Early Process Development and Scale-Up of Orally Active Apomorphine Drug Candidates

Abstract

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.

Natural Product-Inspired Dopamine Receptor Ligands

“…Similarly, a series of N -alkyl-2-methoxy-11-hydroxynoraporphines was synthesized from thebaine ( 44 ) and evaluated for binding affinities at dopamine receptors in rat forebrain tissue . The most selective 11-monohydroxy aporphine was MCL-509 ( 45 ) ( K i D 1 = 1,690 nM, K i D 2 = 44 nM), an orally active Parkinson’s disease drug candidate …”

“…113 The most selective 11-monohydroxy aporphine was MCL-509 (45) (K i D 1 = 1,690 nM, K i D 2 = 44 nM), an orally active Parkinson's disease drug candidate. 114 D 2 receptors exist in two states, either as a functionally inert low-affinity state (D 2 low R) or as a functional high-affinity state (D 2 high R). 115 The high-affinity and low-affinity receptors show a biphasic competition curve and have different binding affinities to various ligands.…”