Multikilogram-Scale Preparation of AZD4635 via C–H Borylation and Bromination: The Corrosion of Tantalum by a Bromine/Methanol Mixture

Douglas, James J.; Adams, Bradley; Benson, Helen; Broberg, Karl; Gillespie, Paul M.; Hoult, Oliver; Ibraheem, A.K.; Janbon, Sophie; Janin, Guillaume; Parsons, Chris D.; Sigerson, Ralph C.; Klauber, David J.

doi:10.1021/acs.oprd.8b00342

Cited by 14 publications

(29 citation statements)

References 12 publications

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“…AZD4635 (16) (Figure 5a) is a potent and selective A 2A R inhibitor that has shown indirect antitumor effects on immune cells [33], and it is currently being evaluated in diverse Phase I (NCT02740985, NCT03381274) and Phase II (NCT04495179, NCT04089553) clinical trials [28]. Therefore, a multikilogram process was developed, with the key step being the Suzuki-Miyaura coupling of pinacol boronate ester 17 (4.11 kg) and aryl bromide 18 (4.37 kg) (Figure 5b) [34]. Although the production of 16 was accomplished in high yields, the main drawback of the process was related to the unexpected corrosion observed inside the reaction vessel of a thermopocket constructed from tantalum.…”

Section: A 2a R Antagonist Azd4635mentioning

confidence: 99%

Iridium- and Palladium-Based Catalysts in the Pharmaceutical Industry

López

Padrón

2022

Catalysts

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Transition metal catalysts play a vital role in a wide range of industrial organic processes. The large-scale production of chemicals relying on catalyzed organic reactions represents a sustainable approach to supply society with end products for many daily life applications. Homogeneous (mainly for academic uses) and heterogeneous (crucial in industrial processes) metal-based catalysts have been developed for a plethora of organic reactions. The search for more sustainable strategies has led to the development of a countless number of metal-supported catalysts, nanosystems, and electrochemical and photochemical catalysts. In this work, although a vast number of transition metals can be used in this context, special attention is devoted to Ir- and Pd-based catalysts in the industrial manufacture of pharmaceutical drugs. Pd is by far the most widely used and versatile catalyst not only in academia but also in industry. Moreover, Ir-based complexes have emerged as attractive catalysts, particularly in asymmetric hydrogenation reactions. Ir- and Pd-based asymmetric reductions, aminations, cross-coupling reactions, and C–H activation are covered herein in the production of biologically active compounds or precursors; adaptation to bulk conditions is particularly highlighted.

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Section: A 2a R Antagonist Azd4635mentioning

confidence: 99%

Iridium- and Palladium-Based Catalysts in the Pharmaceutical Industry

López

Padrón

2022

Catalysts

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“…The three pinacol boronic esters that were screened were all isolated intermediates within the late-stage development portfolio at AstraZeneca, from projects AZD4635 ( 1a ), ceralasertib ( 2a ), and verinurad ( 3a ) . Interestingly, the difference between a pyridine, pyrrolopyridine, and naphthalene had a large effect on the solubility values and solubility profile.…”

Section: High-throughput Solubility Measurementsmentioning

confidence: 99%

“…Each of these intermediates has been manufactured at a pilot scale, and their solubility properties made them challenging and nonideal to isolate. For example, 1a was isolated from heptane at −15 °C in 96% assay and 72% yield, with the remaining mass balance being wasteful losses to the mother liquors because of the inherent solubility of the pinacol boronic ester …”

Section: High-throughput Solubility Measurementsmentioning

confidence: 99%

“…The simple and standard process was successfully applied to numerous intermediates in the late-stage portfolio at AstraZeneca, including AZD4635 ( 1b ), ceralasertib ( 2b ), verinurad ( 3b ), lanabecestat ( 4b ), and AZD5718 ( 6b ), to deliver high-purity, crystalline DEA boronic esters. In all cases, the process and conditions required to isolate the DEA boronic ester were superior to the previous process conditions to deliver the boronic acid (lanabecestat) and pinacol boronic esters (AZD4635, ceralasertib, AZD5718, and verinurad) and provided additional improvements in yield, quality, and robustness.…”

Section: Development Of a Standard Crystallization Process For Dea Bo...mentioning

confidence: 99%

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Diethanolamine Boronic Esters: Development of a Simple and Standard Process for Boronic Ester Synthesis

Inglesby

Agnew

Carter

et al. 2020

Org. Process Res. Dev.

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Herein, we disclose the unique physical properties of diethanolamine (DEA) boronic esters that have facilitated the development of a simple and standard process for their synthesis and isolation using environmentally sustainable solvents. Moreover, their preparation is facile, robust, and scalable and can be telescoped from a solution of boronic acid or boronic ester via esterification/transesterification with DEA, therefore providing wide access from a plethora of reaction types. To date, AstraZeneca has successfully manufactured three DEA boronic esters at the kilogram scale (5, 50, and 100 kg batches), with plans to expand this to more examples in 2020.

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“…Since its inception, the scope of this reaction has been significantly broadened by the development of new metal/ligand systems . Suzuki–Miyaura cross-coupling has found wide use both in academia and industry and is frequently used in the large-scale production of agrochemicals and active pharmaceutical ingredients …”

Section: Pd-catalyzed Cross-coupling Safety Concernsmentioning

confidence: 99%

Potential Safety Hazards Associated with Pd-Catalyzed Cross-Coupling Reactions

Yang

Babij

Good

2019

Org. Process Res. Dev.

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The potential safety hazards associated with Pd-catalyzed cross-coupling reactions have been underappreciated and inadequately discussed. These hazards have not been universally recognized in the past decades, perhaps overshadowed by the ubiquity of this class of chemistry and the desire to pursue new scientific advancements. The awareness of these hazards is further limited by the fact that synthetic chemists who develop these types of reactions on small scales are not typically trained in reactive chemistry hazard evaluation, and existing studies from industrial chemists and chemical engineers are often not published in journals that are commonly read by academic groups and synthetic chemists that typically work on small scales. This review summarizes observations of the exothermic behavior associated with the Pd-catalyzed α-arylation, Buchwald–Hartwig amination, Kumada–Corriu, Mizoroki–Heck, Negishi, Sonogashira, and Suzuki–Miyaura cross-coupling reactions. This exothermic behavior is consistently observed across each subset of cross-coupling reactions and appears to be relatively independent of the nucleophile, electrophile, base, solvent, and catalyst system employed. The magnitude of the exotherms poses potential safety hazards that could result in runaway scenarios in cases where the maximum temperature of a synthesis reaction (MTSR) exceeds the solvent boiling point and/or the onset temperature for reaction mixture decomposition. This contribution will serve as an educational resource to encourage researchers to conduct reaction safety evaluations and to develop control strategies accordingly to mitigate such potential safety risks prior to practicing Pd-catalyzed cross-coupling as well as other transition-metal-catalyzed cross-coupling reactions.

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Multikilogram-Scale Preparation of AZD4635 via C–H Borylation and Bromination: The Corrosion of Tantalum by a Bromine/Methanol Mixture

Cited by 14 publications

References 12 publications

Iridium- and Palladium-Based Catalysts in the Pharmaceutical Industry

Iridium- and Palladium-Based Catalysts in the Pharmaceutical Industry

Diethanolamine Boronic Esters: Development of a Simple and Standard Process for Boronic Ester Synthesis

Potential Safety Hazards Associated with Pd-Catalyzed Cross-Coupling Reactions

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