Stereoselective Addition of 2‑Phenyloxazol-4-yl Trifluoromethanesulfonate to <i>N</i>‑Sulfinyl Imines: Application to the Synthesis of the HCV Protease Inhibitor Boceprevir

The stereoselective addition of 2-phenyloxazol-4-yl trifluoromethanesulfonate to <i>N</i>-sulfinylimines is described. Vinyl anions derived from enol triflate <b>2</b> undergo 1,2-addition with a variety of aldimines to afford the corresponding secondary sulfonamides as single diastereomers. The absolute stereochemistry was confirmed by X-ray crystallography which provides support that the reaction proceeds through an open, nonchelate transition state. This methodology has been applied to the synthesis of the ketoamide fragment of the protease inhibitor boceprevir

Two Novel Pharmaceutical Cocrystals of a Development Compound – Screening, Scale-up, and Characterization

A streamlined methodology for cocrystal screening and scale-up has been developed. There are two parts to this procedure: (1) a high throughput screening approach for the rapid identification of potential cocrystal leads and (2) a new procedure for solvent selection, rapidly mapping the critical region in the ternary phase diagram, and determining a cocrystallization procedure for scale-up. Using this approach, we have discovered and scaled-up two new cocrystal forms of the pharmaceutically active compound <b>1</b> for the treatment of type II diabetes. This approach provided more than 2 g of cocrystal material suitable for biopharmaceutical evaluation. The physicochemical characterization and single crystal X-ray diffraction data of these cocrystals are also presented and discussed

Two Novel Pharmaceutical Cocrystals of a Development Compound – Screening, Scale-up, and Characterization

A streamlined methodology for cocrystal screening and scale-up has been developed. There are two parts to this procedure: (1) a high throughput screening approach for the rapid identification of potential cocrystal leads and (2) a new procedure for solvent selection, rapidly mapping the critical region in the ternary phase diagram, and determining a cocrystallization procedure for scale-up. Using this approach, we have discovered and scaled-up two new cocrystal forms of the pharmaceutically active compound <b>1</b> for the treatment of type II diabetes. This approach provided more than 2 g of cocrystal material suitable for biopharmaceutical evaluation. The physicochemical characterization and single crystal X-ray diffraction data of these cocrystals are also presented and discussed

Synthesis of Antifungal Glucan Synthase Inhibitors from Enfumafungin

An efficient, new, and scalable semisynthesis of glucan synthase inhibitors <b>1</b> and <b>2</b> from the fermentation product enfumafungin <b>3</b> is described. The highlights of the synthesis include a high-yielding ether bond-forming reaction between a bulky sulfamidate <b>17</b> and alcohol <b>4</b> and a remarkably chemoselective, improved palladium­(II)-mediated Corey-Yu allylic oxidation at the highly congested C-12 position of the enfumafungin core. Multi-hundred gram quantities of the target drug candidates <b>1</b> and <b>2</b> were prepared, in 12 linear steps with 25% isolated yield and 13 linear steps with 22% isolated yield, respectively

Asymmetric Synthesis of a Glucagon Receptor Antagonist via Friedel–Crafts Alkylation of Indole with Chiral α‑Phenyl Benzyl Cation

Development of a practical asymmetric synthesis of a glucagon receptor antagonist drug candidate for the treatment of type 2 diabetes is described. The antagonist consists of a 1,1,2,2-tetrasubstituted ethane core substituted with a propyl and three aryl groups including a fluoro-indole. The key steps to construct the ethane core and the two stereogenic centers involved a ketone arylation, an asymmetric hydrogenation via dynamic kinetic resolution, and an <i>anti</i>-selective Friedel–Crafts alkylation of a fluoro-indole with a chiral α-phenyl benzyl cation. We also developed two new efficient syntheses of the fluoro-indole, including an unusual Larock-type indole synthesis and a Sugasawa-heteroannulation route. The described convergent synthesis was used to prepare drug substance in 52% overall yield and 99% ee on multikilogram scales

Asymmetric Synthesis of a Glucagon Receptor Antagonist via Friedel–Crafts Alkylation of Indole with Chiral α‑Phenyl Benzyl Cation

Development of a practical asymmetric synthesis of a glucagon receptor antagonist drug candidate for the treatment of type 2 diabetes is described. The antagonist consists of a 1,1,2,2-tetrasubstituted ethane core substituted with a propyl and three aryl groups including a fluoro-indole. The key steps to construct the ethane core and the two stereogenic centers involved a ketone arylation, an asymmetric hydrogenation via dynamic kinetic resolution, and an <i>anti</i>-selective Friedel–Crafts alkylation of a fluoro-indole with a chiral α-phenyl benzyl cation. We also developed two new efficient syntheses of the fluoro-indole, including an unusual Larock-type indole synthesis and a Sugasawa-heteroannulation route. The described convergent synthesis was used to prepare drug substance in 52% overall yield and 99% ee on multikilogram scales

The Discovery of MK-4256, a Potent SSTR3 Antagonist as a Potential Treatment of Type 2 Diabetes

A structure–activity relationship study of the imidazolyl-β-tetrahydrocarboline series identified MK-4256 as a potent, selective SSTR3 antagonist, which demonstrated superior efficacy in a mouse oGTT model. MK-4256 reduced glucose excursion in a dose-dependent fashion with maximal efficacy achieved at doses as low as 0.03 mg/kg po. As compared with glipizide, MK-4256 showed a minimal hypoglycemia risk in mice