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 ¹, Rui Zhang¹, Michel Leeman ², Christopher R. H. Hale ³, Giorgio Attardo ³, Vijaya B. Gondi ^{3 *}

1 WuXi AppTec Research Chemistry Service, 168 NanHai Road, 10th Avenue, TEDA, Tianjin 300457, China.

2 Symeres, Kadijk 3, 9747 AT Groningen, The Netherlands.

3 Bristol Myers Squibb Company, 1 Squibb Drive, New Brunswick, New Jersey 08903, United States.

* 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.

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