Organic Process Research & Development最新文献

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.

The novel LpxC inhibitor T-1228 is a candidate drug molecule for multidrug-resistant Gram-negative bacterial infection. This report describes the synthesis of the diol unit of T-1228, (S)-1-(4-ethynylphenyl)ethane-1,2-diol, from commercially available 2-bromo-1-(4-iodophenyl)ethan-1-one, achieved in 5 steps and 4 isolations. The stereogenic center of the diol unit was created by means of a highly scalable form of the Corey–Bakshi–Shibata reduction; process parameters were optimized using the Design of Experiments methodology. Using this newly developed process chemistry route, we successfully synthesized 12.5 kg of (S)-1-(4-ethynylphenyl)ethane-1,2-diol in 60% total yield and optical purity >99% ee.

The novel LpxC inhibitor T-1228 is a candidate drug molecule for multidrug-resistant Gram-negative bacterial infection. This report describes the synthesis of the malonamide derivative,(2S)-2-(4-iodo-N-methylbenzamido)-N¹,2-dimethyl-N³-((tetrahydro-2H-pyran-2-yl)oxy)malonamide, containing the quaternary stereogenic core of the novel LpxC inhibitor T-1228 from commercially available diethyl 2-bromo-2-methylmalonate in 8 steps and 2 isolation. The quaternary stereogenic center of the malonamide core was created via enzymatic desymmetrization, by treating the malonic ester derivative, diethyl 2-(((benzyloxy)carbonyl)(methyl)amino)-2-methylmalonate, with porcine liver esterase. To control impurities that could negatively affect the quality of the drug substance, a novel approach for producing the final intermediate, (S)-2-(4-((4-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)phenyl)ethynyl)-N-methylbenzamido)-N¹-hydroxy-N³,2-dimethylmalonamide, was also developed, in which a selective deprotection reaction was incorporated. Using this newly developed process chemistry route, we have successfully synthesized 38.8 kg of the malonamide derivative and 13.5 kg of the final intermediate.

Traditional solid-phase peptide synthesis (SPPS) is limited in its suitability for high-volume peptide/protein manufacturing applications due to its reliance on specialized equipment, high process mass intensity (PMI), and the use of environmentally concerning reagents. To address these limitations, a fully liquid-phase peptide synthesis (LPPS) has been developed and applied to the synthesis of a tirzepatide (30–39) fragment intermediate. This method leverages Fmoc- and Cbz-protecting group strategies to generate two high-purity crystalline pentamers entirely without solid-phase techniques. Subsequent solution-phase assembly of the pentamers yields the desired decapeptide. This green, efficient, and practical route offers a more economical and environmentally favorable alternative to SPPS, delivering a fragment intermediate of superior quality. Additionally, tirzepatide (30–39) decapeptide is a potential common intermediate for numerous other incretin peptides using hybrid SPPS/LPPS methodologies.

Thermal runaway in the final condensation step of the clethodim synthesis has caused severe industrial accidents (e.g., the 2020 Liaoning explosion, with 5 deaths). This study focused on the thermodynamics, kinetics, and thermal stability of this step to ensure process safety. Reaction calorimetry was used to determine the reaction heat, with Δ_rH_m,A = 45,000 J mol^–1 and adiabatic temperature rise ΔT_ad = 35 K. The kinetic parameters were determined, revealing an activation energy E_a of 47,000 J mol^–1, a pre-exponential factor k of 17,185 L mol^–1 s^–1, and the reaction followed second-order kinetics. Differential Scanning Calorimetry and AKTS software revealed that CPHA and clethodim have high thermal decomposition risks, with T_D24 values of 65 and 75 °C, respectively, while EPCO was stable below 300 °C. Risk assessment (T_P, MTSR, MTT, T_D24) showed that the hazard criticality level of normal semibatch feeding was 2, and that of one-time batch feeding was 5, which was of high risk. However, with good mixing, if the time needed to reach T_D24 was considered, the risk would also be under control. The 2020 accident was caused by feed errors and local overheating (no mixing/heat transfer). This work provides kinetic data and safety measures for clethodim production.

