Axial Chirality in the Sotorasib Drug Substance, Part 2: Leveraging a High-Temperature Thermal Racemization to Recycle the Classical Resolution Waste Stream

Beaver, Matthew G.; Brown, Derek B.; Campbell, Kiersten; Fang, Yuan‐Qing; Ford, David D.; Mardirossian, Narbe; Nagy, Kevin D.; Rötheli, Andreas R.; Sheeran, Jillian W.; Telmesani, Reem; Parsons, Andrew T.

doi:10.1021/acs.oprd.2c00177

Cited by 15 publications

(14 citation statements)

References 13 publications

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“…This preparation of M - 1 has been successfully performed on > 500 kg input of rac - 1 and serves to deliver a key intermediate in the synthesis of the KRAS G12C inhibitor sotorasib. Part 2 of this series describes the development of a P - 1 waste recycling protocol achieved through thermal racemization to rac - 1 , which improves the efficiency and greenness of the M - 1 manufacturing process …”

Section: Discussionmentioning

confidence: 99%

“…Part 2 of this series describes the development of a P-1 waste recycling protocol achieved through thermal racemization to rac-1, which improves the efficiency and greenness of the M-1 manufacturing process. 22 ■ EXPERIMENTAL SECTION Representative Procedure for the Preparation of 7-Chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (rac-1). Steps 1a and 1b.…”

Section: Organic Processmentioning

confidence: 99%

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Axial Chirality in the Sotorasib Drug Substance, Part 1: Development of a Classical Resolution to Prepare an Atropisomerically Pure Sotorasib Intermediate

Parsons

Caille

Caporini

et al. 2022

Org. Process Res. Dev.

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Described herein is the discovery and development of a process to prepare an atropisomeric intermediate in the synthesis of the KRAS G12C inhibitor sotorasib. Using high-throughput experimentation, (+)-2,3-dibenzoyl-D-tartaric acid [(+)-DBTA] was identified as an inexpensive and readily available resolving agent that enables separation and isolation of the desired atropisomer through a classical resolution. Subsequent optimization and characterization studies led to a highly selective process, providing the desired atropisomer as a unique three-component cocrystal solvate with a selectivity of >2000:1. This classical resolution has been performed successfully on >500 kg scale and was critical to the commercialization of the sotorasib manufacturing process.

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Section: Discussionmentioning

confidence: 99%

Section: Organic Processmentioning

confidence: 99%

Axial Chirality in the Sotorasib Drug Substance, Part 1: Development of a Classical Resolution to Prepare an Atropisomerically Pure Sotorasib Intermediate

Parsons

Caille

Caporini

et al. 2022

Org. Process Res. Dev.

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“… a Experiments performed at 100 mg scale. b Chiral purity at t 0 = 99.6% ee. c Slurry-to-slurry transformation. d Experiment was performed in a plug-flow reactor. Adapted with permission from ref . Copyright 2022 The American Chemical Society. …”

Section: Synthetic Considerations: Preparing Single Atropisomers On S...mentioning

confidence: 99%

“… 2022 26 2636 2645 . 3 Describes the development of a continuous-flow racemization process to recycle the off-enantiomer of an atropisomeric sotorasib intermediate obtained from the classical resolution. Additionally reports the demonstration of this process on kilogram scale.…”

Section: Key Referencesmentioning

confidence: 99%

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Addressing Atropisomerism in the Development of Sotorasib, a Covalent Inhibitor of KRAS G12C: Structural, Analytical, and Synthetic Considerations

Lanman¹,

Parsons

Zech³

2022

Acc. Chem. Res.

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Conspectus Nearly a century after its first description, configurationally stable axial chirality remains a rare feature in marketed drugs. In the development of the KRASG12C inhibitor sotorasib (LUMAKRAS/LUMYKRAS), an axially chiral biaryl moiety proved a critical structural element in engaging a “cryptic” protein binding pocket and enhancing inhibitor potency. Restricted rotation about this axis of chirality gave rise to configurationally stable atropisomers that demonstrated a 10-fold difference in potency. The decision to develop sotorasib as a single-atropisomer drug gave rise to a range of analytical and synthetic challenges, whose resolution we review here. Assessing the configurational stability of differentially substituted biaryl units in early inhibitor candidates represented the first challenge to be overcome, as differing atropisomer stability profiles called for differing development strategies (e.g., as rapidly equilibrating rotamers vs as single atropisomers). We relied on a range of NMR, HPLC, and computational methods to assess atropisomer stability. Here, we describe the various variable-temperature NMR, time-course NMR, and chiral HPLC approaches used to assess the configurational stability of axially chiral bonds displaying a range of rotational barriers. As optimal engagement of the “cryptic” pocket of KRASG12C was ultimately achieved with a configurationally stable atropisomeric linkage, the second challenge to be overcome entailed preparing the preferred (M)-atropisomer of sotorasib on industrial scale. This synthetic challenge centered on the large-scale synthesis of an atropisomerically pure building block comprising the central azaquinazolinone and pyridine rings of sotorasib. We examined a range of strategies to prepare this compound as a single atropisomer: asymmetric catalysis, chiral chromatographic purification, and classical resolution. Although chiral liquid and simulated moving bed chromatography provided expedient access to initial multikilo supplies of this key intermediate, a classical resolution process was ultimately developed that proved significantly more efficient on metric-ton scale. To avoid discarding half of the material from this resolution, this process was subsequently refined to enable thermal recycling of the undesired atropisomer, providing an even more efficient commercial process that proved both robust and green. While the preparation of sotorasib as a single atropisomer significantly increased both the analytical and synthetic complexity of its development, the axially chiral biaryl linkage that gave rise to the atropisomerism of sotorasib proved a key design element in optimizing sotorasib’s binding to KRASG12C. It is hoped that this review will help in outlining the range of analytical techniques and synthetic strategies that can be brought to bear in addressing the challenges posed by such axially chiral compounds and that this account may provide helpful guidelines for future efforts aimed at the development of such single atropisomer, axially chiral p...

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Crystallization: A Tool for Asymmetric Synthesis and Isolation

Kukor

Hein

2024

Comprehensive Chirality

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Axial Chirality in the Sotorasib Drug Substance, Part 2: Leveraging a High-Temperature Thermal Racemization to Recycle the Classical Resolution Waste Stream

Cited by 15 publications

References 13 publications

Axial Chirality in the Sotorasib Drug Substance, Part 1: Development of a Classical Resolution to Prepare an Atropisomerically Pure Sotorasib Intermediate

Axial Chirality in the Sotorasib Drug Substance, Part 1: Development of a Classical Resolution to Prepare an Atropisomerically Pure Sotorasib Intermediate

Addressing Atropisomerism in the Development of Sotorasib, a Covalent Inhibitor of KRAS G12C: Structural, Analytical, and Synthetic Considerations

Crystallization: A Tool for Asymmetric Synthesis and Isolation

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