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

HRID 970353Notes

Reaction equation

HRID 970353 reaction equation
F[C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[C:13]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].CN1CCOCC1>CN1C(=O)CCC1.C(OCC)(=O)C>[C:16]([O:15][C:13]([N:20]1[CH2:25][CH2:24][N:23]([C:2]2[CH:3]=[C:4]([CH3:12])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=2)[CH2:22][CH2:21]1)=[O:14])([CH3:19])([CH3:17])[CH3:18]

Participants

6

Reactant 3

HCID 79724-MethylmorpholineHCID 143452tert-Butyl piperazine-1-carboxylateHCID 220210255-Fluoro-3-methyl-2-nitroaniline

Product 1

HCID 235419154-(3-Amino-5-methyl-4-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl esterYield 83%

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolventHCID 13387N-methyl-2-pyrrolidoneSolvent

Procedure

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.

Workup

  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

Sources & evidence

ORD record
ord-f84fa49976ec4834ac1fe6288bc1b717
Source dataset
uspto-grants-2007_12
Patent number
US07312215B2

Reaction notes

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