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

Parsons, Andrew T.; Caille, Seb; Caporini, Marc A.; Griffin, Daniel J.; Lovette, Michael A.; Powazinik, William; St‐Pierre, Gabrielle

doi:10.1021/acs.oprd.2c00176

Cited by 16 publications

(21 citation statements)

References 16 publications

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“…163.5,162.5,160.1 (d,1 J C-F = −245.7 Hz), 156.8 (d, 3 J C-F = 6.4 Hz), 153.7, 151.9 (d, 1 J C-F = −250.6 MHz), 149. 5, 148.3, 145.2, 144.3 (d, 2 J C-F = 19.0 Hz), 131.6 (d, 3 J C-F = 10.8 Hz),130.8,127.9,127.8,123.2,122.8 (d,111.7 (d,4 JC-F = 11.7 Hz), 109.7 (dd, 2,3 J C-F = 17.6, 3.7 Hz), 105.7 (d, 2 J C-F = 21.2 Hz), 105.3 (d, 3 J C-F = 3.9 Hz), 51.0, 48.9, 43.5, 41.6, 29.8, 21.7, 21.9, 17.0, 14.8. 19 F-NMR (600 MHz, DMSO-d 6 ): −128.6 (d, J = 5.8 Hz, 1F), −115.6 (d, J = 5.8 Hz, 1F).…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

Development of a Commercial Manufacturing Process for Sotorasib, a First-in-Class KRAS^G12C Inhibitor

Zhang

Griffin

Beaver

et al. 2022

Org. Process Res. Dev.

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A commercial process to manufacture sotorasib (AMG 510), a first-in-class KRASG12C inhibitor, is described. Development efforts focused on rendering a fit-for-purpose early-phase route into a viable long-term commercial process through the reduction of side reactions to improve yield and product quality, as well as reducing cycle times of crystallization processes by improving particle properties and filtration times. These improvements were key to ensuring clinical supply and commercial launch. The final route consists of five synthetic operations from starting material M-1, including a telescoped two-step sequence, and a final form-setting crystallization.

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Section: ■ Experimental Sectionmentioning

confidence: 99%

Development of a Commercial Manufacturing Process for Sotorasib, a First-in-Class KRAS^G12C Inhibitor

Zhang

Griffin

Beaver

et al. 2022

Org. Process Res. Dev.

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

confidence: 99%

“… 2022 26 2629 2635 . 2 Reports the discovery of (+)-2,3-dibenzoyl- d -tartaric acid [(+)-DBTA] as a resolving agent that enables the classical resolution of a key atropisomeric intermediate in the synthesis of sotorasib. Development of a commercial process that provides >2000:1 selectivity on >500 kg scale is described .…”

Section: Key Referencesmentioning

confidence: 99%

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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“…However, when chiral resolution is applied to atropisomers, the yield may be increased by taking advantage of the dynamic nature of the atropisomeric stereocenter. By racemizing the undesired enantiomer by applying heat, a second crop of desired atropisomer can be resolved by crystallization . During our development work to obtain the pure atropisomers of the drug candidates 1 and 2 , a classical salt resolution strategy was explored for a scalable approach, and as an alternative to chromatography .…”

Section: Salt Resolution/crystallization and Asymmetric Synthesismentioning

confidence: 99%

“…By racemizing the undesired enantiomer by applying heat, a second crop of desired atropisomer can be resolved by crystallization. 31 During our development work to obtain the pure atropisomers of the drug candidates 1 and 2, a classical salt resolution strategy was explored for a scalable approach, and as an alternative to chromatography. 2 From an efficiency perspective, it is best to perform a salt resolution as early as possible in the synthesis to minimize processing of the undesired atropisomer.…”

Section: Resolution Through Crystallizationmentioning

confidence: 99%

Approaches to Synthesis and Isolation of Enantiomerically Pure Biologically Active Atropisomers

et al. 2022

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Metrics & MoreArticle Recommendations CONSPECTUS: Atropisomerism is a stereochemical phenomenon exhibited by molecules containing a rotationally restricted σ bond. Contrary to classical point chirality, the two atropisomeric stereoisomers exist as a dynamic mixture and can be interconverted without the requirement of breaking and reforming a bond. Although this feature increases structural complexity, atropisomers have become frequent targets in medicinal chemistry projects. Their axial chirality, e.g., from axially chiral biaryl motifs, gives access to unique 3D structures. It is often desirable to have access to both enantiomers of the atropisomers via a nonselective reaction during the early discovery phase as it allows the medicinal chemistry team to probe the structure activity relationship in both directions. However, once a single atropisomer is selected, it presents several problems. First, the pure single atropisomer may interconvert to the undesired stereoisomer under certain conditions. Second, separation of atropisomers is nontrivial and often requires expensive chiral stationary phases using chromatography or additives if a salt resolution approach is chosen. Other options can be kinetic resolution using enzymes or chiral catalysts. However, apart from the high cost often associated with the two latter methods, a maximum yield of only 50% of the desired atropisomer can be obtained. The ideal approach is to install the chiral atropisomeric axis enantioselectively or employing a dynamic kinetic resolution approach. In theory, both approaches have the potential to provide a single atropisomer in quantitative yield. This Account will discuss the successes/failures and challenges we have experienced in developing methods for resolution/separation and asymmetric synthesis of atropisomeric drug candidates in one of our early phase drug development projects. Suitability for the different methods at various stages of the drug development phase is discussed. Depending on the scale and time available, a separation of a mixture of atropisomers by chromatography was sometimes preferred, whereas asymmetric-or resolution approaches were desired for long-term supply. With the use of chromatography, the impact on separation efficiency and solvent consumption, depending on the nature of the substrate, is discussed. We hope that with this Account the readers will get a better view on the challenges medicinal and process chemists meet when designing new atropisomeric drug candidates and developing processes for manufacture of a single atropisomer.

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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

Cited by 16 publications

References 16 publications

Development of a Commercial Manufacturing Process for Sotorasib, a First-in-Class KRAS^G12C Inhibitor

Development of a Commercial Manufacturing Process for Sotorasib, a First-in-Class KRAS^G12C Inhibitor

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

Approaches to Synthesis and Isolation of Enantiomerically Pure Biologically Active Atropisomers

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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

Cited by 16 publications

References 16 publications

Development of a Commercial Manufacturing Process for Sotorasib, a First-in-Class KRASG12C Inhibitor

Development of a Commercial Manufacturing Process for Sotorasib, a First-in-Class KRASG12C Inhibitor

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

Approaches to Synthesis and Isolation of Enantiomerically Pure Biologically Active Atropisomers

Contact Info

Product

Resources

About

Development of a Commercial Manufacturing Process for Sotorasib, a First-in-Class KRAS^G12C Inhibitor

Development of a Commercial Manufacturing Process for Sotorasib, a First-in-Class KRAS^G12C Inhibitor