Development of a Multikilogram Scale Synthesis of a TRPV1 Antagonist

A highly efficient, regioselective five-step synthesis of the TRPV1 antagonist <b>1</b> is described. The coupling of piperazine <b>7</b> with dichloropyrimidine <b>8</b> proceeded via a regioselective Pd-mediated amination affording product <b>11</b> in excellent yield. Conversion of the penultimate product <b>14</b> afforded <b>1</b> through formation of a magnesium ate complex and trapping with CO₂

Route Development and Multikilogram GMP Delivery of a Somatostatin Receptor Antagonist

Route development and demonstration on multikilogram scale for the first GMP delivery of MK-4256 are described. Key aspects of the convergent route include a regioselective green iodination, one-pot oxadiazole synthesis, and an efficient ketone Pictet–Spengler reaction with diastereomeric upgrade via crystallization to afford 6 kg of API. A recycle procedure augmented the yield of desired diastereomer in the Pictet–Spengler reaction from a mixture of diastereomers heavily enriched in the undesired diastereomer

Convergent, Kilogram Scale Synthesis of an Akt Kinase Inhibitor

The development of a convergent, chromatography-free synthesis of an allosteric Akt kinase inhibitor is described. The route comprised 17 total steps and was used to produce kilogram quantities of the target molecule. A key early transformation, for which both batch and flow protocols were developed, was formylation of a dianion derived by deprotonation and subsequent lithium-halogen exchange from a 2-bromo-3-aminopyridine precursor. Improved reaction yield and practicality were achieved in the continuous processing mode. Further significant process developments included the safe execution of a high temperature and pressure hydrazine displacement, separation of substituted cyclobutane diastereomers by means of chemoselective ester hydrolysis, and a late-stage Suzuki fragment coupling under mild conditions