From Milligram to Kilogram Manufacture of AZD4573: Making It Possible by Application of Enzyme-, Iridium-, and Palladium-Catalyzed Key Transformations

Karlsson, Staffan; Benson, Helen; Cook, Calum; Currie, Gordon S.; Dubiez, Jérome; Emtenäs, Hans; Hawkins, Janet; Meadows, Rebecca E.; Smith, Peter D.; Varnes, Jeffrey

doi:10.1021/acs.oprd.1c00058

Cited by 7 publications

(6 citation statements)

References 25 publications

(34 reference statements)

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“…Furthermore, Tf 2 NPh and the resulting sulfonamide byproduct were difficult to remove by crystallization and carried over into isolated triflate 6 . For these reasons, replacing this reagent with a common reagent, Tf 2 O, was investigated . However, the reaction of pyridone 5 with Tf 2 O and Et 3 N in THF or MeCN gave a complex mixture.…”

Section: Resultsmentioning

confidence: 99%

Early Process Development and Scale-Up of a Positive Allosteric Modulator of the α7 Nicotinic Acetylcholine Receptor

Tajima,

Ito,

Saito

et al. 2024

Org. Process Res. Dev.

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A practical and efficient process was developed for the manufacture of a positive allosteric modulator (PAM) of the α7 nicotinic acetylcholine receptor via an eight-step synthetic route that furnished a high-quality active pharmaceutical ingredient. Highlights of this synthesis include (1) a highly reproducible palladium-catalyzed cyanation; (2) reduction in the number of steps by revisiting the original protection/deprotection strategy; (3) avoidance of the use of halogenated solvents in all of the steps; (4) replacement of reagents that had procurement issues, such as N-phenyltrifluoromethanesulfonimide and Ghosez's reagent, with more commonly used reagents; and (5) no chromatographic purification in any step. This highly efficient process was successfully demonstrated on a pilot scale to yield up to 63.5 kg of the active pharmaceutical ingredient.

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Section: Resultsmentioning

confidence: 99%

Early Process Development and Scale-Up of a Positive Allosteric Modulator of the α7 Nicotinic Acetylcholine Receptor

Tajima,

Ito,

Saito

et al. 2024

Org. Process Res. Dev.

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“…The synthesis of AZD4573 ( 35) demonstrated the superiority of CÀ H activation/borylation over prefunctionalization and palladium-catalyzed borylation on a large scale (Scheme 9). [42] In order to rapidly provide AZD4573 (35), an oncology drug candidate, in sufficient quantities for preclinical and clinical studies, several steps of the medicinal chemistry route had to be modified. One of the changes was the borylation step.…”

Section: Iridiummentioning

confidence: 99%

“…The synthesis of AZD4573 ( 35 ) demonstrated the superiority of C−H activation/borylation over prefunctionalization and palladium‐catalyzed borylation on a large scale (Scheme 9). [42] …”

Section: Preparative Scale Applications Of C−h Activation In Medicina...mentioning

confidence: 99%

Preparative Scale Applications of C−H Activation in Medicinal Chemistry

2023

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C−H activation is an attractive methodology to increase molecular complexity without requiring substrate prefunctionalization. In contrast to well‐established cross‐coupling methods, C−H activation is less explored on large scales and its use in the production of pharmaceuticals faces substantial hurdles. However, the inherent advantages, such as shorter synthetic routes and simpler starting materials, motivate medicinal chemists and process chemists to overcome these challenges, and exploit C−H activation steps for the synthesis of pharmaceutically relevant compounds. In this review, we will cover examples of drugs/drug candidates where C−H activation has been implemented on a preparative synthetic scale (range between 355 mg and 130 kg). The optimization processes will be described, and each example will be examined in terms of its advantages and disadvantages, providing the reader with an in‐depth understanding of the challenges and potential of C−H activation methodologies in the production of pharmaceuticals.

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“…Several more case studies of the successful use of functionalized silicas and resins have been reported by pharmaceutical companies, demonstrating their utility and applicability on an industrial scale. − An additional benefit exhibited by functionalized silica scavengers is the ease of metal recovery via incineration. This is a favorable property, as metal catalysts typically account for approximately 5–20% of total manufacturing costs; hence, recovery and potential recycling of the metal are highly beneficial in making the process as economical as possible .…”

Section: Adsorptionmentioning

confidence: 99%

Palladium Extraction Following Metal-Catalyzed Reactions: Recent Advances and Applications in the Pharmaceutical Industry

Economidou,

Mistry,

Wheelhouse

et al. 2023

Org. Process Res. Dev.

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Palladium-catalyzed cross-coupling reactions are used extensively in the pharmaceutical industry. Therefore, the potential contamination of products with elemental impurities is an issue that any process chemist must consider in the design of a plant process. This is not only to meet regulatory limits, which is unequivocally the primary reason for metal scavenging, but also due to the high cost and limited supply of palladium, driving the need for recovery to recycle. This Review addresses the current approaches for palladium removal from organic solutions, with selected examples of their successful application in industrial-scale processes for pharmaceutical production. Palladium scavengers have been categorized based on their mode of action, i.e., adsorption, extraction/precipitation, and crystallization, to provide a summary of the current state-of-the-art in metal removal. Practical considerations when choosing metal removal methods are briefly discussed, illustrating their intrinsic advantages and drawbacks.

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From Milligram to Kilogram Manufacture of AZD4573: Making It Possible by Application of Enzyme-, Iridium-, and Palladium-Catalyzed Key Transformations

Cited by 7 publications

References 25 publications

Early Process Development and Scale-Up of a Positive Allosteric Modulator of the α7 Nicotinic Acetylcholine Receptor

Early Process Development and Scale-Up of a Positive Allosteric Modulator of the α7 Nicotinic Acetylcholine Receptor

Preparative Scale Applications of C−H Activation in Medicinal Chemistry

Palladium Extraction Following Metal-Catalyzed Reactions: Recent Advances and Applications in the Pharmaceutical Industry

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