Organic Process Research & Development最新文献

This manuscript reports the identification of hydrophobic interaction chromatography (HIC)-shifting, nontoxic linker-payload surrogates as tool molecules for the optimization of maleimide/cysteine conjugations relevant to antibody–drug conjugates (ADCs). These linker/payload (LP) mimics allow conjugation measurement via HIC with mAbs (monoclonal antibodies) bearing engineered or interchain cysteines as conjugation sites. Importantly, the tool molecules are employed to optimize maleimide/cysteine conjugations via modern methods of process development, including high-throughput experimentation and continuous flow. Overall, our studies provide confidence that commercially available, nontoxic LP mimics can be employed successfully to optimize ADC-type conjugations in batch and flow while minimizing materials needs and experimental work in specialized facilities required for potent compound handling.

Evolution of a synthetic process to prepare ABBV-105, a Bruton’s tyrosine kinase (BTK)-inhibitor, on multikilogram scale is described. The first-generation route utilized chiral resolution of the penultimate intermediate (7). Either Bartoli or Leimgruber–Batcho indole synthesis was used to prepare the key intermediate, indole boronate ester (23). As the demand for the API increased, the first-generation route was found to be low-yielding and expensive. It required column chromatography, had multiple alerting structures from the mutagenic impurity assessment, and suffered from lack of robustness. In the second-generation route a novel Ru-catalyzed asymmetric hydrogenation of 1,2,5,6-tetrahydropyridine (21) was developed to establish the stereocenter. Compound 21 was accessed via Suzuki coupling of 23, prepared by Friedel–Crafts acylation, with vinyl bromide (24) in the presence of very low loading of a Pd catalyst (0.15 mol % Pd). Finally, the penultimate intermediate (7) was coupled with acryloyl chloride using an impinging jet to prepare the API. Detailed kinetic and mechanistic work was conducted to control the persistent impurities formed in the API step. The second-generation route was robust, chromatography-free and high-yielding with low mutagenic liability.

Rufinamide {1-[(2,6-difluorophenyl)methyl]-1H-1,2,3-triazole-4-carboxamide} was the first anticonvulsant agent used in the treatment of Lennox–Gastaut syndrome─a rare, complex, and severe childhood-onset epilepsy. It is synthesized by thermal azide–alkyne cycloaddition, which can produce some of the unwanted 1,5-disubstituted triazole byproduct. To address this issue, copper-catalyzed azide–alkyne cycloaddition (CuAAC) methods have been proposed. In this context, we present efficient CuAAC protocols for the synthesis of rufinamide and its precursor, methyl 1-[(2,6-difluorophenyl)methyl]-1H-1,2,3-triazole-4-carboxylate, using triazole Cu-chelating ligands as assisting additives for the CuAAC reactions. We compared the efficacy of tristriazole and monotriazole ligands in milligram-scale screening reactions. Among the more favorable tristriazoles, we chose tris{1-[(2-hydroxyethyl)-1H-1,2,3-triazol-4-yl]methyl}amine (THETA), as an alternative to the THPTA ligand, to develop 0.5 g preparative-scale manual ligand-assisted CuAAC procedures for rufinamide (87–96% with 0.5–2 mol % Cu), and its precursor (96% with 1 mol % Cu). Finally, we demonstrated the easy transfer of this protocol to an automated two-step one-pot process, employing the ChemPU synthesis platform, to obtain rufinamide precursor in quantitative yield (2 mol % Cu loading).

Oxygen-, nitrogen-, and sulfur-containing heterocycles exhibit remarkable biological and pharmaceutical activities that are often found in naturally occurring products, pharmaceutical molecules, and synthetic compounds. Therefore, the synthesis of heterocycle building blocks has gained huge attention in the past decade. Compared with the modification of heterocyclic compounds, the construction of heterocyclic compounds from scratch is more attractive. In this Perspective, we describe our recent advances in the rational design and strategic application of the de novo synthesis of various synthetically and biologically important heterocycles. The organization of the Perspective is categorized in the following order: (a) type of heterocycle, (b) ring size of heterocycle, (c) number of heteroatoms, and (d) fused heterocycles. Moreover, some significant and representative synthetic methodologies and their synthetic applications and brief reaction mechanisms have also been described. We hope that this Perspective will help to provide a guideline for researchers who are interested in this fertile area.

