DP-4088

In this paper, we describe the physicochemical and biopharmaceutical properties of 3-fluoro-2-pyrimidylmethyl 3-(2,2-difluoro-2-(2-pyridyl)ethylamino)-6-chloropyrazin-2-one-1-acetamide, a direct thrombin inhibitor (1, Fig. 1). Three crystalline forms were characterized and studies were planned to investigate the absorption characteristics of the three selected crystalline forms. Due to the short half-life observed in preclinical species, regional absorption studies were also conducted to support potential controlled release formulation development. Results showed that the absorption of 1 was dependent on the surface area of the particles administered as suspensions and was independent of the crystal forms. From Caco-2 cell transport studies, it was determined that the permeability of 1 was high. Based on the low aqueous solubility it would be classified as a class 2 compound in the Biopharmaceutics Classification System. Regional absorption results suggested that the compound was absorbed along the gastrointestinal tract in Beagle dogs, however colonic absorption appeared to be reduced by slower dissolution.

A scaleable route to 2-{3-[(2,2-difluoro-2-(2-pyridyl)ethyl)amino]-6-chloro-2-oxohydropyrazinyl}-N-[(3-fluoro(2-pyridyl))methyl]acetamide (I) is described in which various scaleup issues were addressed to provide a safe, efficient, and robust route for the preparation of multi-kilo amounts of the compoundThe use of expensive and toxic reagents, notably sodium azide, TMS-cyanide, and Deoxo-Fluor, and the need for specialist equipment were overcome in the preparation of the key fluorinated intermediates 2,2-difluoro-2-(2-pyridyl)ethylamine and 2-aminomethyl-3-fluoropyridine.With minimal isolations and through processing of intermediates, the thrombin inhibitor I was isolated in 36% overall yield.