Organic Process Research & Development最新文献

The rigorous assessment of impurities in pharmaceutical drugs is vital to ensuring their safety and efficacy. Recent focus has centered on nitrosamines due to their known mutagenic and carcinogenic potential, initially highlighted by the presence of N-nitrosodimethylamine (NDMA) in a drug in 2018. Subsequently, similar nitrosamines have been found in other pharmaceutical drugs, raising concerns about their potential mutagenic impurities. This underscores the importance of evaluating both actual and potential impurities for bacterial mutagenicity. In alignment with ICH M7 (R2) guidelines, we have undertaken an in-silico study for the identification and control of potential mutagenic impurities in lansoprazole as a case study, which was one of the ranitidine-substituted drugs as recommended by the FDA. Through the synthetic scheme assessments, we identified the actual and potential impurities of lansoprazole. In silico bacterial mutagenicity predictions were carried out using a combination of expert rule-based and statistical rule-based methodologies according to the guidelines outlined in ICH M7 (R2). A total of 35 lansoprazole impurities were evaluated using Derek Nexus, Sarah Nexus, and Case Ultra software, wherein 9 impurities resulted in positive predictions and 26 impurities resulted in negative predictions. The impurities with positive predictions were subsequently subjected to further scrutiny using Mirabilis software to develop a control strategy. Based on the nature of the impurity and its stage of formation/introduction to the process, a hypothetical scenario using an initial concentration of each positively predicted impurity (intermediate/by-product/reagent) at its point of introduction was considered to understand its purge and fate at the final stage. This study provided critical insights into the possible presence of mutagenic impurities and facilitated the development of an appropriate control strategy to ensure the safety of the final drug substance.

A practical manufacturing process for DBPR112, a furanopyrimidine EGFR inhibitor targeting exon 20 insertion, is reported. The first-generation route afforded DBPR112 in 9 steps with an overall yield of 2.2%. A laboratory second-generation process enabled hundred-gram synthesis with an improved yield of 8.8% by streamlining purification and simplifying the introduction of the dimethylamino Michael acceptor. The kilogram-scale third-generation route was further optimized by using IPC data to minimize side product formation, particularly in the Suzuki coupling reaction and amide bond formation steps. Ultimately, 8.8 kg of DBPR112 were produced under GMP conditions with a 24.9% overall yield, supplying API for nonsmall cell lung cancer clinical trials.

The recent COVID-19 pandemic, coupled with the ongoing prevalence of other viral infections such as those caused by H1N1, Ebola, Zika, Nipah, and Chikungunya, has heightened the need for the development of effective antiviral drugs. As an initial measure, more effort was put into repurposing drugs that were readily available. The drug molecules are generally synthesized in batch processes that are time- and labor-consuming. Continuous flow chemistry offers a promising solution by enabling the rapid and scalable synthesis of these drug molecules and addressing the need for swift pharmaceutical responses. This review explores the transformative impact of continuous flow technology on the synthesis of antiviral agents in the past decade. Traditional batch synthesis processes often face challenges associated with scalability, efficiency, and safety, which can be effectively mitigated by continuous flow technology. In this review article, we have comprehensively analyzed the advancements in synthesizing antiviral compounds, such as remdesivir, nirmatrelvir, efavirenz, darunavir, brivudine, oseltamivir, and daclatasvir, by using continuous flow technology. This comprehensive overview serves as a crucial resource for researchers, chemists, and pharmaceutical scientists aiming to advance antiviral therapeutics through innovative synthetic strategies and technological integration.

