Formaldehyde → 1-(2-(2-(2-((4-(1-Methylpiperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide

HRID 592367Notes

Reaction equation

HRID 592367 reaction equation
C=O.[NH:3]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:21]=[C:20]([CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]4([C:33]([NH2:35])=[O:34])[CH2:32][CH2:31]4)[C:19]([C:36]([F:39])([F:38])[F:37])=[CH:18][N:17]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.[C:40](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:40][N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]3[N:21]=[C:20]([CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]4([C:33]([NH2:35])=[O:34])[CH2:31][CH2:32]4)[C:19]([C:36]([F:39])([F:38])[F:37])=[CH:18][N:17]=3)=[CH:13][CH:14]=2)[CH2:5][CH2:4]1

Participants

5

Reactant 3

HCID 712FormaldehydeHCID 5049666Sodium triacetoxyborohydrideHCID 732962871-(2-(2-(2-((4-(Piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide

Product 1

HCID 732964261-(2-(2-(2-((4-(1-Methylpiperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamideYield 88.1%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

Formaldehyde (37 wt % in H2O; 8.8 μL, 0.12 mmol) was added to a solution of 1-(2-(2-(2-((4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide (2) (20 mg, 39 μmol) in MeOH (5.0 mL) under an atmosphere of nitrogen. The resulting mixture was stirred for 10 minutes at room temperature then sodium triacetoxyborohydride (33 mg, 0.16 mmol) was added in one portion and stirring continued for 2.5 hours. The volatiles were removed in vacuo and the residue was diluted with EtOAc (20 mL) and saturated aqueous NaHCO3 (20 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO4 and the volatiles were removed under reduced pressure. The residue was dissolved in DCM (1 mL) to which cyclohexane (5 mL) was added to form a cloudy suspension. The solvent was removed in vacuo and the resulting solid was dried under high vacuum to give the title compound 3 as a white powder (18 mg, 88%); 1H NMR (400 MHz, d6-DMSO) δ 10.15 (s, 1H), 8.67 (s, 1H), 7.66 (d, J=8.5 Hz, 2H), 7.40-7.27 (m, 3H), 7.22 (dd, J=14.4, 8.0 Hz, 3H), 6.99 (s, 1H), 6.01 (s, 1H), 3.21-3.05 (m, 4H), 2.88 (d, J=10.9 Hz, 2H), 2.50-2.30 (m, 1H), 2.21 (s, 3H), 1.99 (s, 2H), 1.79-1.58 (m, 4H), 1.44 (s, 2H), 0.97 (s, 2H). LCMS-A: 5.028 min; m/z 524 [M+H]+.

Workup

  1. stirringstirring
  2. waitcontinued for 2.5 hours
  3. customThe volatiles were removed in vacuo
  4. additionthe residue was diluted with EtOAc (20 mL) and saturated aqueous NaHCO3 (20 mL)
  5. customThe layers were separated
  6. extractionthe aqueous layer was extracted with EtOAc (2×20 mL)
  7. washThe combined organic layers were washed with brine (20 mL)
  8. dry with materialdried over MgSO4
  9. customthe volatiles were removed under reduced pressure
  10. dissolutionThe residue was dissolved in DCM (1 mL) to which cyclohexane (5 mL)
  11. additionwas added
  12. customto form a cloudy suspension
  13. customThe solvent was removed in vacuo
  14. customthe resulting solid was dried under high vacuum

Sources & evidence

ORD record
ord-e0f26a913f1e4e40b48eb63458244481
Source dataset
uspto-grants-2016_01
Patent number
US09238644B2

Reaction notes

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