Tecastemizole, an active metabolite of the histamine H 1 -receptor antagonist Astemizole (Hismanal), crystallizes out in two polymorphic forms (form A and form B). Thermodynamic stability screening results show that form A is more stable and form B is kinetically favorable (metastable) in the temperature range of process interest. A process design switch from a seed controlled growth approach to a solvent mediated interconversion based approach was adopted for reasons of simplicity and robustness during early Phase II development. The effects of dissolution, mass transfer, and surface-controlled growth on the observed interconversion rate were studied under well-defined seeding conditions. The experimental results show a significant effect of operating temperature on the interconversion rate and also show that the rate-limiting step is the growth of form A. Growth controlled kinetic parameters were estimated and are reported here. A nonlinear cooling profile was developed to take advantage of the temperature rate effect on form interconversion. Scale-up of the modified procedure was performed at both pilot and full-scale manufacturing, and the results confirmed the laboratory findings.

The scale-up of a prototype HCV protease inhibitor (1) from gram-scale in the laboratory to kilogram-scale in the pilot plant is described. Key features of the optimization included synthesis of bulk quantities of exomethylene proline intermediate 6, separation the diastereomers of spirocycle 2 without chromatography, isolation of the precursor to 1 to purge by-products which might raise genotoxic structural alerts, and purification of an amorphous drug substance via a crystalline acetic acid solvate.

A recent report suggests that the reaction of dimethylsulfoxonium methylide with esters does not produce a chain‐extended sulfur ylide as previously reported, but rather affords the corresponding carboxylate salt. We have investigated this assertion by using a combination of ab initio molecular orbital calculations, spiking studies, and isotopic labeling. The formation of carboxylate is unambiguously demonstrated to arise through hydrolysis involving adventitious water, principally derived from moisture in commercial trimethylsulfoxonium chloride. Careful vacuum drying of this reagent diminishes the competing hydrolytic pathway resulting in higher yields for the chain‐extension reaction than previously reported.

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