Organic Process Research & Development最新文献

Casdatifan (AB521) is a potent and selective inhibitor of HIF-2α, currently under clinical evaluation for the treatment of clear cell renal cell carcinoma (ccRCC). Here, we report the development of a scalable synthesis of casdatifan, which was used to support its preclinical characterization and the initiation of phase 1 clinical studies. A convergent approach to assembling the tetracyclic scaffold and the development of efficient routes to key intermediates enabled the successful delivery of material to meet clinical development timelines. Crucial to the efficiency of the synthesis was the strategic design of synthetic routes that leverage a combination of substrate and catalyst control to set each of the 5 stereocenters found in the molecule with exquisite selectivity.

Development and optimization of phase-appropriate synthetic technologies to prepare KTX-005, a potent muscarinic acetylcholine receptor agonist, are described in this article. The modular strategy involves three building blocks: commercially available materials dichlorothiadiazole (21), butanethiol (22), and custom-synthesized azabicyclo derivative (18). The highlight of the enabling synthetic strategy toward KTX-005 is a unique thiadiazole ring opening/closing sequence to facilitate both dichlorothiadiazole desymmetrization with butanethiol as well as functionalization of the azabicyclo ring derivative 18.

This report describes a comprehensive differential scanning calorimetry (DSC) evaluation of difluoromethoxy-containing aromatic building blocks. Central to this evaluation is a comparison between DSC thermograms obtained in a glass capillary and those obtained in a gold-plated crucible. The decomposition of difluoromethoxybenzene is shown to be autocatalytic in a glass capillary. A diverse series of difluoromethoxy arenes were evaluated, and most exhibited dichotomous, vessel-dependent decomposition. This distinction raises concerns about glass-facilitated thermal decomposition and safety concerns regarding materials of reactor construction. This study underscores the importance of reactive chemistry evaluations in the development of new fluorinated chemicals, especially when using glass equipment.

1,3,2-Dioxathiolane 2,2-dioxide (DTD) plays a significant role as an electrolyte additive in lithium-ion batteries. It can enhance battery performance, stability, and safety. Additionally, it is a commonly used hydroxylation reagent in organic chemistry. This paper presents a highly efficient, safe preparation, and environmentally friendly continuous DTD synthesis process that does not require catalyst separation. A fixed-bed reactor was constructed with spherical TS-1 as the catalyst and H₂O₂ as the oxidizer. Under optimized reaction conditions, efficient oxidation of ethylene sulfite (ES) was achieved using dimethyl carbonate as a solvent. The process involved controlling the reaction temperatures at gradients of 10 and 5 °C, respectively, maintaining a molar ratio of H₂O₂ to substrate of 1.05:1, a liquid hourly space velocity of 0.6 h^–1, and using a 30 wt % concentration of H₂O₂ at a substrate concentration of 1 mol/L. The conversion rate was up to 99.5%, and the selectivity of DTD was 99.1%. To prevent hydrolysis of DTD, a continuous separation operation was initiated immediately after the completion of the reaction, and the yield of DTD reached 96%. The successful application of this process not only improves the production efficiency of DTD and reduces the production cost but also establishes the foundation for the industrialized continuous production of DTD.

The methodology of solid-phase peptide synthesis (SPPS) has been a key driver behind the significant advancements and growing interest in peptides for drug discovery. SPPS has many advantages, including short production times, automation compatibility, and versatility. However, it is like a black box as the intermediates are not isolated, and the results are unknown until the end of the entire process unless the synthesis is stopped, samples are taken, and analyses are performed to know the course of the synthesis. However, this is time-consuming and impacts cost-effectiveness. A key aspect of SPPS is accurately determining the initial loading of the resin. Overestimating the loading compared to the actual value leads to the use of a greater excess of reagents, which can enhance the purity of the final product but incurs higher economic costs. In contrast, underestimation of loading can lead to the formation of deletion peptides. The most widely used method to calculate resin loading is via the incorporation of an Fmoc derivative and then removal of the Fmoc group with piperidine, followed by the UV spectrophotometric determination of the dibenzofulvene-piperidine adduct. This operation requires halting the synthetic process, and it is time-consuming. Herein, the quantitative use of the refractometry index is proposed for the online determination of resin loading. This approach enables real-time monitoring of the reaction, allowing the process to be stopped when the desired loading is achieved or to add more coupling reagents to improve loading.