Synthesis of Difamilast

Difamilast is synthesised in two steps by chemical reaction using the monobenzylated protocatechuic acid ethyl ester as a raw material. The specific synthesis steps are as follows:

Step 1: Synthesis of Difamilast Oxazole Methanol 15.8

Synthesis of difamilast commenced with the monobenzylated protocatechuic acid ethyl ester 15.1. Phenol 15.1 was first converted into the corresponding isopropyl ether, which was subsequently debenzylated under palladium-catalyzed hydrogenation conditions to generate the phenolic intermediate 15.3. Difluoromethylation of 15.3 was accomplished by introducing sodium chlorodifluoroacetate 15.4 in the presence of potassium carbonate at an elevated temperature. The decarboxylative C? O bond-forming reaction presumably proceeded via a difluorocarbene species. The difluoromethylated product was treated with acid followed by ester hydrolysis under a basic medium to furnish benzoic acid derivative 15.5. Benzoic acid 15.5 was subsequently transformed into benzamide 15.6 via a benzoyl imidazole intermediate. Condensation of benzamide 15.6 with 1-acetoxy-3-chloroacetone 15.7 produced an oxazole derivative, which was subsequently saponified and recrystallized from 50% aqueous MeOH to generate alcohol 15.8.

Step 2: Preparation of Difamilast

First, an activation?displacement process transformed alcohol 15.8 into bromide 15.9 via a mesylate intermediate. Alkyl bromide 15.9 was then treated with potassium phthalimide to incorporate the nitrogen center via an S_N2-type displacement. Methylamine-mediated phthalimide deprotection and subsequent salt formation produced amine 15.11 as a hydrochloride salt in 69% yield over 3 steps. Finally, hydrochloride salt 15.11 was treated with aqueous sodium bicarbonate to generate a free amine, which was subjected to amide bond formation with 2-ethoxybenzoic acid 15.12 to deliver difamilast after recrystallization from aqueous EtOH.