Guided optimization of a crystallization-induced diastereomer transformation to access a key navoximod intermediate

Kukor, Andrew J.; St-Jean, Frédéric; Stumpf, Andreas; Malig, Thomas C.; Piechowicz, Katarzyna A.; Kurita, Kenji L.; Hein, Jason E.

doi:10.1039/d3re00077j

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Cited by 3 publications

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References 21 publications

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“…This racemization converts the mother liquors back into a racemic mixture, which is subsequently crystallized . Furthermore, this technique has been studied in crystallization-induced diastereomeric transformation, − in particular the epimerization of an axially chiral compound, which was successfully scaled in industrial applications . Although deracemization processes based on the batch-mode are becoming more successful, skill gaps still remain to realize continuous crystallization.…”

Section: Introductionmentioning

confidence: 99%

Semicontinuous Temperature Cycle-Induced Deracemization Using an Axially Chiral Naphthamide

Oketani,

Naito,

Hisaki

2024

Org. Process Res. Dev.

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Section: Introductionmentioning

confidence: 99%

Semicontinuous Temperature Cycle-Induced Deracemization Using an Axially Chiral Naphthamide

Oketani,

Naito,

Hisaki

2024

Org. Process Res. Dev.

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Stereochemical Editing via Coupled Epimerization and Optical Resolution to Sustainably Manufacture a Key Adagrasib Building Block

Snead,

Roshandel,

Chen

2023

Org. Process Res. Dev.

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Practical Manufacturing Process for Baloxavir Marboxil: Effective Selection and Replacement of Protective Group toward Enhancement of Crystallization-Induced Diastereomer Transformation

Fukui,

Shibahara,

Maki

et al. 2024

Org. Process Res. Dev.

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Baloxavir marboxil (BXM) is an influenza antiviral drug that exploits a cap-dependent endonuclease (CEN) inhibitor. The synthesis route used in the initial CMC development study had several problems hampering scale-up, such as poor stereochemical outcome which decreased the yield, usage of a corrosive reagent, and a cumbersome protocol for the key step. We addressed these problems to enable practical and operation-friendly manufacture of BXM at a larger production scale for early and successive CMC development. The new route includes the following steps: (1) a magnesium-mediated alkoxy displacement reaction to prepare an intermediate without loss of optical purity and (2) diastereoselective preparation of an intermediate via a dehydration condensation reaction with a crystallization-induced diastereomer transformation (CIDT) process. This facile route enabled scalable manufacturing to supply BXM.

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Guided optimization of a crystallization-induced diastereomer transformation to access a key navoximod intermediate

Abstract: The recently reported crystallization-induced diastereomer transformation (CIDT) of a precursor to navoximod was investigated using online HPLC via a modified EasySampler probe that enables selective solution phase sampling of heterogeneous...

Cited by 3 publications

References 21 publications

Semicontinuous Temperature Cycle-Induced Deracemization Using an Axially Chiral Naphthamide

Semicontinuous Temperature Cycle-Induced Deracemization Using an Axially Chiral Naphthamide

Stereochemical Editing via Coupled Epimerization and Optical Resolution to Sustainably Manufacture a Key Adagrasib Building Block

Practical Manufacturing Process for Baloxavir Marboxil: Effective Selection and Replacement of Protective Group toward Enhancement of Crystallization-Induced Diastereomer Transformation

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