The Synthesis Of Coumarin Anticoagulants Warfarin And It's Analogs

Coumarin anticoagulants, called oral anticoagulant are a pharmaceutical taken orally to participate intravital metabolism. Varities had been applied to clinic such as dicoumarol or ethyl biscoumacetate, warfarin(benzyl acetone coumarin) and acenocoumarol(4-nitrobenzyl acetone coumarin also called nicoumalone). Dicoumarol is usually shared with heparin, because it was absorbed slowly as taken orally. On the countrary, warfarin and acenocoumarol were absorbed rapidly and completely as taken orally. Their concentration in blood will reach the pinnacle within 2-4 hours. The characteristics of lasting continuance and high biologic utilization made them especially adaptive to those who must maintain anticoagulation long-term. Presently, the numbers of people with thrombophlebitis, pulmonary and myocardial infarction are increased sharply, while domestic demand to warfarin has mainly been depending on importation. Therefore, high-yield and economical synthesis for these compound was evident. Our study began from the synthesis of substituted benzaldehyde explored the best routes. Eight substituted benzalacetone were prepared via the improvement of technics of benzalacetone, The products were proved by IR, 1H NMR. Then, warfarin and its analogs acenocoumarol, 4-hydroxybenzyl acetone coumarin, 4-methoxybenzyl acetone coumarin, 4-chlorbenzyl acetone coumarin, 4-butylbenzyl acetone coumarin, thiofuran acetone coumarin, furan acetone coumarin was synthesized by Michael addition reaction of 4-hydroxycoumarin and substituted benzaleacetone without any catalyst. The yield were all more than 60%. The products were proved by IR, 1H NMR. The factors affected the reaction were investigated. This procedure was simple with easy final-treatment, seems to be amenable to large-scale application. We got a better result by the improvement of synthesis of 4-hydroxycoumarin and sodium warfarin, the purity was more than 98%, the yield was more than 90%.