Iodoethane → (r)-2-(3-Chloro-4-ethoxybenzyl)morpholine

Temperature

55 °C

N-BOC-(R)-2-(3-chloro-4-hydroxybenzyl)morpholine, example 7, intermediate (a) (52 mg, 0.16 mmol), was dissolved in acetone (1.5 mL) with potassium carbonate (44 mg, 0.32 mmol) and iodoethane (38 uL, 0.47 mmol) added in one portion. The reaction was then heated to 55° C. and shaken at that temperature for 16 hrs. The reaction mixture was filtered, washing with acetone (1 mL×2) and the liquor evaporated under a high flow of nitrogen. The residue was dissolved in tetrahydrofuran: ethanol (1:1, 4 mL) and polymer supported thiophenol (0.43 g, 0.64 mmol), MP-carbonate (0.24 g, 0.64 mmol) and diisopropylethylamine (119 uL, 0.68 mmol) added. The reaction was shaken for 24 hrs, then filtered and concentrated under a high flow of nitrogen. The crude residue was dissolved in TFA (20% v/v solution in dichloromethane, 2.0 mL) and shaken for 3 hrs at room temperature. The reaction mixture was added directly to an SCX-2 column (2 g) and washed with dichloromethane (2 mL×2) and methanol (2 mL×2). The SCX-2 column was then washed with ammonia (2N in methanol, 3×2 mL). Combined ammonia washes were concentrated in vacuo. The residue was then purified by preparative HPLC to yield the desired morpholine example 28 as a colorless oil (17 mg).

1. additionadded in one portion
2. filtrationThe reaction mixture was filtered
3. washwashing with acetone (1 mL×2)
4. customthe liquor evaporated under a high flow of nitrogen
5. dissolutionThe residue was dissolved in tetrahydrofuran: ethanol (1:1, 4 mL)
6. additionadded
7. stirringThe reaction was shaken for 24 hrs
8. filtrationfiltered
9. concentrationconcentrated under a high flow of nitrogen
10. dissolutionThe crude residue was dissolved in TFA (20% v/v solution in dichloromethane, 2.0 mL)
11. stirringshaken for 3 hrs at room temperature
12. additionThe reaction mixture was added directly to an SCX-2 column (2 g)
13. washwashed with dichloromethane (2 mL×2) and methanol (2 mL×2)
14. washThe SCX-2 column was then washed with ammonia (2N in methanol, 3×2 mL)
15. concentrationCombined ammonia washes were concentrated in vacuo
16. customThe residue was then purified by preparative HPLC

ORD record

ord-3f1fdb250c414ccdb5e33e812bc7a127

Source dataset

uspto-grants-2008_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07323466B2