Toluene → 5-Amino-3-benzyloxy-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide

HRID 1349503Notes

Reaction equation

HRID 1349503 reaction equation
[CH2:1]([O:8][C:9]1[C:10](=[O:35])[C:11](C(O)=O)=[CH:12][N:13]([CH2:26][CH:27]([O:30][CH3:31])[O:28][CH3:29])[C:14]=1[C:15](=[O:25])[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.C([N:45](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCCC1>[Cl:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][NH:16][C:15]([C:14]1[N:13]([CH2:26][CH:27]([O:30][CH3:31])[O:28][CH3:29])[CH:12]=[C:11]([NH2:45])[C:10](=[O:35])[C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:25]

Participants

6

Reactant 4

HCID 1140TolueneHCID 8471TriethylamineHCID 199401P,P-Diphenylphosphinic azideHCID 230776405-Benzyloxy-6-(3-chlorobenzylcarbamoyl)-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid

Product 1

HCID 588591465-Amino-3-benzyloxy-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 5-benzyloxy-6-(3-chlorobenzylcarbamoyl)-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (1 g) obtained in Example 161, Step 4 in tetrahydrofuran (15 ml)-toluene (15 ml) were added triethylamine (0.61 ml) and diphenylphosphoryl azide (0.47 ml) and the mixture was stirred at room temperature for 30 min. The solvent was evaporated, and the residue was dissolved in tetrahydrofuran (8 ml). Triethylamine (0.61 ml) and diphenylphosphoryl azide (0.47 ml) were added again and 2 hr later, and 3 hr later, triethylamine (1.22 ml, 0.61 ml) and diphenylphosphoryl azide (0.94 ml, 0.47 ml) were respectively added, and stirring was continued. After confirmation of disappearance of the starting material, 9-fluorenylmethanol (7.7 g) and toluene (10 ml) were added, and the mixture was stirred under reflux with heating. After 20 min, triethylamine (2.5 ml) was added, and stirring was continued with heating for 1.5 hr. The mixture was concentrated, water was added to the residue and the mixture was extracted twice with ethyl acetate. The combined ethyl acetate layer was washed with brine, dried and concentrated. The residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:1-chloroform:methanol=15:1) to give 5-amino-3-benzyloxy-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (886 mg).

Workup

  1. customThe solvent was evaporated
  2. dissolutionthe residue was dissolved in tetrahydrofuran (8 ml)
  3. additionTriethylamine (0.61 ml) and diphenylphosphoryl azide (0.47 ml) were added again and 2 hr later
  4. addition3 hr later, triethylamine (1.22 ml, 0.61 ml) and diphenylphosphoryl azide (0.94 ml, 0.47 ml) were respectively added
  5. stirringstirring
  6. additionAfter confirmation of disappearance of the starting material, 9-fluorenylmethanol (7.7 g) and toluene (10 ml) were added
  7. stirringthe mixture was stirred
  8. temperatureunder reflux
  9. temperaturewith heating
  10. waitAfter 20 min
  11. additiontriethylamine (2.5 ml) was added
  12. stirringstirring
  13. temperaturewith heating for 1.5 hr
  14. concentrationThe mixture was concentrated
  15. additionwater was added to the residue
  16. extractionthe mixture was extracted twice with ethyl acetate
  17. washThe combined ethyl acetate layer was washed with brine
  18. customdried
  19. concentrationconcentrated

Sources & evidence

ORD record
ord-18a626334fce4501ae9b2ea882da6a78
Source dataset
uspto-grants-2007_05
Patent number
US07211572B2

Reaction notes

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