Pyridine → 1-(1-(3-(hydroxymethyl)phenyl)-3-(thiophen-2-yl)-1H-pyrazol-5-yl)-3-(2,3,4-trifluorophenyl)urea

HRID 1696584Notes

Reaction equation

HRID 1696584 reaction equation
[Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([N:16]2[C:20]([NH2:21])=[CH:19][C:18]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)=[N:17]2)[CH:13]=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.N1C=CC=CC=1.[F:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]=[C:41]=[O:42])=[C:36]([F:43])[C:35]=1[F:44].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CO.O>[OH:8][CH2:9][C:10]1[CH:11]=[C:12]([N:16]2[C:20]([NH:21][C:41]([NH:40][C:37]3[CH:38]=[CH:39][C:34]([F:33])=[C:35]([F:44])[C:36]=3[F:43])=[O:42])=[CH:19][C:18]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)=[N:17]2)[CH:13]=[CH:14][CH:15]=1

Participants

8

Reactant 4

HCID 1049PyridineHCID 2724141Tetrabutylammonium FluorideHCID 27333932,3,4-Trifluorophenyl isocyanateHCID 672726531-(3-((t-butyldimethylsilyloxy)methyl)phenyl)-3-(thiophen-2-yl)-1H-pyrazol-5-amine

Product 1

HCID 115830961-(1-(3-(hydroxymethyl)phenyl)-3-(thiophen-2-yl)-1H-pyrazol-5-yl)-3-(2,3,4-trifluorophenyl)ureaYield 73%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

To a solution of 1-(3-((t-butyldimethylsilyloxy)methyl)phenyl)-3-(thiophen-2-yl)-1H-pyrazol-5-amine (available from ethyl 3-(5-amino-3-(thiophen-2-yl)-1H-pyrazol-1-yl)benzoate using general method C followed by protection with TBSCl) (0.5 g, 1.3 mmol) in THF (3 mL) was added pyridine (0.10 g, 1.3 mmol) and 1,2,3-trifluoro-4-isocyanatobenzene (0.27 g, 1.6 mmol). The reaction mixture was stirred at room temperature for 22 hours. Water was added and the solid was filtered, washed with H2O and dried under vacuum to obtain the crude product. To a solution of the crude product in THF was added TBAF (1.6 mL, 1.0 M). The reaction mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure. Ethyl acetate was added into the residue and then 1N—HCl (5 drops) was added. The organic layer was washed with water, dried (Na2SO4) and evaporated under reduced pressure to obtain the crude product. The crude was dissolved in methanol and the solid filtered and dried under vacuum to yield 1-(1-(3-(hydroxymethyl)phenyl)-3-(thiophen-2-yl)-1H-pyrazol-5-yl)-3-(2,3,4-trifluorophenyl)urea (0.42 g, 73% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.13 (brs, 1H), 8.99 (s, 1H), 7.85 (m, 1H), 7.4-7.6 (m, 6H), 7.28 (m, 1H), 7.11 (dd, J=3.6, and 4.8 Hz, 1H), 6.86 (s, 1H), 5.39 (t, J=6.0 Hz, 1H), 4.62 (d, J=6.0 Hz, 2H); MS (EI) m/z: 445.0 (M+H+).

Workup

  1. filtrationthe solid was filtered
  2. washwashed with H2O
  3. customdried under vacuum
  4. customto obtain the crude product
  5. stirringThe reaction mixture was stirred at room temperature for 3 hours
  6. customThe solvent was removed under reduced pressure
  7. additionEthyl acetate was added into the residue
  8. addition1N—HCl (5 drops) was added
  9. washThe organic layer was washed with water
  10. dry with materialdried (Na2SO4)
  11. customevaporated under reduced pressure
  12. customto obtain the crude product
  13. filtrationthe solid filtered
  14. customdried under vacuum

Sources & evidence

ORD record
ord-005a854caf24456c92e370829f328494
Source dataset
uspto-grants-2012_04
Patent number
US08163756B2

Reaction notes

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