Synthesis of Ponesimod

Ponesimod is synthesised using isothiocyanate as a raw material by chemical reaction. The specific synthesis steps are as follows:

A three-component coupling of isothiocyanate 16.1, n-propylamine, and 2-bromoacetyl bromide 16.2 was utilized to construct the thiazolidine-4-one core 16.3. The regioselectivity of this cyclization was shown to be heavily dependent on the choice of the halogenated acetic acid derivative; in this case, 2-bromoacetyl bromide 16.2 gave high regioselectivity for the desired 16.3 (41:1, 16.3:16.4) compared to methyl 2-bromoacetate (1:10, 16.3:16.4), for example. Subsequent aldol-type condensation with aldehyde 16.5 was telescoped to yield phenol 16.6 in a high overall yield from starting isothiocyanate 16.1. The final step involved the SN2 attachment of commercially available chiral chloropropanediol 16.7 to phenol 16.6 in the presence of base to ultimately afford ponesimod.

Description of Ponesimod

Ponesimod was approved in 2021 for the treatment of relapsing forms of multiple sclerosis (MS). This medication was developed by the Janssen Pharmaceutical Companies of Johnson & Johnson and is an orally administered, selective sphingosine-1-phosphate (S1P) receptor 1 (S1P1) agonist. Binding of the agonist leads to internalization of this receptor and inhibition of lymphocyte egress from lymph nodes, which reduces the number of lymphocytes in the blood and limits their circulation to inflammation sites.