Bromotrichloromethane → Ethyl 2-(4-amino-5-{4-[({[4-(trifluoromethyl)pyridin-2-yl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazin-6-yl)-1,3-oxazole-4-carboxylate

Temperatur

-78 °C

To a solution of THF (16 mL) was added ethyl N-[(4-amino-5-{4-[({[4-(trifluoromethyl)pyridin-2-yl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazin-6-yl)carbonyl]serinate (Example 221) (437 mg, 0.76 mmol) which was cooled to −78° C. DAST (0.14 mL, 1.07 mmol) was added and the reaction proceeded for 1 h while stirring under N2. Additional DAST (0.14 mL, 1.07 mmol) was added and the solution was stirred for 30 min. The acetone/dry ice cooling bath was replaced with an ice/water bath and DBU (0.41 mL, 2.75 mmol) and BrCCl3 (0.27 mL, 2.75 mmol) were added and the solution was allowed to warm to rt over 17 h. Additional DBU (0.41 mL, 2.75 mmol) and BrCCl3 (0.27 mL, 2.75 mmol) were added and the solution was allowed to stir for 6 h. The reaction mixture was transferred to a separatory funnel, diluted with EtOAc (50 mL), washed with aq saturated NaHCO3 (50 mL) and H2O (50 mL). The aqueous fraction was back extracted with DCM (3×30 mL). The combined organic layers were dried (MgSO4), evaporated in vacuo and flashed 5:4:1 v/v/v DCM/EtOAc/MeOH resulting in the isolation of 33 mg of the title compound (0.060 mmol, yield 8%). 1H-NMR (DMSO-d6) δ 9.93 (s, 1H), 9.77 (s, 1H), 8.70 (s, 1H), 8.55 to 8.54 (d, J=5.0 Hz, 1H), 8.30 (s, 1H), 8.06 (s, 1H), 7.95 (s, 1H), 7.64 to 7.61 (d, J=8.8 Hz, 2H), 7.42 to 7.40 (d, J=8.8 Hz, 2H), 7.38 to 7.36 (d, J=6.2 Hz, 1H), 4.28 to 4.23 (q, J=7.6 Hz, 2H), 1.28 to 1.25 (t, J=7.1 Hz, 3H); MS [M+H]+=553.1; LCMS RT=3.04 min.

1. stirringthe solution was stirred for 30 min
2. temperatureto warm to rt over 17 h
3. stirringto stir for 6 h
4. customThe reaction mixture was transferred to a separatory funnel
5. washwashed with aq saturated NaHCO3 (50 mL) and H2O (50 mL)
6. extractionThe aqueous fraction was back extracted with DCM (3×30 mL)
7. dry with materialThe combined organic layers were dried (MgSO4)
8. customevaporated in vacuo

ORD-Eintrag

ord-040233e16b024647bb6f137cf015d880

Quelldatensatz

uspto-grants-2009_07

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US07563791B2