There are 3 types of Warfarin:
1. Racemic Warfarin
As there are different types different synthetic routes are required. Firstly, looking at the racemic Warfarin followed by the asymetric Warfarin (S- and R- Warfarin).
Racemic Warfarin Synthesis:
The usual synthetic route for racemic Warfarin involves a base/acid catalysed Michael condensation reaction of 4-hydroxycoumarin with benzalacetone. These reactants are either refluxed in water for approximately 4-8 hours or refluxed with pyridine which gives a saturated yield. The mechanism is shown below:
The yield when this reaction is reflux with water is 48%.
During recent years it has been found that one of the possible enantiomers usually has a pharmacological profile that is superior to the racemate. Hence pharmaceutical companies have been replacing exisiting racemic drugs with their pure enantiomeric form.
In the case of Warfarin it was found that S-Warfarin is the superior enantiomer being 6 times more active than R-Warfarin. There are 2 main methods to form a pure enantiomeric form of Warfarin.
1. Asymmetric hydrogenation: This was developed by DuPont Merk Pharmaceutical. It involves the a DuPHOS-Rh(I) catalysed hydrogenation of racemic Warfarin to give the desired enantiomer. Below is the reaction scheme for this synthesis:
This exclusive product is then used in the rest of the synthesis. First reacting it with NaOH to form the sodium salt of the product:
This, then, depending on the enantiomer that is desired, the sodium salt is hydrogenated using either (R,R)-Et-DuPHOS-Rh(I) or (S,S)-Et-DuPHOS-Rh(I) to give S-Warfarin and R-Warfarin respectively:
This route gives enantioselectivities of 82-86% e.e in methanol and 88% e.e in 3:2 isopropanol-methanol. Acidification and a single recrystallisation of the crude product gave R- and S- Warfarin in >98% e.e.
2. Hetero-Diels-Alder cycloaddition: This method was developed in 2001 and the key feature is that it does not use racemic Warfarin as a starting material. Instead it involves a hetero-Diels-Alder cycloaddition of a iso-propenyl ether to 4-hydroxycoumarin (via the use of dry dioxane and a Tietze Base with 5A Molecular sieves at a temperature of 80ºC):
Here S-Warfarin has been synthesised with an e.e of 95%.