The goal of sustainable and efficient chemical production has led to an increased focus on continuous processes, especially in the production of fine chemicals or active pharmaceutical ingredients. However, developing and optimizing continuous processes can be challenging. Autonomous online optimization can help facilitate this process. This article presents a fully automated flow chemistry platform for optimizing flash chemistry (reaction times less than 1 s), using online mass spectrometry and global optimization algorithms, such as Bayesian optimization and SNOBFIT, for autonomous online optimization of chemical reactions. The algorithms were tuned and statistically evaluated using simulated optimization runs. Subsequently, they were applied in a practical case study, using a mixing-sensitive example of flash chemistry as a model system to investigate online reaction optimization. Automated response factor fitting was used to obtain quantitative data directly during reaction monitoring. This approach allowed the extraction of meaningful data without the need for postprocessing. The use of an initial design of experiments (DoE) approach was advantageous as it provides a well-discovered experimental space and often leads to a minimal number of subsequent experiments for optimization. Although random starting points may require fewer total experiments, the DoE approach offers greater reliability in achieving optimal results. Comparative analysis between Bayesian optimization and SNOBFIT indicates that Bayesian optimization outperforms SNOBFIT, achieving better results with fewer experimental iterations. Thus, Bayesian optimization has proven to be a powerful tool for autonomous optimization of chemical processes.

Bruton’s tyrosine kinase (BTK) is involved in B-cell receptor signaling and has been clinically validated as a target by small molecule inhibition for the treatment of a variety of cancers. ABBV-992 (1) was identified as a novel, potent, selective BTK inhibitor and advanced to Phase I clinical trials. An enantioselective synthesis of 1 was developed and scaled to provide 63 g for preclinical characterization. The route features a diazotization enabled by flow chemistry, a novel, selective partial reduction of a pyridone, a stereoselective Ellman imine reduction, and an improved acrylamide formation using 3-chloropropionyl chloride in a masked acrylate strategy.

The synthetic process used to manufacture valbenazine ditosylate (API of INGREZZA) has proven to be highly selective and robust, but opportunities remain for greener chemistry performance and continuous improvement enabled via simplification of process operations by truncating the manufacturing time and by reducing the overall process waste and environmental footprint during the first three most critical transformations. Neurocrine’s next-generation commercial process was developed encompassing principles of Pharmaceutical Green Chemistry ( Org. Process Res. Dev. 2006, 10, 315−319) and employs strategies for accelerated reaction kinetics, simplified reaction medium, and elimination of unnecessary workup procedures for greater process efficiency and operational agility. The new, greener process has delivered greater efficiency and sustainability by reducing the time of manufacture by 43% and reducing material use by 45% while concomitantly improving the overall process yield by 5% and reducing water use by 32%.

DB Mesylate is a common intermediate used in the production of cEt amidites, supporting part of AstraZeneca’s oligonucleotide portfolio. The current process to manufacture DB Mesylate includes eight stages with three isolated intermediates and is well understood. This paper covers the implementation of a flow process to resolve the throughput, yield, and manufacturing challenges associated with the key acetal deprotection stage.

Nitrogen-containing compounds, especially those with chiral amine structures, play a pivotal role in the field of organic active pharmaceutical ingredients. Traditional racemate resolution and chemical synthesis methods for the preparation of chiral amines suffer drawbacks such as high cost and environmental pollution. Over the past decades, stereoselective synthesis of nitrogen-containing compounds by biocatalytic methods such as imine reductase (IRED)-mediated transformation has become increasingly prominent. The prominence of imine reductases lies in their capacity to catalyze the reductive amination of aldehydes or ketones with primary or secondary amines, as well as their broader substrate scope. Furthermore, imine reductases exhibit diverse catalytic cycling systems that are unaffected by adverse reaction equilibria. This article focuses on the development of drug molecules or intermediates in biocatalytic synthesis mediated by imine reductase.

Oligomeric proanthocyanidins (OPCs) have a variety of biological functions, but the formation of 4,8-interflavan bonds faces scaling-up difficulties due to the challenging control of stereoselectivity and the degree of polymerization. Here we report a process to produce procyanidin B3 (1) by mainly optimizing the condensation reaction and improving benzylation, C4 activation, and one-pot hydrogenolysis reactions. In an optimized seven-step process, the product 1 was achieved by only one-step chromatography in the case of poor crystallinity of polyphenols. This strategy provided effective access to the stereoselective synthesis of the title compound and other C4–C8 connected OPCs.