Process Development for the Synthesis of Monocyclic β‑Lactam Core 17

Process development and multikilogram synthesis of the monocyclic β-lactam core <b>17</b> for a novel pyridone-conjugated monobactam antibiotic is described. Starting with commercially available 2-(2,2-diethoxyethyl)­isoindoline-1,3-dione, the five-step synthesis features several telescoped operations and direct isolations to provide significant improvement in throughput and reduced solvent usage over initial scale-up campaigns. A particular highlight in this effort includes the development of an efficient Staudinger ketene–imine [2 + 2] cycloaddition reaction of <i>N</i>-Boc-glycine ketene <b>12</b> and imine <b>9</b> to form racemic β-lactam <b>13</b> in good isolated yield (66%) and purity (97%). Another key feature in the synthesis involves a classical resolution of racemic amine <b>15</b> to afford single enantiomer salt <b>17</b> in excellent isolated yield (45%) with high enantiomeric excess (98%)

Kiloscale Buchwald–Hartwig Amination: Optimized Coupling of Base-Sensitive 6‑Bromoisoquinoline-1-carbonitrile with (<i>S</i>)‑3-Amino-2-methylpropan-1-ol

This work describes the optimization and scale-up of a Buchwald–Hartwig amination reaction for the preparation of a pharmaceutical intermediate. This C–N bond formation is challenged by the use of a chiral primary amine, which both adds cost and favors formation of biaryl byproducts. In order to develop a scalable process, a number of factors had to be investigated including catalyst selection and stoichiometry of the chiral amine. These all needed to be optimized while maintaining low palladium levels in the isolated product. The reaction was found to be most effective using Pd­(dba)₂ with BINAP and Cs₂CO₃ in THF. When executed on 2.5 kg scale, these conditions provided 2.06 kg of the desired product in 80% yield with only 73 ppm residual palladium. To date, this process has been successfully executed to produce more than 12 kg of compound <b>(</b><i><b>S</b></i><b>)-3</b>