Belzutifan’s route started with 3,4-dihydrocoumarin (33.1) and proceeded in three steps:
Step 1: Synthesis of the indanone core 33.8. 3,4-Dihydrocoumarin (33.1) could be regioselectively brominated with NBS under Lewis acid conditions to generate intermediate 33.2, paving the way for the subsequent tandem lactone ring opening/SNAr reaction (Figure 1). The desired ring-opening product was successfully generated by treating 33.2 with K2CO3 in NMP and H2O, which spontaneously participated in the SNAr reaction in the presence of 3,5-difluorobenzonitrile (33.3) and 18-crown-6 to generate intermediate 33.5. After isopropanoate (i-PrOAc) extraction, the crude product was reacted with oxalyl chloride in MTBE/DMF to generate the corresponding acyl chloride 33.6, which underwent an intramolecular Friedel–Crafts reaction in the presence of AlCl3. This series of reactions started with the bromination of intermediate 33.2 to generate indanone 33.7. The introduction of methyl sulfone was achieved using sodium methanesulfonate under copper-mediated conditions to generate 33.8 in 78% yield.
Step 2: Synthesis of indanone ketal 33.13. Starting from indanone 33.8, the keto group was protected to its corresponding ketal intermediate 33.9 before developing a continuous-flow light-mediated benzylic bromination step (Figure 2). Thus, intermediate 33.11 could be free-radical brominated with 1,3-dibromo-5,5-dimethylhydantoin (33.10) in acetonitrile in the presence of citric acid and visible light to generate a crude reaction mixture that was carefully quenched with 2,6-butane and 1,3-dimethoxybenzene. The brominated product 33.11, which showed limited stability when isolated, was directly oxidized in a continuous flow process to generate the ketone 33.13 via a modified Kornblum oxidation with 2-methylpyridine N-oxide (33.12).
Step 3: The presence of three consecutive chiral centers on the indene ring was ensured. First, the introduction of the chiral alcohol 33.14 was accomplished by asymmetric reduction under transfer hydrogenation conditions using (R,R)-Ru-diphenylethylenediamine ((R,R)-Ru-DPEN) and formic acid/triethylamine in acetonitrile to afford the (R)-hydroxyketone with high selectivity (Figure 3). The reduction step was immediately quenched with aqueous hydrochloric acid to promote the cleavage of the acetal group, resulting in the crystallization of intermediate 33.14 from water in 91% overall yield and greater than 99% enantiomeric excess. Next, intermediate 33.14 was α-fluorinated by reaction with Selectfluor and catalytic methanesulfonic acid to generate a mixture of fluorinated stereoisomers (33.15), which immediately underwent Noyori asymmetric transfer hydrogenation after quenching the excess fluorinating agent with triethylamine. Under these hydrogenation conditions (RuCl(R,R)-TsDPEN/triethylamine/formic acid/methanesulfonic acid), the reduction of the ketone occurred with high selectivity while promoting the dynamic kinetic resolution (DKR) of the adjacent fluorinated substituents in a one-pot reaction. Although acid-mediated acetal byproducts were observed in this reaction sequence, the desired stereoisomer 33.16 was isolated from 33.14 in 80% yield (99:1 enantiomeric ratio) by quenching the reaction with water. Finally, the final stereocenter was established by deoxyfluorination of intermediate 33.16 using perfluoro-1-butanesulfonyl fluoride (PBSF, 33.17). In this reaction, selective deprotonation of the desired alcohol using DBU was crucial. This reaction completely reversed the stereochemistry and afforded Belzutifan (33) in 73% yield and 99.8% purity by recrystallization from water.
