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

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 5 g 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.

1. customfollowed with a magnetic stir bar
2. customThe vial was capped
3. customReaction progress
4. customAfter reaction completion the reaction solvent
5. customwas removed in-vacuo
6. dissolutionThe residue was dissolved with DCM(1.4 ml)
7. additionThe DCM solution was charged onto an analogix Si35 SF10−8 gram column
8. washThe compound was eluted with EtOAc/Hexanes, 5-15%, 20 min
9. dissolutionThe mixture was dissolved with DMSO (1 ml)
10. custompurified by reverse phase HPLC
11. customa Gemini 5 g 30×100 mm column, neutral acetonitrile/0.1% formic acid in water, 50-80%, 7 min gradient
12. washThe desired product eluted at 6.8 minutes
13. concentrationThe desired fractions were concentrated to a residue

ORD record

ord-83f8a3f4873f449e8ff8d01b1432c021

Source dataset

uspto-grants-2015_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08975291B2