Organic Process Research & Development最新文献

Epsilon-lysine branched (ε-Kb) glucagon-like peptide-1 (GLP-1) analogs comprise a prominent class of peptide therapeutics, altering the outlook for illnesses such as type 2 diabetes and obesity, in turn necessitating manufacturing on up to ton scales. Nevertheless, the lack of sustainable approaches to ε-Kb GLP-1s has raised concerns about the viability of making ε-Kb GLP-1s with current manufacturing methods. We report a solid-phase peptide synthesis (SPPS) approach to ε-Kb GLP-1s demonstrated by a four-α-disubstituted unnatural amino acid (uAA) containing GLP-1 triple agonist as a substrate. Our approach to ε-Kb GLP-1s encompassed efficient DMF-free SPPS, which required addressing solvent quality issues and metal-free Lys(Alloc) removal, for which a His iodination side reaction had to be tackled. Minimizing the footprint of the synthesis was achieved by a dual strategy, eliminating postcoupling washes and recycling the SPPS waste stream, while FeCl₃/AcOH cleavage of ε-Kb GLP-1 peptide resin marks the expansion of TFA-free resin cleavage from 10AA to ∼40AA peptides. Taken together, our approach constitutes the first truly sustainable SPPS route to ε-Kb GLP-1s, opening up a new frontier in the commercially viable and environmentally responsible manufacturing of this notable class of incretin peptide drugs.

Lenalidomide, an anticancer drug, was synthesized using greener reaction conditions. Unlike conventional methods that utilize egregious organic solvents and expensive reagents or catalysts, our approach employs ecofriendly reaction media, cost-effective reagents, and simplified downstream processing. These modifications lead to improved green chemistry metrics, as reflected by a favorable complete E-factor (cEF) and process mass intensity (PMI). The optimized process has been successfully scaled up, affording an overall isolated yield of 62%.

Amines are widely used to synthesize pharmaceuticals, dyes, polymers, and other key molecules. To effortlessly synthesize amines from primary amides using the sequential flow process, identifying an optimal agent for the flow dehydration step is crucial. In this study, we developed a continuous flow method to convert primary amides to primary amines using sequential dehydration and hydrogenation reactions. We first optimized the dehydration step of primary amides using batch and flow conditions and then optimized the hydrogenation of nitriles under flow conditions using a pseudo solution. The dehydration step was efficiently catalyzed by cerium oxide in the presence of trichloroacetonitrile, which served as a water acceptor via a water-transfer reaction. Subsequently, selective hydrogenation was achieved using trichloroacetoamide, which is the hydrated form of trichloroacetonitrile, as the hydrogen chloride source. This integrated flow process enabled the synthesis of various primary amines with high selectivity and operational continuity, demonstrating promise for applications in the continuous flow synthesis of fine chemicals and pharmaceuticals

Safety during process development and production is paramount in the wider chemical industry, including the pharmaceutical industry. To address this challenge, members in the thermal hazards and process safety working group within the International Consortium for Innovation and Quality in Pharmaceutical Development teamed up to share, in a precompetitive collaboration, industry best practices. Initial contributions from the group have focused on thermal hazards. In this third article, we concentrate on dust explosion hazards, which are highly pertinent to the pharmaceutical industry due to the handling of dry powders, including but not limited to isolated intermediates, final active pharmaceutical ingredients, and excipients. Various unit operations such as charging, blending, and milling are capable of generating dust clouds that can potentially ignite, resulting in a flash fire or explosion. Therefore, in this effort, we asked each participating company to provide their best practices and methods used to characterize and assess this hazard. Furthermore, the authors investigated various engineering and mitigation strategies deployed when handling materials known to cause dust explosion hazards.

The Claisen–Schmidt condensation is a crucial step in synthesizing isoxazoline ectoparasiticides; however, efficient water removal in α,α,α-trifluorotoluene (TFT) is impeded by persistent emulsions that prevent Dean–Stark operation and require repeated azeotropic distillation with fresh solvent. We introduce a continuous in-line solvent-recycling method using a hydrophobic membrane separator equipped with a new stainless-steel diaphragm backer, which overcomes long-standing durability issues in halogenated solvents. The system continuously dehydrates the distillate and recycles dry solvent back to the reactor, enabling extended continuous operation. Implemented from gram to kilogram scale for chalcone intermediates, this approach achieves rapid conversion while maintaining a dry recycle stream, reducing solvent consumption and handling, and avoiding multiple heat–cool cycles. Compared to the traditional batch process, the membrane-based loop decreases solvent use, improves PMI, and is expected to lower operating costs. This practical workflow integrates with standard equipment and offers a broadly applicable route to more sustainable production of isoxazoline intermediates.

