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This article delineates the systematic identification, synthesis, and impurity control methods used during the manufacturing process development of tecovirimat, an antiviral drug that treats monkeypox. Critical impurities were synthesized, and their chemical structure was confirmed through NMR analysis, GC, and HPLC mass spectrometry. The results established a thorough approach to identify, address, and control impurities to produce high-quality tecovirimat drug substance in accordance with International Conference on Harmonization (ICH)-compliant standards. This study is the first of its kind to evaluate both process and genotoxic impurities in tecovirimat, demonstrating effective control measures during commercial sample investigations and scaling up to a 60-kg batch size. The findings highlight the importance of critical impurity characterization and control in pharmaceutical development and production to ensure the safety and efficacy of the final product.
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A facile synthetic pathway for sildenafil has been developed. This approach is characterized by a ligand-free Ullmann-type copper-catalyzed coupling reaction to construct sildenafil and its derivative, pyrrazolo[4,3-d]pyrimidin-7-one ring, with yields of 79% and 82%, respectively, in a convergent fashion by connecting key building blocks halo-pyrazole moiety 16c with 2-ethoxybenzamidine and 2-ethoxy-5-[(4-methylpiperazin-1-yl)sulfonyl]benzamidine in a one-pot reaction. Thus, this approach circumvents the need to use nitric/sulfuric acid for nitration, a costly Pd-catalyst for reduction, and coupling agents encountered in the reported processes.
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Amides are important intermediates in organic chemistry and the pharmaceutical industry, but their low reactivity requires catalysts and/or severe reaction conditions for esterification. Here, a novel approach was devised to convert amides into esters without the use of transition metals. The method effectively overcomes the inherent low reactivity of amides by employing dimethylsulfate-mediated reaction to activate the C-N bonds. To confirm the proposed reaction mechanism, control experiments and density functional theory (DFT) calculations were conducted. The method demonstrates a wide array of substrates, including amides with typical H/alkyl/aryl substitutions, N,N-disubstituted amides, amides derived from alkyl, aryl, or vinyl carboxylic acids, and even amino acid substrates with stereocentres. Furthermore, we have shown the effectiveness of dimethylsulfate in removing acyl protective groups in amino derivatives. This study presents a method that offers efficiency and cost-effectiveness in broadening the esterification capabilities of amides, thereby facilitating their increased utilization as synthetic compounds in diverse transformations.
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We present an improved copper-catalyzed cyclization for an efficient synthesis of benzimidazoles from o-bromoarylamine and nitriles, under mild and ligand-free conditions. The optimal conditions yielded exceptional products of up to 98%, demonstrating the broad applicability of this synthetic strategy in generating a wide range of valuable imidazole derivatives. This methodology enables the efficient synthesis of various substituted benzimidazole derivatives and offers an environmentally friendly alternative to conventional methods. By eliminating the use of harsh reagents and high temperatures associated with traditional synthesis approaches, this method proves to be more efficient and robust. Notably, we successfully applied this synthetic approach to the synthesis of bendazol and thiabendazole, yielding 82% and 78%, respectively, on a 100 gram scale.
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A facile synthesis of benzimidazoles was described by a one-pot process containing acylation-cyclization of N-arylamidoxime. This method provided an alternative synthesis of benzimidazoles with a certain diversity of substituted groups in acceptable yields (up to 96%). More importantly, the construction of bis-benzimidazole (8), the key intermediate for making telmisartan, was achieved by adopting this method that enabled avoiding the undesired nitration with nitric/sulfuric acid and the cyclization in polyphosphoric acid in the existing operations.
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Citrus is one of the largest output fruits in the word. In China, the major orange variety is the Citrus reticulate Blanco (Ponkan). The peels are discarded as waste material, its comprehensive utilization is urgently needed. In this work, hydrodistillation method was developed to extract citrus essential oil (EO) from Blanco peel. With the optimal extraction conditions, the EO yield was more than 3%. By GC-MS analysis, 53 compounds were identified from the citrus EO. Terpenes compounds accounted for 71.2%, especially d-limonene (major composition) accounted for 58.9%. The obtained citrus EO showed remarkable antibacterial activity against Cutibacterium acnes (C. acnes, Formerly P. acnes) and common microorganisms such as S. aureus, B. subtilis, and E. coli. Even compared with the common antibiotics (such as erythromycin, clindamycin, and tetracycline) for acne therapy, its antibacterial activity against C. acnes is more excellent. This work provides a potential therapy material for the treatment of acne.