How is Risdiplam synthesised?

Synthesis of Risdiplam

The SNAr reaction between amine 194 and bromopyridine 195 furnished 196 in good yield. Nitro reduction via hydrogenation in the presence of a platinum catalyst preceded treatment with di-tert-butyl malonate in anisole at elevated temperatures to give pyridopyrimidone 197 in high overall yield over the two steps. Tosylation formed sulfonate 198, which then participated in a Suzuki coupling with 200 (which originated from aryl chloride 199 via Miyaura coupling) to establish the framework of risdiplam. Risdiplam was formed after N-Boc deprotection of 201 with n-propanolic HCl and was isolated after pH adjustment.

Introduction of Risdiplam

Risdiplam was approved by the USFDA for the treatment of spinal muscular atrophy caused by a mutation leading to a deficiency in the survival motor neuron (SMN) protein. It is an orally administered SMN2-directed RNA splicing modifier that acts by activating an alternative gene SMN2 to produce full-length and functional SMN protein. This medication was developed by Roche, PTC Therapeutics Inc., and the SMA Foundation.