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 2117180Notes

Reaction equation

HRID 2117180 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(N[C:60](=[O:72])[CH2:61][C:62]([NH:64][C:65]2[CH:70]=[CH:69][C:68]([F:71])=[CH:67][CH:66]=2)=[O:63])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:72])[CH2:61][C:62]([NH:64][C:65]2[CH:70]=[CH:69][C:68]([F:71])=[CH:67][CH:66]=2)=[O:63])[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 131727132N1-(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-ea443d947f6947dea7116976a6fd761b
Source dataset
uspto-grants-2008_10
Patent number
US07439246B2

Reaction notes

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