2,6-Lutidine → tert-butyl 3-(5-chloro-2-fluorophenyl)-2,3-dihydro-1H-pyrrole-1-carboxylate

Temperatur

23 °C

Palladium(II) acetate (106 mg, 0.473 mmol, 0.020 equiv) was added to a vigorously stirred, deoxygenated mixture of tert-butyl 2,5-dihydro-1H-pyrrole-1-carboxylate (4.00 g, 23.6 mmol, 1 equiv) and 5-chloro-2-fluorobenzenediazonium tetrafluoroborate (10.4 g, 42.5 mmol, 1.80 equiv) in water and carbon tetrachloride (1:1, 150 mL) at 23° C., and the resulting mixture was stirred for 20 hours. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution (200 ml) and dichloromethane (2×200 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was dissolved in toluene (200 mL), and the resulting solution concentrated in vacuo to facilitate azeotropic removal of residual water. 2,6-Lutidine (5.51 mL, 47.3 mmol, 2.00 equiv) and trifluoroacetic anhydride (1.67 mL, 11.8 mmol, 0.500 equiv) were then sequentially added to a solution of the residue in toluene (150 mL) at −20° C. The resulting mixture was kept at −20° C. for 5 hours, then allowed to slowly warm to 23° C. After 16 hours at 23° C., the reaction mixture was heated at reflux for 30 minutes. The reaction mixture was allowed to cool to 23° C., then partitioned between ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate solution (100 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (hexanes initially, grading to 30% EtOAc in hexanes) to give tert-butyl 3-(5-chloro-2-fluorophenyl)-2,3-dihydro-1H-pyrrole-1-carboxylate (17-1) as an orange oil. LRMS m/z (M+H CH3) 283.0 found, 283.1 required.

1. customdeoxygenated
2. stirringthe resulting mixture was stirred for 20 hours
3. customThe reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution (200 ml) and dichloromethane (2×200 mL)
4. dry with materialThe combined organic layers were dried over sodium sulfate
5. concentrationconcentrated
6. dissolutionThe residue was dissolved in toluene (200 mL)
7. concentrationthe resulting solution concentrated in vacuo
8. customremoval of residual water
9. waitAfter 16 hours at 23° C.
10. temperaturethe reaction mixture was heated
11. temperatureat reflux for 30 minutes
12. temperatureto cool to 23° C.
13. custompartitioned between ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate solution (100 mL)
14. dry with materialThe organic layer was dried over sodium sulfate
15. concentrationconcentrated
16. customThe residue was purified by flash column chromatography (hexanes initially

ORD-Eintrag

ord-f7f32202c92b42e58707d433a01fb96c

Quelldatensatz

uspto-grants-2008_03

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US07348440B2