A green and facile synthesis of an industrially important quaternary heterocyclic intermediates for baricitinib

BACKGROUND: Baricitinib, with a 2-(1-(ethylsulfonyl)azetidin-3-yl)acetonitrile moiety at N-2 position of the pyrazol skeleton, is an oral and selective reversible inhibitor of the JAK1 and JAK2 and displays potent anti-inflammatory activity. Several research-scale synthetic methods have been reported for the preparation of key quaternary heterocyclic intermediates of baricitinib. However, they were all associated with several drawbacks, such as the expensive materials, usage of pollutional reagents, and poor yields. RESULTS: In this manuscript, we established a green and cost-effective synthesis of 2-(1-(ethylsulfonyl)azetidin-3-ylidene)acetonitrile and tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate for further scale-up production of baricitinib. This synthetic method employs commercially available and low-cost starting material benzylamine and an industry-oriented reaction of green oxidation reaction in microchannel reactor to yield important quaternary heterocyclic intermediates. CONCLUSION: Generally, this procedure is reasonable, green and suitable for industrial production.