Trifluoroacetic acid → 5-Ethyl-2-{4-[({6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinyl}pyrimidine

HRID 423526Notes

Reaction equation

HRID 423526 reaction equation
[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25](OC(C)(C)C)=O)[CH2:21][CH2:20]3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(O)(C(F)(F)F)=O.ClC1[N:45]=[CH:44][C:43]([CH2:46][CH3:47])=[CH:42][N:41]=1>C(Cl)Cl>[CH2:46]([C:43]1[CH:42]=[N:41][C:25]([N:22]2[CH2:23][CH2:24][CH:19]([CH2:18][O:17][C:14]3[CH:15]=[N:16][C:11]([C:8]4[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=4)=[CH:12][CH:13]=3)[CH2:20][CH2:21]2)=[N:45][CH:44]=1)[CH3:47]

Participants

5

Reactant 3

HCID 6422Trifluoroacetic acidHCID 35727632-Chloro-5-ethylpyrimidineHCID 249943331,1-Dimethylethyl 4-[({6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate

Product 1

HCID 249946495-Ethyl-2-{4-[({6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinyl}pyrimidineYield 92%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

1,1-Dimethylethyl 4-[({6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate (prepared as in Example 73, Step 2, 0.15 g, 0.34 mmol) was dissolved in CH2Cl2 (10 mL). TFA (0.35 mL) was added and the mixture was stirred at ambient temperature for 5 h. An excess of TFA and CH2Cl2 was removed under reduced pressure and the residue was taken up in DMSO (6 mL). Potassium carbonate (1 g) was added, followed by addition of 2-chloro-5-ethylpyrimidine (63 μL, 0.50 mmol). The reaction mixture was degassed, purged with N2 and heated at 100° C. overnight. The mixture was cooled to ambient temperature and poured into water and extracted with EtOAc. The combined organic extract was washed with water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a light brown solid. The crude product was triturated with hot hexane containing 1% of MeOH to give 0.14 g (92%) of the title compound as a cream-white solid. 1H NMR (400 MHz, CDCl3): δ 8.40 (d, 1H, J=2.7 Hz), 8.19 (bs, 2H), 8.13 (d, 2H, J=8.6 Hz), 8.00 (d, 2H, J=8.6 Hz), 7.73 (d, 1H, J=8.5 Hz), 7.35-7.25 (m, 1H), 4.90-4.75 (m, 2H), 3.94 (d, 2H, J=6.1 Hz), 3.08 (s, 3H), 3.00-2.90 (m, 2H), 2.55-2.40 (m, 2H), 2.25-2.10 (m, 1H), 2.00-1.90 (m, 2H), 1.50-1.30 (m, 2H), 1.19 (t, 3H, J=7.5 Hz); LRMS (APCI), m/z 453 (M+H).

Workup

  1. customAn excess of TFA and CH2Cl2 was removed under reduced pressure
  2. additionPotassium carbonate (1 g) was added
  3. customThe reaction mixture was degassed
  4. custompurged with N2
  5. temperatureheated at 100° C. overnight
  6. temperatureThe mixture was cooled to ambient temperature
  7. additionpoured into water
  8. extractionextracted with EtOAc
  9. extractionThe combined organic extract
  10. washwas washed with water and brine
  11. dry with materialdried over Na2SO4
  12. filtrationfiltered
  13. concentrationthe filtrate was concentrated
  14. customto give the crude product as a light brown solid
  15. customThe crude product was triturated with hot hexane containing 1% of MeOH

Sources & evidence

ORD record
ord-943e4f3a0ac54c3b935a46672237954b
Source dataset
uspto-grants-2012_01
Patent number
US08101634B2

Reaction notes

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