Reaction #69456

Reaction equation

HCl

lithium bis(trimethylsilyl)amide

methyl 3-acetyl-5-bromo-4-hydroxybenzoate

morpholine-4-carbonyl chloride

→

methyl 3-bromo-4-hydroxy-5-(3-morpholino-3-oxopropanoyl)benzoate

Yield 90.2%

Solvents

THF

water

DCM

Conditions

Workup

1. 1
   Temperaturemaintained at this temperature for 1 h
2. 2
   TemperatureThe solution was cooled back to −65° C.
3. 3
   Temperaturethen cooled to −30° C.
4. 4
   ExtractionHCl 2N (300 mL) until pH 7, the aqueous solution was extracted with DCM (3×)
5. 5
   DryingThe combined extracts were dried over MgSO4
6. 6
   Otherevaporated
7. 7
   OtherThe crude product was triturated in MTBE

Procedure

To a solution of lithium bis(trimethylsilyl)amide (1.41 L, 1406 mmol) at −65° C. under nitrogen was added dropwise methyl 3-acetyl-5-bromo-4-hydroxybenzoate (120 g, 439 mmol) in THF (1.2 L). The solution was allowed to warm to 0° C., and maintained at this temperature for 1 h. The solution was cooled back to −65° C. and morpholine-4-carbonyl chloride (0.055 L, 483 mmol) was added. The mixture was stirred at room temperature for 2 h then cooled to −30° C., DCM (1.5 L) and water (1 L) were added followed by dropwise addition of HCl 6N (500 mL) then HCl 2N (300 mL) until pH 7, the aqueous solution was extracted with DCM (3×). The combined extracts were dried over MgSO4 and evaporated. The crude product was triturated in MTBE to obtain methyl 3-bromo-4-hydroxy-5-(3-morpholino-3-oxopropanoyl)benzoate (153 g, 90%) as a beige solid. Mass Spectrum: m/z [M+H]+=388.

Source