Potassium Carbonate → Tert-butyl 4-[4-(2-fluoroethoxy)phenyl]piperazine-1-carboxylate

Temperature

50 °C

To a solution of tert-butyl 4-(4-hydroxyphenyl)-piperazine-1-carboxylate (1.0 g, 3.59 mmol) in DMSO (12 mL) was added potassium carbonate (745 mg, 5.39 mmol), potassium iodide (18 mg, 0.11 mmol) and 1-bromo-2-fluoroethane (294 μL, 3.95 mmol). The reaction stirred at 50° C. overnight. The next day, additional amounts of potassium carbonate (745 mg, 5.39 mmol), 1-bromo-2-fluoroethane (134 μL, 1.79 mmol), and potassium iodide (18 mg, 0.11 mmol) were added. The reaction mixture continued to stir at 50° C. After 5 h the reaction mixture was cooled to room temperature, quenched with water (10 mL), and extracted with EtOAc (3×50 mL). The combined organic layers were washed with water (100 mL), brine (50 mL), dried over Na2SO4, and concentrated to obtain a brown solid. The crude material was purified using silica gel chromatography (1:4 hexanes:EtOAc) to obtain tert-butyl 4-(4-(2-fluoroethoxy)phenyl)piperazine-1-carboxylate as a white solid (440 mg, 38% yield). 1H NMR (300 MHz, DMSO-d6): δ 6.92-6.84 (m, 4H), 4.78 (m, 1H), 4.62 (m, 1H), 4.20 (m, 1H), 4.10 (m, 1H), 3.45 (dd, 4H, J=5.2, 5.0 Hz), 2.96 (dd, 4H, J=5.3, 5.0 Hz), 1.42 (s, 9H); 19F NMR (282.4 MHz, DMSO-d6): δ−222.04 (m, 1F); 13C NMR (75.5 MHz, DMSO-d6): δ 153.8, 152.1, 145.5, 117.9, 115.1, 83.2 (81.1), 78.9, 67.4 (67.2), 49.7, 43.2, 28.0; HRMS calcd. for C17H25FN2O3: 325.19220 found 325.19230.

1. stirringto stir at 50° C
2. temperatureAfter 5 h the reaction mixture was cooled to room temperature
3. customquenched with water (10 mL)
4. extractionextracted with EtOAc (3×50 mL)
5. washThe combined organic layers were washed with water (100 mL), brine (50 mL)
6. dry with materialdried over Na2SO4
7. concentrationconcentrated
8. customto obtain a brown solid
9. customThe crude material was purified

ORD record

ord-1b8eca4475184ba28e763e107aeb254d

Source dataset

uspto-grants-2013_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08491868B2