A strategy for the rapid, material-efficient development of crystallization processes centred around the use of process analytical technology (PAT) is presented and demonstrated on an active pharmaceutical ingredient (API) currently in development at Pfizer's Sandwich laboratories. PAT is implemented at scales as small as 1 mL in high-throughput equipment, enabling the early acquisition of key data to select the best crystallization approach. At a larger scale, PAT offers a window into process kinetics and, for the case study discussed in this contribution, highlighted vulnerabilities of the process arising from the formation of a labile solvate. A combination of online and off-line analyses provided the basis for a full assessment of the process.

Tetramethyl orthosilicate (TMOS) is shown to be an effective reagent for direct amidation of aliphatic and aromatic carboxylic acids with amines and anilines. The amide products are obtained in good to quantitative yields in pure form directly after workup without the need for any further purification. A silyl ester as the putative activated intermediate is observed by NMR methods. Amidations on a 1 mol scale are demonstrated with a favorable process mass intensity.

Novel PARP inhibitor 1 is a promising new candidate for treatment of breast and ovarian cancer. A modified synthetic route to 1 has been developed and demonstrated on 7 kg scale. In order to scale up the synthesis to multikilogram scale, several synthetic challenges needed to be overcome. The key issues included significant thermal hazards present in a Leimgruber–Batcho indole synthesis, a low-yielding side-chain installation, a nonrobust Suzuki coupling and hydrogen cyanide generation during a reductive amination. In addition to these issues, changing from intravenous to oral delivery required a new salt form and therefore a new crystallization procedure. This contribution describes development work to solve these issues and scaling up of the new process in the pilot plant.

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We report the discovery and optimization of an amine-promoted Friedel–Crafts alkylation of cinnamaldehyde with 4-hydroxymethyl phenol. This reaction has been used successfully on commercial scale (200 kg) in the context of the manufacture of fesoterodine, a muscarinic antagonist used for the treatment of overactive bladder. Reductive aminations of diisopropylamine and lactol 4 are also discussed, as well as the resolution of the racemic amine rac -2 into its enantiomerically pure form.