Development of a Multistage Technology for the Industrial Synthesis of the Levosimendan API and Enantiomeric Separation of Intermediates

Authors

DOI:

https://doi.org/10.24959/ophcj.25.322447

Keywords:

Levosimendan, 4,5-dihydropyridazine-3(2H)-one, enantiomers separation, diastereomeric salts, S,S-2,3-bis-(4-methoxybenzoiloxy)butanedioic acid

Abstract

A method for obtaining Levosimendan suitable for industrial application has been developed. Two literature routes for the synthesis have been evaluated. It has been found that the use of enantiopure (R)-2-chloropropionyl chloride in the initial step is ineffective due to racemization at the stage of the synthesis based on the malonic ester. Instead, a reported method based on the synthesis of the Levosimendan precursor, 6-(4-aminophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (1), from racemic 2-bromopropionyl bromide has been modified to allow for scale-up and adaptation to industrial processes. A practical resolution method has been developed to isolate the (R)-enantiomer of amine 1 from the racemic mixture with a high enantiomeric purity (the content of (R)-enantiomer is up to 99%). It has been shown that (R)-1 can be converted to Levosimendan in a high yield without the stereochemical purity loss at the chiral center.

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  • The author received no specific funding for this work.

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Published

2025-06-24

How to Cite

(1)
Sokolenko, L. V.; Sokolenko, T. M.; Filatov, A. A.; Shchehlov, O. D.; Rudiuk, V. V.; Yagupolskii, Y. L. Development of a Multistage Technology for the Industrial Synthesis of the Levosimendan API and Enantiomeric Separation of Intermediates. J. Org. Pharm. Chem. 2025, 23, 35-47.

Issue

Vol. 23 No. 2 (2025)

Section

Original Researches

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