Boron trifluoride etherate → Benzyl 6a-(5-bromo-2-fluoro-phenyl)-3,3a,4,6-tetrahydro-1H-pyrrolo[3,4-c]isoxazole-5-carboxylate

Temperature

-78 °C

A 1.6 M hexanes solution of n-butyl lithium (25.4 mL, 40.6 mmol) is added drop wise to a −78° C. solution of 4-bromo-1-fluoro-2-iodobenzene (12.22 g, 40.6 mmol) in tetrahydrofuran (60 mL) to give a yellow solution that is stirred at −78° C. for 15 minutes. Boron trifluoride etherate (5.14 mL, 40.6 mmol) is added to a separate −78° C. solution of benzyl 3,3a,4,6-tetrahydropyrrolo[3,4-c]isoxazole-5-carboxylate (5 g, 20.3 mmol) in tetrahydrofuran (60 mL) and the mixture is stirred at −78° C. for 5 minutes. This solution is added to the previously prepared −78° C. organolithium mixture via cannula. The combined mixture is stirred for 30 minutes at −78° C. The mixture is quenched with saturated aqueous ammonium chloride and warmed to room temperature. The mixture is extracted with ethyl acetate (3×) and the organic extracts are combined, dried over sodium sulfate, filtered and the solvent removed in vacuo. The crude product is purified over silica gel with a 35 minute 5% to 100% ethyl acetate in hexanes gradient to give the title compound (2.27 g, 27%). ES/MS (m/e): (79Br/81Br) 421/423 (M+H).

1. customto give a yellow solution that
2. stirringthe mixture is stirred at −78° C. for 5 minutes
3. stirringThe combined mixture is stirred for 30 minutes at −78° C
4. customThe mixture is quenched with saturated aqueous ammonium chloride
5. temperaturewarmed to room temperature
6. extractionThe mixture is extracted with ethyl acetate (3×)
7. dry with materialdried over sodium sulfate
8. filtrationfiltered
9. customthe solvent removed in vacuo
10. customThe crude product is purified over silica gel with a 35 minute 5% to 100% ethyl acetate in hexanes gradient

ORD record

ord-434047a74e1346d088b592e3585c8f64

Source dataset

uspto-grants-2014_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08841293B1