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Introduction

The document discusses the synthesis of three types of Warfarin: Racemic, S-Warfarin, and R-Warfarin, highlighting their different synthetic routes. Racemic Warfarin is synthesized through a Michael condensation reaction, while S-Warfarin, the more pharmacologically active enantiomer, can be produced via asymmetric hydrogenation or hetero-Diels-Alder cycloaddition. The latter methods yield high enantioselectivities, with S-Warfarin achieving an enantiomeric excess of up to 95%.

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5 views5 pages

Introduction

The document discusses the synthesis of three types of Warfarin: Racemic, S-Warfarin, and R-Warfarin, highlighting their different synthetic routes. Racemic Warfarin is synthesized through a Michael condensation reaction, while S-Warfarin, the more pharmacologically active enantiomer, can be produced via asymmetric hydrogenation or hetero-Diels-Alder cycloaddition. The latter methods yield high enantioselectivities, with S-Warfarin achieving an enantiomeric excess of up to 95%.

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flashhunter02
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Synthesis:

There are 3 types of Warfarin:

1. Racemic Warfarin

2. S-Warfarin

3. R-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%.

Asymetric Synthesis:

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%.

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