Properties and synthesis of milrinone

Abstract

Milrinone, 1,6-dihydro-2-methyl-6-oxo-(3,4’-bipyridine)-5-carbonitrile, is a positive inotropic cardiotonic agent with vasodilator properties that acts as selective phosphodiesterase 3 inhibitor in cardiac and vascular smooth muscle. Trade names of milrinone are Primacor, Corotrop, Corotrope, and Milrila. Milrinone, an amrinone derivative, is 20 to 50 times more active than amrinone and possesses reduced propensity to side effects. The use of milrinone has created controversy in the medical as the result of increased mortality rate among patients that received high amounts of milrinone in oral form. Research show that it can be beneficial for patients with severe congestive heart failure when used as short-time intravenous therapy. Milrinone properties, stability, as well as mechanism of action and synthesis under laboratory and industry conditions have been described in this paper. For industrial purposes milrinone is synthesized by condensation of cyanoacetamide with 4-(dimethylamino)-3-(4-pyridinyl)-3-buten-2-one and 4-ethoxy-3-(4-pyridinyl)-3-buten-2-one in presence of a base, or by the reaction of 1-(4-pyridinyl)-2-propanone with ethoxymethylenmalononitrile or 4-alkoxy-3-(4-pyridinyl)-3-buten-2-one with malononitrile without the use of external base. The starting compound for these syntheses is 4-picoline. Alternative synthesis of milrinone starts from 2-methyl-3-(4-pyridylidiene)-1,1,5-tricyano-1,4pentadiene-5-carboxamide and 2-methyl-6-oxo-1,6-dihydro-3,4’-bipyridine-5-carboxamide. Lastly, methods for milrinone synthesis in laboratory, injection preparation and purification have been summarized.

Milrinon (Primacor®, Corotrop®, Corotrope® ili Milrila®) pripada grupi bipiridinskih kardiotonika i vazodilatatora koji selektivno inhibiraju enzim fosfodiesterazu 3 (PDE-3). Primenjuje se u terapiji kongestivne srčane insuficijencije dugi niz godina. Mirlinon hemijski predstavlja 1,6-dihidro-2-metil-6-okso-(3,4’-bipiridin)-5-karbonitril-laktat. U literaturi postoje podaci o mogućem letalnom ishodu prilikom dugotrajne oralne primene ovog leka, zbog čega se daje intravenski, u kratkom vremenskom periodu. U radu je, na osnovu literaturnih podataka, dat pregled osnovnih svojstava, mehanizam delovanja i stabilnost milrinona, kao i načini za njegovo laboratorijsko i industrijsko dobijanje. Na kraju je dat način prečišćavanja kao i postupak izrade injekcija.