Diisopropylethylamine → N1-(3-Fluoro-4-(6-(2-morpholinopyridin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yloxy)phenyl)-N3-(4-fluorophenyl)malonamide

HRID 347576Notes

Reaction equation

HRID 347576 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([NH2:30])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]2=[CH:15][C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH:19]=3)=[CH:17][N:13]2[N:12]=[CH:11][N:10]=1.Cl.FC1C=C([CH:59]([C:63]([NH:65][C:66]2[CH:71]=[CH:70][C:69]([F:72])=[CH:68][CH:67]=2)=[O:64])[C:60](N)=[O:61])C=CC=1OC1C2=C(C)C(OCCN3CCOCC3)=CN2N=CN=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:30][C:60](=[O:61])[CH2:59][C:63]([NH:65][C:66]2[CH:71]=[CH:70][C:69]([F:72])=[CH:68][CH:67]=2)=[O:64])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]2=[CH:15][C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:24]4[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)[CH:19]=3)=[CH:17][N:13]2[N:12]=[CH:11][N:10]=1

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 210816163-Fluoro-4-(6-(2-morpholinopyridin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yloxy)benzenamineHCID 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 salt2×

Product 1

HCID 58799032N1-(3-Fluoro-4-(6-(2-morpholinopyridin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yloxy)phenyl)-N3-(4-fluorophenyl)malonamideYield 37%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of 3-fluoro-4-(6-(2-morpholinopyridin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yloxy)benzenamine (15 mg, 0.037 mmol) and 3-(4-fluorophenylamino)-3-oxopropanoic acid (8 mg, 0.04 mmol, Compound A of Example 25) in DMF (1 mL) were added DIEA (0.1 mL, 0.57 mmol) and TBTU (13 mg, 0.04 mmol). The reaction mixture was stirred at room temperature overnight and then purified using preparative HPLC. The fraction containing the desired product was collected and concentrated in vacuo. The residue was neutralized with 1 N NH4OH and concentrated again. The solid that formed was filtered, washed with 1 N NH4OH, dissolved in MeOH/H2O, and lyophilized to give the title compound (8 mg, 37%). 1H NMR (DMSO-d6) δ 10.49 (s, 1H), 10.23 (s, 1H), 8.63 (s, 1H), 8.55 (s, 1H), 8.06 (s, 1H), 8.00 (d, 1H, J=7.5 Hz), 7.70 (m, 1H), 7.50 (m, 2H), 7.30–7.45 (m, 3H), 7.04–7.17 (m, 3H), 6.85–6.92 (m, 2H), 3.36 (s, 4H), 3.44 (s, 6H); MS(ESI) m/z 586.2 (M+H)+.

Workup

  1. custompurified
  2. additionThe fraction containing the desired product
  3. customwas collected
  4. concentrationconcentrated in vacuo
  5. concentrationconcentrated again
  6. customThe solid that formed
  7. filtrationwas filtered
  8. washwashed with 1 N NH4OH
  9. dissolutiondissolved in MeOH/H2O

Sources & evidence

ORD record
ord-0b2c604bc8c54717ae7e1f09624cc9a8
Source dataset
uspto-grants-2007_02
Patent number
US07173031B2

Reaction notes

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