3-(2-bromoacetyl)-10,11-dihydro-5H-Benzo[d]naphtho[2,3-b]pyran-8(9H)-one

Uses

3-(2-Bromoacetyl)-10,11-dihydro-5H-benzo[d]naphtho[2,3-b]pyran-8(9H)-one is an antiviral agent and Velpatasvir (V116000) intermediate. Velpatasvir is a NS5A inhibitor in patients with hepatitis C (HCV) infection.

Synthesis

3-Vinyl-10,11-dihydro-5H-dibenzo[c,g]benzopyran-8(9H)-one (9.98 g, 36.1 mmol) was used as a starting material, which was dissolved in a stirred solvent mixture of THF (70 mL), DMSO (70 mL) and H2O (35 mL). N-bromosuccinimide (NBS, 6.75 g, 37.9 mmol) was added at once and the reaction mixture was stirred at room temperature for 33 min. After completion of the reaction, the reaction solution was diluted with ethyl acetate (EtOAc) and washed sequentially with water twice and brine once. The organic phase was dried with anhydrous magnesium sulfate (MgSO4), filtered and concentrated under reduced pressure. The crude bromohydrin obtained was suspended in dichloromethane (DCM, 200 mL) and activated manganese dioxide (MnO2, 62.7 g, 722 mmol) was added. After stirring for 15 h at room temperature, the reaction mixture was filtered through diatomaceous earth and the filter cake was washed several times with DCM. The combined filtrates (~400 mL) were treated with methanol (MeOH, ~100 mL) and the mixture was gradually concentrated under reduced pressure to allow the solids to precipitate out of solution. When the volume of liquid was reduced to about 200 mL, the solid was collected by filtration and washed with MeOH. The concentration, precipitation, filtration, and rinsing processes were repeated more than twice, resulting in three batches of 3-(2-bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one in powder form (total 7.49 g, 56% two-step yield).

References

[1] Patent: WO2013/75029, 2013, A1. Location in patent: Page/Page column 140; 141; 142
[2] Patent: US2013/309196, 2013, A1. Location in patent: Paragraph 0366
[3] Patent: US2014/178336, 2014, A1
[4] Patent: US2015/361073, 2015, A1