1,4-Difluoro-2-isocyanatobenzene → 1-(4-Chloro-5-(1-ethyl-7-((4-methoxybenzyl)(methyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(2,5-difluorophenyl)urea

HRID 1430525Notes

Reaction equation

HRID 1430525 reaction equation
[CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:6]([CH2:7][N:8]([CH3:31])[C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([C:22]4[CH:27]=[C:26]([NH2:28])[C:25]([F:29])=[CH:24][C:23]=4[Cl:30])[C:15](=[O:21])[N:16]3[CH2:19][CH3:20])=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[F:34][C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=1[N:42]=[C:43]=[O:44]>N1C=CC=CC=1>[Cl:30][C:23]1[C:22]([C:14]2[C:15](=[O:21])[N:16]([CH2:19][CH3:20])[C:17]3[C:12]([CH:13]=2)=[CH:11][N:10]=[C:9]([N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:33][CH:32]=2)[CH3:31])[CH:18]=3)=[CH:27][C:26]([NH:28][C:43]([NH:42][C:36]2[CH:37]=[C:38]([F:41])[CH:39]=[CH:40][C:35]=2[F:34])=[O:44])=[C:25]([F:29])[CH:24]=1

Participants

4

Reactant 2

HCID 27332661,4-Difluoro-2-isocyanatobenzene2×HCID 896061707-((4-methoxybenzyl)(methyl)amino)-3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-1,6-naphthyridin-2(1H)-one

Product 1

HCID 867136661-(4-Chloro-5-(1-ethyl-7-((4-methoxybenzyl)(methyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(2,5-difluorophenyl)ureaYield 94.4%

Reagents, catalysts & solvents 1

HCID 1049PyridineSolvent

Procedure

A solution of Example A4 (250 mg, 0.535 mmol) in pyridine (2 mL) was treated with 2,5-difluorophenyl isocyanate (91 mg, 0.589 mmol) and stirred at RT overnight. Additional 2,5-difluorophenyl isocyanate (30 μL, 0.256 mmol) was added and stirred at RT for 4 h. The mixture was concentrated to near-dryness, treated with EtOAc and brine and the resulting solid was collected via filtration and dried to afford 1-(4-chloro-5-(1-ethyl-7-((4-methoxybenzyl)(methyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(2,5-difluorophenyl)urea (314 mg, 94% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.31 (s, 2H), 8.51 (s, 1H), 8.19 (d, J=8.6 Hz, 1H), 7.98 (m, 1H), 7.78 (s, 1H), 7.56 (d, J=10.9 Hz, 1H), 7.29 (m, 1H), 7.18 (d, J=8.4 Hz, 2H), 6.89-6.78 (m, 3H), 6.33 (s, 1H), 4.85 (s, 2H), 4.19 (q, J=7.1 Hz, 2H), 3.70 (s, 3H), 3.13 (s, 3H), 1.13 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 622.2 [M+H]+.

Workup

  1. stirringstirred at RT for 4 h
  2. concentrationThe mixture was concentrated to near-dryness
  3. additiontreated with EtOAc and brine
  4. filtrationthe resulting solid was collected via filtration
  5. customdried

Sources & evidence

ORD record
ord-48b9e763d70144f7828f4223b40c4eee
Source dataset
uspto-grants-2015_01
Patent number
US08940756B2

Reaction notes

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