Organic Process Research & Development最新文献

N-(2,6-Dimethylphenyl)-6-hydroxypicolinamide (1) has been identified as a highly effective ligand for copper-catalyzed C–N and C–O bond-forming reactions, with prevailing application in the industrial synthesis of pharmaceutical intermediates and fine chemicals. We report an innovative synthetic route to 1 via three sequential steps: (i) formation of an acyl chloride intermediate, (ii) amidation by the Schotten–Baumann reaction, and (iii) copper-catalyzed hydroxylation, executed in a telescoped one-pot process. The optimal reaction conditions for the hydroxylation of step 3 were obtained with the aid of design of experiments (DoE) study. Three generations of the process were developed and are reported. This telescoped process was used for multiple kilo-batch productions, and a 67% reduction in material costs compared to the previous reports was realized. The improvement mainly stems from superior atom economy, minimized solvent consumption, and the avoidance of intermediary purification operations.

Although ligand design has dominated efforts to optimize palladium-catalyzed cross-coupling reactions, the choice of palladium source is often driven by convenience rather than systematic evaluation. To address whether a universally effective Pd precursor exists or if performance depends on ligand class and reaction conditions, we employ high-throughput experimentation (HTE) to generate a data set of >450 reactions systematically comparing precursor effects across diverse ligand families. Using the Buchwald–Hartwig amination of a sterically demanding substrate as a model reaction, we found that the palladium source can have a tremendous influence on reaction outcome─comparable in magnitude to ligand choice itself. However, precursor sensitivity varies dramatically across four distinct ligand classes: biarylphosphines exhibit robust, source-insensitive performance, while monophosphines and certain bulky ligands show pronounced sensitivity to the Pd source, with a fourth class remaining inactive regardless of the precursor. These trends are rationalized through a kinetic framework emphasizing precursor stability under reaction conditions and competing off-cycle deactivation pathways. Along the way, we discover an unprecedented base-promoted decomposition pathway for MeNAP-type precatalysts, explaining the discrepancies between in situ use and preformed catalysts. Extension to Suzuki–Miyaura coupling confirms analogous ligand-dependent trends. For HTE applications with in situ precatalyst formation, [Pd(tBu-indenyl)Cl]₂ emerges as the most robust choice, while commonly used Pd(OAc)₂ and Pd₂(dba)₃ require caution. MeNAP precursors can be effectively used in high-throughput screening workflows, provided that precautions are taken to mitigate their instability under basic conditions. Beyond the catalytic efficiency, these findings have important implications for the reproducibility and comparability of ligand screening studies, where the precursor choice can mask or amplify ligand effects.

The radiolabeled FAPI-46 has been extensively employed as a diagnostic and therapeutic agent for malignancies. Based on our endeavor to reproduce the synthetic route of FAPI-46, we systematically elucidate the practical challenges encountered. Then, our effort in optimizing the synthetic route of FAPI-46 characterized by practicality, cost-effectiveness, and high reproducibility was presented here. Initially, we have explored four routes for synthesizing the key intermediate 19, among which the one that obtained 24 via the Pd₂(dba)₃-catalyzed C–N coupling between methyl quinoline-4-carboxylate 20 and silyl-protected 3-hydroxypropylamine 23, followed by desilylation and sulfonylation of the hydroxyl group of 24, proved to be the optimal route to obtain 19. Subsequently, the condensation of lithium quinoline-4-carboxylate 34 with nitrile-pyrrole-substituted amine 8 using N,N,N′N′-tetramethylchloroformamidinium hexafluorophosphate (TCFH) as the condensing agent to afford 9 demonstrated a notably streamlined process and satisfactory yield. This feasible and robust strategy offered a valuable procedure for the large-scale production of FAPI-46 and its analogues containing the quinoline-4-carboxylic acid scaffold.

The presence of effervescent gas bubbles in liquid–gas biphasic streams adversely affects liquid chromatography-based PAT (process analytical technologies) in all critical steps of the analysis, from injection to measurement, presenting significant obstacles for CPV (continuous process validation). This article describes a unique, multiconfiguration rotary valve capable of adopting configurations essential for the removal of the gas bubbles from the biphasic stream using an automated trap-purge technique. The multiple, function-specific configurations of the valve prevent the gas bubbles entering the chromatography stream and minimizes system dead-volume in the analytical workflow enabling precise execution of the trap-purge method for inline analysis. The currently disclosed PAT reliably reported purity of the desired product in the output stream of a continuous transfer-hydrogenation process. This work paves the way for high-frequency continuous process validation of multiphase flow reactions in line with process validation guidance of regulatory agencies that oversee fine-chemical manufacturing.

