ABSTRACT
A chromatography-free asymmetric synthesis of GDC-6036 (1) was achieved via a highly atroposelective Negishi coupling of aminopyridine 5 and quinazoline 6b catalyzed by 0.5 mol % [Pd(cin)Cl]2 and 1 mol % (R,R)-Chiraphite to afford the key intermediate (Ra)-3. An alkoxylation of (Ra)-3 with (S)-N-methylprolinol (4) and a global deprotection generates the penultimate heterobiaryl intermediate 2. A controlled acrylamide installation by stepwise acylation/sulfone elimination and final adipate salt formation and crystallization delivered high-purity GDC-6036 (1).
ABSTRACT
A highly efficient asymmetric synthesis of the IDO inhibitor navoximod, featuring the stereoselective installation of two relative and two absolute stereocenters from an advanced racemic intermediate, is described. The stereocenters were set via a crystallization-induced dynamic resolution along with two selective ketone reductions: one via a biocatalytic ketoreductase transformation and one via substrate-controlled hydride delivery from LiAlH(Ot-Bu)3. Following this strategy, navoximod was synthesized in 10 steps from 2-fluorobenzaldehyde and isolated in 23% overall yield with 99.7% ee and high purity.
Subject(s)
Enzyme Inhibitors , Indoles , Enzyme Inhibitors/pharmacology , Imidazoles , StereoisomerismABSTRACT
Magnesium ethoxide has been shown to be a mild, safe, and scalable alternative to trimethylaluminum for the direct addition of amines to aryl nitriles to access cyclic amidines. A variety of electronically diverse oxa-, thia-, and diazepine products were successfully synthesized in moderate to high yields. Further elaboration of these compounds to 5,6-dihydroimidazobenzoxazepines, a privileged class of pharmacologically active heterocycles, highlights the utility of this method.
ABSTRACT
In this report, we disclose our findings regarding the remarkable effect of a low-level impurity found in the solvent used for a ruthenium-catalyzed direct arylation reaction. This discovery allowed for the development of a robust and high-yield arylation protocol that was demonstrated on a multikilogram scale using carboxylate as the cocatalyst. Finally, a practical, scalable, and chromatography-free synthesis of the biaryl core of Anacetrapib is described.
Subject(s)
Oxazolidinones/chemical synthesis , Ruthenium/chemistry , Catalysis , Molecular Structure , Oxazolidinones/chemistry , Solvents/chemistry , StereoisomerismABSTRACT
A practical enantioselective synthesis of renin inhibitor MK-1597 (ACT-178882), a potential new treatment for hypertension, is described. The synthetic route provided MK-1597 in nine steps and 29% overall yield from commercially available p-cresol (7). The key features of this sequence include a catalytic asymmetric hydrogenation of a tetrasubstituted ene-ester, a highly efficient epimerization/saponification sequence of 4 which sets both stereocenters of the molecule, and a short synthesis of amine fragment 2.
Subject(s)
Cresols/chemistry , Cyclopropanes/antagonists & inhibitors , Cyclopropanes/chemical synthesis , Cyclopropanes/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Piperidines/chemistry , Pyridines/antagonists & inhibitors , Pyridines/chemical synthesis , Pyridines/pharmacology , Renin/antagonists & inhibitors , Catalysis , Cyclopropanes/chemistry , Enzyme Inhibitors/chemistry , Hydrogenation , Hypertension/drug therapy , Molecular Structure , Pyridines/chemistry , Renin/chemistry , StereoisomerismABSTRACT
A practical large-scale chromatography-free synthesis of EP4 antagonist MF-310, a potential new treatment for chronic inflammation, is presented. The synthetic route provided MF-310 as its sodium salt in 10 steps and 17% overall yield from commercially available pyridine dicarboxylate 7. The key features of this sequence include a unique regioselective reduction of succinimide 2 controlled by the electronic properties of a remote pyridine ring, preparation of cyclopropane carboxylic acid 3 via a Corey-Chaykovsky cyclopropanation, and a short synthesis of sulfonamide 5.
Subject(s)
Chemistry, Organic/methods , Chemistry, Pharmaceutical/methods , Cyclopropanes/chemical synthesis , Heterocyclic Compounds, 3-Ring/chemical synthesis , Receptors, Prostaglandin E/antagonists & inhibitors , Succinimides/chemistry , Carboxylic Acids/chemistry , Chemistry, Organic/instrumentation , Chemistry, Pharmaceutical/instrumentation , Crystallization , Cyclopropanes/chemistry , Drug Design , Electronics , Heterocyclic Compounds, 3-Ring/chemistry , Models, Chemical , Molecular Structure , Receptors, Prostaglandin E, EP4 Subtype , Stereoisomerism , Sulfonamides/chemistry , Technology, PharmaceuticalABSTRACT
Owing to slow rotation of a sterically constrained dimethylamide substituent, two slowly interconverting enantiomers of a preclinical candidate for pharmaceutical development, 1, (6-(3-Chloro-4-fluoro-benzyl)-4-hydroxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-[2,6]naphthyridine-1-carboxylic acid dimethylamide) are observed by chiral chromatography. Isolation of pure enantiomer by preparative chiral chromatography followed by enantiopurity analysis over time allowed for a study of the kinetics of enantiomer interconversion under a variety of conditions. Relatively slow racemization was observed in alcohol solvents, with a half life on the order of 5-10 h. A dramatic influence of aqueous buffer pH on racemization was noted, with higher pH leading to rapid racemization within a few minutes, and lower pH leading to essentially no racemization for periods up to a week. A hypothesis explaining this unusual effect of pH on carboxamide bond rotation is offered, and some suggestions for potential utility of such a system are considered.
Subject(s)
Amides/chemistry , Chromatography, High Pressure Liquid/methods , Dimethylamines/chemistry , Naphthyridines/chemistry , Optical Rotation , Circular Dichroism , Hydrogen-Ion Concentration , Spectrophotometry, UltravioletABSTRACT
We report herein a simple, scalable, transition-metal-free approach to the synthesis of alpha-aryl methyl ketones from diazonium tetrafluoroborate salts under mild conditions. This methodology uses easily accessible and nontoxic starting material and was applied to the multi-kilogram-scale preparation of 1-(3-bromo-4-methylphenyl)propan-2-one.
Subject(s)
Ketones/chemistry , Transition Elements/chemistry , Catalysis , Chromatography, High Pressure Liquid , Hydrocarbons, Brominated/chemical synthesis , Magnetic Resonance Spectroscopy , Metals/chemistry , Propane/analogs & derivatives , Propane/chemical synthesis , Solvents , Spectrometry, Mass, Electrospray IonizationABSTRACT
A stereoselective synthesis of (R)-beta-amino acid 1 via a beta-lactam intermediate is discussed.
