Practical Synthesis of 5-Fluoro-2-(piperidin-4-yloxy)pyrimidin-4-amine, a Key Intermediate in the Preparation of Potent Deoxycytidine Kinase Inhibitors

A practical synthesis of 5-fluoro-2-(piperidin-4-yloxy)pyrimidin-4-amine, a key intermediate in the preparation of a new class of potent deoxycytidine kinase (dCK) inhibitors, is described. The commercially available 2,4-dichloro-5-fluoropyrimidine (12) is converted in four telescoped steps to tert-butyl 4-(4-amino-5-fluoropyrimidin-2-yloxy)piperidine-1-carboxylate (6a) which upon deprotection gives 5-fluoro-2-(piperidin-4-yloxy)pyrimidin-4-amine dihydrochloride (1a) in about 68% overall yield. This process proved to be an economical alternative to a Mitsunobu-based synthesis.