Development and Scale-Up of an Enabling Synthetic Route to KTX-005, a Muscarinic Acetylcholine Receptor Agonist for the Potential Treatment of Schizophrenia

Hanchao Zheng , Rui Zhang , Michel Leeman , Christopher R. H. Hale , Giorgio Attardo , Vijaya B. Gondi  ^*

* Email: gondib@gmail.com

ABSTRACT

Development and optimization of phase-appropriate synthetic technologies to prepare KTX-005, a potent muscarinic acetylcholine receptor agonist, are described in this article. The modular strategy involves three building blocks: commercially available materials dichlorothiadiazole (21), butanethiol (22), and custom-synthesized azabicyclo derivative (18). The highlight of the enabling synthetic strategy toward KTX-005 is a unique thiadiazole ring opening/closing sequence to facilitate both dichlorothiadiazole desymmetrization with butanethiol as well as functionalization of the azabicyclo ring derivative 18.