Reacción #70809

Ecuación de reacción

methyl 6-bromo-1-isopropyl-1H-indole-4-carboxylate

1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane ditetrafluoroborate

nitroethane

→

methyl 6-bromo-3-fluoro-1-isopropyl-1H-indole-4-carboxylate

Rendimiento 20.7%

Condiciones de reacción

Tratamiento posterior

1. 1
   Otrofollowed with a magnetic stir bar
2. 2
   OtroThe vial was capped
3. 3
   OtroReaction progress
4. 4
   OtroAfter reaction completion the reaction solvent
5. 5
   Otrowas removed in-vacuo
6. 6
   workup.DISSOLUTIONThe residue was dissolved with DCM (1.4 ml)
7. 7
   workup.ADDITIONThe DCM solution was charged onto an analogix Si35 SF10-8 gram column
8. 8
   LavadoThe compound was eluted with EtOAc/Hexanes, 5-15%, 20 min
9. 9
   workup.DISSOLUTIONThe mixture was dissolved with DMSO (1 ml)
10. 10
    Otropurified by reverse phase HPLC
11. 11
    Otro5μ 30×100 mm column, neutral acetonitrile/0.1% formic acid in water, 50-80%, 7 min gradient
12. 12
    LavadoThe desired product eluted at 6.8 minutes
13. 13
    ConcentraciónThe desired fractions were concentrated to a residue

Procedimiento

To a 20 ml vial was added methyl 6-bromo-1-isopropyl-1H-indole-4-carboxylate (50.0 mg, 0.169 mmol), (selectfluor) 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane ditetrafluoroborate (78 mg, 0.219 mmol) followed with a magnetic stir bar and nitroethane (2 ml). The vial was capped and the reaction stirred at room temperature. Reaction progress was monitored by LCMS. After reaction completion the reaction solvent was removed in-vacuo. The residue was dissolved with DCM (1.4 ml). The DCM solution was charged onto an analogix Si35 SF10-8 gram column. The compound was eluted with EtOAc/Hexanes, 5-15%, 20 min. The desired product and side MW629 co-eluted. The mixture was dissolved with DMSO (1 ml) and purified by reverse phase HPLC using a Gemini 5μ 30×100 mm column, neutral acetonitrile/0.1% formic acid in water, 50-80%, 7 min gradient. The desired product eluted at 6.8 minutes and the side product MW 629 at 9.5 minutes. The desired fractions were concentrated to a residue. LCMS and NMR support the desired structure and analytical HPLC showed 100% purity. The product, methyl 6-bromo-3-fluoro-1-isopropyl-1H-indole-4-carboxylate (11 mg, 0.035 mmol, 20.53% yield), was obtained as a white solid. 1H NMR (400 MHz, METHANOL-d4) δ 7.95 (t, J=1.77 Hz, 1H), 7.78 (d, J=1.77 Hz, 1H), 7.47 (d, J=2.53 Hz, 1H), 4.76-4.84 (m, J=1.64, 6.65, 6.65, 13.36 Hz, 1H), 3.96 (s, 3H), 1.50 (d, 6H). MS (ES)[M+H]+315.1.

Fuente