Dichloromethane → HCID 59232187, compound

HRID 1099288Notes

Reaction equation

HRID 1099288 reaction equation
C(Cl)Cl.[NH2:4][C:5]1[C:10]2=[C:11]([C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]4[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:31]=4[F:40])=[O:28])=[C:22]([F:41])[CH:21]=3)[CH:12]=[C:13]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:9]2[N:8]=[CH:7][N:6]=1.[CH3:42][N:43]=[C:44]=[O:45]>C1COCC1>[NH2:4][C:5]1[C:10]2=[C:11]([C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:28])[NH:29][C:30]4[CH:35]=[C:34]([C:36]([F:39])([F:37])[F:38])[CH:33]=[CH:32][C:31]=4[F:40])=[C:22]([F:41])[CH:21]=3)[CH:12]=[C:13]([CH:14]3[CH2:19][CH2:18][N:17]([C:44]([NH:43][CH3:42])=[O:45])[CH2:16][CH2:15]3)[N:9]2[N:8]=[CH:7][N:6]=1

Participants

5

Reactant 3

HCID 6344DichloromethaneHCID 12228Methyl IsocyanateHCID 59231938HCID 59231938, compound

Product 1

HCID 59232187HCID 59232187, compoundYield 60.3%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a flask containing 3 ml of methylene chloride was added 1-[4-(4-amino-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl]-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea (Example 111) (75 mg, 0.141 mmol, 1.0 eq). To this suspension was added THF dropwise until complete dissolution occurs. To this solution was added methyl isocyanate (8.8 μl, 0.148 mmol, 1.05 eq.) and reaction allowed to stir at room temperature for 17 h. Reaction solution was concentrated to dryness and residue dissolved in EtOAc. Wash 2× with saturated sodium bicarbonate, 1× brine, layers separated, organics dried (Na2SO4), filtered, condensed and purified via flash chromatography (1:1 THF:hexanes). The purified fractions collected and concentrated to dryness. Residue was stirred in hexanes and filtered to obtain title compound (50 mg, 60.2% yield). 1H-NMR (DMSO-d6) δ 9.41 (d, J=2.8 Hz, 1H), 9.25 (d, J=2.3 Hz, 1H), 8.65 (dd, J=7.5, 2.4 Hz, 1H), 8.25 (t, J=8.6 Hz, 1H), 7.90 (s, 1H), 7.51 (m, 1H), 7.41 (m, 1H), 7.32 (dd, J=12.4, 2.0 Hz, 1H), 7.23 (dd, J=8.5, 1.4 Hz, 1H), 6.57 (s, 1H) 6.44 (q, J=4.3 Hz, 1H), 4.05 (d, J=13.3 Hz, 2H), 3.28 (m, 1H), 2.80 (t, J=12.2 Hz, 2H), 2.56 (d, J=4.5 Hz, 3H), 1.95 (d, J=11.3 Hz, 2H), 1.52 (m, 2H); MS [M+H]+=589; LCMS RT=3.11 min.

Workup

  1. dissolutiondropwise until complete dissolution
  2. additionTo this solution was added
  3. customReaction solution
  4. concentrationwas concentrated to dryness and residue
  5. dissolutiondissolved in EtOAc
  6. washWash 2× with saturated sodium bicarbonate, 1× brine, layers
  7. customseparated
  8. dry with materialorganics dried (Na2SO4)
  9. filtrationfiltered
  10. customcondensed
  11. custompurified via flash chromatography (1:1 THF:hexanes)
  12. customThe purified fractions collected
  13. concentrationconcentrated to dryness
  14. stirringResidue was stirred in hexanes
  15. filtrationfiltered

Sources & evidence

ORD record
ord-034b892bda43424d831e44d6232b3fa5
Source dataset
uspto-grants-2012_03
Patent number
US08143393B2

Reaction notes

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