Crystallisation: When being inclusive makes a difference

23 July 2004

All organic chemists recognise the value of crystallisation as a purification method. Where chiral compounds are concerned, crystallisation can often (though not always) effect an upgrade in enantiomeric purity. For compounds with an ionisable functional group, salt formation provides another tool for the chemist seeking enhanced purity via crystallisation. For non-ionisable compounds, the options would seem to be more limited. Or are they?

Merck process chemists working on the aprepitant project, needed to find a way of upgrading the enantiomeric purity of the secondary alcohol below, and were having difficulties achieving this via direct crystallisation. Following a report on the enantiomeric upgrading of tertiary acetylenic alcohols (F. Toda et al., Chemistry Letters, 1986, 1905), they found that their alcohol forms a crystalline inclusion complex with DABCO. Crystallisation of this inclusion complex from heptane upgraded the alcohol e.e. from 92% to >99%!

It was subsequently found that the racemic alcohol also forms a (more stable) DABCO complex, both as a racemic compound and as a conglomerate. The homochiral DABCO complex is, in fact, a product of kinetic control. The Merck team were, nevertheless, able to control the conditions to reliably produce the desired product on multi-kilogram scale.

An interesting story — worth a read*.

* K.B. Hansen et al.,Tetrahedron Asymmetry, 2003, 14, 3581