Synthesis of BACE Inhibitor LY2886721. Part II. Isoxazolidines as Precursors to Chiral Aminothiazines, Selective Peptide Coupling, and a Controlled Reactive Crystallization

Abstract

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.

Process Development and Synthesis of Birinapant: Large Scale Preparation and Acid-Mediated Dimerization of the Key Indole Intermediate

“…Application of these conditions on >100-g-scale, however, resulted in ca. 1–1.5% of the monofluorinated derivative 28 , which was confirmed by independent synthesis . More importantly, we were unable to remove 28 by recrystallization of 27 or at a later stage in the synthesis.…”

Dietary Polyphenols: A Multifactorial Strategy to Target Alzheimer’s Disease

“…Various molecules have been studied and evaluated for their inhibitory action against BACE1 including macrocyclic lactones, hydroethylenes, aminoethylenes, aminoimidazoles, aminobenzthiazines, spiropiperidines, etc. [108,109,110,111,112,113,114].…”

Stepwise dissolution and composition determination of samples of multiple crystals using a dissolution medium containing aqueous alcohol and fluorocarbon phases

“…[8][9][10][11][12][13][14] Crystallisations do not always decrease the level of specic impurities to an acceptable level. [15][16][17][18][19][20][21][22][23] In such cases, knowledge of the location or locations of impurities within batches of crystalline material can be important in designing a strategy for the management of specic impurities. The distribution of a specic impurity within a multi-particle batch of crystalline solid may not necessarily be uniform or localised, and in general it would be best to assume that the concentration of impurities can vary both within individual particles and from particle to particle.…”