Palladium-Catalyzed C–O Coupling of a Sterically Hindered Secondary Alcohol with an Aryl Bromide and Significant Purity Upgrade in the API Step

Simmons, Eric M.; Fenster, Michaël D. B.; Zhu, J.; Katipally, Kishta

doi:10.1021/acs.oprd.8b00022

Cited by 17 publications

(8 citation statements)

References 20 publications

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“…Taken together, these data suggest that reduced steric congestion around the alcohol is a crucial factor in reaction efficiency, with the geometric constraints of the cyclic systems reinforcing these factors relative to acyclic systems. Moreover, 3 a , 3 k and 3 q were isolated with no significant erosion in enantio‐ or diastereomeric purity, highlighting the utility of the method to incorporate chiral substrates …”

Section: Resultsmentioning

confidence: 92%

Palladium Catalyzed C−O Coupling of Amino Alcohols for the Synthesis of Aryl Ethers

Mikus¹,

Sanchez²,

Fridrich

et al. 2019

Adv Synth Catal

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Amine containing aryl ethers are common pharmacophore motifs that continue to emerge from drug discovery efforts. As amino alcohols are readily available building blocks, practical methodologies for incorporating them into more complex structures are highly desirable. We report our efforts to explore the application of Pd-catalyzed CÀ O coupling methods to the arylation of 1,2-and 1,3-amino alcohols. We established general and reliable conditions, under which we explored the scope and limitations of the transformation. The insights gained have been valuable in employing this methodology within a fastmoving drug discovery environment, which we anticipate will be of general interest to the synthesis and catalysis communities. Scheme 1. Selected examples of pharmaceuticals containing amino aryl ethers. Scheme 3. Challenging substrates and limitations of the reaction. a) Conversion was assessed by LC/MS analysis. b) Formation of a mixture of N-, O-and bis-arylated products was observed.

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Section: Resultsmentioning

confidence: 92%

Palladium Catalyzed C−O Coupling of Amino Alcohols for the Synthesis of Aryl Ethers

Mikus¹,

Sanchez²,

Fridrich

et al. 2019

Adv Synth Catal

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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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“…The most successful ligands have been the bulky Buchwald dialkylbiaryl phosphine ligands, such as 2-di( tert -butyl)phosphino-2′,4′,6′-triisopropyl-3-methoxy-6-methylbiphenyl (RockPhos). − RockPhos has been used in 90% of our Pd-catalyzed aryl–ether formation libraries, and only one other method has been used. In the past few years, bulky ligands, such as 5-[di(1-adamantyl)phosphino]-1′,3′,5′-triphenyl-1′ H -[1,4′]bipyrazole (AdBippyPhos), 2-(di- tert -butylphosphino)-2′,4′,6′-triisopropyl-3,6-dimethoxy-1,1′-biphenyl (tBuBrettPhos), and 2-(adamantylcyclohexylphosphino)-2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl (AdCyBrettPhos) have expanded the scope of Pd-catalyzed aryl/alkyl ether bond formation, and β-hydride elimination with secondary alcohols no longer seems to be an issue. − These newer ligands have not yet been used in a library synthesis but are being incorporated into our C–O bond forming HTE screening set. As has been done in the past for other literature reported methods, these ligands will be tested for robustness and substrate scope to determine if they are ready for use with complex medicinal chemistry scaffolds and in library synthesis.…”

Section: Pd Catalysismentioning

confidence: 99%

The Chosen Few: Parallel Library Reaction Methodologies for Drug Discovery

et al. 2021

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Parallel library synthesis is an important tool for drug discovery because it enables the synthesis of closely related analogues in parallel via robust and general synthetic transformations. In this perspective, we analyzed the synthetic methodologies used in >5000 parallel libraries representing 15 prevalent synthetic transformations. The library data set contains complex substrates and diverse arrays of building blocks used over the last 14 years at AbbVie. The library synthetic methodologies that have demonstrated robustness and generality with proven success are described along with their substrate scopes. The evolution of the synthetic methodologies for library synthesis over the past decade is discussed. We also highlight that the combination of parallel library synthesis with high-throughput experimentation will continue to facilitate the discovery of library-amenable synthetic methodologies in drug discovery.

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Palladium-Catalyzed C–O Coupling of a Sterically Hindered Secondary Alcohol with an Aryl Bromide and Significant Purity Upgrade in the API Step

Cited by 17 publications

References 20 publications

Palladium Catalyzed C−O Coupling of Amino Alcohols for the Synthesis of Aryl Ethers

Palladium Catalyzed C−O Coupling of Amino Alcohols for the Synthesis of Aryl Ethers

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

The Chosen Few: Parallel Library Reaction Methodologies for Drug Discovery

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