tert-Butanol → Methyl 2-((tert-butoxycarbonyl)amino)-3-nitrobenzoate

HRID 1831012Notes

Reaction equation

HRID 1831012 reaction equation
C([C:4]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])(O)=O.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:24])C=CC=CC=1.C([N:36]([CH2:39]C)CC)C.[C:41]([OH:45])([CH3:44])([CH3:43])[CH3:42]>CN(C)C=O>[C:41]([O:45][C:39]([NH:36][C:4]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])=[O:24])([CH3:44])([CH3:43])[CH3:42]

Participants

6

Reactant 4

HCID 6386tert-ButanolHCID 8471TriethylamineHCID 199401P,P-Diphenylphosphinic azideHCID 43994772-(Methoxycarbonyl)-6-nitrobenzoic acid

Product 1

HCID 9965968Methyl 2-((tert-butoxycarbonyl)amino)-3-nitrobenzoateYield 86.7%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
27.5 °C

Procedure

Methyl 2-carboxy-3-nitrobenzoate [MNA] obtained in Reference Example 2 (164 kg) was dissolved in dimethylformamide [DMF] (242 kg), diphenylphosphoryl azide [DPPA] (204 kg) was added thereto at room temperature, and triethylamine (87 kg) was added dropwise while maintaining at 20 to 35° C. After stirring at 20 to 30° C. for about 3 hours, t-butyl alcohol (930 kg) was added to the reaction solution. The temperature was risen to 85 to 90° C. over 3 to 5 hours, and the solution was stirred for 1 to 2 hours under reflux (85 to 90° C.). The reaction solution was cooled, concentrated, and the residue was dissolved in ethyl acetate (1400 L). The solution was washed successively with a mixture of 15% hydrochloric acid (160 L) and water (1890 L), water (660 L), 5% aqueous sodium bicarbonate solution (1100 kg) and water (660 L), and the organic layer was concentrated under reduced pressure. Methanol (300 kg) was added thereto, and concentrated under reduced pressure. A seed crystal (15 kg) and methanol (450 kg) were added to the residue, and the mixture was heated to 50 to 60° C. to dissolve it. After cooled to 5° C., crystals were separated, washed with cold methanol (100 L), and dried to give methyl 2-t-butoxycarbonylamino-3-nitrobenzoate [BAN] (187.0 kg, 86.7%). The mother liquor and the washing were concentrated under reduced pressure, and cooled. The precipitated crystals were centrifuged, washed with cold methanol, and dried to give second crystal of BAN.

Workup

  1. waitThe temperature was risen to 85 to 90° C. over 3 to 5 hours
  2. stirringthe solution was stirred for 1 to 2 hours
  3. temperatureunder reflux (85 to 90° C.)
  4. temperatureThe reaction solution was cooled
  5. concentrationconcentrated
  6. dissolutionthe residue was dissolved in ethyl acetate (1400 L)
  7. washThe solution was washed successively with a mixture of 15% hydrochloric acid (160 L) and water (1890 L), water (660 L), 5% aqueous sodium bicarbonate solution (1100 kg) and water (660 L)
  8. concentrationthe organic layer was concentrated under reduced pressure
  9. additionMethanol (300 kg) was added
  10. concentrationconcentrated under reduced pressure
  11. additionA seed crystal (15 kg) and methanol (450 kg) were added to the residue
  12. temperaturethe mixture was heated to 50 to 60° C.
  13. dissolutionto dissolve it
  14. temperatureAfter cooled to 5° C.
  15. customcrystals were separated
  16. washwashed with cold methanol (100 L)
  17. customdried

Sources & evidence

ORD record
ord-891b273137c44ee8a8be5fea0ca7beec
Source dataset
uspto-grants-2006_06
Patent number
US07067546B2

Reaction notes

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