2,2,2-Trifluoroethanol → (R)-2-(4-(2,2,2-trifluoroethoxy)-3-trifluoromethylbenzyl)morpholine

Temperature

105 °C

To a suspension of sodium hydride (43 mg, 1.08 mmol) in N,N-dimethyl formamide (3 mL) at 0° C. was added 2,2,2-trifluroethanol (108 mg, 1.08 mmol), and the resultant mixture stirred for 5 mins. N-Boc-(R)-2-(4-fluoro-3-trifluoromethylbenzyl)morpholine, example 2, intermediate (b) (98 mg, 0.27 mmol) was added in one portion as a solution in N,N-dimethyl formamide (1.5 mL) and the reaction mixture warmed to 105° C. and stirred at that temperature for 6 hrs. The reaction was cooled to room temperature and poured into water (20 ml). The suspension was extracted with ethyl acetate (20 mL×2). Combined organic extracts were washed with water (25 mL×2) and brine (25 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica; 20% ethyl acetate/isohexane) to yield the desired product as a colorless oil (87 mg) and used directly in the next reaction. The crude material was deprotected using TFA (20% v/v in dichloromethane, 2 mL) over 3 hrs, poured onto an SCX-2 column (2 g) and washed with dichloromethane (2 mL×2) and dichloromethane: methanol (1:1, 2 mL×2). The column was then washed with ammonia (2N solution in methanol, 2 mL×3) and the ammonia washes were concentrated in vacuo to yield the desired morpholine example 37 a colorless oil (59 mg).

1. temperatureThe reaction was cooled to room temperature
2. extractionThe suspension was extracted with ethyl acetate (20 mL×2)
3. washCombined organic extracts were washed with water (25 mL×2) and brine (25 mL)
4. dry with materialdried (MgSO4)
5. filtrationfiltered
6. concentrationconcentrated in vacuo
7. customThe residue was purified by column chromatography (silica; 20% ethyl acetate/isohexane)

ORD record

ord-0ee4db0ff5e54ca5ad802ea020028ba8

Source dataset

uspto-grants-2008_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07323466B2