Enantioselective Synthesis of Janus Kinase Inhibitor INCB018424 via an Organocatalytic Aza-Michael Reaction

Janus kinases (JAKs) are crucial signal transducers for a variety of cytokines, growth factors, and interferons. Inhibition of JAKs has advanced the basic and clinical studies of tyrosine kinase inhibitors as anticancer, anti-inflammation, and antiallograft rejection agents. It has been suggested that inhibition of JAKs can be beneficial for patients with myeloproliferative disorders and inflammatory conditions such as rheumatoid arthritis. INCB018424 was discovered as an inhibitor of JAKs and is currently under clinical development.

In view of its structural features, we envisioned that INCB018424 could be prepared from suitable chiral β-amino carbonyl compounds. The catalytic asymmetric aza-Michael reaction is a powerful method for the synthesis of these compounds. Although the use of transition metal complexes with chiral ligands is well-documented, the use of organo-catalysts in asymmetric aza-Michael reactions offers a unique advantage by not requiring metal removal from drug substance in large scale production.

In organocatalytic aza-Michael reactions, the acceptors are activated either by hydrogen bonding of the organocatalysts to the carbonyl group of the acceptors or by imminium formation between α,β-unsaturated aldehydes and the organocatalysts. Jørgensen reported the successful use of proline-derived organocatalysts in the addition of nitrogen-containing heterocycles such as triazoles and tetrazoles to α,β-unsaturated aldehydes. We envisioned that the extension of Jørgensen’s chemistry to the aza-Michael addition of substituted pyrazoles to aldehyde using suitable organocatalysts would provide an efficient asymmetric synthetic route to INCB018424.

The synthesis of Michael donor via a Suzuki coupling of protected pyrazole pinacol borate and the protected chlorodeazapurine. 4-Iodo-1H- pyrazole or 4-bromo-1H-pyrazole was treated with ethyl vinyl ether to give the protected pyrazoles respectively. Halogen-magnesium exchange of the protected pyrazoles followed by addition of borate afforded the pyrazole pinacol borate in good yield. Treatment of compound 5 with NaH and 2-(trimethylsilyl)ethoxyethyl chloride (SEM-Cl) afforded the SEM-protected in 89% yield. Suzuki coupling of the SEM-protected product with pyrazole pinacol borate furnished the intermediate which was hydrolyzed in situ to give the key Michael donor in 82% yield for two steps.

On the basis of the mechanism proposed by Jørgenson, it was conceivable that the enantioselectivity could be improved by the modulation of steric hindrance of the organocatalyst. Catalyst (R)-2 was purchased from a commercial source and catalysts (R)-3 and (R)-4 were synthesized according to literature procedures (see experimental details in the Supporting Information).





Qiyan Lin,* David Meloni, Org. Lett., Vol. 11, No. 9, 2009