Trifluoroacetic acid → 4-[3-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridine

Temperature

230 °C

The reaction was performed on a custom-made flow system consisting of a Dionex P580 pump and a HP 6890 Series Gas Chromatography oven used as a heating source. The GC oven was equipped with a stainless steel coil reactor (53 mL volume) made from Supelco stainless steel tube (ID=2.1 mm). After heating to 230° C. using toluene as a system solvent, a mixture of cyclopentene (1.77 g, 26.0 mmol) and trifluoroacetic acid (0.30 g, 2.60 mmol) in toluene (1.0 mL), a mixture of 5-(3-fluoro-4-(trifluoromethyl)phenyl)oxazole (0.30 g, 1.30 mmol), cyclopentene (1.77 g, 26.0 mmol) and trifluoroacetic acid (0.30 g, 2.60 mmol) in toluene (1.0 mL) and finally a mixture of cyclopentene (1.77 g, 26.0 mmol) and trifluoroacetic acid (0.30 g, 2.60 mmol) in toluene (1.0 mL) were injected onto the stainless steel coil reactor in sequential order. The system was run at a flow rate of 0.35 mL/min equaling to a nominal residence time of tR=150 min and an effective residence time of tR,eff=120 min taking the 25% volume expansion of toluene at 230° C. into account (R. E. Martin et al., Eur. J. Org. Chem. 2012, 47-52). A 750 psi back-pressure regulator with a protection guard (filled with sand/glass wool) was used at the exit of the reactor to maintain system pressure. The reaction mixture was collected in a round bottom flask, triethylamine (5 mL) was added and the solvent mixture removed under reduced pressure. Purification by flash chromatography (50 g SiO2, Telos-cartridge) eluting with a 0 to 50% EtOAc/n-heptane gradient provided the title compound (183 mg, 50%) as a slightly brown solid. MS: 282.5 (M+H)+.

1. customThe GC oven was equipped with a stainless steel coil reactor (53 mL volume)
2. customan effective residence time of tR,eff=120 min
3. customat 230° C.
4. additionA 750 psi back-pressure regulator with a protection guard (filled with sand/glass wool)
5. temperatureto maintain system pressure
6. customThe reaction mixture was collected in a round bottom flask
7. additiontriethylamine (5 mL) was added
8. customthe solvent mixture removed under reduced pressure
9. customPurification by flash chromatography (50 g SiO2, Telos-cartridge)
10. washeluting with a 0 to 50% EtOAc/n-heptane gradient

ORD record

ord-2e58b52f05124d4c9f8cab09ae4e7257

Source dataset

uspto-grants-2015_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09187429B2