Organic Process Research & Development最新文献

The development and execution of a nickel-catalyzed borylation/palladium-catalyzed Suzuki telescoped process utilizing the inexpensive NiCl₂·6H₂O precatalyst for the borylation step are reported. The development of the borylation reaction was guided by a preliminary mechanistic investigation to understand the origin of the dehalogenated side product. The borylation stream was telescoped into a Suzuki coupling to form a bis-heteroaryl bond in the pentacyclic core of afimetoran, an antagonist of toll-like receptors 7/8 (TLR 7/8). The optimization of the Suzuki reaction and kilogram-scale demonstration of the telescoped process showcase the viability of utilizing nickel catalysis in the development of scalable routes to clinical APIs.

Converting spectral data to concentration is beneficial for effective crystallization process monitoring, enabling timely insights into supersaturation profiles. Calibration models are essential in this process, as they transform spectral information into concentration data. While various calibration strategies exist in the literature, they typically involve three stages: Stage 1 for baseline correction, Stage 2 for regressor selection, and Stage 3 for model form selection. In this study, we systematically evaluated all common strategies within each stage, combining them through a Design of Experiments (DoE) approach using a single paracetamol (PCM) and p-acetoxyacetanilide (PAA) crystallization system. The results showed that Savitzky–Golay Second Derivative (SGSD) performed best for baseline correction (Stage 1), while selecting spectral data from a specific range yielded the highest accuracy in regressor selection (Stage 2). For model selection (Stage 3), Partial Least Squares Regression (PLSR), Principal Component Regression (PCR), and Artificial Neural Network (ANN) were assessed with three optimized models deployed to monitor four crystallization runs in real time. During deployment, PLSR demonstrated the most moderate concentration prediction. However, when comparing all three model forms, the standard deviation of predicted concentrations ranged from 4% to 6% for PCM and 10% to 30% for PAA, with similar performance across all models. Validation against offline High-Performance Liquid Chromatography (HPLC) data showed relative errors of 0–12% for PCM, while PAA predictions had higher errors ranging from 0 to 50⁺%, largely due to PAA’s lower concentration range (10–20 g/L) compared to that of PCM (100–350 g/L). These findings indicate that while online models provide useful real-time approximations, precise measurements still require offline validation.

The synthesis of mirogabalin was studied for industrial production and an alternative to Daiichi–Sankyo’s method was established. The developed synthesis involves the introduction of a two-carbon unit with the stereoselective 1,4-selective addition of lithioacetonitrile to alkylidene malonate and one-carbon degradation by the Hofmann rearrangement. The precursor for the Hofmann rearrangement was readily prepared from the 1,4-adduct via a one-pot reaction involving decarboxylation, hydrolysis, and hydration.

Cross-coupling reactions have revolutionized synthetic chemistry by significantly expanding the scope of carbon–carbon (C–C) and carbon–heteroatom bond formation, making them invaluable tools in the design and synthesis of pharmaceuticals, natural products, and advanced materials. Despite recent advancements in making these reactions more sustainable, some challenges remain, such as the requirement for high temperatures and extended reaction times. In recent decades, flow chemistry has emerged as a powerful solution, with microreactor technology offering numerous advantages for cross-coupling reactions. These include improved reaction efficiency, better heat and mass transfer, and the potential for more environmentally friendly conditions. This review aims to provide a concise and up-to-date guide on recent advancements in flow chemistry as applied to Pd-catalyzed cross-coupling reactions, including Suzuki, Heck, Sonogashira, Negishi, Stille, and Buchwald couplings. By presenting unified schemes for these reactions, the aim of this review is to provide quick and helpful comparisons to readers in order to select optimal reaction conditions based on their starting materials, streamlining the decision-making process in synthetic chemistry.

(+)-Biotin plays an essential role as a cofactor in many biological systems and is used to supplement the diets of humans and animals. One of the most elegant chemical production processes involves the asymmetric hydrogenation/desymmetrization of a meso-anhydride to yield the key lactone intermediate. However, relatively high catalyst loadings limit the attractiveness of this route. A number of strategies have been investigated to improve the efficiency of the hydrogenation process, and an improved two-step process has been developed, which significantly reduces the amount of expensive chiral catalyst required and pairs this with a cheap, readily available nickel catalyst, producing the key chiral lactone without a reduction in the enantioselectivity.