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.
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.
Appropriate control of impurities from all sources is critically important during the development of a pharmaceutical product. One class of impurity that has gained considerable attention over the ...past few years is extractables and leachables. We report a model for assessment of the risk posed by leachable impurities for a small-molecule drug substance. The first step of this study consists of a high-level assessment of the risk posed by leachable impurities in the drug substance, by taking into account the drug product’s route of administration. In the case of parenteral route of administration, a more comprehensive process-specific second step risk assessment is typically warranted. This second step consists of risk assessment of polymer component(s) for the potential to release leachable impurities, risk scoring, and classification. For high-risk components, risk mitigation studies can be performed in step 3, such as leachable impurity removal via component pre-flush with the process solvent, extractables’ studies under harsher conditions, and toxicity assessments.
Enantiomerically pure sulfinimines (thiooxime S-oxides 10), important building blocks in the asymmetric synthesis of amine derivatives, are prepared in good to excellent yields in one step from ...aromatic, heteroaromatic, and aliphatic aldehydes. This protocol involves treating commercially available (R)- or (S)-menthyl p-toluenesufinate (Andersen reagent 4) with LiHMDS, followed by the aldehyde, affording (E)-10 exclusively. The sulfinimines 10 are formed via a Peterson-type olefination reaction of silylsulfinamide anion 13 with the aldehyde. Anion 13 is generated by reaction of lithium menthoxide (12a) with bis(trimethylsilyl)sulfinamide 11, which is formed in the reaction of 4 with LiHMDS. The other product formed is O-(trimethylsilyl)menthol (12c), which is isolated in >80% yield for recycling. Two other less efficient methods for the asymmetric synthesis of 10 are discussed: (i) the asymmetric oxidation of sulfenimines 6 with chiral nonracemic oxaziridines and (ii) the reaction of metal aldimines, prepared from nitriles, with 4. All of these protocols fail with ketones.
An efficient method was developed for synthesis of 2-acetylbenzo(b)thiophene (2a), the key intermediate for zileuton (1). Synthesis involves treatment of 2-chlorobenzaldehyde (5a) with ...tert-butylmercaptan (6) to form 2-(tert-butylthio)benzaldehyde (7a), which upon treatment with HBr in water gave the disulfide derivative 2,2′-disulfanediyldibenzaldehyde (8a) in 97% yield. Finally, the reaction of 8a with acetylacetone (9) and 1-chloroacetone (10) gave 2-acetylbenzo(b)thiophene (2a) in 94% yield. The methodology is general and suitable for the preparation of its derivatives, 2b-d.
An efficient synthesis of (
S)-(−)-acromelobic acid (
1
) and (
S)-(−)-acromelobinic acid (
2
) is described via asymmetric hydrogenation protocol. Asymmetric hydrogenation of dehydroamino acid ...derivative
23
using (
R,
R)-Rh(DIPAMP)(COD)BF
4 catalyst followed by removal of the protective groups afforded (
S)-(−)-acromelobic acid (
1
) in >98% ee. The key intermediate
23
was prepared from citrazinic acid (
8
). The dehydroamino acid derivative
33
required for the synthesis of
(
S)-(−)-
2
was prepared from 2,5-lutidine (
27
), which upon hydrogenation using (
S,
S)-Rh(Et-DuPHOS)(COD)BF
4 catalyst afforded
(
S)-(+)-
34
in 93% yield and >96% ee. Removal of protective groups in
(
S)-(+)-
34
afforded (
S)-(−)-acromelobinic acid (
2
) in good overall yield.
The total synthesis of (
S)-(−)-acromelobic acid (
1
) and (
S)-(−)-acromelobinic acid (
2
) via catalytic asymmetric hydrogenation in >96% ee's and good overall yield is described.
A series of 3,7-dihydroimidazo1,2
apyrazine-3-ones were prepared from 2-amino-3,5-dibromopyrazine. The concise synthesis of coelenterazine (
5j
), in three steps, 48% overall yield and >99% purity ...exemplifies the strategy. Further, the synthetic approach facilitated the regiospecific incorporation of carboxyalkyl linkers on the 3,7-dihydroimidazo1,2
apyrazine-3-one nucleus that are required for bioconjugation. Peroxymonocarbonate, an electrophilic oxidant, was used to initiate ‘pseudo-flash’ chemiluminescence from this class of molecules.
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Open-angle glaucoma (OAG) is a chronic and degenerative condition that causes optic nerve damage and potential blindness. The objective of this review is to provide a brief overview on OAG with ...emphasis on the importance of prostaglandin analogues for eye care. Bimatoprost (6) is an important prostaglandin analogue widely used in several medications for the treatment of open-angle glaucoma. A literary review of the various approaches reported for the synthesis of bimatoprost (6) drug substance is presented. In addition, the reported bimatoprost (6) synthetic routes are assessed to identify strengths and weaknesses from a drug substance process chemistry perspective. A summary of bimatoprost (6) synthetic routes assessment is also provided based on drug substance quality, process, and environmental considerations.
