A stable 3-aminocyclobutane-1,1-dicarboxylic acid diethyl ester oxalate and its use in the preparation of 3-(cholanoyl-amido)cyclobutane-1,1-dicarboxylic acid

By converting 3-aminocyclobutane-1,1-dicarboxylic acid diethyl ester into its oxalate form, the instability of 3-aminocyclobutane under high temperature, light, alkaline and oxidative conditions was solved, enabling the preparation of a high-purity and stable intermediate. This simplified the operation process, improved the reliability of the process and the quality of the product, and made it suitable for large-scale production.

CN122356191APending Publication Date: 2026-07-10YUNNAN INST OF MATERIA MEDICA +2
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Patent Information

Authority / Receiving Office
CN Β· China
Patent Type
Applications(China)
Current Assignee / Owner
YUNNAN INST OF MATERIA MEDICA
Filing Date
2026-04-28
Publication Date
2026-07-10

AI Technical Summary

Technical Problem

In the existing technology, 3-aminocyclobutane-1,1-dicarboxylic acid ester is unstable and is easily degraded, especially under high temperature, light, alkaline and oxidative conditions, making purification difficult. This makes it difficult to control the purity of its downstream product, 3-(cholate valerate)cyclobutane-1,1-dicarboxylic acid, which seriously restricts the scale-up of the process and the large-scale production of the active pharmaceutical ingredient.

Method used

The unstable free amine intermediate is converted into its stable oxalate form, and this salt is directly used in the subsequent amide condensation reaction. By reacting 3-aminocyclobutane-1,1-dicarboxylic acid diethyl ester with oxalic acid in ethanol and controlling the crystallization temperature at 0~5℃, high-purity oxalate crystals are obtained and directly participate in the condensation reaction, thus avoiding the instability problem of free amine.

Benefits of technology

It significantly improves the stability and purity of intermediates, simplifies the operation process, reduces costs, improves the reliability and reproducibility of the process, meets the requirements of large-scale production, and ensures stable and controllable product quality.

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Abstract

This invention belongs to the fields of medicinal chemistry and organic synthesis, specifically relating to a stable 3-aminocyclobutane-1,1-dicarboxylic acid diethyl oxalate and its application in the preparation of 3-(cholate-valerate)cyclobutane-1,1-dicarboxylic acid. This invention effectively solves the technical bottlenecks of poor stability, difficulty in purification, and storage by converting unstable free 3-aminocyclobutane-1,1-dicarboxylic acid diethyl oxalate into a specific organic acid salt form. More importantly, this invention discovers that this organic acid salt can be directly used as a reaction intermediate, and can be used efficiently in subsequent amide condensation reactions with cholic acid or its active derivatives without the separation of free amines. This method significantly improves the purity and yield of the key intermediate and its downstream product 3-(cholate-valerate)cyclobutane-1,1-dicarboxylic acid. The process is stable and simple to operate, providing a stable, controllable, and economical preparation route for the industrial production of 3-(cholate-valerate)cyclobutane-1,1-dicarboxylic acid, a key active pharmaceutical ingredient in the liver cancer prodrug LLC-202.
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