Odevixibat was synthesized by using 3-mercaptoether anisole as the starting material and reacting with the intermediate amine fragment 12.4. The specific reaction route is as follows:
3-Mercaptoether anisole 12.5 was dibrominated with bromine in methanol to produce dibromodisulfide 12.6, which was then oxidized to sulfonyl chloride 12.7 in a one-pot process. In an SN2 reaction, tertiary amine 12.4 reacted with arylsulfonyl chloride 12.7 to produce 12.8. This compound was treated with copper powder and K2CO3 in DMF to form 12.9. Under the protection of p-methoxybenzyl bromide, the sulfonamide nitrogen was first demethylated, and then the sulfide group was introduced by SNAr reaction to finally give phenol 12.10. The peptide side chain was then constructed and O-alkylated with tert-butyl bromoacetate, followed by removal of the protecting group under acidic conditions to give 12.11. Next, two consecutive amidation reactions were carried out using the activating agent TBTU. Amine 12.12 was coupled with 12.11, followed by removal of the tert-butyl group with trifluoroacetic acid (TFA). A second amidation reaction with amine 12.14, accompanied by in situ removal of the tert-butyl group, provided odevixibat (12) in 66% yield.
