Patent ID: 8871904
Filing Date: 2014-10-28
Classification: A61K,A61P,C07D,C07K,Y02P

Abstract:
1. A process for preparing a compound of Formula 4 comprising the steps of: i) providing an N-alkoxycarbonyl-3-azabicyclo[3.3.0]octane; ii) forming a 2-anion of the N-alkoxycarbonyl-3-azabicyclo[3.3.0]octane in the presence of a chelating agent; iii) treating the anion of step ii) with carbon dioxide to produce a cis-/trans-mixture of N-alkoxycarbonyl-octahydrocyclopenta[c]pyrrole-1-carboxylic acids; iv) treating the mixture of step iii) with a strong base to produce an essentially pure trans-N-alkoxycarbonyl-octahydrocyclopenta[c]pyrrole-1-carboxylic acid; v) forming a salt with an optically active amine; vi) crystallizing the salt; vii) esterifying the acid provided in step vi); viii) removing the N-alkoxycarbonyl group to produce (1S,3aR,6aS)-t-butyl-octahydrocyclopenta[c]pyrrole-1-carboxylate, t-butyl ester; ix) reacting the bicyclic aminoester of step viii) with a protected amino acid of Formula 26, wherein Z is an amine protecting group, in the presence of a coupling reagent, to produce an amide-ester of Formula 27; x) removing the protecting group Z from the amide-ester of step ix) to produce the amino compound of Formula 28; xi) reacting the amino compound of Formula 28 with a protected amino acid of Formula 29 in the presence of a coupling reagent to produce a tripeptide of Formula 30; xii) removing the protecting group Z in the tripeptide of Formula 30 to produce a free amino-tripeptide of Formula 31; xiii) reacting the amino-tripeptide of Formula 31 with pyrazine-2-carboxylic acid in the presence of a coupling reagent to produce an amide-tripeptide ester of Formula 33; xiv) hydrolyzing the ester of the amide-tripeptide ester of Formula 33 to produce an amide-tripeptide acid of Formula 34; xv) reacting the amide-tripeptide acid of Formula 34 with an aminohydroxy-amide of Formula 43 in the presence of a coupling reagent to produce a hydroxy-tetrapeptide of Formula 36; and xvi) oxidizing the hydroxy group of Formula 36 to produce the compound of Formula 4