An overview of Parkinson’s disease (PD) prevalence, diagnosis, and currently available treatment options is provided. A comprehensive list of different classes of marketed pharmaceutical drug ...products and the syntheses of various drug substances are summarized based on published literature.
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.
Glecaprevir was identified as a potent HCV NS3/4A protease inhibitor, and an enabling synthesis was required to support the preclinical evaluation and subsequent Phase I clinical trials. The enabling ...route to glecaprevir was established through further development of the medicinal chemistry route. The key steps in the synthesis involved a ring-closing metathesis (RCM) reaction to form the 18-membered macrocycle and a challenging fluorination step to form a key amino acid. The enabling route was successfully used to produce 41 kg of glecaprevir, sufficient to support the preclinical evaluation and early clinical development.
The preceding article described the development of the large-scale synthetic route to macrocycle 3 of glecaprevir (1), a potent HCV protease inhibitor. This article describes the development of the ...synthesis of the difluoromethyl-substituted cyclopropyl amino acid 4, its conversion to the fully elaborated side chain, amino sulfonamide 2, and the subsequent final coupling to form glecaprevir. The synthesis of amino acid 4 consists of four key transformations: (a) formation of the difluoromethyl-substituted cyclopropane ring of (±)-diester 15 via Knoevenagel condensation and Corey–Chaykovsky cyclopropanation, (b) diastereoselective hydrolysis of (±)-diester 15 to yield (±)-monoacid 14a–b, (c) conversion of (±)-monoacid 14a–b to (±)-amino ester 10 via a Curtius rearrangement, and (d) resolution of (±)-amino ester 10 followed by saponification to give the desired (1R,2R)-amino acid 4. The large-scale synthetic route to amino acid 4 was successfully used to produce the fully elaborated side chain 2 and ultimately the amount of glecaprevir required to support the late-stage clinical development.
Glecaprevir was identified as a potent hepatitis C virus (HCV) protease inhibitor, and a large-scale synthesis was required to support the late-stage clinical trials and subsequent commercial launch. ...The large-scale synthetic route to glecaprevir required the development of completely new synthetic approaches to the two key structural features: the 18-membered macrocycle 3 and the difluoromethyl-substituted cyclopropyl amino acid 4. In this first manuscript, we describe the route development for the macrocycle 3; the second manuscript will describe the development of a new synthetic route to the difluoromethyl-substituted cyclopropyl amino acid 4 and the final assembly of glecaprevir. The large-scale synthetic route to the macrocycle employed a unique intramolecular etherification reaction as the key step in the macrocycle synthesis, avoiding the scalability limitations of the ring-closing metathesis (RCM) reaction of the enabling route. The large-scale synthetic route to the macrocycle was successfully used to produce the amount of glecaprevir required to support the late-stage clinical development.
Laboratory experiments were performed using minimally disturbed sedimentary rocks to measure the coupled diffusion and abiotic reaction of trichloroethene (TCE) through rock core samples. Results ...showed that, for all rock types studied, TCE dechlorination occurred, as evidenced by generation of acetylene, ethene, and/or ethane daughter products. First-order bulk reaction rate constants for TCE degradation ranged from 8.3 × 10–10 to 4.2 × 10–8 s–1. Observed reaction rate constants showed a general correlation to the available ferrous iron content of the rock, which was determined by evaluating the spatial distribution of ferrous iron relative to that of the rock porosity. For some rock types, exposure to TCE resulted in a decrease in the effective diffusivity. Scanning electron microscopy (SEM) indicated that the decrease in the effective diffusivity was due to a decrease in the porosity that occurred after exposure to TCE. Overall, these coupled diffusion and reaction results suggest that diffusion of TCE into rock matrices as well as the rate and extent of back-diffusion may be substantially mitigated in rocks that contain ferrous iron or other naturally occurring reactive metals, thereby lessening the impacts of matrix diffusion on sustaining dissolved contaminant plumes in bedrock aquifers.
A practical, scalable synthetic process for a sulfonamide was developed featuring a Semmler–Wolff aromatization as the key step. The optimized reaction conditions using HCl in HOAc give directly the ...desired naphthylamine in high yield as opposed to a naphthylacetamide commonly formed in the Semmler–Wolff reactions. One little known byproduct of anomalous rearrangement, ketoamine, was observed and a mechanism proposed to explain its formation. Employing the optimized process, 360 kg was prepared to support drug development.
Despite the reported successes and advantages involving the use of amphiphilic surfactants, most notably TPGS-750-M, to enable a multitude of synthetic transformations to be conducted in water, ...implementation of this methodology within the pharmaceutical industry has been relatively limited. In this paper, we will disclose the key results and learnings from a multicompany collaboration focused on a reproducibility study involving some of the most commonly used reaction types in the pharmaceutical industry, specifically amidation, SNAr, nitro reduction, reductive amination, and multiple Pd-catalyzed transformations in water. The key to this study will be the presentation of results not just from the originally reported TPGS-750-M conditions but also under the water-only control and with three different surfactants, as well as on both small (i.e., ≤500 mg) and mid (∼10 g) scales.
Acylperrhenate reagents promote hydroxyl-directed syn-oxidative polycyclizations of primary and secondary hydroxypolyenes, forming bis- and tristetrahydrofuranyl alcohols with excellent ...trans-stereoselectivity for each tetrahydrofuran ring. The combination of dichloroacetylperrhenate/dichloroacetic anhydride affords stereoselective syn-oxidative bicyclization to bistetrahydrofuranyl alcohol products, whereas trifluoroacetylperrhenate/trifluoroacetic anhydride or trichloroacetylperrhenate/trichloroacetic anhydride are more suitable for stereoselective formation of tristetrahydrofuranyl alcohols from acyclic hydroxytrienes. In the tricyclization reaction chirality induction from a single stereogenic hydroxyl group affords diastereoselective formation of six additional stereocenters in a single step. However, we have found that the growing polytetrahydrofuran chain can exert chelation effects upon the alkoxyrhenium intermediate, thus diminishing the degree of product diastereoselectivity. These syn-oxidative cyclization synthesis strategies mimic a possible pathway for the biosynthesis of many polycyclic ether natural products, including the tristetrahydrofuran acetogenin goniocin (1).
