Studies of X–Ni–C6F4I···X–Ni–C6F4I halogen-bonded networks reveal pronounced differences between fluoride (X = F) and other halides: the 19F-MAS NMR spectrum is a sensitive probe of the halogen bond.

An environmentally benign iron-catalyzed nonclassical Polonovski reaction has been developed and scaled up to accomplish the challenging N-demethylation of MCL-509 Methyl to secondary amine MCL-509 Amine.HCl, key intermediates on the route to potential Parkinson's treatment, MCL-509. The optimized reaction proceeded via the N-oxide in 2 h at room temperature in methanol/water using a mild stoichiometric oxidant and iron catalysis to yield the crystalline amine as its HCl salt directly from the reaction solution in typically 84% yield and 96% purity, after requiring only a screening filtration and facile solvent swap. This reaction was a great improvement in every aspect over the chloroformate-mediated and classical von Braun reactions utilized previously, especially for environmental, health, safety, and operability reasons. Robustness on scale was proven by the minimal technical transfer support required and the lack of any issues with all manufacturing batches produced in reproducible yields and consistent quality.

Nickel fluoride complexes of the type [Ni(F)(L)2(ArF)] (L = phosphine, ArF = fluorinated arene) are well-known to form strong halogen and hydrogen bonds in solution and in the solid state....

The manufacturing route to a novel apomorphine Parkinson’s drug candidate (MCL-509) has been developed from a mg laboratory scale to that suitable for use on a 20–50 L scale. While the synthetic sequence could not be bettered, all six reaction steps required significant improvement for scale-up. Hazardous and toxic reagents and hazardous steps were removed; all concentrations to dryness and chromatographic purifications were eliminated; isolations were operationally simplified, and plant cycle times were shortened. Two pairs of steps (1 and 2; 5 and 6) were successfully telescoped, and steps 3, 4, and 5 were re-imagined such that all three steps were substantially redeveloped with alternative reagents. Now relying solely on crystallizations for isolation, the yield, purity, and color of each intermediate was greatly improved. All six process steps were easily transferred to the pilot plant with only minimal accommodation work required prior to manufacture on a 20–50 L scale per batch. Thus, the manufacturing campaign performed essentially as expected and without issues while delivering an approximate 10-fold increase in material yield alongside the requisite quality improvements.