Development and Scale-Up of an Asymmetric Synthesis of AZD8186 Using the Fukuyama Modification of the Mitsunobu Reaction

Moore, Peter R.; Muir, James; Dubiez, Jérome; Leslie, Kevin; Tomlin, Paula; McCormick, Marc; Janbon, Sophie; Cornwall, Philip; Ryberg, Per; Berg, R.A.

doi:10.1021/acs.oprd.1c00133

Cited by 6 publications

(4 citation statements)

References 29 publications

(25 reference statements)

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“…Similarly, crystallization was used by AstraZeneca following a Heck cross coupling reaction to give intermediate 50 en route to a compound for treatment of breast and prostate cancer (Scheme 27). 92 Crystallization from TBME resulted in a final palladium content of 50 ppm in compound 50 and, as the catalytic step was at the early stages of the synthetic route, no additional metal scavenging steps were required. The process was demonstrated on a 5.50 kg scale, enabling the production of >15 kg of intermediate 50.…”

Section: Without Additivesmentioning

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: Without Additivesmentioning

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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“…During the scale-up of the asymmetric synthesis of this drug candidate, a Ru-catalyzed enantioselective transfer hydrogenation of ketone 32 was employed for the preparation of chiral secondary alcohol 33 (Scheme 9b). 31 A 0.5 mol % loading of RuCl[(S,S)-MsDPEN](p-cymene) (C8) enabled a complete conversion of ketone 32 at a kilogram scale. The desired alcohol enantiomer 33 was obtained in 84% yield and >99% ee.…”

Section: Asymmetric (Transfer) Hydrogenationmentioning

confidence: 99%

“…The phosphoinositide-3-kinase β inhibitor AZD8186 ( 34 ) is currently undergoing clinical development for treating breast and prostate cancer. During the scale-up of the asymmetric synthesis of this drug candidate, a Ru-catalyzed enantioselective transfer hydrogenation of ketone 32 was employed for the preparation of chiral secondary alcohol 33 (Scheme b) . A 0.5 mol % loading of RuCl[( S , S )-MsDPEN]( p -cymene) ( C8 ) enabled a complete conversion of ketone 32 at a kilogram scale.…”

Section: Asymmetric Transition Metal Catalysismentioning

confidence: 99%

Enantioselective Transformations in the Synthesis of Therapeutic Agents

Yang

Stolarzewicz

et al. 2023

Chem. Rev.

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The proportion of approved chiral drugs and drug candidates under medical studies has surged dramatically over the past two decades. As a consequence, the efficient synthesis of enantiopure pharmaceuticals or their synthetic intermediates poses a profound challenge to medicinal and process chemists. The significant advancement in asymmetric catalysis has provided an effective and reliable solution to this challenge. The successful application of transition metal catalysis, organocatalysis, and biocatalysis to the medicinal and pharmaceutical industries has promoted drug discovery by efficient and precise preparation of enantio-enriched therapeutic agents, and facilitated the industrial production of active pharmaceutical ingredient in an economic and environmentally friendly fashion. The present review summarizes the most recent applications (2008–2022) of asymmetric catalysis in the pharmaceutical industry ranging from process scales to pilot and industrial levels. It also showcases the latest achievements and trends in the asymmetric synthesis of therapeutic agents with state of the art technologies of asymmetric catalysis.

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“…24 Despite the good yield, stoichiometric byproducts triphenylphosphine oxide and the hydrazine from DEAD were generated, and chromatography was needed to achieve purification. Though the Mitsunobu reaction was employed successfully on a several kilogram scale (see, for example, a recent report 25 ), it was done as a late-stage modification, probably justifying the wastes formed. Recently, a version of the Mitsunobu protocol, catalytic in both azo and phosphine reagents, was developed 26 as well as a fully organocatalytic one, 27 but to the best of our knowledge, none of these advances were used on a large scale.…”

Section: (S)-glycidylmentioning

confidence: 99%

Review on Synthetic Approaches toward Rivaroxaban (Xarelto), an Anticoagulant Drug

Mladentsev

Kuznetsova

Skvortsova

et al. 2022

Org. Process Res. Dev.

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Venous thromboembolism including deep vein thrombosis and pulmonary embolism is an abundant and dangerous disease with significant relapse probability and mortality. In pursuit of an effective treatment, Bayer created Rivaroxaban, nowadays known under the brand name Xarelto, that was approved by the FDA in 2011. By 2022, the number of main indications for the drug has been increased 10-fold as well as the drug's prevalence in the field of thrombosis treatment. It is therefore apparent that with growing prescriptions new synthetic pathways are highly desirable, especially those utilizing inexpensive and safe reagents in environmentally benign protocols. The present work reviews the literature concerning Rivaroxaban preparation with an emphasis on the applicability of synthetic pathways on a large scale. Within the synthetic sequences, common intermediates are discussed in detail and relevant comparisons are made. Our main purpose is to provide an overview of the subject in its current state, paying attention to advances made and suggesting possible directions for further development.

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Development and Scale-Up of an Asymmetric Synthesis of AZD8186 Using the Fukuyama Modification of the Mitsunobu Reaction

Cited by 6 publications

References 29 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

Enantioselective Transformations in the Synthesis of Therapeutic Agents

Review on Synthetic Approaches toward Rivaroxaban (Xarelto), an Anticoagulant Drug

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