Dicoumarol, methylation

Coum rinic Acid Compounds. These synthetic phyUoquinone derivatives and congeners have been employed as anticoagulants since the isolation of 3,3 -methylenebis(4-hydroxy-2H-l-benzopyran-2-one) [66-76-2] (bis-4-hydroxycoumarin or dicoumarol) (1) from spoiled sweet clover in 1939. The ingestion of the latter was responsible for widespread and extensive death of bovine animals at that time. The parent compound for the synthesis of many congeners is 4-hydrocoumarin, which is synthesized from methyl salicylate by acetylation and internal cyclization. The basic stmctures of these compounds are shown in Figure 2, and their properties Hsted in Table 6 (see Coumarin). 

Hydroxycoumarin [1076-38-6] can be synthesized by cyclization of acetyl methyl salicylate. It is a coumatin metaboHte occurring in spoiled hay. Derivatives of 4-hydroxycoumarin such as dicoumarol [66-76-2] warfarin [81-81-2] cyclocoumarol [518-20-7] ethylbis—coumaracetate [548-00-5] and bis-4-hydroxycoumarin [25892-93-7] are synthetic blood anticoagulants (see Blood, coagulants and anticoagulants). 

Dicoumarol Dicoumarol, 3,3 -methylene-bis(4-hydroxycoumarin) (24.1.8), is synthesized from 4-hydroxycoumarine (24.1.7), which is in turn synthesized from salicylic acid methyl ester by cyclization to a chromone derivative using sodium or sodium methoxide or from o-oxyacetophenone by reacting it with diethylcarbonate in the presence of sodium ethoxide. Condensation of the resulting 4-hydroxycoumarin with formaldehyde as a phenol component gives dicoumarol [6-9],... 

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