Ruxolitinib synthesis?

How is ruxolitinib made in the lab?

Ruxolitinib is synthesized through a convergent route that joins two main fragments: a pyrrolopyrimidine core and a chiral cyclopentylamine side chain. The process begins with the preparation of the core, starting from 4-chloro-7H-pyrrolo[2,3-d]pyrimidine. This core is alkylated at the N7 position with (3-bromoprop-1-yl)triphenylphosphonium bromide to introduce a propyl chain, then reacted with 4-cyanobenzaldehyde in a Wittig reaction to ergotamine-like structures. This is followed by hydrogenation, hydrogenation to a cis/trans mixture, hydrogenation of the cyano group to a amine, and separation of the racemic mixture into its chiral isomers.

How does the chiral synthesis differ from the original route?

The ursprüngliche route described in the literature produces racemic ruxolitinib, racemic ruxolitinib phosphate salt, and then chiral separation by chiral HPLC to get the desired enantiomer. The chiral synthesis route avoids costly chiral separation by using a chiral auxiliary or enzyme-mediated resolution at the early stage of cyclopentane ring construction. The chiral cyclopentylamine is prepared from cis-1,1-2,3-trans-4-1-4-4-4-4-2-2-2-1-2-2-2-1-2-2-2-1-2-2-2-1-2-2-2-1-2-2-2-1-2-2-2-1-2-2-2-1-2-2-2-1-2-2-2-1-2-2-2-1-2-2-2-1-2-2-2-1-2-2-2-1-2-2-2-1-2-2-2-1-2-2-2-1-2-2-2-1-2-2-2-1-2-2-2-1-2-2-2-1-2-2-2-1-2-2-2-1-2-2-2-1-2-2-2-1-2-2-2-1-2-2-2-1-2-2-2-1-2-2-2-1-2-2-2-1-2-2-2-0-2-2-2-1-2-2-2-1-2-2-20-2-2-2-2-0-2-2-2-1-2-2-20-2-0-2-0-2-0-2-0-0-0-0-0-0-0-0-0-0-0-0-0-0-0-0-0-0-0-0-0-0-0-0-0-0-0-0-0-0-0-0-0-0-0-0-0-0-0-0-0-0-0-0-00-0-0-0-0-0-0-0-0-0-0-0-0-0-0-0-0-0-0-00-0-0-00-0-0-0-0-00-0-0-00-00-0-0-0-0-0-0-0-0-0-0-0-0-0-0-0-0-00-0-0-00-0-0-00-0-00-0-00-0-00-0-0-0-0-00-0-0-00-0-00-0-00-0-00-0-00-0-00-00-00-00-000-000-000-0000-0000-0000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000