Diisocyanates (DIs) are valuable building blocks used to manufacture various polyurethane (PU) materials which are annually produced on megaton scales via phosgenation of petroleum derived diamines. While phosgene-free methods have been developed for decagram or smaller quantities of diisocyanates, none have been implemented at scales deemed viable for commercialization. We previously reported a phosgene-free flow chemistry approach toward biobased aliphatic diisocyanates on gram-scales for polyurethane applications. Herein, we report significant improvements upon this strategy toward the scalable preparation of renewable 1,7-heptamethylene diisocyanate (7HDI) via Curtius rearrangement of an in situ diacyl azide in continuous flow. Reaction optimization and reactor configuration led us to obtain >10-fold throughput increase coupled with a significant improvement in overall purity of isolated 7HDI. To demonstrate scalability, 120 g of 7HDI was prepared within a continuous 8-h process, offering 71% isolated yield and >99% purity. The resulting 7HDI was further used to prepare a 100% renewable thermoplastic PU with material properties that rival commercial petroleum-derived products.

This study presents an efficient and high-yield continuous-flow process for the nitration of 2-(propylthio)pyrimidine-4,6-diol. First, to address the solubility limitations of the AcOH/HNO₃ system, the H₂SO₄/HNO₃ system was developed. Second, optimization of the continuous flow parameters significantly enhanced the reaction yield to approximately 97.5%. Finally, refinement of the postreaction processing achieved an isolated yield of 92.4%, which is over 12.4% higher than previously reported yields. The primary factor limiting the yield was ring opening of the pyrimidine ring. The key to yield enhancement was the appropriate combination of sulfuric and nitric acid concentrations coupled with precise temperature control enabled by the continuous-flow reactor.

α-Methylproline is a key starting material (KSM) for important drugs, such as Daridorexant, Veliparib, Trofinetide, Enlicitide chloride, and Usnoflast. A practical and scalable asymmetric synthesis of (S)-2-methylproline and its derivatives has been disclosed here using a diketopiperazine intermediate-based strategy that leverages the memory of chirality. Commencing from an inexpensive starting material, l-proline, it proceeds through dimerization and alkylation, followed by hydrolysis under mild conditions, avoiding column chromatography to furnish enantiomerically pure (S)-2-methylproline.HCl, which was also converted to (S)-Boc-2-methylproline and (S)-2-methylproline methyl ester.HCl. In contrast to prior multistep approaches, which rely on expensive chiral auxiliaries and hazardous reagents, this concise three-step route offers operational simplicity, scalability, and superior stereochemical control, making it an attractive method for the synthesis of proline-derived building blocks for peptidomimetics and pharmaceutical applications.

Nitrosamine impurities, particularly nitrosamine drug substance-related impurities (NDSRIs), have emerged as a critical concern in pharmaceutical manufacturing due to their potential carcinogenicity. Regulatory agencies now require rigorous risk assessments and confirmatory testing to ensure product safety, considering all nitrogen atom alert groups. In this study, we present a novel strategy that combines the nitrosation assay procedure (NAP) with ¹⁵N-enriched nitrosating reagents and ¹⁵N NMR spectroscopy to detect and characterize nitrosamine formation. This method enables qualitative analysis of nitrosamines and provides valuable insight into the nitrosation reactivity of pharmaceutical compounds. The diagnostic chemical shift range for N–NO groups was validated, and the method was applied to a series of known nitrosamines and NDSRIs derived from active pharmaceutical ingredients and intermediates. The ¹⁵N-enriched NAP test proved effective in identifying nitrosamines, even in complex matrices, and distinguishing between isomeric and degradation products. This integrated approach provides a robust and rapid tool for nitrosamine risk assessment and supports regulatory compliance by confirming or excluding nitrosamine formation under stress conditions.

The development of a concise synthesis of crisaborole (1), a phosphodiesterase 4 (PDE4) inhibitor, is described. There are several challenges with the initial commercial synthesis that were drivers for process redesign and simplification, most notably the need for protection/deprotection steps. Key bond disconnections and reordering of steps were evaluated to streamline the process focusing on greener options for manufacture and eliminating protecting groups. The resulting alternate synthesis features a similar Miyaura borylation to install the key boron atom but provides a more direct route to crisaborole through an important crystalline intermediate for impurity purge. Other challenges addressed by the alternate route include avoiding environmentally undesirable reagents DMF and boric acid (both included on the REACH list of substances of very high concern), reducing palladium usage, and eliminating the use of a palladium scavenging treatment. Successful demonstration of the alternate route for crisaborole has been achieved at pilot plant scale and ultimately has been validated at commercial scale consistent with ICH Q11 principles. The route was approved for commercial use to supply crisaborole in 2023 and to date has produced approximately 750 kg of the crisaborole drug substance.

Over functionalization of sugars under condition-dependent constraints without disrupting their native architecture remains a significant challenge in vaccine development. Here, we report an AI-guided, automated flow platform with variable reaction conditions that enables azide incorporation at the C2 and C2–C4 positions of l-rhamnose and l-fucose derivatives, achieving yields of up to 90–97%. This approach delivers a safe handling of NaN₃, minimum human intervention, and approximately 3000-fold enhancement in space–time yield compared to conventional batch synthesis. Subsequent in-flow Cu-catalyzed azide–alkyne cycloaddition (CuAAC) affords mono- and ditriazoles, offering a scalable route to glycoconjugates for both medicinal and material applications.