An important objective during pharmaceutical development is minimizing impurities in drug substances and drug products to levels that minimize patient risk. Regulatory guidelines such as ICH Q3A and ICH Q3B provide impurity qualification thresholds for nonmutagenic impurities, but these guidelines are intended for commercial products and when applied during early clinical development this can lead to increased drug development time and resource use. This publication presents the results of a survey conducted by the International Consortium for Innovation and Quality in Pharmaceutical Development DruSafe member companies, which aimed to gather industry experiences using non-ICH Q3A/B impurity qualification thresholds. The survey revealed that many companies implement higher qualification thresholds during early development phases, with a shift toward strict ICH Q3A/B controls in later phases. Justifications for higher thresholds often include scientific rationale based on literature, Health Authority (HA) guidance, and toxicological principles. The findings suggest that global HAs are generally accepting of higher qualification thresholds during early development, provided there is an adequate justification. This publication discusses the implications of these findings for impurity management strategies and the potential for harmonizing regulatory approaches to impurity qualification.

An improved synthetic process for isoquinoline-based antispasmodic drugs (drotaverine and papaverine) has been developed that avoids the bulk use of metal cyanides traditionally employed in the preparation of arylacetonitrile intermediates. The industrial-scale synthesis of arylacetonitrile typically involves highly toxic metal cyanides, which pose significant safety and environmental hazards. The improved process replaces the low-yielding arylacetonitrile intermediate with a substituted nitrostyrene, thereby eliminating the need for metal cyanides on the industrial scale. Additionally, the implementation of in situ reactions at the n–1 and n–2 stages, coupled with an aqueous-phase reaction in the initial step, enhances sustainability both economically and environmentally. This approach results in 83% overall yields from substituted nitrostyrene 11 and 55.5% yield of nitrostyrene 11 from catechol 3, concise synthetic route, and reduced use of bulk solvents compared to the previously opted lengthy, lower-yielding routes through nitrile claiming 31% overall yield of nitrile 5 from catechol 3 and 56.5% overall yield from nitrile 5 to the active pharmaceutical ingredient.

Characterizing the crystallization kinetics is essential for robust process design and successful scale-up execution. The accuracy of this step is dependent on key considerations, such as crystallization methods, process monitoring tools, data processing techniques, and kinetic modeling approaches. These factors often limit the effective comparison and synergistic application of findings from multiple sources, particularly in the academic domain. In this work, we seek to examine how scale, operation mode, and particle size measurement techniques influence the trends in kinetic constants for secondary nucleation and crystal growth. This study builds on prior efforts toward extracting kinetic trends using small-scale crystallization experiments to support early characterization and prediction. The focus here is to investigate the behavior of the kinetic parameters in response to changes in solvent composition. Our central hypothesis is that, while absolute values of kinetic parameters will change between scales and methodologies, the general trend (e.g., which solvents promote a given rate) will be comparable. We thus investigate two strategies for estimating kinetics in academic literature: batch desupersaturation experiments at a 5 mL suspension volume and continuous antisolvent mixed suspension mixed product removal (MSMPR) crystallization experiments at the 300 mL scale. Our results indicate that the general shape of kinetic trends (i.e., solvent comparison) translates across scales and between methods, but with significant differences in the magnitude of the estimated kinetic parameters. These results highlight the significance of standardized scale-down, material-sparing experiments for the early identification of optimal operating regions and narrowing of the design space to be investigated at larger scales.

Enarodustat (brand name Enaroy) is an oral hypoxia-inducible factor prolyl hydroxylase (PHD) inhibitor for the treatment of renal anemia in chronic kidney disease (CKD) patients. Establishing a commercial synthetic route for drug substances is essential for ensuring stable delivery to patients. To overcome challenges associated with the medicinal chemistry route, such as avoiding a cryogenic reaction and column purification, we devised a synthetic route incorporating the dichlorotriazolopyridine derivative 14 as a key intermediate, with the regioselective introduction of a phenethyl group onto it as a key step. This key step was resolved through a nucleophilic substitution employing a malonate derivative. We prepared the key intermediate by improving a known reaction which gave extremely low yields. After thorough investigation, we achieved a kilogram-scale synthesis, successfully overcoming these challenges. The overall yield was 23% in 8 chemical steps, with a purity suitable for human administration.

Herein, we report advanced applications of the direct inject liquid chromatography (DILC) system as a powerful automated tool for monitoring reaction conversions in flow reactions for the first time. The DILC system has proven highly effective in flow reactions by facilitating reaction optimization, enhancing sustainability, and minimizing human intervention. Our successful demonstration of DILC in flow mode paves the way for its potential application as an in-process control (IPC) tool to monitor both homogeneous and heterogeneous batch reactions at manufacturing scale. Building on these achievements, the implementation of DILC in flow mode not only streamlines process optimization and analytical workflows but also lays the groundwork for future advancements in automated IPC technologies.