Розробка багатостадійної технології промислового синтезу АФІ левосимендану та енантіомерного розділення проміжних продуктів

• Date: 2025
• Main Authors: Sokolenko, Liubov V., Sokolenko, Taras M., Filatov, Andrey A., Shchehlov, Oleksandr D., Rudiuk, Vitalii V., Yagupolskii, Yurii L.
• Format: Article
• Language: English
• Published: National University of Pharmacy 2025
• Subjects: левосимендан; 4,5-дигідропіридазин-3(2Н)-он; розділення енантіомерів; діастереомерні солі; S,S-2,3-біс-(4-метоксибензоїлокси)бутандіова кислота
• Online Access: https://ophcj.nuph.edu.ua/article/view/322447
• Journal Title: Journal of Organic and Pharmaceutical Chemistry

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.