Journal of Organic Chemistry 2008-02-01

Scalable synthesis of the VEGF-R2 kinase inhibitor JNJ-17029259 using ultrasound-mediated addition of MeLi-CeCl3 to a nitrile.

Michael Reuman, Sandra Beish, Jeremy Davis, Mark J Batchelor, Martin C Hutchings, David F C Moffat, Peter J Connolly, Ronald K Russell

Index: J. Org. Chem. 73(3) , 1121-3, (2008)

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Abstract

The preparation of the selective VEGF-R2 kinase inhibitor 10 (JNJ-17029259) is described in which the key precursor, 4-(5-isoxazolyl)benzonitrile, undergoes clean transformation to the corresponding cumylamine derivative with CeCl(3)-MeLi in THF. This high-yielding cerium mediated transformation is robust, reproducible, and readily scalable based on a requirement for the anhydrous CeCl(3) to be milled and subjected to ultrasound treatment prior to addition of methyllithium.