Sodium hydride → [(2R)-4-methylmorpholin-2-yl]methyl 4-(4-fluorophenyl)piperazine-1-carboxylate

(R)-(4-Methyl-morpholin-2-yl)-methanol (Intermediate 11; 100 mg, 0.76 mmol) was added to a suspension of NaH (60% dispersion in oil; 90.0 mg, 2.28 mmol) in anhydrous THF (7 mL) and stirred under nitrogen for 30 min. 4-(4-Fluorophenyl)-piperazine-1-carboxylic acid 4-nitrophenyl ester (Intermediate 6; 314 mg, 0.91 mmol) was added and the reaction mixture was stirred at room temperature for 48 h. The reaction mixture was filtered through celite and the solid washed with THF (10 mL). The filtrates were combined and the solvent removed in vacuo. The residue was purified by column chromatography (normal phase silica, 5 g Isolute-Si column, gradient 1-5% MeOH in DCM) and then reverse phase HPLC (YMC ODS-A 100×20 mm, 5 μm, 25 mL/min, gradient 20% to 100% (over 7 min) then 100% (3 min) MeOH in 10% MeOH/water). The pure product was taken up in DCM (5 mL), filtered, and dried in vacuo to give [(2R)-4-methylmorpholin-2-yl]methyl 4-(4-fluorophenyl)piperazine-1-carboxylate (100 mg, 28%) as a colourless gum.

1. stirringthe reaction mixture was stirred at room temperature for 48 h
2. filtrationThe reaction mixture was filtered through celite
3. washthe solid washed with THF (10 mL)
4. customthe solvent removed in vacuo
5. customThe residue was purified by column chromatography (normal phase silica, 5 g Isolute-Si column, gradient 1-5% MeOH in DCM)
6. customYMC ODS-A 100×20 mm, 5 μm, 25 mL/min, gradient 20% to 100% (over 7 min)
7. custom100% (3 min) MeOH in 10% MeOH/water
8. filtrationfiltered
9. customdried in vacuo

ORD record

ord-c2269a9beb7d4bdaa17a65023e6198ce

Source dataset

uspto-grants-2010_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07851471B2