Hydrochloric Acid → (4-Methylmorpholin-2-yl)methyl 4-(4-fluorobenzyl)piperazine-1-carboxylate dihydrochloride salt

Temperature

0 °C

(4-Methyl-morpholin-2-yl)-methanol (1.05 g, 8.0 mmol) and DIPEA (2.79 ml, 16.0 mmol were dissolved in DCM (80 mL) and the reaction mixture was cooled to 0° C. and p-nitrophenyl chloroformate (3.23 g, 16.0 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was divided into 4 batches and concentrated in vacuo. One portion was dissolved in DMF (20 mL) and 1-(4-fluoro-benzyl)-piperazine (0.39 g, 2 mmol) added and the resulting reaction mixture stirred at room temperature for 24 h. The solvent was removed in vacuo and the residue was taken up in DCM (30 mL). The organic layer was washed with 1.0M Na2CO3 solution (3×30 mL), dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by column chromatography (normal phase, 20 g, Strata SI-1, silica gigatube, 20 mL/min, gradient 0% to 5% MeOH in DCM, residue dry loaded). The solvents were removed in vacuo and the residue was dissolved in DCM (50 mL), filtered and 2M HCl in Et2O (2 mL, 4 mmol) added. The solvent was removed in vacuo and the residue was dried in a vacuum oven overnight to give the (4-methylmorpholin-2-yl)methyl 4-(4-fluorobenzyl)piperazine-1-carboxylate dihydrochloride salt (0.375 g, 44%) as a white solid.

1. temperatureto warm to room temperature
2. concentrationconcentrated in vacuo
3. dissolutionOne portion was dissolved in DMF (20 mL)
4. customthe resulting reaction mixture
5. stirringstirred at room temperature for 24 h
6. customThe solvent was removed in vacuo
7. washThe organic layer was washed with 1.0M Na2CO3 solution (3×30 mL)
8. dry with materialdried (MgSO4)
9. customthe solvents were removed in vacuo
10. customThe residue was purified by column chromatography (normal phase, 20 g, Strata SI-1, silica gigatube, 20 mL/min, gradient 0% to 5% MeOH in DCM, residue dry loaded)
11. customThe solvents were removed in vacuo
12. dissolutionthe residue was dissolved in DCM (50 mL)
13. filtrationfiltered
14. customThe solvent was removed in vacuo
15. customthe residue was dried in a vacuum oven overnight

ORD record

ord-4df06653736a494eac229daea6678137

Source dataset

uspto-grants-2010_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07851471B2