RESUMEN
This article outlines the process development leading to the manufacture of 800 g of BMS-986189, a macrocyclic peptide active pharmaceutical ingredient. Multiple N-methylated unnatural amino acids posed challenges to manufacturing due to the lability of the peptide to cleavage during global side chain deprotection and precipitation steps. These issues were exacerbated upon scale-up, resulting in severe yield loss and necessitating careful impurity identification, understanding the root cause of impurity formation, and process optimization to deliver a scalable synthesis. A systematic study of macrocyclization with its dependence on concentration and pH is presented. In addition, a side chain protected peptide synthesis is discussed where the macrocyclic protected peptide is extremely labile to hydrolysis. A computational study explains the root cause of the increased lability of macrocyclic peptide over linear peptide to hydrolysis. A process solution involving the use of labile protecting groups is discussed. Overall, the article highlights the advancements achieved to enable scalable synthesis of an unusually labile macrocyclic peptide by solid-phase peptide synthesis. The sustainability metric indicates the final preparative chromatography drives a significant fraction of a high process mass intensity (PMI).
Asunto(s)
Compuestos Macrocíclicos , Compuestos Macrocíclicos/química , Compuestos Macrocíclicos/síntesis química , Péptidos Cíclicos/química , Péptidos Cíclicos/síntesis química , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/química , Péptidos/química , Péptidos/síntesis química , Técnicas de Síntesis en Fase Sólida , Estructura MolecularRESUMEN
The development of an improved short and efficient commercial synthesis of the JAK2 inhibitor, a complex pyrrolopyridine, BMS-911543, is described. During the discovery and development of this synthesis, a Pd-catalyzed C-H functionalization was invented which enabled the rapid union of the key pyrrole and imidazole fragments. The synthesis of this complex, nitrogen-rich heterocycle was accomplished in only six steps (longest linear sequence) from readily available materials.
Asunto(s)
Compuestos Heterocíclicos con 3 Anillos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Catálisis , Compuestos Heterocíclicos con 3 Anillos/síntesis química , Compuestos Heterocíclicos con 3 Anillos/química , Humanos , Janus Quinasa 2/antagonistas & inhibidores , Janus Quinasa 2/metabolismo , Ligandos , Estructura Molecular , Paladio/química , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/químicaRESUMEN
The development and demonstration of short, robust and chromatography-free sequences for the preparation of a (1R,2S)-1-amino-2-vinylcyclopropane-carboxylic acid-derived sulfonamide and ethyl ester in ≥99% ee are described. Both compounds are common building blocks in multiple preparations of potent HCV NS3 protease inhibitors. The robustness of the asymmetric cyclopropanation of (E)-N-benzylideneglycine ethyl ester under phase transfer catalysis conditions is significantly improved based on a detailed mechanistic investigation that included an analysis of the catalyst decomposition pathway, a postulated model for the stereo-selectivity that was guided by calculations and rigorous quality control of the starting materials and reagents. Wet milling has been demonstrated to dramatically accelerate this phase transfer reaction. A bench stable benzylidene-protected primary 1-amino-2-vinylcyclopropane amide intermediate was isolated and its reliable enantiomeric enrichment was achieved by a controlled crystallization process. A chemical resolution procedure was identified using di-p-toluoyl-(D)-tartaric acid to access (1R,2S)-1-amino-2-vinyl-cyclopropanecarboxylic ester in high ee.
Asunto(s)
Ciclopropanos/síntesis química , Ésteres/química , Compuestos de Vinilo/síntesis química , Antivirales/síntesis química , Antivirales/química , Ciclopropanos/química , Ésteres/síntesis química , Estructura Molecular , Transición de Fase , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/química , Compuestos de Vinilo/químicaRESUMEN
An enantioselective synthesis of the CGRP antagonist BMS-846372, amenable to large scale preparation, is presented. This new synthesis showcases a chemo- and enantioselective reduction of a cyclohepta[b]pyridine-5,9-dione as well as a Pd-catalyzed alpha-arylation reaction to form the key carbon-carbon bond and set the absolute and relative stereochemistry.
Asunto(s)
Péptido Relacionado con Gen de Calcitonina/antagonistas & inhibidores , Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Catálisis , Compuestos Heterocíclicos de 4 o más Anillos/química , Estructura Molecular , EstereoisomerismoRESUMEN
[reaction: see text] A zirconocene-mediated ring contraction of 4-vinylfuranosides generated either from d-arabinose or d-glucose is followed by sequential oxidation to the ketone and alkynyl Grignard addition. The resulting cis-cyclobutanediols are subjected in turn to thermal rearrangement and intramolecular oxymercuration-demercuration. The regiochemistry of the final ring closure is controlled by the nature of R.
RESUMEN
[reaction: see text] The ring contraction induced by treatment of 4-vinylfuranosides with zirconocene in the presence of boron trifluoride etherate can be rendered highly diastereoselective by proper adjustment of substituent stereochemistry. The two competing transition states that are seemingly involved appear to be usefully sensitive to nonbonded steric interactions.