3,4-Bis(4-nitrofurazan-3-yl)furoxan (DNTF) is a high-performance hydrogen-free explosive, its conventional route exhibits that the reaction mechanisms remain ambiguous, high thermal risk and the yield is relatively low. This work clarifies the oxidation/sulfonation mechanism, identifies the cause of oxidant loss, and develops an efficient and safe synthesis. First, the key intermediate 3-(4-aminofurazan-3-yl)-4-(nitrofurazan-3-yl)furoxan (ANTF) and the by-product 3-(4-aminofurazan-3-yl)-4-(amino sulfonic acid furazan-3-yl)furoxan (SNFF) were detected by HPLC-MS technique, it was also discovered and verified that SNFF can catalyze the decomposition of Caro’s acid, causing oxidant collapse by catalytically cleaving the O–O bond of peroxymonosulfuric acid, releasing O₂. Besides, density functional theory (DFT) calculation results show that oxidation reaction initiates at the amino group distal to the furoxan oxygen, with the second nitro conversion as the highest-energy step. Furthermore, it is proposed that a sulfonation reaction occurs between 3,4-bis(4-aminofurazan-3-yl)furoxan (DATF) and sulfur trioxide, followed by oxidation to generate SNFF. Notably, reaction calorimetry results showed that the oxidation process still carries a significant risk of a thermal runaway, where both excessively quick and slow feeding rates influence the yield of the oxidation process and enhanced reaction temperature and concentration of Caro’s acid indeed increase the oxidation capacity while suppressing sulfonation side reaction. By considering the balance of thermal risk and optimal process parameters, the DNTF yield could reach 75% with >99% purity.

We present a newly developed, data-assisted workflow at Bayer that integrates Bayesian optimization (BO) with CIME4R, an open-source data visualization tool with explainable AI features, to facilitate chemical reaction optimization. The workflow leverages the efficiency of BO for navigating high-dimensional reaction spaces while using CIME4R to visualize the algorithm’s decision-making process, exploration of the reaction space, and the influence and interactions of individual variables. These visualizations aid the interpretation of complex data sets and provide a platform for scientists to efficiently develop a deeper understanding of machine-learning-guided optimization campaigns, thereby improving accessibility and user trust, as well as decision-making efficiency. We demonstrate the workflow in a case study involving a new class of oxime amide ligands evaluated in Ullmann-type C–N cross-coupling reactions. This data-science-driven approach enabled the rapid identification of high-yielding conditions by sampling only 0.5% of the full parameter space within 4 days of experimental work. Feature-importance analysis revealed the solvent, propylene glycol methyl ether, as the most influential parameter, followed by K₃PO₄ as the preferred base.

JNJ-6231 was discovered as a second-generation long-acting RSV inhibitor and served as a follow-up candidate to our previous candidate JNJ-7950. Early development synthetic route investigation identified a diastereomerically pure spiro-cyclobutyl amine, an alkyl chloride containing a benzimidazole, and a chiral difluoromethyl-containing carboxylic acid as the three key building blocks to synthesize JNJ-6231. The investigation culminated in developing an enzymatic amination for the stereoselective synthesis of spiro-cyclobutyl amine with high diastereoselectivity. Subsequently, the amide group present in the spiro-cyclobutyl amine building block was regioselectively alkylated with an alkyl chloride in the presence of a free amine by employing computationally guided catalytic phase-transfer conditions. Diastereomeric salt resolution was investigated for the synthesis of chiral difluoromethyl-containing carboxylic acid. Finally, the free amine was coupled to a chiral difluoromethyl-containing carboxylic acid to give JNJ-6231. The developed synthetic route was significantly shorter, higher yielding, and employed overall safer reagents, solvents, and reaction conditions, demonstrating the integration of certain green chemistry principles in the route investigation.

Continued progress toward the development and implementation of nonprecious-metal-catalyzed transformations provides opportunities for strategic flexibility. This Review highlights reports of homogeneous nonprecious metal catalysis published from March to June 2024 that are of special relevance to process chemistry. This is a continuation of a triannual series, developed as a component of a precompetitive alliance among process chemistry groups at Abbvie, Boehringer Ingelheim, and Pfizer. We hope that the research highlighted will motivate and inspire the development of valuable, robust processes leveraging the distinct reactivity of nonprecious metal catalysts.