tert-butyl 2-(2-methoxy-2-oxoethyl)morpholine-4-carboxylate synthesis

Yield:766539-39-3 45%

Reaction Conditions:

with potassium carbonate in tetrahydrofuran at 20;

Steps:

F

Intermediate F; Preparation of tert-butyl 2-(2-hvdroxyethyl)morpholine-4-carboxvlate; Methyl morpholin-2-yl acetate (5.0 g, 31.4 mmol) was diluted with THF (10 ml.) and water (10 ml.) and treated with potassium carbonate (4.34 g, 31.4 mmol). The thick suspension slowly went into solution. Di-terf-butyl dicarbonate (6.85 g, 31.4 mmol) was added and the reaction mixture was stirred at rt overnight. The reaction mixture was then extracted with THF and EtOAc. The organic layer was dried (MgSO₄) and concentrated under reduced pressure. The sticky oil was triturated with ether and the resulting solid was collected by vacuum filtration (3.7 g, 45%). The mixture was diluted in THF (20 ml_) and treated with a solution of sodium hydroxide (2 N, 5 ml_) and stirred overnight. The reaction mixture was concentrated under reduced pressure and then diluted with water and EtOAc. The pH of the aqueous layer was adjusted to 5, and the organic layer was separated, dried (MgSO₄) and concentrated under reduced pressure. The solid (2 g, 8.15 mmol) was then dissolved in THF (10 mL) and treated with a borane solution (1 M in THF, 16 mL, 16.4 mmol) and the mixture stirred at rt for 12h. The reaction mixture was then diluted with methanol (100 mL) and stirred at rt overnight. The solution was then concentrated under reduced pressure and then diluted with DCM. The solution was filtered through a layer of silica to remove the borane salts, and the filtrate was concentrated under reduced pressure to give an oil (1.8 g, 96%): HPLC MS RT = 2.22 min, MH⁺ = 232.2; ¹H NMR (DMSO-cfe ) δ: 4.46 (1 H, t), 3.81-3.73 (2H₁ m), 3.72-3.64 (1 H, br d), 3.45 (2H, t), 3.40-3.29 (3H, m), 2.93-2.73 (1 H, br s), 1.55-1.48 (2H, m), 1.39 (9H, s).

References:

WO2008/70150,2008,A1 Location in patent:Page/Page column 61-62