Acetic Acid → HCID 19046232, compound

Temperature

23 °C

Ethyl 2-naphthylacetate (11.6 g) was dissolved in ethanol (100 mL) and treated with solid sodium ethoxide (3.5 g) and then dropwise with n-butyl nitrite (7.6 mL). The reaction was stirred at 23° C. for 18 h and treated with acetic acid (5 mL) and stirred for 1 h. The ethanol was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate and evaporated under reduced pressure. The residue was chromatographed on silica gel with hexanes/ethyl acetate (5:1 to 3:1) as eluent. The crude residue (5.6 g) was taken up in ether (300 mL) cooled to 0° C. and treated with lithium aluminum hydride solution (45 mL, 1M in tetrahydrofuran) dropwise. The mixture was heated to reflux for 5 h and cooled. It was quenched by the sequential addition of ethyl acetate (5 mL) water (1.5 mL), sodium hydroxide solution (3M, 1.5 mL) and water (4 mL). The solid was filtered and the solution was dried with magnesium sulfate. The solvent was removed at reduced pressure and the solid was triturated with hexanes/butyl chloride (1:1, 100 mL). Of the crude 2-naphthylglycinol (2.6 g) thus obtained, 1.2 g was dissolved in tetrahydrofuran and treated with triethylamine (1 mL) and cooled in an ice water bath. Treatment of the mixture with 2,6-difluorobenzoyl chloride (1 mL) was followed by stirring at room temperature for 1 h. The mixture was diluted with dichloromethane and water. The organic phase was washed sequentially with sodium bicarbonate solution (saturated aqueous) and 1N hydrochloric acid. The solvent was dried with magnesium sulfate and removed under reduced pressure. The residue was chromatographed on silica gel with hexanes/ethyl acetate (5:1 to 1:1) as eluent. The product was treated with benzene (20 mL), thionyl chloride (3 mL) was added and the mixture heated at reflux for 2.5 h. The solvent was removed under reduced pressure and the residue was treated with methanol (20 mL) and NaOH (50% aqueous, 1.5 mL), and heated at reflux for 1 h. The mixture was evaporated under reduced pressure and the residue was partitioned between water and ethyl acetate. The ethyl acetate layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was chromatographed on silica gel using hexanes/ethyl acetate (5:1) as eluent to afford the title compound (0.68 g) as an oil which quickly solidified: mp 68°-70° C., 1H NMR (CDCl3): 15 8.0-7.0 (m,10H, aryl H), 5.6 (m, 1H,CH), 4.9 (m, 1H,CH), 4.4 (m, 1H,CH).

1. stirringstirred for 1 h
2. customThe ethanol was removed under reduced pressure
3. customthe residue was partitioned between ethyl acetate and water
4. dry with materialThe organic phase was dried over magnesium sulfate
5. customevaporated under reduced pressure
6. customThe residue was chromatographed on silica gel with hexanes/ethyl acetate (5:1 to 3:1) as eluent
7. temperaturecooled to 0° C.
8. additiontreated with lithium aluminum hydride solution (45 mL, 1M in tetrahydrofuran) dropwise
9. temperatureThe mixture was heated
10. temperatureto reflux for 5 h
11. temperaturecooled
12. customIt was quenched by the sequential addition of ethyl acetate (5 mL) water (1.5 mL), sodium hydroxide solution (3M, 1.5 mL) and water (4 mL)
13. filtrationThe solid was filtered
14. dry with materialthe solution was dried with magnesium sulfate
15. customThe solvent was removed at reduced pressure
16. customthe solid was triturated with hexanes/butyl chloride (1:1, 100 mL)

ORD record

ord-27ebac39e364439fa985f8a3d3eef3c5

Source dataset

uspto-grants-1997_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05633271