Organic Process Research & Development最新文献

Antibody–drug conjugates (ADCs) are becoming increasingly established as a mainstream therapeutic modality for oncology, with more than a dozen compounds already approved for marketing and hundreds of clinical trials ongoing. ADCs are a hybrid construct combining, via chemical conjugation, biologic (monoclonal antibody) and small-molecule (drug-linker) moieties into a single drug substance. They also present significant technical and strategic challenges for chemistry, manufacturing, and controls (CMC). Within the IQ Consortium, a Working Group (WG) on Small Molecule Considerations for ADC Development has been established to assess current biopharmaceutical industry practices specific to the drug-linker moiety and to provide recommendations for future development. This paper presents results and analysis from a survey of IQ member companies covering a variety of drug-linker topics, including control of small-molecule impurities, starting material (SM) designation, considerations for clinical versus commercial stages, and interactions with regulatory agencies. Survey data, perspectives, and forward-looking proposals from the WG are provided. Additionally, this work provides the foundation for a subsequent series of papers from the WG, which will go into more depth on (1) post-conjugation purification operations, (2) a proposal for alignment on SM selection, and (3) post-approval synthesis changes and comparability. The overall goals are to offer visibility and insight into the current state of drug-linker development for ADCs and to provide tools to facilitate discussions between companies and regulatory agencies on future directions.

We herein report the evolution of decagram syntheses of a single enantiomer of immuno-PET linker-chelator (1R,2R)-RESCA-TFP (1) from commercially available (1R,2R)-1,2-diaminocyclohexane. The syntheses feature a reductive amination, a trialkylation, a saponification followed by EDCI-promoted TFP ester formation, and finally a t-Bu ester global deprotection. While the first-generation synthesis required chromatographic purification of process intermediates and 1, the second-generation synthesis implemented salt formation and direct isolation by filtration, thus eliminating all preparative purification operations.

By combining the unique targeting ability of monoclonal antibodies with the cancer-killing ability of cytotoxins, antibody–drug conjugates (ADCs) exhibit unique properties that preclude them from being viewed strictly as either a biologic or a small molecule. Instead, they are more accurately considered as hybrid compounds with unique attributes. In the absence of a formal regulatory guidance for Chemistry, Manufacturing, and Controls (CMC) development specific to ADCs, biopharmaceutical industry companies and regulatory agencies follow existing regulatory guidelines for small molecule drugs and monoclonal antibodies. Conventional regulatory strategies involve the need to understand material attributes and their potential impact to downstream quality. Control strategies for both small and large molecule development should consider the origin and significance of impurities as they relate to the final ADC drug substance. This understanding is also used to help designate a starting material (SM) for CMC regulatory filings. While historically regulatory authorities have treated the drug-linker as a drug substance, it is in fact an intermediate in the ADC process. This paper discusses how the principles of ICH Q11 for SM designation for drug substance (e.g., the ADC) can be applied to the drug-linker moiety to support identification of suitable SMs for ADCs. It also highlights key ADC factors, including the structure of the hybrid conjugate and specific manufacturing steps such as the post-conjugation purification by ultrafiltration/diafiltration, that should be incorporated into the SM designation process and the overall control strategy for small molecule impurities.

In this study, we developed an enhanced and efficient kilogram-scale synthesis method for ketamine hydrochloride. We discovered that using N-bromosuccinimide (NBS) instead of HBr/H₂O₂ improved the conversion rate of the bromination reaction from 88% to 99% and led to a milder and steadier reaction. Besides, CH₃NH₂/K₂CO₃ was used in the methylamination reaction to shorten the reaction time from 80 to 15 h, with an 80% yield of 1-((2-chlorophenyl) (methylimino) methyl) cyclopentanol hydrochloride (6) and 99.5% purity. Furthermore, the residue on ignition of ketamine hydrochloride decreased from 3.00% to below 0.10% with extra aqueous base washing. Several related impurities of ketamine hydrochloride were also assessed, and the clarity and color of the ketamine hydrochloride solution were investigated. In summary, the optimized process was industrially scalable and able to control the final quality of ketamine hydrochloride.

