Acetic Anhydride → Ethyl 3-(acetyloxy)-6-(3-chloro-4-fluorobenzyl)-4-methoxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate

HRID 18009

Reaction equation

HRID 18009 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:11][CH:10]=[C:9]([O:21][CH3:22])[C:8]=2[C:7]1=[O:23].OO.NC(N)=O.P([O-])([O-])(O)=O.[K+].[K+].S(=O)(O)[O-].[Na+].[C:46]([O:49]C(=O)C)(=[O:48])[CH3:47]>ClCCl.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C1(C)C=CC=CC=1>[C:46]([O:49][C:10]1[N:11]=[C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:13]2[CH2:14][CH2:15][N:6]([CH2:5][C:4]3[CH:24]=[CH:25][C:26]([F:27])=[C:2]([Cl:1])[CH:3]=3)[C:7](=[O:23])[C:8]=2[C:9]=1[O:21][CH3:22])(=[O:48])[CH3:47]

Participants

9

Reactant 5

HCID 7918Acetic AnhydrideHCID 24450Potassium Phosphate, DibasicHCID 31294Carbamide PeroxideHCID 23665763Sodium BisulfiteHCID 59455605Ethyl 6-(3-chloro-4-fluorobenzyl)-4-methoxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate

Product 1

HCID 59455606Ethyl 3-(acetyloxy)-6-(3-chloro-4-fluorobenzyl)-4-methoxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate

Reagents, catalysts & solvents 3

HCID 1140TolueneSolventHCID 6344DichloromethaneSolventHCID 9845Trifluoroacetic anhydrideSolvent

Conditions

Temperature
20 °C

Procedure

To a cold (5° C.) mixture of ethyl 6-(3-chloro-4-fluorobenzyl)-4-methoxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate (199 g, 0.51 mol) and urea hydrogen peroxide (100 g, 1.06 mol) in dichloromethane (1.5 L), trifluoroacetic anhydride was added dropwise over a period of 45 minutes. The resultant homogeneous solution was stirred at 20° C. for 30 minutes and cooled back to 5° C. The reaction mixture was treated with aqueous potassium hydrogen phosphate (pH of aqueous extract increased to ˜8), followed by slow addition of freshly prepared aqueous sodium bisulfite solution with the temperature of the product mixture maintained below 25° C. The organic extract was separated and the aqueous fraction extracted with toluene (2×). The organic extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Without further purification, a solution of this intermediate N-oxide (˜280 g) and acetic anhydride (239 mL, 2.5 mol) in toluene (2 L) was heated at 110° C. for 16 hours. The product mixture was concentrated under vacuum. The resultant oil was concentrated from toluene (300 mL, twice) and stored under vacuum overnight. The acetate product was used in the following step without further purification.

Workup

  1. additionwas added dropwise over a period of 45 minutes
  2. temperaturecooled back to 5° C
  3. temperaturemaintained below 25° C
  4. extractionThe organic extract
  5. customwas separated
  6. extractionthe aqueous fraction extracted with toluene (2×)
  7. dry with materialdried over anhydrous sodium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated under vacuum
  10. customWithout further purification
  11. concentrationThe product mixture was concentrated under vacuum
  12. concentrationThe resultant oil was concentrated from toluene (300 mL
  13. customstored under vacuum overnight
  14. customThe acetate product was used in the following step without further purification

Sources & evidence

ORD record
ord-24675255afd245cc91c2a4368071526f
Source dataset
uspto-grants-2010_06
Patent number
US07741315B2

Linked notes

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