Isopropenyl chloroformate → Prop-1-en-2-yl (4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)carbamate

HRID 1257167Notes

Reaction equation

HRID 1257167 reaction equation
[NH2:1][C:2]1[C:3]([F:24])=[CH:4][C:5]([Cl:23])=[C:6]([C:8]2[C:9](=[O:22])[N:10]([CH2:20][CH3:21])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH3:19])[CH:12]=3)[CH:7]=1.C([O-])(O)=O.[Na+].Cl[C:31]([O:33][C:34]([CH3:36])=[CH2:35])=[O:32]>CCOC(C)=O>[Cl:23][C:5]1[C:6]([C:8]2[C:9](=[O:22])[N:10]([CH2:20][CH3:21])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH3:19])[CH:12]=3)=[CH:7][C:2]([NH:1][C:31](=[O:32])[O:33][C:34]([CH3:36])=[CH2:35])=[C:3]([F:24])[CH:4]=1

Participants

5

Reactant 3

HCID 93846Isopropenyl chloroformate2×HCID 516892Sodium BicarbonateHCID 690386333-(5-Amino-2-chloro-4-fluorophenyl)-1-ethyl-7-(methylamino)-1,6-naphthyridin-2(1h)-one

Product 1

HCID 89611463Prop-1-en-2-yl (4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)carbamateYield 77.5%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent2×

Procedure

A suspension of Example A5 (0.154 g, 0.444 mmol) in EtOAc (2.5 mL) was treated with satd. NaHCO3 (2.5 mL) and isopropenyl chloroformate (0.046 mL, 0.422 mmol) and the biphasic mixture stirred vigorously at RT for 3.5 h. Additional isopropenyl chloroformate (20 μL) was added and the mixture was stirred at RT overnight. The mixture was diluted with additional EtOAc and satd. NaHCO3 and the layers separated. The organic layer was washed with brine, dried over MgSO4 and concentrated to dryness. The resulting residue was dissolved in pyridine (1.5 mL), cooled to 0° C., treated with isopropenyl chloroformate (15 μL) and allowed to warm to RT. The mixture was re-cooled to 0° C., treated with additional isopropenyl chloroformate (7 μL) and allowed to warm to RT. The mixture was once again cooled to 0° C., treated with isopropenyl chloroformate (5 μL), allowed to warm to RT and stirred overnight. The mixture was concentrated to dryness, treated with brine and extracted with EtOAc (2×). The combined organics were dried over MgSO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford prop-1-en-2-yl (4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)carbamate (141 mg, 74% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.80 (s, 1H), 8.40 (s, 1H), 7.75 (s, 1H), 7.64 (s, 1H), 7.55 (d, J=10.5 Hz, 1H), 7.05 (d, J=5.0 Hz, 1H), 6.23 (s, 1H), 4.73 (m, 2H), 4.13 (q, J=7.1 Hz, 2H), 2.85 (d, J=4.9 Hz, 3H), 1.91 (s, 3H), 1.20 (t, J=7.0 Hz, 3H), MS (ESI) m/z: 431.1 [M+H]+.

Workup

  1. customNaHCO3 and the layers separated
  2. washThe organic layer was washed with brine
  3. dry with materialdried over MgSO4
  4. concentrationconcentrated to dryness
  5. dissolutionThe resulting residue was dissolved in pyridine (1.5 mL)
  6. temperaturecooled to 0° C.
  7. additiontreated with isopropenyl chloroformate (15 μL)
  8. temperatureto warm to RT
  9. temperatureThe mixture was re-cooled to 0° C.
  10. additiontreated with additional isopropenyl chloroformate (7 μL)
  11. temperatureto warm to RT
  12. temperatureThe mixture was once again cooled to 0° C.
  13. additiontreated with isopropenyl chloroformate (5 μL)
  14. temperatureto warm to RT
  15. stirringstirred overnight
  16. concentrationThe mixture was concentrated to dryness
  17. additiontreated with brine
  18. extractionextracted with EtOAc (2×)
  19. dry with materialThe combined organics were dried over MgSO4
  20. concentrationconcentrated to dryness
  21. custompurified via silica gel chromatography (EtOAc/Hex)

Sources & evidence

ORD record
ord-97c8693c0d9942b797d249fc9dfe9467
Source dataset
uspto-grants-2013_06
Patent number
US08461179B1

Reaction notes

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