Two Approaches to the Chemical Development and Large-Scale Preparation of a Pyrimidyl Tetrazole Intermediate

Two new routes to a pyrimidyl tetrazole intermediate are described. The first-generation route featured an iron-catalyzed cross-coupling between 4-butanylmagnesium bromide and a 4-chloropyrimidine derivative to afford an alkene-bearing pyrimidine intermediate. A subsequent intramolecular Heck cyclization afforded the desired bicyclic core, which was subsequently converted to the corresponding carboxylic acid via hydroboration and Oxidation. This route was rapidly defined and used to prepare the initial 0.3 kg of the pyrimidyl tetrazole intermediate, which supported early toxicology and clinical studies of a drug candidate. A second-generation, eight-step route to the pyrimidyl tetrazole intermediate was defined and demonstrated on multikilogram scale in a 21% overall yield. The key transformation in this sequence was a copper(I) mediated cyclization of an iodopyrimidine, affording the bicyclic core of the target in quantitative yield. Due to the larger scale involved for the second generation approach, significant process safety evaluation was undertaken for a number of steps in this route, and the highlights of these studies are presented.