Acetaldehyde → 2-(2-(2-(2-((4-(1-Ethylpiperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide

HRID 1485252Notes

Reaction equation

HRID 1485252 reaction equation
[CH:1](=O)[CH3:2].[NH:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:22]=[C:21]([CH2:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[CH2:31][C:32]([NH2:34])=[O:33])[C:20]([C:35]([F:38])([F:37])[F:36])=[CH:19][N:18]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(Cl)Cl>[CH2:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]3[N:22]=[C:21]([CH2:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[CH2:31][C:32]([NH2:34])=[O:33])[C:20]([C:35]([F:38])([F:37])[F:36])=[CH:19][N:18]=3)=[CH:14][CH:15]=2)[CH2:6][CH2:5]1)[CH3:2]

Participants

6

Reactant 3

HCID 177AcetaldehydeHCID 5049666Sodium triacetoxyborohydrideHCID 601646962-(2-(2-(2-((4-(Piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide

Product 1

HCID 712093622-(2-(2-(2-((4-(1-Ethylpiperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamideYield 42.3%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6344DichloromethaneSolvent

Procedure

Acetaldehyde (84.5 μL, 1.51 mmol) was added to a suspension of 2-(2-(2-(2-((4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (11) (91.0 mg, 0.188 mmol) in anhydrous methanol (10 mL) under an atmosphere of nitrogen. Sodium triacetoxyborohydride (0.638 g, 3.01 mmol) was then added in one portion and the reaction was stirred at room temperature for 24 hours. The volatiles were removed in vacuo and the residue was diluted with EtOAc (35 mL) and sat. aq. NaHCO3 (40 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×35 mL), the combined organic layers were washed with water (30 mL), brine (30 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the residue dissolved in DCM (5 mL) and MeOH (2 mL). Cyclohexane (20 mL) was added and the solvent removed in vacuo to afford a tan solid which was purified by column chromatography on silica gel (0-100% EtOAc in petroleum benzine 40-60° C.; then 0-75% MeOH in EtOAc) to yield a white solid. The solid was suspended in DCM (5 mL) and cyclohexane (20 mL) and filtered to afford the title compound (31) (40.7 mg, 42%) as an off-white solid; 1H NMR (400 MHz, d6-DMSO) δ 10.13 (s, 1H), 8.65 (s, 1H), 7.66 (d, J=8.6 Hz, 2H), 7.43 (s, 1H), 7.26-7.12 (m, 6H), 6.92 (s, 1H), 3.50 (s, 2H), 3.14-3.06 (m, 2H), 3.05-2.92 (m, 4H), 2.43 (tt, J=11.7, 3.7 Hz, 1H), 2.33 (q, J=7.2 Hz, 2H), 1.93 (td, J=11.5, 2.1 Hz, 2H), 1.73 (dd, J=11.8, 2.0 Hz, 2H), 1.62 (ddd, J=24.8, 12.4, 3.6 Hz, 2H), 1.01 (t, J=7.2 Hz, 3H); LCMS Method C: rt 4.90 min; m/z 512 [M+H]+.

Workup

  1. customThe volatiles were removed in vacuo
  2. additionthe residue was diluted with EtOAc (35 mL) and sat. aq. NaHCO3 (40 mL)
  3. customThe layers were separated
  4. extractionthe aqueous layer was extracted with EtOAc (2×35 mL)
  5. washthe combined organic layers were washed with water (30 mL), brine (30 mL)
  6. dry with materialdried over Na2SO4
  7. customThe solvent was removed under reduced pressure
  8. dissolutionthe residue dissolved in DCM (5 mL)
  9. additionCyclohexane (20 mL) was added
  10. customthe solvent removed in vacuo
  11. customto afford a tan solid which
  12. customwas purified by column chromatography on silica gel (0-100% EtOAc in petroleum benzine 40-60° C.
  13. customthen 0-75% MeOH in EtOAc) to yield a white solid
  14. filtrationcyclohexane (20 mL) and filtered

Sources & evidence

ORD record
ord-4b866f4de7c147e597ca3917a9ffee7d
Source dataset
uspto-grants-2016_08
Patent number
US09421205B2

Reaction notes

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