Peer-reviewedCC BY 4.0Organic Process Research and Development
Scalable Synthesis of a Masked Thiophenol as an Air-Stable, Odorless Intermediate to the Aurora Kinase Inhibitor Tozasertib (VX-680)
Abstract
The use of thiophenols on process scales is fraught with challenges relating to their toxicity, malodor, and air sensitivity. We previously demonstrated that the Ni-catalyzed C–S coupling of aryl iodides and thiourea provides a discovery-scale route to S-aryl isothiouronium salts, which serve as bench stable, odorless, and highly crystalline surrogates of thiophenols. Here, we report the process optimization of this methodology for the synthesis of a key intermediate to kinase inhibitor tozasertib (VX-680). The corollary is a reduction in catalyst loading to 0.5 mol %, elimination of NMP solvent, and introduction of a direct crystallization, giving 95% yield on a 100 g scale.
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BibTeX
@article{herzog2026scalable,
title = {{Scalable Synthesis of a Masked Thiophenol as an Air-Stable, Odorless Intermediate to the Aurora Kinase Inhibitor Tozasertib (VX-680)}},
author = {Richard Herzog and Olivia L Munns and Valentin Magné and Stephen P Argent and Liam T Ball},
journal = {Organic Process Research and Development},
year = {2026},
month = aug,
doi = {10.1021/acs.oprd.6c00143},
url = {https://hal.science/hal-05760747v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Scalable Synthesis of a Masked Thiophenol as an Air-Stable, Odorless Intermediate to the Aurora Kinase Inhibitor Tozasertib (VX-680)
AU - Richard Herzog
AU - Olivia L Munns
AU - Valentin Magné
AU - Stephen P Argent
AU - Liam T Ball
PY - 2026
DA - 2026/08/06
JO - Organic Process Research and Development
DO - 10.1021/acs.oprd.6c00143
UR - https://hal.science/hal-05760747v1
AB - The use of thiophenols on process scales is fraught with challenges relating to their toxicity, malodor, and air sensitivity. We previously demonstrated that the Ni-catalyzed C–S coupling of aryl iodides and thiourea provides a discovery-scale route to S-aryl isothiouronium salts, which serve as bench stable, odorless, and highly crystalline surrogates of thiophenols. Here, we report the process optimization of this methodology for the synthesis of a key intermediate to kinase inhibitor tozasertib (VX-680). The corollary is a reduction in catalyst loading to 0.5 mol %, elimination of NMP solvent, and introduction of a direct crystallization, giving 95% yield on a 100 g scale.
SN - 1083-6160
SN - 1520-586X
ER -