A method for asymmetric synthesis of a chiral intermediate of ubijapin

Through the asymmetric synthesis of chiral intermediates of ubagepan, ketoesters are used as raw materials, combined with enamination, molecular lactam cyclization, trifluoroethylation and chiral acid crystallization-induced dynamic resolution, which solves the problems of low stereoselectivity and high cost in the existing technology and realizes efficient and low-cost large-scale production.

CN119431222BActive Publication Date: 2025-10-17HANGZHOU ALLSINO CHEM
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Patent Information

Application Number
CN202411558542.0
Authority / Receiving Office
CN · China
Patent Type
Patents(China)
Current Assignee / Owner
Filing Date
2024-11-04
Publication Date
2025-10-17
Estimated Expiration
2044-11-04

AI Technical Summary

Technical Problem

The existing technologies for the synthesis of chiral intermediates of ubagepan have problems such as low stereoselectivity, high cost, and difficulty in process scale-up, especially the limitations of high-performance liquid chromatography chiral resolution, noble metal catalysis, and enzyme-catalyzed reactions.

Method used

Using N-Boc-protected ketoester as raw material, the intermediate is formed by enamination of the ketone and cyclization of the molecular lactam. After trifluoroethylation, the Boc is removed under acidic conditions. The dynamic kinetic resolution is induced by crystallization of chiral acid, combined with catalytic hydrogenation to control the chirality, avoiding expensive metal catalysis and enzyme catalysis, and achieving efficient large-scale production.

Benefits of technology

The method realizes the large-scale production of chiral intermediates of ubagepan with high efficiency and low cost, reduces the generation of waste solvents and production costs, is suitable for industrial applications, avoids the use of high-performance liquid chromatography and expensive metal catalysis, and improves production efficiency.

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Abstract

The application provides a method for asymmetrically synthesizing a chiral intermediate of ubijetan, which is characterized by the following steps: taking an N-Boc protected ketone ester as a raw material, carrying out enamine of the ketone, intramolecular amide cyclization to form an intermediate II, obtaining the intermediate III through trifluoroethylation, removing Boc under an acidic condition to obtain an intermediate IV, achieving the purpose of dynamic kinetic chiral resolution through an imine intermediate state under the crystallization induction of 5-nitrosalicylaldehyde and a chiral acid, realizing selective construction of C-3 chiral, selectively controlling chiral of C-5 and C-6 positions when carrying out catalytic hydrogenation of a double bond in a C-3 position of a substrate, and obtaining a fragment A. The method is efficient, mild and suitable for scale-up production, avoids high performance liquid chromatography chiral resolution, avoids a step of expensive metal catalytic coupling, avoids application of an enzyme catalytic reaction condition with high technical barriers, and greatly improves the scale-up property and industrial production efficiency of the process.
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