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

HRID 705773Notes

Reaction equation

HRID 705773 reaction equation
[NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH2:28][C:29]([NH2:31])=[O:30])[C:17]([C:32]([F:35])([F:34])[F:33])=[CH:16][N:15]=3)=[C:9]([O:36][C:37]([F:40])([F:39])[F:38])[CH:8]=2)[CH2:3][CH2:2]1.C=O.[C:43](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(Cl)Cl>[CH3:43][N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH2:28][C:29]([NH2:31])=[O:30])[C:17]([C:32]([F:34])([F:35])[F:33])=[CH:16][N:15]=3)=[C:9]([O:36][C:37]([F:38])([F:40])[F:39])[CH:8]=2)[CH2:3][CH2:2]1

Participants

6

Reactant 3

HCID 712FormaldehydeHCID 5049666Sodium triacetoxyborohydrideHCID 866758482-(2-(2-(2-((4-(Piperidin-4-yl)-2-(trifluoromethoxy)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide

Product 1

HCID 601622492-(2-(2-(2-((4-(1-Methylpiperidin-4-yl)-2-(trifluoromethoxy)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamideYield 93%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6344DichloromethaneSolvent

Procedure

To a suspension of 2-(2-(2-(2-((4-(piperidin-4-yl)-2-(trifluoromethoxy)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (10) (0.039 g, 0.069 mmol) in anhydrous methanol (4 mL) was added a 37% aq. solution of formaldehyde (0.020 mL, 0.28 mmol) under an atmosphere of nitrogen followed by sodium triacetoxyborohydride (0.073 g, 0.34 mmol). The reaction was stirred at room temperature for 3 hours. The volatiles were then removed in vacuo and the residue was diluted with EtOAc (50 mL) and sat. aq. NaHCO3 (30 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×30 mL), the combined organic layers were washed with brine (40 mL), dried (MgSO4), filtered and concentrated in vacuo to give a gum which was taken up in DCM (˜10 mL) and methanol (˜1 mL) and concentrated in vacuo. The process was repeated with only DCM twice. The resulting gum was then suspended in diethyl ether (5 mL) and the solvent was removed in vacuo. The procedure was repeated to give the title compound (11) (0.037 g, 93% yield) as a white fluffy solid: 1H NMR (400 MHz, d6-DMSO) δ 9.79 (s, 1H), 8.59 (s, 1H), 7.60 (d, J=8.3 Hz, 1H), 7.39 (s, 1H), 7.28 (dd, J=8.4, 1.9 Hz, 1H), 7.26-7.23 (m, 1H), 7.23-7.19 (m, 1H), 7.18-7.08 (m, 3H), 6.89 (s, 1H), 3.45 (s, 2H), 3.08-2.93 (m, 4H), 2.90-2.83 (m, 2H), 2.57-2.52 (m, 1H, obscured by residual solvent signal), 2.19 (s, 3H), 1.96 (td, J=11.5, 2.0 Hz, 2H), 1.80-1.72 (m, 2H), 1.65 (ddd, J=24.6, 12.4, 3.7 Hz, 2H). LCMS Method C: rt 5.11 min; m/z 582.1 [M+H]+.

Workup

  1. customThe volatiles were then removed in vacuo
  2. additionthe residue was diluted with EtOAc (50 mL) and sat. aq. NaHCO3 (30 mL)
  3. customThe layers were separated
  4. extractionthe aqueous layer was extracted with EtOAc (2×30 mL)
  5. washthe combined organic layers were washed with brine (40 mL)
  6. dry with materialdried (MgSO4)
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customto give a gum which
  10. concentrationmethanol (˜1 mL) and concentrated in vacuo
  11. customthe solvent was removed in vacuo

Sources & evidence

ORD record
ord-2aa12349bff54b4bae2be4f527953b8c
Source dataset
uspto-grants-2015_11
Patent number
US09174946B2

Reaction notes

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