Hydrogen Peroxide → 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-ol

Temperature

0 °C

To a solution of BF3.OEt2 (120 mL, 0.948 mol) in dichloromethane (200 mL) at 0° C. was added H2O2 (50% aqueous solution, 4.6 mL, 0.0790 mol). The reaction mixture was stirred at 0° C. for 30 min and then cooled to −20° C. In a separate flask, 2-[4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl]-propan-2-ol from previous step (20 g, 0.0564 mol) was dissolved in dichloromethane (400 mL) using indirect heat to achieve complete dissolution. This solution was then added rapidly via canula (addition time=20 min) to the peroxide solution. The reaction temperature during the addition was between −15° C. and −25° C. After the addition was complete, the reaction temperature was raised to −15° C. and maintained at that temperature for an additional 40 min. The reaction mixture was quenched by the addition of Na2SO3 (200 mL, 20% aqueous solution) and ethanolamine (33% aqueous solution, 300 mL). Both reagents were added at a rate so as to maintain the internal temperature below 0° C. The cooling bath was removed and the reaction mixture was stirred for 2 h and then poured into a separatory funnel. The layers were separated and the aqueous phase was extracted with ethyl acetate (100 mL). The combined organic layers were washed with 5% aqueous citric acid (100 mL), 10% aqueous NaHCO3 (100 mL), water (2×100 mL), and brine (100 mL) and then dried, filtered and concentrated in vacuo to afford an orange foam. The crude material was loaded onto a Florisil® column using tetrahydrofuran as the loading solvent and the column was eluted with 30% ethyl acetate/heptane. The fractions containing the desired product were collected and concentrated in vacuo and then recrystallized from ethyl acetate/heptane. The solids were collected and washed with heptane to afford 9.1 g (52%) of the desired product as an off-white solid. The filtrate was concentrated in vacuo and purified on silica gel using 40% ethyl acetate/heptane as the eluent to afford and additional 2.5 g (14%) of the desired product. Total yield of 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-ol was (11.6 g, 66%). Reverse phase HPLC: 3.75 min (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). LC/MS; (M+H)+=313.2

1. temperaturecooled to −20° C
2. temperatureusing indirect heat
3. dissolutiondissolution
4. additionThe reaction temperature during the addition
5. customwas between −15° C. and −25° C
6. additionAfter the addition
7. temperaturethe reaction temperature was raised to −15° C.
8. temperaturemaintained at that temperature for an additional 40 min
9. customThe reaction mixture was quenched by the addition of Na2SO3 (200 mL, 20% aqueous solution) and ethanolamine (33% aqueous solution, 300 mL)
10. additionBoth reagents were added at a rate so as
11. temperatureto maintain the internal temperature below 0° C
12. customThe cooling bath was removed
13. stirringthe reaction mixture was stirred for 2 h
14. additionpoured into a separatory funnel
15. customThe layers were separated
16. extractionthe aqueous phase was extracted with ethyl acetate (100 mL)
17. washThe combined organic layers were washed with 5% aqueous citric acid (100 mL), 10% aqueous NaHCO3 (100 mL), water (2×100 mL), and brine (100 mL)
18. customdried
19. filtrationfiltered
20. concentrationconcentrated in vacuo
21. customto afford an orange foam
22. washthe column was eluted with 30% ethyl acetate/heptane
23. additionThe fractions containing the desired product
24. customwere collected
25. concentrationconcentrated in vacuo
26. customrecrystallized from ethyl acetate/heptane
27. customThe solids were collected
28. washwashed with heptane

ORD record

ord-e2a26f1b885f4249b816efbd4905eca4

Source dataset

uspto-grants-2010_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07820814B2