Lithium hexamethyldisilazane → N-{5-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide

Temperatur

0 °C

To a solution of methyl 3-(2,5-difluorophenylsulfonamido)-4-fluorobenzoate (40 g, 116 mmol) in dry THF (500 mL) at −10° C., LiHMDS (1M in THF, 406 mmol, 406 mL) was added dropwise and the solution was allowed to stir for 1 h at 0° C. A solution of 2-chloro-4-methylpyrimidine (17.8 g, 139 mmol) in THF (50 mL) was then added dropwise to the solution of ester and base at 0° C. over 20 min. The solution was allowed to stir 1 h at rt. TLC showed the reaction was complete. The reaction was quenched by addition of the saturated aqueous NH4Cl (300 mL) at 0° C. The reaction mixture was extracted with EtOAc (500 mL×3). The combined organic layers were washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by flash column on silica gel, eluting with DCM. This solution was evaporated to obtain a solid. The orange solid was triturated with a small amount of EtOAc and filtered, rinsing with diethyl ether to give the title compound of Step B (31 g, 60.8% yield). 1H NMR (400 MHz, CDCl3) δ ppm 13.72-13.77 (br, 1H), 8.57-8.61 (m, 0.4H), 8.38-8.42 (m, 1H), 8.13-8.19 (m, 0.4H), 7.97-8.02 (m, 1H), 7.78-7.82 (m, 0.4H), 7.57-7.63 (m, 1H), 7.52-7.57 (1.4H), 7.02-7.30 (m, 4.2H), 6.91-6.93 (m, 1H), 5.93 (s, 1H), 4.40 (s, 1H). MS (ES+): 442 [M+H]+.

1. stirringto stir 1 h at rt
2. customThe reaction was quenched by addition of the saturated aqueous NH4Cl (300 mL) at 0° C
3. extractionThe reaction mixture was extracted with EtOAc (500 mL×3)
4. washThe combined organic layers were washed with water and brine successively
5. dry with materialdried over Na2SO4
6. filtrationfiltered
7. concentrationconcentrated under reduced pressure
8. customto give the crude product, which
9. customwas purified by flash column on silica gel
10. washeluting with DCM
11. customThis solution was evaporated
12. customto obtain a solid
13. customThe orange solid was triturated with a small amount of EtOAc
14. filtrationfiltered
15. washrinsing with diethyl ether

ORD-Eintrag

ord-4b2d0c705abd4f64a6e39acd25b45d03

Quelldatensatz

uspto-grants-2016_01

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US09233956B2