Application of an Enantiomerically Pure Bicyclic Thiolactone in the Synthesis of a Farnesyl Transferase Inhibitor

An efficient manufacturing route to a novel farnesyl transferase inhibitor is described. The target molecule is a pro-drug, and its synthesis is complicated by the presence of labile functionality. The Medicinal Chemistry synthesis required trityl mercaptan to introduce a thiol group stereospecifically. An important objective of a new route was avoidance of such an atom-inefficient protecting group, and this was achieved by use of a bicyclic thiolactone. Reduction of the thiolactone with DIBAL afforded a masked aldehyde which participated cleanly in the key reductive amination step without loss of stereochemical integrity. The reported procedure for making the thiolactone was found to give inconsistent results. Development work resulted in a telescoped process that was operated successfully and reproducibly on the large scale. Removal of an N-Boc protecting group in the final step of the drug synthesis required careful choice of conditions to avoid cleaving other ester groups in the molecule. An impurity formed in the deprotection step was identified as the S-tert-butyl analogue arising from attack of the tert-butyl cation on the methionine residue; its identity was confirmed by independent synthesis.