4-Methylmorpholine → 4-(3-Amino-5-methyl-4-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester

To a stirred solution of 3-fluoro-5-amino-6-nitrotoluene (10 g, 58.79 mmol) in anhydrous NMP (160 mL) under nitrogen was added BOC-piperazine (39 g, 209.4 mmol) and 4-methylmorpholine (25.9 mL). The resulting dark solution was heated to reflux for 72 h, cooled to room temperature and diluted with ethyl acetate (4000 mL). The organic layer was washed with water (8×1500 mL), brine (1×1500 mL), dried over sodium sulfate and evaporated in vacuo. The resulting dark oil was dissolved in boiling absolute ethanol (800 mL) and concentrated to a total volume of 400 mL and left to stand overnight at room temperature. The solution was further cooled to −20° C. for 5 h and the resulting solid was filtered off and dried in vacuo to give 16.3 g (83%) of a light yellow solid. 1H NMR (500 MHz, CDCl3) δ 6.16 (brs, 1H), 6.04 (brs, 1H), 3.70–3.60 (m, 4H), 3.38–3.25 (m, 4H), 2.53 (s, 3H), 1.48 (s, 9H); LCMS (M+H)+ m/z 337.

1. temperatureThe resulting dark solution was heated
2. temperatureto reflux for 72 h
3. washThe organic layer was washed with water (8×1500 mL), brine (1×1500 mL)
4. dry with materialdried over sodium sulfate
5. customevaporated in vacuo
6. dissolutionThe resulting dark oil was dissolved
7. concentrationconcentrated to a total volume of 400 mL
8. waitleft
9. temperatureThe solution was further cooled to −20° C. for 5 h
10. filtrationthe resulting solid was filtered off
11. customdried in vacuo

ORD record

ord-ee1f4de0cf144672a8d9042aa0caf66f

Source dataset

uspto-grants-2007_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07223757B2