ABSTRACT
A robust process to manufacture AMG 232 was developed to deliver drug substance of high purity. Highlights of the commercial process development efforts include the following: (i) use of a novel bench-stable Vilsmeier reagent, methoxymethylene- N, N-dimethyliminium methyl sulfate, for selective in situ activation of a primary alcohol intermediate; (ii) use of a new crystalline and stable isopropyl calcium sulfinate reagent ensuring robust preparation of a sulfone intermediate; (iii) development of a safe ozonolysis process conducted in an aqueous solvent mixture in either batch or continuous manufacturing mode; and (iv) control of the drug substance purity by crystallization of a salt rejecting impurities effectively. The new process was demonstrated to afford the drug substance (99.9 LC area %) in 49.8% overall yield from starting material DLAC (1).
Subject(s)
Acetates/chemical synthesis , Ozone/chemistry , Piperidones/chemical synthesis , Acetates/chemistry , Acetates/isolation & purification , Molecular Structure , Piperidones/chemistry , Piperidones/isolation & purificationABSTRACT
We describe a systematic study of how macrocyclization in the P1-P3 region of hydroxyethylamine-based inhibitors of ß-site amyloid precursor protein (APP)-cleaving enzyme (BACE1) modulates in vitro activity. This study reveals that in a number of instances macrocyclization of bis-terminal dienes leads to improved potency toward BACE1 and selectivity against cathepsin D (CatD), as well as greater amyloid ß-peptide (Aß)-lowering activity in HEK293T cells stably expressing APPSW. However, for several closely related analogs the benefits of macrocyclization are attenuated by the effects of other structural features in different regions of the molecules. X-ray crystal structures of three of these novel macrocyclic inhibitors bound to BACE1 revealed their binding conformations and interactions with the enzyme.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Ethylamines/chemistry , Amyloid Precursor Protein Secretases/metabolism , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/genetics , Amyloid beta-Protein Precursor/metabolism , Aspartic Acid Endopeptidases/metabolism , Binding Sites , Cathepsin D/metabolism , Crystallography, X-Ray , HEK293 Cells , Humans , Macrocyclic Compounds/chemical synthesis , Macrocyclic Compounds/chemistry , Macrocyclic Compounds/metabolism , Protein Binding , Protein Structure, TertiaryABSTRACT
Aldehyde-bisulfite adducts dervied from unstable parent aldehydes were reductively alkylated in a direct fashion with a variety of amines. This approach features the use of 2-picoline borane as the reducing agent and a protic solvent for the reaction media and has been successfully applied to the synthesis of a DPP-IV inhibitor and a variety of other amines.
Subject(s)
Amines/chemistry , Dipeptidyl Peptidase 4/agonists , Dipeptidyl Peptidase 4/chemistry , Morpholines/chemistry , Picolines/chemistry , Sulfites/chemistry , Aldehydes , Alkylation , Amination , Boranes/chemistryABSTRACT
A process for the regioselective amination of unsymmetrical 3,5-substituted pyridine N-oxides has been developed utilizing cheap, readily available saccharin as an ammonium surrogate. High conversions of the corresponding saccharin adducts have been achieved under mild reaction conditions. In situ deprotection under acidic conditions allows for a one-pot process to substituted aminopyridines. High regioselectivities were obtained from a variety of 3,5-disubstituted pyridine N-oxides.
Subject(s)
Aminopyridines/chemical synthesis , Pyridines/chemistry , Quaternary Ammonium Compounds/chemistry , Saccharin/chemistry , Amination , Aminopyridines/chemistry , Combinatorial Chemistry Techniques , Molecular Structure , StereoisomerismABSTRACT
A microwave-assisted, telescoped synthesis, involving a Michael-type addition followed by intramolecular cyclization, provides an effective entry to the polysubstituted 3-bromo-2(1H)-pyridinone core.
Subject(s)
Esters/chemical synthesis , Esters/radiation effects , Microwaves , Pyridones/chemical synthesis , Pyridones/radiation effects , Cyclization , Esters/chemistry , Molecular Structure , Pyridones/chemistry , StereoisomerismABSTRACT
Wacker-type cyclisation reactions provide an effective entry into the dioxabicyclo[3.2.1]octane core of the zaragozic acid analogues.
Subject(s)
Antifungal Agents/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Octanes/chemical synthesis , Cyclization , Farnesyl-Diphosphate Farnesyltransferase/antagonists & inhibitors , Molecular Structure , StereoisomerismABSTRACT
[reaction: see text] A study of new nucleophilic addition/ring-closure (NARC) sequences has resulted in the development of a stereoselective synthetic route to 3-deoxy-8-oxatropanes. The new sequences consisted of either a syn or anti aldol addition, employing an omega-alkenoyl sultam, followed by two-step bicyclic ring construction involving, consecutively, ring-closing metathesis and intramolecular oxymercuration.
