ABSTRACT
A practical synthesis of 2-[3-(4-fluoro-3-pyridin-3-yl-phenyl)-imidazo[1,2-a]pyrimidin-7-yl]-propan-2-ol (1), an oral GABA(A) alpha(2/3)-selective agonist, is described. The five-step process, which afforded 1 in 40% overall yield, included imidazopyrimidine 2 and pyridine boronic acid 4 as key fragments. The synthesis is highlighted by consecutive Pd-catalyzed coupling steps to assemble the final free base 1 in high yield and regioselectivity. A novel method for Pd removal in the final step is also described.
Subject(s)
GABA Agonists/chemical synthesis , Palladium/chemistry , Propanols/chemical synthesis , Pyrimidines/chemical synthesis , Allosteric Regulation , Boronic Acids/chemistry , Catalysis , Imidazoles/chemistry , Molecular Structure , Oxidation-Reduction , Pyridines/chemistry , Pyrimidines/chemistry , StereoisomerismABSTRACT
An efficient asymmetric synthesis of a selective estrogen receptor modulator (SERM) that has a dihydrobenzoxathiin core structure bearing two stereogenic centers is reported. The stereogenic centers were established by an unprecedented chiral sulfoxide-directed stereospecific reduction of an alpha,beta-unsaturated sulfoxide to the saturated sulfide in one step. Studies to elucidate the mechanism for this reduction are reported. Highly efficient Cu(I)-mediated ether formation was used to install the ether side chain, and selective debenzylation conditions were developed to remove the benzyl protecting groups on the phenols.
Subject(s)
Boranes/chemistry , Estrogen Receptor Modulators/chemical synthesis , Safrole/analogs & derivatives , Safrole/chemistry , Magnetic Resonance Spectroscopy , Mass Spectrometry , Oxidation-Reduction , StereoisomerismABSTRACT
Imidazo[1,2-a]pyrimidine can be arylated at the 3-position with aryl bromides in the presence of base and a catalytic amount of palladium. This provides an efficient one-step synthesis of 3-arylimidazo[1,2-a]pyrimidines from the unsubstituted heterocycle. [reaction: see text]
