1,2-Dibromoethane → 4-[(3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl)-amino]-benzoic acid ethyl ester

HRID 1360257Notes

Reaction equation

HRID 1360257 reaction equation
[CH2:1]([O:3][C:4](=[O:31])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:30])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3C=CC=CC=3)=[C:15]([N+:27]([O-])=O)[CH:14]=2)=[CH:7][CH:6]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].BrCCBr>CN(C=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:31])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:13]2[CH:18]=[CH:17][C:16]3[O:19][CH2:20][CH2:21][NH:27][C:15]=3[CH:14]=2)=[O:30])=[CH:7][CH:6]=1)[CH3:2]

Participants

6

Reactant 3

HCID 78391,2-DibromoethaneHCID 11430Potassium CarbonateHCID 667887614-(4-Benzyloxy-3-nitro-benzoylamino)benzoic acid ethyl ester

Product 1

HCID 667888474-[(3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl)-amino]-benzoic acid ethyl esterYield 41.8%

Reagents, catalysts & solvents 2

HCID 23938PalladiumCatalystHCID 6228DimethylformamideSolvent

Procedure

Steps 5 and 6. A solution of 4-(4-benzyloxy-3-nitro-benzoylamino)-benzoic acid ethyl ester (26 g, 63 mmol) in DMF (2644 mL) was treated with 10% palladium on carbon (5.3 g). The reaction vessel was evacuated and filled with hydrogen. The mixture was stirred at room temperature for 4 hours, then the catalyst was filtered, washing with a small quantity of dimethylformamide. The resulting solution, containing crude 4-(3-amino-4-hydroxy-benzoylamino)-benzoic acid ethyl ester, was concentrated to a volume of 300 mL, and treated with K2CO3 (34.1 g, 247 mmol) and 1,2-dibromoethane (46.4 g, 247 mmol). The resulting mixture was warmed at 70° C. and stirred for 18 hours. The mixture was then concentrated to a volume of 100 mL and diluted with ethyl acetate and water. The organic phase was separated, washed three times with water, dried over sodium sulfate and evaporated. The residue was taken up in methanol and sonicated. The white solid was filtered, yielding pure 4-[(3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl)-amino]-benzoic acid ethyl ester (8.6 g). The filtrate was evaporated and the residue purified by flash chromatography (toluene/acetonitrile gradient) providing further 2 g of material. 4-[(3,4-Dihydro-2H-benzo[1,4]oxazine-6-carbonyl)-amino]-benzoic acid ethyl ester was thus obtained as a white solid, 10.6 g (52%), MS (ISP): m/e=327.0 (M+H+); δH (300 MHz; d6-DMSO) 10.27 (1H, s), 7.92 (4H, s), 7.16-7.19 (2H, m), 6.75 (1H, d), 6.04 (1H, s), 4.29 (2H, q), 4.19 (2H, s), 3.32 (2H, s), 1.32 (3H, t).

Workup

  1. customThe reaction vessel was evacuated
  2. additionfilled with hydrogen
  3. filtrationthe catalyst was filtered
  4. washwashing with a small quantity of dimethylformamide
  5. additionThe resulting solution, containing crude 4-(3-amino-4-hydroxy-benzoylamino)-benzoic acid ethyl ester
  6. concentrationwas concentrated to a volume of 300 mL
  7. temperatureThe resulting mixture was warmed at 70° C.
  8. stirringstirred for 18 hours
  9. concentrationThe mixture was then concentrated to a volume of 100 mL
  10. additiondiluted with ethyl acetate and water
  11. customThe organic phase was separated
  12. washwashed three times with water
  13. dry with materialdried over sodium sulfate
  14. customevaporated
  15. customsonicated
  16. filtrationThe white solid was filtered

Sources & evidence

ORD record
ord-c255f00987454e0d9f6e29862fa34cd0
Source dataset
uspto-grants-2011_02
Patent number
US07879845B2

Reaction notes

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