Elimination reactions in pharmacy: part one

Besides understanding basic principles of a reaction like the mechanisms and how to apply them to solve problems, perhaps you would appreciate an organic reaction better if I present some real-life situations especially related to pharmacy which involve elimination reactions.

The first example is elimination in the synthesis of a well known drug tamoxifen. Tamoxifen is an anti-estrogen antagonist which is used to treat breast cancer that is estrogen receptor positive. It works by binding to the estrogen receptor on the cancer cells thus stopping the uncontrolled cell growth fuelled by estrogen activity.

Tamoxifen tablet 20 mg (Nolvadex is the brand name)

A 3-D structure of tamoxifen

Here is how tamoxifen is originally made:

First, the main skeleton of tamoxifen is made by addition of a Grignard reagent, phenyl magnesium bromide (PhMgBr) which is a good nucleophile to the ketone group. This produces a tertiary alcohol. This tertiary alcohol is then treated with sulfuric acid. Here a dehydration happens. It is an E1 elimination as a carbocation is formed (favoured by it being tertiary and benzylic at the same time).

The freely rotating bond (coloured green) allows the three substituents at the carbon (blue) adjacent to the positively charged one to change positions like this:

So in an E1 elimination like this, there is no stereocontrol (stereospecificity). As the proton (coloured red) gets removed, a mixture of E- and Z-isomers are produced.

This method to make tamoxifen is apparently not satisfactory because we can’t get purely tamoxifen. There are better, improved ways to produce pure tamoxifen. Check out this website: http://www.ch.ic.ac.uk/local/projects/h_tanner/introsynth.html