Water → HCID 11673971, compound

Temperature

10 °C

To a suspension of sodium hydride (50 mg, 1.25 mmol) in N,N-dimethyl formamide (0.5 mL) at 0° C. was added 2,2,2-trifluroethanol (125 mg, 1.25 mmol), and the resultant mixture stirred for 5 mins. N-Benzyl-(R)-2-(4-fluoro-3-chlorobenzyl)morpholine, example 27, intermediate (a) (100 mg, 0.31 mmol) was added in one portion as a solution in N,N-dimethyl formamide (1.0 mL) via syringe and the reaction mixture warmed to 10° C. and shaken at that temperature for 18 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 (20 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 light yellow oil (38 mg) and used directly in the next reaction. The material was dissolved in 1,2-dichloroethane (2 mL), and 1-chloro-ethyl-chloroformate (33 mg, 0.23 mmol) added in one portion. The resulting mixture was heated at 90° C. for 24 hrs. The reaction was then concentrated in vacuo. The residue was dissolved in methanol (10 mL), and heated at 80° C. for 5 hrs. The reaction was cooled to room temperature and concentrated in vacuo. The residue was dissolved in dichloromethane and poured onto an SCX-2 column (2 g) and washed with dichloromethane (2 mL×2) and methanol (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 example 40 as a yellow oil (20 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 (20 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-d3bc69cc4df94d3c9aec5c964cb96e89

Source dataset

uspto-grants-2008_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07323466B2