application Number
CN202610288223.5
Authority / Receiving Office
CN · China
Patent Type
Applications(China)
Current Assignee / Owner
Filing Date
2026-03-10
Publication Date
2026-06-05

AI Technical Summary

Technical Problem

The existing preparation process of chlormastine fumarate has problems such as low yield, complicated operation and high product quality risk. In particular, racemization or configuration inversion is prone to occur during the intermediate separation process, which leads to a decrease in optical purity.

Method used

By using specific chiral resolving agents such as L-di(3,5-dinitrobenzoyl)tartaric acid or L-dichlorobenzoyltartaric acid to react with racemic N-methyl-2-(2-chloroethyl)pyrrolidine, the resolving efficiency and purity can be improved through salt formation, crystallization, and acid-adjusting displacement operations, while avoiding the risk of racemization under acidic conditions.

Benefits of technology

This method achieves an efficient and simple separation process, improves product yield and purity, reduces production costs, and stably prepares high-purity chlormastine fumarate, meeting the optical purity requirements of the pharmacopoeia.

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Abstract

The invention provides a method for resolving a clemastine fumarate intermediate. The method comprises the following steps: 1) reacting racemic N-methyl-2-(2-chloroethyl) pyrrolidine with a chiral resolving agent in a first organic solvent to obtain a diastereoisomer salt solution; 2) cooling, crystallizing and purifying the material after the reaction in the step 1), and filtering to obtain R-N-methyl-2-(2-chloroethyl) pyrrolidine resolving agent salt; and 3) dissolving the R-N-methyl-2-(2-chloroethyl) pyrrolidine resolving agent salt obtained in the step 2) in a second organic solvent-water two-phase system, adjusting the pH value to 9-13, then carrying out liquid separation to obtain an organic phase, and concentrating to obtain R-N-methyl-2-(2-chloroethyl) pyrrolidine, wherein the chiral resolving agent is selected from at least one of L-di (3, 5-dinitrobenzoyl) tartaric acid and L-di-p-chlorobenzoyl tartaric acid. The resolution efficiency of racemic N-methyl-2-(2-chloroethyl) pyrrolidine is remarkably improved by using a specific chiral resolving agent, and large-scale production which is simple and convenient to operate and controllable in cost is realized by combining cooling crystallization and two-phase acid regulation replacement.
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