The finding that the widely used peptide coupling reagents DIC and Oxyma form the toxic H-CN (McFarland, A. D. Org. Process Res. Dev. 2019, 23, 2099) has prompted studies aimed at H-CN minimization, attained, for example, by solvent engineering (Erny, M. Org. Process Res. Dev. 2020, 24, 1341) and by substituting DIC with TBEC (Manne, S. R. Org. Process Res. Dev. 2022, 26, 2894). Here, an integrated study of TBEC/Oxyma as peptide couplers is reported, focusing not only on the performance of TBEC in the couplings but also on its cost, hazards associated with its use, sustainability of the route of synthesis, the end of life strategies, as well as the potential impact of impurities in the reagent on the synthesis. TBEC/Oxyma-mediated peptide couplings in NBP/EtOAc (1:4) proceeded with minimal racemization, free of precipitation, and radical side reactions irrespective of TBEC quality. These results hold great promise for broad adoption of TBEC/Oxyma in suitable green media as a coupling strategy for sustainable peptide synthesis from an R&D lab to a manufacturing plant.

5-Methyl-2-pyridinesulfonamide is a regulatory starting material of endothelin receptor antagonist clazosentan. The original route to the key sulfonamide relied on the textbook conversion of the corresponding thiophenol to the intermediate sulfonyl chloride followed by its quenching with aqueous ammonia. However, this route suffered from a wide range of issues such as a low overall yield (29%), challenging aqueous workups and isolations, and the formation of a genotoxic benzyl chloride impurity. Therefore, we developed a conceptually novel production route for 5-methyl-2-pyridinesulfonamide. The new process relied on selectively oxidizing the thiophenol to the intermediate sulfinate salt followed by an electrophilic amination of the nucleophilic sulfinate sulfur-atom with hydroxylamine-O-sulfonic acid (HOSA). This oxidation/electrophilic amination sequence worked as a “one-pot” procedure by simply adding HOSA to the reaction mixture after complete oxidation of the thiophenol with 70% aq. t-BuOOH. The process was extensively optimized with regard to the oxidation step, increasing the stability of HOSA in the reaction mixture, and the final isolation of 5-methyl-2-pyridinesulfonamide. The new process was performed on a 22 kg scale, delivering the desired product as a white solid in 69% overall yield and excellent purity (>99.9% a/a).

The ability to quickly generate and identify crystalline solids for organic compounds in a parallel fashion requires a rapid, adaptable crystallization screening strategy that delivers reliable, valuable, and consistent results. The key to the system is a standard platform small-scale (0.5–2 mg) crystallizer screening array that reproducibly crystallizes compounds and facilitates the presentation of crystallization samples to both an automated polarized light microscope and an instrument capable of PXRD analysis. Data science technologies were leveraged to streamline the workflow of data visualization and processing. The fully developed workflow successfully used both single-crystal and PXRD analyses to identify multiple polymorphs of a test compound in a single screening experiment on 200 mg of input material with commercially available crystallizers and instruments to perform a highly detailed crystallization screening study. The methods and techniques described herein are fully transferrable to those working in the synthetic organic chemistry field.

We report the development of a novel method for the synthesis of Azoxystrobin, which employs trimethylamine as a catalyst. This appealing catalytic system offers several advantages, including low cost, excellent reactivity, easy recovery, and the ability to be used repeatedly with minimal environmental impact. Mechanistic studies and density functional theory (DFT) calculations suggest that the involvement of a highly active quaternary ammonium salt intermediate is likely responsible for the efficient catalysis. This can be attributed to the low steric hindrance, flexible bare nature of the lone pair of electrons on the nitrogen atom, and low activation energy barrier of trimethylamine. These findings hold great promise for the mass production of Azoxystrobin.

The development of a scalable process for the manufacture of a potent and selective JAK1 inhibitor intended for the inhaled treatment of asthma is described. The initial milligram-scale synthetic protocols were unsuitable for larger-scale synthesis, which led to a systematic evaluation of the reaction conditions to identify the optimized reaction conditions for the Suzuki/Buchwald–Hartwig coupling, deprotection of the tosyl group, chemoselective nitro-reduction, and developing mild conditions for the amide coupling of a sensitive amino acid. This work also highlights mitigating critical issues associated with the synthesis of poorly soluble compounds, slurry-to-slurry metal-catalyzed coupling protocols. The optimized amide coupling conditions using chiral amino acid produced the desired active pharmaceutical ingredient (API) in high overall yield and good high-performance liquid chromatography (HPLC) purity.