In the copper salt catalyzed ether formation from aryl bromides or iodides and phenols, 2,2,6,6-tetramethylheptane-3,5-dione (TMHD) was found to greatly accelerate the ordinarily difficult reaction, ...making it occur under more moderate temperatures and reaction times. A series of aryl halides and phenols were shown to form ethers in NMP as the solvent, cesium carbonate as the base, and CuCl and TMHD as the catalysts. The reaction was shown to tolerate electron-rich aryl bromides and electron-neutral phenols.
AB680 is a highly potent small-molecule CD73 inhibitor discovered and developed by Arcus Biosciences, currently in clinical trials for the treatment of pancreatic cancer. Herein, we report a concise ...synthesis of 4,6-dichloro-1H-pyrazolo3,4-bpyridine 3, which is the central azaindazole core of AB680. The process consists of four synthetic operations and three isolations, including a PMB-protected pyrazole formation, a telescoped two-step cyclization and aromatization sequence, and finally a one-pot PMB deprotection and chlorination to furnish 3. This chemistry was successfully scaled up to provide >200 g of 3 in 44% overall yield and 97.6% HPLC purity. Overall, the route developed toward 3 represents an efficient construction of an azaindazole core, which is a synthetically challenging yet prevalent structural motif.
Palladium-catalyzed cyanation of aryl bromides is a powerful approach to install a functional group commonly found in active pharmaceutical ingredients starting from readily available precursors. The ...development of a robust cyanation of a bromo benzoic acid to generate an intermediate en route to etrumadenant is described. Full conversion with catalyst loading as low as 0.13 mol % was enabled by study of the catalyst preactivation step, which was affected by trace water levels. Details of the scale-up of this process to the hundred-kilogram batch size are included.
2-(2H-Tetrazol-2-yl)benzoic acid 1 and analogs were prepared via Cu(I) catalyzed C–N coupling of 2-iodo or 2-bromo benzoic acids with 5-(ethylthio)-1H-tetrazole followed by reductive cleavage of ...the thioether bond. The C–N coupling was regioselective toward the N2-position on tetrazole. The scope of this methodology was demonstrated on a series of 2-halobenzoic acid substrates in moderate yields.
The development of a concise asymmetric synthesis of the antiviral development candidate letermovir is reported, proceeding in >60% yield over a total of seven steps from commercially available ...materials. Key to the effectiveness of this process is a novel cinchonidine-based PTC-catalyzed aza-Michael reaction to configure the single stereocenter.
Herein, we present a strategy for the preparation of 3′-fluorinated nucleoside analogues via the aminocatalytic, electrophilic fluorination of readily accessible and bench-stable 2′-ketonucleosides. ...Initially developed to facilitate the manufacture of 3′-fluoroguanosine (3′-FG)a substructure of anticancer therapeutic MK-1454this strategy has been extended to the synthesis of a variety of 3′-fluoronucleosides. Finally, we demonstrate the utility of the 2′-ketonucleoside synthon as a platform for further diversification and suggest that this methodology should be broadly applicable to the discovery of novel nucleoside analogues.
A kilogram-scale synthesis of a key fragment of Ulevostinag (MK-1454), a cyclic dinucleotide agonist of the stimulator of interferon genes (STING), is described. Ulevostinag comprises two non-natural ...nucleoside derivatives linked together via two P-chiral phosphorothioate groups. The strategy utilized to prepare one of these nucleosides, namely, 3′-deoxy-3′-α-fluoro-guanosine (3′-FG), hinges on a diastereoselective α-fluorination of a key keto-nucleoside derivative, followed by substrate-directed reduction of the ketone. Herein, we describe the development of a robust and scalable synthesis of this intermediate, a 3′-deoxy-2′-keto-guanosine derivative, from guanosine. Salient features of the approach include activation of the 2′ and 3′-alcohol groups of guanosine as a bis-tosylate, which enables regioselective E2 elimination to simultaneously deoxygenate the 3′-position and generate the 2′-ketone.
The application of bicyclo1.1.1pentanes (BCPs) as phenyl bioisosteres has garnered significant attention, as these structural motifs can improve the physiochemical profiles of drug candidates. ...Despite the potential of using 1-bicyclo1.1.1pentylpyrazoles (BCPPs) as 1-phenylpyrazole bioisosteres, this area remains underexplored because of the relative lack of reliable synthetic methods for the preparation of BCPPs. Herein we address this synthetic gap and report the development of novel and scalable routes to generate a host of BCPPs.
An efficient route to the HCV antiviral agent uprifosbuvir was developed in 5 steps from readily available uridine in 50% overall yield. This concise synthesis was achieved by development of several ...synthetic methods: (1) complexation-driven selective acyl migration/oxidation; (2) BSA-mediated cyclization to anhydrouridine; (3) hydrochlorination using FeCl
3
/TMDSO; (4) dynamic stereoselective phosphoramidation using a chiral nucleophilic catalyst. The new route improves the yield of uprifosbuvir 50-fold over the previous manufacturing process and expands the tool set available for synthesis of antiviral nucleotides.
An efficient route to the HCV antiviral agent uprifosbuvir was developed in 5 steps from readily available uridine in 50% overall yield.
A simple and efficient process to prepare Uprifosbuvir intermediate, 2′-deoxy-α-2′-chloro-β-2′-methyluridine (1), from bis-pivaloyl tertiary alcohol 5a is described. The key discoveries are a novel ...BSA-promoted anhydrouridine formation catalyzed by HCl as an additive and a milder safe Me2SiCl2-promoted chlorination of anhydrouridine. These discoveries collectively enabled the establishment of a robust process toward compound 1, which was demonstrated successfully at the plant scale.
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