Methanol → (4-Morpholin-4-yl-phenyl)-acetic acid methyl ester

Temperature

25 °C

A mixture of 4-morpholinoacetophenone (4.61 g, 22 mmol), sulfur (2.16 g, 67 mmol), and morpholine (6 mL, 67 mmol) was heated at 80° C. for 1h then heated under reflux for 18 h. The hot reaction mixture was poured into warm ethanol. Upon cooling to 25° C., a precipitate formed. The precipitate was filtered to provide a tan solid (4.16 g). This crude tan solid was then treated with concentrated acetic acid (16 mL), concentrated sulfuric acid (2.4 mL), and water (3.6 mL). The resulting reaction mixture was heated under reflux for 4 h and then poured into water. The water was removed in vacuo to provide crude (4-morpholin-4-yl-phenyl)-acetic acid as a brown oil (8.20 g). This crude (4-morpholin-4-yl-phenyl)-acetic acid was dissolved in methanol (100 mL) and then slowly treated with concentrated sulfuric acid (1 mL). The reaction mixture was heated under reflux for 66 h. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo to remove methanol. The residue was diluted with water (200 mL) and then treated with a 10% aqueous sodium hydroxide solution until pH=9. The aqueous phase was extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 to 1/1 hexanes/ethyl acetate gradient elution) afforded (4-morpholin-4-yl-phenyl)-acetic acid methyl ester (2.22 g, 42% for 3 steps) as a yellow oil: EI-HRMS m/e calcd for C13H17NO3 (M+) 235.1208, found 235.1214.

1. temperatureThe reaction mixture was heated
2. temperatureunder reflux for 66 h
3. concentrationconcentrated in vacuo
4. customto remove methanol
5. additionThe residue was diluted with water (200 mL)
6. additiontreated with a 10% aqueous sodium hydroxide solution until pH=9
7. extractionThe aqueous phase was extracted with ethyl acetate (3×100 mL)
8. washThe combined organic extracts were washed with a saturated aqueous sodium chloride solution (1×100 mL)
9. dry with materialdried over sodium sulfate
10. filtrationfiltered
11. concentrationconcentrated in vacuo
12. washFlash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 to 1/1 hexanes/ethyl acetate gradient elution)

ORD record

ord-a85ee55add0f49068863b694b09bb4fc

Source dataset

uspto-grants-2002_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06384220B2