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A strategy for the salt selection of NBI-75043 is presented and summarized in a decision-tree format. This is followed by the first scale-up of the process, confirmation of a new polymorph, and description of a method for its conversion to the initial form.

3,5-Dimethylphenylmagnesium bromide reacts with triisopropyl borate to give 3,5-dimethylphenylboronic acid and bis(3,5-dimethylphenyl)borinic acid. Conditions were found which allowed the clean preparation of bis(3,5-dimethylphenyl)borinic acid, which was coupled with a vinyl triflate using Suzuki crosscoupling conditions. Both aryl groups were efficiently transferred from boron in the Suzuki step. IntroductionEndothelin receptor antagonists have generated considerable interest as pharmaceutical agents due to the involvement of endothelin in conditions such as pulmonary hypertension, congestive heart failure, and renal failure. 1 PD 0182783 (1) is a potent endothelin A antagonist which was considered for the treatment of pulmonary hypertension. 2 Early toxicological studies required the rapid synthesis of 3 kg of 1. After briefly exploring Negishi-type cross-coupling strategies utilizing an arylzincate, 3 the Suzuki cross-coupling reaction 4 was investigated to form the penultimate methyl ester 2. 5

Systematic surface energy modifications to glass substrates can induce nucleation and improve crystallization outcomes for small molecule active pharmaceutical ingredients (APIs) and proteins. A comparatively broad probe for function is presented in which various APIs, proteins, organic solvents, aqueous media, surface energy motifs, crystallization methods, form factors, and flat and convex surface energy modifications were examined. Replicate studies (n ≥ 6) have demonstrated an average reduction in crystallization onset times of 52(4)% (alternatively 52 ± 4%) for acetylsalicylic acid from 91% isopropyl alcohol using two very different techniques: bulk cooling to 0 °C using flat surface energy modifications or microdomain cooling to 4 °C from the interior of a glass capillary having convex surface energy modifications that were immersed in the solution. For thaumatin and bovine pancreatic trypsin, a 32(2)% reduction in crystallization onset times was demonstrated in vapor diffusion experiments (n ≥ 15). Nucleation site arrays have been engineered onto form factors frequently used in crystallization screening, including microscope slides, vials, and 96- and 384-well high-throughput screening plates. Nucleation using surface energy modifications on the vessels that contain the solutes to be crystallized adds a layer of useful variables to crystallization studies without requiring significant changes to workflows or instrumentation.

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