Development of a Scalable Synthesis for an Inhaled pan-JAK Inhibitor

Gontcharov, Alexander; Magano, Javier; Samp, Lacey; Houck, Tim L.; Rose, Peter R.; Rane, Anil; Coe, Jotham W.; Kortum, Steven W.; Chung, Sung Tae; Jones, Peter; Pattavina, David

doi:10.1021/acs.oprd.9b00253

Cited by 5 publications

(4 citation statements)

References 11 publications

(10 reference statements)

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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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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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show abstract

“…The yield for 22 was 86% in situ (Scheme 4). Gontcharov and coworkers [14] from Pfizer developed a robust multi-kilogram scale synthetic route for PF-06263276 23 [15]. 23 is an inhaled pan-JAK inhibitor in clinical development for the treatment of chronic obstructive pulmonary disease.…”

Section: Peer Reviewmentioning

confidence: 99%

“…Organics 2022, 3, FOR PEER REVIEW 14 Graham and coworkers [35] from AstraZeneca developed an improved manufacturing route to ceralasertib 71 [13], an ATR inhibitor currently tested as a drug for treating cancer. The new method features an improved Suzuki-Miyaura coupling between 70 and 16 that simplifies the workup and crystallization required by simply performing a solvent swap to 2-methyltetrahydrofuran (2-MeTHF).…”

Section: Scheme 11 Synthesis Of An Intermediate En Route To Lumacaftormentioning

confidence: 99%

Recent Applications of Pd-Catalyzed Suzuki–Miyaura and Buchwald–Hartwig Couplings in Pharmaceutical Process Chemistry

2022

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Cross-coupling reactions have changed the way complex molecules are synthesized. In particular, Suzuki–Miyaura and Buchwald–Hartwig amination reactions have given opportunities to elegantly make pharmaceutical ingredients. Indeed, these reactions are at the forefront of both the stages of drug development, medicinal chemistry, and process chemistry. On the one hand, these reactions have given medicinal chemists a resource to derivatize the core compound to arrive at scaffold rapidly. On the other hand, these cross couplings have offered the process chemists a smart tool to synthesize the development candidates safely, quickly, and efficiently. Generally, the application of cross-coupling reactions is broad. This review will specifically focus on their real (pharma) world applications in large-scale synthesis appearing in the last three years.

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“…Gontcharov and coworkers 9 from Pfizer developed a robust multi-kilogram scale synthetic route for PF-06263276 23, 10 an inhaled pan-JAK inhibitor in clinical development for the treatment of chronic obstructive pulmonary disease. A Suzuki-Miyaura coupling is required between an aryl fragment and cyano-substituted indazole to produce a key intermediate for the new synthesis route.…”

Section: Scheme 3 Synthesis Of Azd6738mentioning

confidence: 99%

Recent Applications of Pd-Catalyzed Suzuki-Miyaura and Buchwald-Hartwig Couplings in Pharmaceutical Process Chemistry.

Takale¹,

Kong²,

Thakore³

2021

Preprint

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Cross coupling reactions have changed the way complex molecules are synthesized. In particular, Suzuki-Miyaura and Buchwald-Hartwig amination reactions have given opportunities to elegantly make pharmaceutical ingredients. Indeed, these reactions are forefront at both the stages of drug development, medicinal chemistry, and process chemistry. On one hand, these reactions have given medicinal chemists a tool to derivatize the core molecule to arrive at scaffold rapidly. On the other hand, these cross couplings have offered the process chemists a smart tool to synthesize the development candidates safely, quickly, and efficiently. Generally, the application of cross coupling reactions is broad, and this review will specifically focus on their real (pharma) world applications in large scale synthesis those appeared in last two years.

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Development of a Scalable Synthesis for an Inhaled pan-JAK Inhibitor

Cited by 5 publications

References 11 publications

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

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

Recent Applications of Pd-Catalyzed Suzuki–Miyaura and Buchwald–Hartwig Couplings in Pharmaceutical Process Chemistry

Recent Applications of Pd-Catalyzed Suzuki-Miyaura and Buchwald-Hartwig Couplings in Pharmaceutical Process Chemistry.

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