Scalable Asymmetric Syntheses of Foslevodopa and Foscarbidopa Drug Substances for the Treatment of Parkinson’s Disease

Abstract

Foslevodopa (FLD, levodopa 4′-monophosphate, 3) and foscarbidopa (FCD, carbidopa 4′-monophosphate, 4) were identified as water-soluble prodrugs of levodopa (LD, 1) and carbidopa (CD, 2), respectively, which are useful for the treatment of Parkinson’s disease. Herein, we describe asymmetric syntheses of FLD (3) and FCD (4) drug substances and their manufacture at pilot scale. The synthesis of FLD (3) employs a Horner–Wadsworth–Emmons olefination reaction followed by enantioselective hydrogenation of the double bond as key steps to introduce the α-amino acid moiety with the desired stereochemistry. The synthesis of FCD (4) features a Mizoroki–Heck reaction followed by enantioselective hydrazination to install the quaternary chiral center bearing a hydrazine moiety.

Catalytic Asymmetric α-Functionalization of α-Branched Aldehydes

“…In a recent variation of the aminocatalytic α-hydrazination of α-branched aldehydes pioneered by Brässe and Barbas, independently, an industrial group at AbbVie Inc. (North Chicago, IL, USA) has reported the α-hydrazination of aldehyde 16 as a key step in the total synthesis of foscarbidopa, a phosphate prodrug of carbidopa for the treatment of Parkinson’s disease ( Scheme 6 ) [ 53 ]. Under optimized conditions using tetrazole-proline catalyst C2 and TFA as additives in acetonitrile, the hydrazine-aldehyde 17 was obtained in 84% yield and 57% ee .…”

Parkinson’s Disease: Advances in Treatment and the Syntheses of Various Classes of Pharmaceutical Drug Substances

“…The (±)-aldehyde product (152) was isolated as its bisulfite adduct (±)-153. In the next step, the bisulfite adduct (153) was cleaved in situ with sodium bicarbonate, and the aldehyde intermediate (152) was phosphorylated using tetrabenzyl pyrophosphate (142, TBPP) to provide (±)-aldehyde 154 in 92% yield over the two steps. The (±)-aldehyde 154 was converted preferentially to the (S)-enantiomer of hydrazine intermediate 156 using catalyst (R)-155 with excellent conversion (93%) in 60% ee, which was increased to >99% ee upon crystallization.…”

“…Finally, hydrogenolysis of (S)-acid 157 using Pd/C as catalyst enabled isolation of foscarbidopa (149) in 97% yield and >99% ee. 153 With foslevodopa (139) and foscarbidopa (149) in hand, the viability of this prodrug combination in continuous subcutaneous dosing studies was assessed both in preclinical and Phase I clinical trials. 152 One year stability at high concentration of foslevodopa (139) and foscarbidopa (149) aqueous solution (e.g., 240:12 and 360:18 mg/mL respectively) across a wide pH range (6.5−9.2) showed excellent pharmacokinetic profile (PK) and tolerability were observed in preclinical species.…”

Fueling the Pipeline via Innovations in Organic Synthesis

“…Regioselective larger-scale routes to both FLD and FCD were subsequently developed in collaboration with process chemistry. 34 With FLD/FCD in hand, we assessed their stability, solubility, and effectiveness in continuous SC dosing studies both preclinically and in PhI clinical trials. 30 We were surprised to find excellent stability (<2% change for >1 year) at high concentration (e/g/, 240/12 and 360/18 mg/mL) across a wide pH range (6.5−9.2) with excellent PK and tolerability in preclinical species.…”

“…This solid form isolation was a key step forward in building confidence to pursue alternative routes to FCD. Regioselective larger-scale routes to both FLD and FCD were subsequently developed in collaboration with process chemistry …”