PF-04449913, a smoothened receptor (SMO) inhibitor, is currently being studied for the treatment of hematological-based cancers.  To support on-going drug development, a practical, scalable synthesis was desired to address the key synthetic challenge: effective installation of the <i>anti</i>-stereogenic centers at the 2,4-positions of the core piperidine.  Development of a commercial process for PF-04449913 has resulted in a concise, asymmetric synthesis which features an enzymatic transamination with concurrent dynamic kinetic resolution (DKR) of an intermediate 4-piperidone to establish the two stereogenic centers required in only a single step.  This highly efficient reaction renders the desired <i>anti</i>-amino piperidine in &gt;10:1 d.r. and &gt;99% ee.  In total, PF-04449913 is rapidly constructed in only five steps with 40% overall yield.  The development of a commercial process for PF-04449913 is described herein.

Commercial route development of an SMO inhibitor

254th National Meeting (2017)

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