2-(4-Fluorophenyl)acetyl isocyanate → 1-(3-Fluoro-4-(5-methyl-6-(2-(4-methylpiperazin-1-yl)ethoxy)pyrrolo[2,1-f][1,2,4]triazin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea, bis-hydrochloride salt

HRID 347504Notes

Reaction equation

HRID 347504 reaction equation
[ClH:1].Cl.[F:3][C:4]1[CH:5]=[C:6]([NH:31][C:32]([NH:34][C:35](=[O:44])[CH2:36][C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)=S)[CH:7]=[CH:8][C:9]=1[O:10][C:11]1[C:16]2=[C:17]([CH3:30])[C:18]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)=[CH:19][N:15]2[N:14]=[CH:13][N:12]=1.FC1C=CC(CC(N=C=O)=[O:54])=CC=1>C1COCC1.Cl.FC1C=C(C(C(NC2C=CC(F)=CC=2)=O)C(N)=O)C=CC=1OC1C2=C(C)C(OCCN3CCOCC3)=CN2N=CN=1>[ClH:1].[ClH:1].[F:3][C:4]1[CH:5]=[C:6]([NH:31][C:32]([NH:34][C:35](=[O:44])[CH2:36][C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)=[O:54])[CH:7]=[CH:8][C:9]=1[O:10][C:11]1[C:16]2=[C:17]([CH3:30])[C:18]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)=[CH:19][N:15]2[N:14]=[CH:13][N:12]=1

Participants

5

Reactant 2

HCID 231530882-(4-Fluorophenyl)acetyl isocyanateHCID 1317262361-(3-Fluoro-4-(5-methyl-6-(2-(4-methylpiperazin-1-yl)ethoxy)pyrrolo[2,1-f][1,2,4] triazin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)thiourea, bis-hydrochloride salt2×

Product 1

HCID 1317262421-(3-Fluoro-4-(5-methyl-6-(2-(4-methylpiperazin-1-yl)ethoxy)pyrrolo[2,1-f][1,2,4]triazin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea, bis-hydrochloride saltYield 46%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 131726240(3-Fluoro-4-(5-methyl-6-(2-morpholinoethoxy)pyrrolo[2,1-f][1,2,4]triazin-4-yloxy)phenyl)-N3-(4-fluorophenyl)malonamide, hydrochloride saltSolvent2×

Procedure

To a solution of 3-fluoro-4-(5-methyl-6-(2-(4-methylpiperazin-1-yl)ethoxy)pyrrolo[2,1-f][1,2,4]triazin-4-yloxy)benzenamine (20 mg, 0.05 mmol, Compound B of Example 45) in 1 mL of THF at room temperature was added a solution of 2-(4-fluorophenyl)acetyl isocyanate in toluene (0.36 M, 0.18 mL, Compound C of Example 4) and the solution was allowed to stir overnight. HPLC analysis and LC-MS analysis indicated the completion of the reaction and the organic solvent was thus removed under reduced pressure. The residue was purified on preparative HPLC. The title compound (15 mg, 46%) was finally obtained as a 2.HCl salt after a work-up similar to that described for Compound D of Example 36. 1H NMR (DMSO-d6) δ 11.02 (s, 1H), 10.58 (s, 1 if), 8.04 (s, 11H), 7.99 (s, 1H), 7.70(d, 1H), 7.35 (m, 4H), 7.16 (m, 2H), 4.44 (br.s, 2H), 3.40–3.70 (m, 12H), 2.81 (s, 3H), 2.39 (s, 3H); MS(ESI+) m/z 580.1 (M+H)+.

Workup

  1. customthe completion of the reaction
  2. customthe organic solvent was thus removed under reduced pressure
  3. customThe residue was purified on preparative HPLC

Sources & evidence

ORD record
ord-adf54c1ab064450ba2c54c978946cc0d
Source dataset
uspto-grants-2007_02
Patent number
US07173031B2

Reaction notes

Loading…