OPTIMIZATION AND SCALE-UP OF AN ASYMMETRIC ROUTE TO THE LTB4 INHIBITOR ONTAZOLAST

An efficient asymmetric synthesis of the LTB4 inhibitor Ontazolast is described, Commercially available (S)-alpha-pinene, which contains a 9 3.5% enantiomeric excess tee) of the desired isomer, can be oxidized u sing phase transfer conditions to the corresponding (R)-hydroxy ketone . Condensation of this keto alcohol with 2-(aminomethyl)pyridine provi des an intermediate imine that can be alkylated with cyclohexylmethyl bromide or iodide, The alkylation proceeds with nearly complete transf er of chirality under mild conditions, Cleavage of the chiral auxiliar y and isolation of the resulting (S)-pyridylamine by crystallization w ith L-tartaric acid furnishes the key amine building block in >99% ee and in excellent overall yield. The tartrate salt is then directly con verted to the final product, The reaction sequence is described on a m ultigram scale.