Blood Coagulation
Mechanism of Action
Side Effects
The Future


Racemic synthesis

A classic way of synthesising racemic warfarin is by the base (or acid) catalysed Michael condensation reaction of 4-hydroxycoumarin with benzalacetone either in water or piperidine2,3.
racemic synthesis  
The mechanism for this reaction is as follows:

The yield for this synthesis when carried out in water2 (4-8 h reflux) is typically 40 %. Higher yields3 can be obtained by carrying out the reaction in methanol (20 h reflux), isolating the product formed and hydrolysing with acid. Typical yields are 93 %.

Asymmetric synthesis

There has been increasing interest in the pharmaceutical industry to replace existing racemic drugs by their pure enantiomeric form due to the fact that one enantiomer often has a pharmacological profile superior to the racemate. In this case, S-warfarin is found to be 5 times more potent as an anticoagulant than R-warfarin. Preparation of  enantiomerically pure warfarin can be made by the classical resolution of the racemate using quinidine/quinine salts4 or chromatographic separation. However, these methods are limited to small scale preparations.

1. Asymmetric hydrogenation

In 1996, researchers at the Dupont Merck pharmaceutical company developed a practical asymmetric synthesis of R- and S- warfarin starting from the racemate and using  DuPHOS-Rh(I) catalysed hydrogenation.5

asymmetric synthesis 1

Using this method, S-warfarin was obtained in 83% enantiomeric excess (e.e) , and R-warfarin in 86% e.e

2. Hetero-Diels-Alder cycloaddition

The previous synthesis used racemic warfarin as its starting material. A novel approach to asymmetric synthesis of warfarin using simpler starting materials was developed in 2001. It proceeds by a  hetero-Diels-Alder cycloaddition.6

asymmetric synthesis 2  

In this reaction, S-warfarin was obtained in 95 % e.e