(2R)-2-Deoxy-2-fluoro-2-Methyl-D-erythro-pentonic acid-g-lactone 3,5-bis(4-chlorobenzoate) synthesis

Yield: 24.3 g

Reaction Conditions:

with triethylamine in tetrahydrofuran at 20;

Steps:

1 ((2R, 3R, 4R) 3(4chlorobenzoyloxy) 4fluoro4methyl5oxotetrahydrofuran2yl)methyl 4chlorobenzoate(1b)
((2R, 3R, 4R) 3(benzoyloxy) 4fluoro4methyl5oxotetrahydrofuran2yl)benzoate (1a, 44.50g, 119.5mmol) inanhydrous methanol It was suspended in (240mL). Methanol (2.3mL, 10mmol, 8.3mol%) and a catalytic amount of 25 wt%sodium methoxide in, was added at room temperature. After 2 hours, the reaction was complete as indicated by TLC (20%EtOAc in hexanes). After concentration under reduced pressure, the residue mixture of ethyl ether and hexane (1: 2v / v) totriturated with (200 mL), the crude intermediate lactone, yielded a. The solid was collected by filtration, rinsed with hexanes (3× 40mL). The crude intermediate round bottom flask dried 1L loaded, was dissolved in anhydrous THF (500mL). 4chlorobenzoylchloride (46mL, 358mmol) was added at room temperature. The mixture was cooled in an icewaterbath and thenwas added triethylamine (100mL, 717mmol). The cloudy mixture was stirred at room temperature overnight. The reaction byadding water (60 mL) is stopped, after which the solution was concentrated under reduced pressure. The residue was dilutedwith ethyl acetate (200 mL), washed with water, brine (each 2 × 100mL). The organic layer was concentrated under reducedpressure, (in hexane, 20% EtOAc) and the residue was purified by column chromatography to afford the product as a fluffysolid in pale yellow. Dry the product (0.2mmHg, 50 ° C, 2 hours),

References:

GILEAD PHARMASSET LLC;CHUN, BYOUNG-KWON;DU, JINFA;RACHAKONDA, SUGUNA;ROSS, BRUCE S;SOFIA, MICHAEL JOSEPH;PAMULAPATI, GANAPATI REDDY;CHANG, WONSUK;ZHANG, HAI-REN;NAGARATHNAM, DHANAPALAN JP2015/227337, 2015, A Location in patent:Paragraph 0213