Efficient synthesis of tert-butyl 3-cyano-3-cyclopropyl-2-oxopyrrolidine-4-carboxylates: Highly functionalized 2-pyrrolidinone enabling access to novel macrocyclic Tyk2 inhibitors

Yusuke Sasaki; Hidekazu Tokuhara; Yusuke Ohba; Atsutoshi Okabe; Masaharu Nakayama; Hideyuki Nakagawa; Robert Skene; Isaac Hoffman; Hua Zou; Masato Yoshida

doi:10.1016/j.bmcl.2020.126963

Efficient synthesis of tert-butyl 3-cyano-3-cyclopropyl-2-oxopyrrolidine-4-carboxylates: Highly functionalized 2-pyrrolidinone enabling access to novel macrocyclic Tyk2 inhibitors

Bioorg Med Chem Lett. 2020 Mar 1;30(5):126963. doi: 10.1016/j.bmcl.2020.126963. Epub 2020 Jan 13.

Authors

Affiliations

¹ Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26‑1, Muraoka‑Higashi 2‑chome, Fujisawa, Kanagawa 251‑8555, Japan. Electronic address: [email protected].
² Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26‑1, Muraoka‑Higashi 2‑chome, Fujisawa, Kanagawa 251‑8555, Japan.
³ Takeda California, Inc., 10410 Science Center Drive, San Diego, CA 92121, United States.

PMID: 31980341
DOI: 10.1016/j.bmcl.2020.126963

Abstract

Herein we report an efficient method for the synthesis of a highly functionalized 2-pyrrolidinone, tert-butyl 3-cyano-3-cyclopropyl-2-oxopyrrolidine-4-carboxylate, from readily available starting materials. Utility of this compound was demonstrated in the synthesis of a novel series of macrocyclic Tyk2 inhibitors, leading to the identification of a potent and selective macrocyclic Tyk2 inhibitor (26).

Keywords: 2-Pyrrolidinone; Kinase; Macrocycle; Tyk2.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Humans
Jurkat Cells
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis*
Protein Kinase Inhibitors / pharmacology
Pyrrolidinones / chemical synthesis*
Pyrrolidinones / pharmacology
Structure-Activity Relationship
TYK2 Kinase / antagonists & inhibitors*

Substances

Protein Kinase Inhibitors
Pyrrolidinones
TYK2 Kinase
TYK2 protein, human