Trifluoroacetic acid → 2-(2-(2-(2-((4-(Piperidin-4-yl)-2-(trifluoromethoxy)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide

HRID 2272438Notes

Reaction equation

HRID 2272438 reaction equation
[NH2:1][C:2](=[O:47])[CH2:3][C:4]1[CH:46]=[CH:45][CH:44]=[CH:43][C:5]=1[CH2:6][CH2:7][C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:11]=[C:10]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)=[CH:21][C:20]=2[O:38][C:39]([F:42])([F:41])[F:40])[N:9]=1.FC(F)(F)C(O)=O>C(Cl)Cl.CCOC(C)=O.CO>[NH3:1].[NH:28]1[CH2:29][CH2:30][CH:25]([C:22]2[CH:23]=[CH:24][C:19]([NH:18][C:10]3[N:9]=[C:8]([CH2:7][CH2:6][C:5]4[CH:43]=[CH:44][CH:45]=[CH:46][C:4]=4[CH2:3][C:2]([NH2:1])=[O:47])[C:13]([C:14]([F:16])([F:17])[F:15])=[CH:12][N:11]=3)=[C:20]([O:38][C:39]([F:41])([F:40])[F:42])[CH:21]=2)[CH2:26][CH2:27]1

Participants

7

Reactant 2

HCID 6422Trifluoroacetic acidHCID 86675847tert-Butyl 4-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-(trifluoromethoxy)phenyl)piperidine-1-carboxylate

Product 2

HCID 222AmmoniaYield 1%HCID 866758482-(2-(2-(2-((4-(Piperidin-4-yl)-2-(trifluoromethoxy)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamideYield 159.2%

Reagents, catalysts & solvents 3

HCID 887MethanolSolvent2×HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

tert-Butyl 4-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-(trifluoromethoxy)phenyl)piperidine-1-carboxylate (I50) (0.062 g, 0.093 mmol) was dissolved in dry DCM (6 mL) under an atmosphere of nitrogen. Trifluoroacetic acid (0.142 mL, 1.86 mmol) was added to the solution and the reaction was stirred at room temperature for 20 hours. Volatiles were removed in vacuo, EtOAc (50 mL) and 2 M aq. NaOH (50 mL) were added to the residue and the layers were separated. The aqueous layer was extracted with EtOAc (2×70 mL), the combined organics were washed with water (50 mL), brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo to give an off-white solid. The crude material was purified by silica gel chromatography (12 g Si Cartridge, 0-100% EtOAc in petroleum benzine 40-60° C., then 0-100% methanol in EtOAc, then 1% ammonia in methanol), to give the title compound (10) (0.042 g, 80% yield) as a white solid; 1H NMR (400 MHz, d6-DMSO) δ 9.78 (s, 1H), 8.59 (s, 1H), 7.59 (d, J=8.3 Hz, 1H), 7.39 (s, 1H), 7.29-7.17 (m, 3H), 7.18-7.06 (m, 3H), 6.90 (s, 1H), 3.45 (s, 2H), 3.09-2.92 (m, 6H), 2.71-2.53 (m, 3H), 1.71 (d, J=11.7 Hz, 2H), 1.49 (qd, J=12.1, 3.7 Hz, 2H). LCMS Method C: rt 5.07 min; m/z 568.1[M+H]+.

Workup

  1. customVolatiles were removed in vacuo, EtOAc (50 mL) and 2 M aq. NaOH (50 mL)
  2. additionwere added to the residue
  3. customthe layers were separated
  4. extractionThe aqueous layer was extracted with EtOAc (2×70 mL)
  5. washthe combined organics were washed with water (50 mL), brine (50 mL)
  6. dry with materialdried (MgSO4)
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customto give an off-white solid
  10. customThe crude material was purified by silica gel chromatography (12 g Si Cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.

Sources & evidence

ORD record
ord-df6e5d059704433b8e346723c9ef2c77
Source dataset
uspto-grants-2015_09
Patent number
US09120761B2

Reaction notes

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