Gallou, Fabrice (2023) Alternative synthesis of 5-(1H-Pyrazol-4-yl)-2-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3-yl}phenol. Helvetica Chimica Acta, 106 (3). e202200186.

Abstract

Spinal Muscular Atrophy (SMA) is a heritable cause of infant mortality in 1/6000 births. The majority of patients with Type 1 SMA die by age of 22 months unless they receive intensive supportive care intervention, which can prolong life but does not reverse the loss of skeletal muscle function. Thus infants with Type 1 SMA have the most to gain by a potential Survival Motor Neuron (SMN) gene splice modulator such as BRANAPLAM. BRANAPLAM showed increased exon 7 inclusion and upregulated SMN protein expression in both SMA patient fibroblasts and SMNΔ7 5025-mouse myoblasts. Herein we describe the chemical synthesis of this compound for toxicological as well as clinical studies.
The original synthesis utilized sequential Suzuki cross-couplings to form biaryl intermediates 4’ and 6’, which is synthetically efficient. However, the intrinsic risk of producing the persistent dioxin (“Health Assessment Document for Polychlorinated Dibenzo-p-dioxins”; U.S. Environmental Protection Agency. U. S. Government Printing Office: Washington, DC, 1985; EPA 600/8-84-014F.;“Estimating Exposure to Dioxin-Like Compounds, Vol. I: Executive Summary”, external review draft; Office of Health and Environmental Assessment Office of Research and Development. U.S. Government Printing Office: Washington, DC, June 1994; EPA/600/6-88/005Ca.; “Estimating Exposure to Dioxin-Like Compounds, Vol. II: Properties, Sources, Occurrence and Background Exposures”; external review draft; Office of Health and Environmental Assessment, Office of Research and Development. U.S. Government Printing Office: Washington, DC, June 1994; EPA/60/W6-88/005Cb.) impurities into the final API prompted us to investigate an alternative synthesis route to avoid the involvement of polyhalogenated phenol intermediate such as 3b (Scheme 1).

Item Type:	Article
Date Deposited:	25 Apr 2023 00:45
Last Modified:	25 Apr 2023 00:45
URI:	https://oak.novartis.com/id/eprint/49005