1,8-Diazabicyclo(5.4.0)undec-7-ene → 3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-7-(tetrahydrofuran-3-ylamino)-1,6-naphthyridin-2(1H)-one

HRID 1430435Notes

Reaction equation

HRID 1430435 reaction equation
[NH2:1][C:2]1[C:3]([F:23])=[CH:4][C:5]([Cl:22])=[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13](Cl)[CH:12]=3)[CH:7]=1.[O:24]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25]1.C1CCN2C(=NCCC2)CC1>CN1C(=O)CCC1>[NH2:1][C:2]1[C:3]([F:23])=[CH:4][C:5]([Cl:22])=[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:29][CH:26]2[CH2:27][CH2:28][O:24][CH2:25]2)[CH:12]=3)[CH:7]=1

Participants

5

Reactant 3

HCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 3365553Oxolan-3-amineHCID 877715763-(5-Amino-2-chloro-4-fluorophenyl)-7-chloro-1-ethyl-1,6-naphthyridin-2(1h)-one

Product 1

HCID 896061853-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-7-(tetrahydrofuran-3-ylamino)-1,6-naphthyridin-2(1H)-oneYield 25%

Reagents, catalysts & solvents 1

HCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
180 °C

Procedure

To a solution of Example A3 (2.0 g, 5.7 mmol) in NMP (10 mL) was added tetrahydro-furan-3-ylamine (1.5 g, 17.2 mmol) and DBU (1.7 g, 11.4 mmol). Nitrogen was bubbled through the mixture for 5 min and then it was heated in the microwave at 180° C. for 1 h. The reaction mixture was cooled to RT, poured into water and extracted with EtOAc (3×). The combined organics were washed with brine, dried over Na2SO4, concentrated under reduced pressure and purified by silica gel chromatography to give 3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-7-(tetrahydrofuran-3-ylamino)-1,6-naphthyridin-2(1H)-one (0.57 g, 25% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.39 (s, 1H), 7.66 (s, 1H), 7.27 (d, J=6.4 Hz, 1H), 7.18 (d, J=11.2 Hz, 1H), 6.72 (d, J=9.6 Hz, 1H), 6.33 (s, 1H), 5.31 (s, 2H), 4.46-4.42 (m, 1H), 4.08 (q, J=6.8 Hz, 2H), 3.89-3.81 (m, 2H), 3.75-3.69 (m, 1H), 3.55-3.52 (m, 1H), 2.22-2.17 (m, 1H), 1.83-1.79 (m, 1H), 1.20 (t, J=6.8 Hz, 3H).

Workup

  1. customNitrogen was bubbled through the mixture for 5 min
  2. temperatureThe reaction mixture was cooled to RT
  3. additionpoured into water
  4. extractionextracted with EtOAc (3×)
  5. washThe combined organics were washed with brine
  6. dry with materialdried over Na2SO4
  7. concentrationconcentrated under reduced pressure
  8. custompurified by silica gel chromatography

Sources & evidence

ORD record
ord-82d97333eade4f708e899f411eb1ef45
Source dataset
uspto-grants-2015_01
Patent number
US08940756B2

Reaction notes

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