Organic Process Research & Development最新文献

An effective and sustainable protocol for synthesizing oligopeptides via flow chemistry is established herein. Pentafluorophenyl (Pfp) esters readily guide the formation of the desired peptide segments in the presence of nearly equal amounts of nucleophilic amino acid esters as substrates. Although the amino acid Pfp esters are stable, they enable rapid completion of the reactions with nucleophilic amino acids, even with N-methyl amino acid esters. Unlike traditional methods for producing oligopeptides, our process avoids the use of additives and the formation of deficient peptides and other byproducts. To further demonstrate the advantages of the reaction protocol, a flow system was developed using a cartridge filled with 1,8-diazabicyclo[5.4.0]undec-7-ene polymer to facilitate Fmoc-group deprotection. The continuous flow reaction enables sequential peptide elongation to form oligopeptides with high purities and yields. Furthermore, gram-scale synthesis via long-term automated operation is successful, and the continuous-flow system can have ever-increasing practical applications. This powerful methodology should provide solutions to many long-standing problems in organic synthesis, e.g., formation of byproducts and involvement of multiple steps.

The syntheses of therapeutically important μ-opioid receptor antagonists such as naloxone and naltrexone use noroxymorphone as a key late-stage intermediate, which is manufactured from the poppy-derived alkaloids oripavine or thebaine. However, it would be advantageous to instead use morphine as the starting material, which is cheaper and more abundant. In this paper, we describe the conversion of morphine into a dienol acetate required for installation of the C14 hydroxyl group of noroxymorphone. Our approach is more efficient than previously described approaches and uses a one-pot Albright–Goldman oxidation/dienol acetate formation sequence of an allylic alcohol as the key feature. This synthesis has been successfully applied on multikilogram scales. A brief investigation of the scope of the one-pot Albright–Goldman oxidation/dienol ester formation on other substrates is also described.

Influenza A virus (IAV) is a highly contagious pathogen responsible for significant global morbidity and mortality, with an estimated 1 billion infections annually. Onradivir, a next-generation PB2 inhibitor derived from Pimodivir, shows superior activity against drug-resistant IAV variants but faces manufacturing challenges. We report a scalable 7-step synthesis featuring two key innovations: (1) a silver-catalyzed radical cyclopropylation (89.5% conversion) replacing hazardous Grignard reagents; (2) a streamlined one-pot Miyaura–Suzuki coupling achieving 66% yield for intermediate 8. The route eliminates column chromatography through strategic recrystallizations, reduces Pd catalyst loading, and employs cost-effective ethyl acetate solvent. Process optimizations at 15 g scale demonstrate a consistent 5.8% yield for the API (representing a 7-fold improvement over the original method), with all intermediates either crystallized or telescoped to minimize purification losses. The developed methodology facilitates the commercial development of Onradivir and provides a general platform for the synthesis of structurally complex PB2 inhibitors.

A safe, robust, and scalable process for synthesizing purpurin 18 (PP18) has been developed. Conventional methods for producing PP18 from chlorophyll a or its derivatives have faced challenges in yield and operability, with no reports of large-scale production. Spirulina powder, which is readily available and cost-effective, was selected for isolating and purifying chlorophyll a. A precipitation method established by Watanabe et al. was refined to achieve a simple procedure yielding high recovery and excellent purity. Reaction conditions for converting chlorophyll a into PP18 were then optimized based on Q-TOF-MS (quadrupole time-of-flight mass spectrometry) analysis. A two-step oxidation mechanism via a keto-carboxylic acid intermediate was clarified, leading to substantial improvements in reaction conditions and yields. This process was successfully scaled up using 1200 kg of Spirulina powder, providing 10.5 kg of chlorophyll a and subsequently 3.9 kg of PP18. This appears to be the first report of the kilogram-scale manufacturing of PP18, providing important insights for diverse fields that utilize chlorophyll a derivatives.