A chemoenzymatic route is disclosed for the synthesis of the antidepressant drug Moclobemide, a reversible and selective inhibitor of the monoamine oxidase A (MAO-A) enzyme. The reactivities of 4-chlorobenzoic acid and ethyl 4-chlorobenzoate with 4-(2-aminoethyl)morpholine have been studied by using immobilized lipases as biocatalysts in organic media. The optimal reaction conditions were found using a well-known and commercially available lipase, Candida antarctica lipase type B (CAL-B), which efficiently catalyzes the aminolysis reaction of ethyl 4-chlorobenzoate. After CAL-B was identified as the best enzyme for this biotransformation, an optimization study of the reaction conditions was performed, analyzing the influence of different parameters such as ester and amine concentrations, CAL-B loading, organic solvent type, temperature, and reaction time. This has allowed the synthesis of the desired Moclobemide in a high isolated yield (86%) at the gram scale.

CC-99677 is an irreversible inhibitor of mitogen-activated protein kinase (MAPK)-activated protein kinase 2 (MK2) that sustainably reduces production of proinflammatory cytokines in vitro. The design and development of a concise synthetic route enabled production of multikilogram quantities for early-stage clinical trials. Continued synthesis at increasing scale required an improved route to fragment 21 to bypass the energetic chemical reactions and attendant process safety challenges posed within the enabling route. Subsequently, protecting groups and counterions were optimized and an improved API recrystallization was developed for the intended commercial route. Over the course of development, the step count was reduced from 19 to 7 (a 63% reduction), and overall yield increased from 1.3 to 37% (a nearly 30-fold improvement) while improving robustness, safety characteristics, and control overcritical quality attributes required of a commercial process.

AMG 193 is an MTA-cooperative PRMT5 inhibitor that has shown promising antitumor activity in the clinic. Despite a five-month development window from molecule identification to multi-kg manufacture of this small molecule drug substance, a robust process was developed, featuring multiple bio- and chemocatalytic steps. In particular, two wild-type enzymes were applied to the synthesis of key building blocks, including the formation of a chiral morpholine fragment, which was further improved through directed evolution. Additionally, a selective Ir-catalyzed C–H borylation, followed by a Pd-catalyzed Suzuki coupling and cyclization, was executed in a single pot, enabling rapid access to the naphthyridine core. Altogether, the development of this convergent synthesis has enabled a continued supply of AMG 193 for clinical studies.

The presence of nitrosamines in pharmaceutical products presents significant challenges for the industry, primarily due to the potential carcinogenic risks they pose to patients. Among these, N-nitrosodimethylamine (NDMA) has garnered attention as one of the first nitrosamines identified in products such as Valsartan, Ranitidine, and Metformin. NDMA is a polar compound with weak retention on most stationary phases, making it susceptible to matrix interferences. A prevalent issue is the coelution of NDMA and N,N-dimethylformamide (DMF), a common solvent and precursor for NDMA. DMF is typically present in much higher concentrations, which can lead to false positives and an overestimation of NDMA concentration due to interference from ¹⁵N DMF and ¹³C DMF. Conversely, elevated DMF concentrations can induce ion suppression, resulting in false negatives. Consequently, accurately quantifying NDMA remains a challenge even when utilizing high-resolution or tandem mass spectrometry techniques. To address these issues, we developed a robust HPLC-MS method employing an Evosphere AQUA column, which enables the good separation of NDMA from DMF and other sample matrices. This method permits accurate quantification of NDMA in the presence of DMF at concentrations up to 1,000,000 times greater. We achieved a quantitation limit of 0.3 ng/mL using a single quadrupole mass spectrometer, such as QDa, which corresponds to 3 ng/g NDMA relative to a 100 mg/mL Metformin HCl sample concentration, less than 10% acceptable intake of NDMA (32 ng/g). The method has been successfully validated according to ICH guidelines, demonstrating specificity, sensitivity, accuracy, precision, and robustness. The application of this method was further illustrated through the analysis of NDMA in Metformin drug products, including both immediate-release and extended-release formulations.