An efficient synthesis of LY2886721 (1) in five steps and 46% overall yield from the chiral nitrone cycloadduct 2 is presented. Minimizing formation of a des-fluoro impurity during hydrogenolysis to cleave the isoxazolidine ring and remove the benzyl chiral auxiliary was a key challenge. Installation of the aminothiazine moiety required careful stoichiometry control of the reagents BzNCS and CDI, including in situ conversion monitoring, to minimize byproduct formation. A remarkably regioselective peptide coupling afforded 1 without competing acylation at the aminothiazine nitrogen or bis-acylation. Consideration of the combined chemistry and crystallization process identified an optimal solvent system for the peptide coupling and a reactive crystallization that afforded 1 in high purity and with physical property control. A slurry milling operation near the end of the crystallization, followed by "pH cycles" to digest fines formed during milling, significantly reduced the crystal aspect ratio and provided desirable API bulk density and powder flow properties.

Two novel (bifunctional) chelating agents, TAME-Hex A and B, which are polyaminopolycarboxylic acids based on the tripodal TAME [tris(aminomethyl)ethane] structure, have been designed and synthesized. The chelators show very good stability with gallium(III) ions and thus are highly effective

A scalable, asymmetric synthesis of (3aS,6aS)-6a-(5-bromo-2-fluorophenyl)-1-((R)-1-phenylpropyl)tetrahydro-1H,3H-furo [3,4-c]isoxazole, a key intermediate in the synthesis of LY2886721, is reported. Highlights of the synthesis include the development of an asymmetric [3 + 2] intramolecular cycloaddition facilitated by trifluoroethanol, and the development of a new synthesis of (R)-N-(1-phenylpropyl)hydroxylamine tosylate which proceeds through a p-anisaldehyde imine and avoids the formation of toxic hydrogen cyanide gas as a byproduct. The synthesis proceeds over four steps and provides the product in 36% overall yield.

Aminocarboxylic acids (hydrazinocarboxylic acids) and esters P 0270 TAME-Hex A -A Novel Bifunctional Chelating Agent for Radioimmunoimaging.-[synthesis of TAME-Hex A (Ia) and TAME-Hex B (Ib) as gallium(III) chelating agents] -(ARSLANTAS, E.; SMITH-JONES, P. M.; RITTER, G.; SCHMIDT*, R. R.; Eur.