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

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

 

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

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