Although mechanochemical synthesis has gained widespread application, our understanding and enhancement of the control of the reaction need to be improved. In this work, we confirm that the mechanochemical reaction of the active pharmaceutical ingredient dantrolene is controlled by diffusion-controlled kinetics. On this basis, we demonstrate a novel approach to modulate mechanochemical reactivity through a diffusion enhancement strategy mediated by supramolecular interactions. The method employs a highly efficient spiral gas–solid two-phase flow technique, in which urea, an additive that can establish supramolecular interactions with 1-aminohydantoin hydrochloride, is introduced into the reaction system to substantially enhance diffusion, thus facilitating the efficient synthesis of dantrolene. Notably, in this diffusion enhancement process, the weakening of mechanical forces triggers the nucleation and growth of the active substrate to form structurally well-defined eutectic crystals that inhibit the reaction. This strategy reduces the mechanochemical reaction time of dantrolene and its analogs to less than 30 s. In addition, thiourea and acetamide, which are structurally similar to urea, promote the reaction, and their effects correlate with the number of supramolecular sites of action.

A new approach to midazolam through Michael addition of 2-aminobenzophenone with a nitroolefin as a key step is reported. We devised a telescoped four-step synthesis using only one single protecting group, resulting in an excellent atom economy.

In the development of a route to an advanced intermediate, methyl 1-amino-7-(benzyloxy)thieno[3,2-f]quinoline-2-carboxylate (1), significant safety hazards were identified in both the tandem cyanation/nitro reduction and tert-butyl nitrite (TBN)-mediated Sandmeyer reactions. The cyanation exhibited substantial thermal accumulation and severe decomposition due to the use of dimethyl sulfoxide (DMSO) as a solvent, resulting in a Criticality 5 risk level according to Stoessel. Similarly, the TBN-mediated Sandmeyer reaction showed strong decomposition, further compounding the safety concerns. In response to these hazards, a new route was developed. Process safety evaluations played a crucial role in guiding the development of this safer route, which was successfully implemented, leading to substantial improvements in safety, yield, and overall efficiency. This success underscores the critical importance of integrating process safety evaluation during the early stages of process and route development.

The use of doubly protected morpholino guanosine in the synthesis of PMO sequences generates a reactive para-quinone methide byproduct upon deprotection with concentrated ammonium hydroxide. Thiols are explored as potential scavengers to control the formation of PMO-alkylation impurities caused by para-quinone methide. The optimal concentration of thiol for effective control is determined.

A second-generation route to the cereblon fragment of ARV-471, vepdegestrant, an orally available proteolysis targeting chimera (PROTAC) submitted to the FDA for NDA review to treat metastatic breast cancer, is reported. With the new, more convergent route, the chiral cyclic imide moiety is installed as a key fragment via reductive amination with a linker fragment.

Two steps in the batch synthesis of Vepdegestrant, namely, N-Boc deprotection and acetal hydrolysis, utilize homogeneous acids as catalysts. In order to streamline these processes, various types of common commercially available heterogeneous solid acids have been evaluated to develop a packed bed reactor (PBR)-enabled flow process. Zeolite H-BEA and amorphous silica–alumina Siral 40 have been shown to facilitate the N-Boc deprotection at 150 °C, a temperature lower than that for thermolytic de-Boc (200 °C). For acetal hydrolysis, only Brønsted acids catalyze the reaction at 100 °C. Brønsted acid site (BAS) quantification by n-propylamine temperature-programmed desorption (TPD) indicates that reactivity toward acetal hydrolysis has a strong dependence on the acid strength rather than the total acid site density. Tungstated zirconia (WZ) demonstrates the optimal reactivity without forming other impurities despite having the lowest density of BASs compared with other solid acid catalysts. The presence of surface polytungstate WO_x has contributed to the different reactivity in WZ catalysts. Higher reactivity is observed on WZ catalysts with lower surface W concentration, 4.8 W atoms/nm² (WZ-Powder), where polytungstate WO_x are the primary surface species, in contrast to 6.9 W atoms/nm² (WZ-0.7 mm), on which bulk WO₃ dominates. Flow evaluation in a PBR over granular WZ-0.7 mm has achieved steady-state operation at full conversion for 140 min at 120 °C with a theoretical mean residence time of 8.4 min. Compared to the batch process, the continuous flow process intensified step unit operations by minimizing the requirement for workups, reducing the step PMI from 33 to 17.