Water → HCID 67073257, compound

Temperature

0 °C

Sodium hydride (50 mg, 1.25 mmol) was washed twice with isohexane and then suspended in anhydrous N,N-dimethyl formamide (0.5 mL), under an atmosphere of nitrogen and cooled to 0° C. Then cyclopropylmethanol (90 mg, 1.25 mmol) was added. When effervescence had finished intermediate (a), N-Benzyl-(R)-2-(3-chloro-4-fluorobenzyl)morpholine (0.10 g, 0.31 mmol) was added as a solution in N,N-dimethyl formamide (1.0 mL). The reaction was then warmed to 100° C. (bath temperature) for 6 hrs and cooled to room temperature. The mixture was poured into water (25 mL) and extracted with ethyl acetate (25 mL). The organic layer was washed with brine (10 mL×2), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica; 20% ethyl acetate/isohexane) to give a residue that was added to an SCX-2 column (10 g) as a solution in dichloromethane, washed with dichloromethane (6 mL×2) and methanol (6 mL×2). The SCX-2 column was then washed with ammonia (2N in methanol, 3×6 mL). Combined ammonia washes were concentrated in vacuo to yield the desired product as colorless oil (85 mg). N-Benzyl-(R)-2-(4-cyclopropylmethoxy-3-chlorobenzyl)morpholine (82 mg, 0.22 mmol) was then dissolved in 1,2-dichloroethane (3 mL) and treated with 1-chloro-ethyl-chloroformate (94 mg, 0.66 mmol) and heated at 85° C. for 3 hrs. The reaction mixture was then concentrated in vacuo. The residue was dissolved in methanol (7 mL) and heated at 75° C. for 2.5 hrs. The reaction mixture was then concentrated in vacuo. The crude residue was dissolved in dichloromethane (1 mL) and the solution poured onto a SCX-2 column (2 g), eluting with dichloromethane (2 ml×2) and methanol (2 mL×2). The column was then washed with ammonia (2N in methanol, 2 mL×2). The ammonia washes were concentrated in vacuo. The crude residue was purified by preparative chiral HPLC to yield the desired morpholine example 27 as a yellow oil (10 mg).

1. temperatureThe reaction was then warmed to 100° C. (bath temperature) for 6 hrs
2. temperaturecooled to room temperature
3. extractionextracted with ethyl acetate (25 mL)
4. washThe organic layer was washed with brine (10 mL×2)
5. dry with materialdried (MgSO4)
6. filtrationfiltered
7. concentrationconcentrated in vacuo
8. customThe residue was purified by column chromatography (silica; 20% ethyl acetate/isohexane)
9. customto give a residue that
10. washwashed with dichloromethane (6 mL×2) and methanol (6 mL×2)
11. washThe SCX-2 column was then washed with ammonia (2N in methanol, 3×6 mL)
12. concentrationCombined ammonia washes were concentrated in vacuo

ORD record

ord-339312540c034e9ab1fa2986618d4a4a

Source dataset

uspto-grants-2008_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07323466B2