Processes for preparing JAK inhibitors and related intermediate compounds
The present invention is related to processes for preparing chiral substituted pyrazolyl pyrrolo[2,3-d]pyrimidines of Formula III, and related synthetic intermediate compounds. The chiral substituted pyrazolyl pyrrolo[2,3-d]pyrimidines are useful as inhibitors of the Janus Kinase family of protein tyrosine kinases (JAKs) for treatment of inflammatory diseases, myeloproliferative disorders, and other diseases.
1. A process of preparing a composition comprising an enantiomeric excess of the (R)-enantiomer of a compound of Formula III′:
comprising:
(a) treating a composition comprising an enantiomeric excess of the (S)-enantiomer of a compound of Formula I″:
with a compound of Formula D-1′:
in the presence of cesium carbonate in acetonitrile under conditions sufficient to form the racemate of the compound of Formula I″;
(b) passing said composition comprising said racemate of said compound of Formula I″ through a chiral chromatography unit using a mobile phase and collecting a composition comprising an enantiomeric excess of the (R)-enantiomer of said compound of Formula I″; and
(c) reacting said compound of Formula I″ with boron trifluoride diethyl etherate, followed by aqueous ammonium hydroxide to form a composition comprising an enantiomeric excess of the (R)-enantiomer of said compound of Formula III′;
wherein * is a chiral carbon.