Development of a Nitrene-Type Rearrangement for the Commercial Route of the JAK1 Inhibitor Abrocitinib

Connor, Christina G.; DeForest, Jacob C.; Dietrich, Phil; M., Nga; Doyle, Kevin M.; Eisenbeis, Shane A.; Greenberg, Elizabeth; Griffin, Sarah H.; Jones, Brian P.; Jones, Kris; Karmilowicz, Michael J.; Kumar, Rajesh; Lewis, Chad A.; McInturff, Emma; McWilliams, J. Christopher; Mehta, R. H.; Nguyen, Bao D.; Rane, Anil; Samas, Brian; Sitter, Barbara; Ward, Howard W.; Webster, Mark E.

doi:10.1021/acs.oprd.0c00366

Cited by 20 publications

(12 citation statements)

References 23 publications

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“…A recent example of the use of an IRED involves the development of a commercial route to the JAK1 inhibitor abrocitinib by Pfizer . The commercial route involves a biocatalytic reductive amination using a highly selective IRED to afford the desired cis -amino ester intermediate in 74% yield with a >99:1 diastereomeric ratio (Scheme )…”

Section: Expanding the Scope Of Biocatalysismentioning

confidence: 99%

Streamlining Design, Engineering, and Applications of Enzymes for Sustainable Biocatalysis

Sheldon

Brady

2021

ACS Sustainable Chem. Eng.

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In this Perspective we show how an expansion of the scope and impact of biocatalysis in industrial organic synthesis is enabled by streamlining the underpinning biocatalyst and bioprocess engineering. We begin by discussing how the underlying need for waste reduction and high (enantio)selectivities fostered the introduction of biocatalysis as a sustainable technology for the industrial synthesis of active pharmaceutical ingredients (APIs). We continue by showing how advances in molecular biology, in particular gene sequencing and protein engineering, enabled the development of more and better enzymes, thereby broadening the industrial scope of biocatalysis. Further process improvements are provided through protein engineering for enzyme immobilization and integration of enzyme production with in vivo immobilization. Finally, the use of immobilized enzymes in continuous operation (biocatalysis in flow) facilitates the sequential integration of multi-step reactions into enzymatic or chemo-enzymatic cascade processes, thus enabling the complete, cost-effective, and environmentally attractive production of APIs.

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Section: Expanding the Scope Of Biocatalysismentioning

confidence: 99%

Streamlining Design, Engineering, and Applications of Enzymes for Sustainable Biocatalysis

Sheldon

Brady

2021

ACS Sustainable Chem. Eng.

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“…While just a few years ago no biocatalytic reductive amination had been reported above a gram scale, Pfizer has now engineered and developed an IRED for commercial manufacture of abrocitinib, a JAK1 inhibitor being developed for atopic dermatitis. This work was originally disclosed in a patent application, 10 and the process development of the manufacturing route 11 and the biocatalytic process were recently published. 12 In the original route used for scale-up, cis-1,3diaminocyclobutane 6 was prepared by cryogenic reductive amination of 5 with a 4:1 cis:trans ratio.…”

Section: Biocatalytic Imine Reductions and Reductive Aminationsmentioning

confidence: 99%

Highlights of the Recent Patent Literature─Focus on Biocatalysis Innovation

Hughes¹

2022

Org. Process Res. Dev.

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This review surveys recent advances in biocatalysis, with a primary focus on contributions from the patent literature since 2018, including reductive aminations, nitro reductions, amidations, carbon–carbon bond formation catalyzed by lipases and aldolases, and cascade biocatalysis. Examples of processes that have been designed and developed for the industrial preparation of pharmaceutical intermediates are highlighted.

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“…A total biocatalyst loading up to 10 % w/w can lead to acceptable levels of foaming and emulsification in extractive work‐ups [93–94] . In addition to this, less than 5 % w/w total biocatalyst loading has previously been adopted in two‐enzyme processes for pharmaceutical manufacturing employing lyophilised clarified cell‐free extracts [95–102] . The selected thresholds for final product concentration [51] and biocatalyst loading (Table 6) lead to target biocatalyst yield ranging from 10—50 g product /g biocatalyst .…”

Section: Towards Industrial Utilitymentioning

confidence: 99%

Recent Developments and Challenges for the Industrial Implementation of Polyphosphate Kinases

et al. 2021

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Polyphosphate kinases (PPKs) have emerged as valuable candidates to address the unmet need for scalable recycling of the common enzyme cofactor adenosine‐5’‐triphosphate (ATP) because they use cheap, freely available and stable polyphosphate (polyP) salts as the phosphate donor. The aim of this review is not only to present recent efforts in the characterisation of PPKs but also to provide an overview of the challenges associated with their implementation in chemical manufacturing. In assessing the current status of polyP‐driven biocatalysts, we identify gaps that need to be filled for successful adoption of these biocatalysts in industry. Guidelines for a wider adoption of PPKs are also provided.

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Development of a Nitrene-Type Rearrangement for the Commercial Route of the JAK1 Inhibitor Abrocitinib

Cited by 20 publications

References 23 publications

Streamlining Design, Engineering, and Applications of Enzymes for Sustainable Biocatalysis

Streamlining Design, Engineering, and Applications of Enzymes for Sustainable Biocatalysis

Highlights of the Recent Patent Literature─Focus on Biocatalysis Innovation

Recent Developments and Challenges for the Industrial Implementation of Polyphosphate Kinases

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