Tris(hydroxymethyl)aminomethane → HCID 178514074, compound

HRID 1946261Notes

Reaction equation

HRID 1946261 reaction equation
[N:1]1([CH2:7][C:8]2[CH:22]=[CH:21][C:11]3[NH:12][C:13]([C:15]4[CH:19]=[CH:18][N:17](N)[N:16]=4)=[N:14][C:10]=3[CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1.C(O)C([NH2:39])(CO)CO>C1COCC1>[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]([C:19]2[C:15]([C:13]3[NH:12][C:11]4[CH:21]=[CH:22][C:8]([CH2:7][N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)=[CH:9][C:10]=4[N:14]=3)=[N:16][NH:17][CH:18]=2)[C:31]([NH2:39])=[O:32])=[CH:26][CH:25]=1

Participants

5

Reactant 3

HCID 6503Tris(hydroxymethyl)aminomethaneHCID 709554-Fluorophenyl isocyanateHCID 178514254HCID 178514254, compound

Product 1

HCID 178514074HCID 178514074, compoundYield 20%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To 3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-ylamine (Example 1E) (100 mg, 0.33 mmol), in THF (2 ml), was added 4-fluorophenyl isocyanate and the mixture was stirred for about 16 hours at room temperature. Resin-supported tris-amine (800 mg, 4 mmol/g) was added and the mixture agitated for a further 4 hours. The resin was removed by filtration, the filtrate was treated with 1N KOH (2 ml, MeOH:THF; 1:3) and the solution stirred for approximately 16 hours. The mixture was then partitioned between EtOAc and H2O. The aqueous layer was further extracted with EtOAc and then the combined organic fractions washed with brine, dried (MgSO4) and evaporated to dryness. The crude solid was dissolved in DCM and triturated with hexanes to give a solid which was collected by filtration. The solid was purified by flash column chromatography [SiO2, EtOAc-MeOH (90:10)] to give 1-(4-fluorophenyl)-N-[3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-urea (30 mg, 20%) as a yellow solid (LC/MS (acidic method): Rt 2.01 min, [M−H+]− 434).

Workup

  1. stirringthe mixture agitated for a further 4 hours
  2. customThe resin was removed by filtration
  3. additionthe filtrate was treated with 1N KOH (2 ml, MeOH:THF; 1:3)
  4. stirringthe solution stirred for approximately 16 hours
  5. customThe mixture was then partitioned between EtOAc and H2O
  6. extractionThe aqueous layer was further extracted with EtOAc
  7. washthe combined organic fractions washed with brine
  8. dry with materialdried (MgSO4)
  9. customevaporated to dryness
  10. dissolutionThe crude solid was dissolved in DCM
  11. customtriturated with hexanes
  12. customto give a solid which
  13. filtrationwas collected by filtration
  14. customThe solid was purified by flash column chromatography [SiO2, EtOAc-MeOH (90:10)]

Sources & evidence

ORD record
ord-19f07992bd084f688646fc05247ece96
Source dataset
uspto-grants-2013_03
Patent number
US08399442B2

Reaction notes

Loading…