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Synfacts 2012; 8(4): 0351
DOI: 10.1055/s-0031-1290309
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of LY2784544

Contributor(s):
Philip Kocienski
Mitchell D, * Cole KP, Pollock PM, Coppert DM, Burkholder TP, Clayton JR. Eli Lilly and Company, Indianapolis, USA
Development and a Practical Synthesis of the JAK2 Inhibitor LY2784544.

Org. Process Res. Dev. 2012;
16: 70-81
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Publication History

Publication Date:
20 March 2012 (online)

 
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Key words

LY2784544 - Janus kinase inhibitors - vanadium catalysis - aminomethylation - N-arylation

Significance

LY2784544 is a Janus kinase 2 (JAK2) inhibitor that is under development for the treatment of myeloproliferative neoplasms. The synthesis depicted delivered >100 kg of the target molecule and features a new aminomethylation reaction (E → G) involving N-methylmorpholine N-oxide and vanadium catalysis.


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Comment

The authors speculate that the aminomethylation reaction of E involves a primary radical derived from N-methylmorpholine. An alternative ionic mechanism based on an iminium salt is unlikely since N-methylenemorpholinium chloride ­reacts preferentially at the methyl group in E (Mannich-type reaction).


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