Trifluoroacetic acid → 1-Methylethyl 4-[({6-[2-fluoro-4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate

HRID 423521Notes

Reaction equation

HRID 423521 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[N:17]=[CH:16][C:15]([O:18][CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29](C)([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=1.C(O)(C(F)(F)F)=O.C(N(C(C)C)CC)(C)C.ClC(OC(C)C)=O>C(Cl)Cl.CCOC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[N:17]=[CH:16][C:15]([O:18][CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=1

Participants

7

Reactant 4

HCID 6422Trifluoroacetic acidHCID 7917Isopropyl chloroformateHCID 81531DiisopropylethylamineHCID 249943361,1-Dimethylethyl 4-[({6-[2-fluoro-4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate

Product 1

HCID 591777471-Methylethyl 4-[({6-[2-fluoro-4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylateYield 71%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

1,1-Dimethylethyl 4-[({6-[2-fluoro-4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate (prepared as in Example 76, 47 mg, 0.10 mmol) was dissolved in CH2Cl2 (3 mL) and treated with TFA (0.20 mL). The mixture was stirred at ambient temperature for 6 h. The mixture was then cooled to 0° C. in an ice bath, and diisopropylethylamine (1.0 mL) was added, followed by addition of isopropyl chloroformate (1.0M in toluene, 0.12 mL, 0.12 mmol). The reaction mixture was allowed to warm to ambient temperature, and stirred overnight, then diluted with EtOAc, 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 purified by chromatography on a silica gel column eluted with 25% EtOAc/CH2Cl2 to give 32 mg (70%) of the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ 8.40 (d, 1H, J=2.9 Hz), 8.20-8.10 (m, 1H), 7.90-7.75 (m, 3H), 7.50 (dd, 1H, Ja=8.8 Hz, Jb=3.0 Hz), 4.90-4.80 (m, 1H), 4.25-4.15 (m, 2H), 4.00 (d, 2H, J=6.1 Hz), 3.18 (s, 3H), 2.95-2.80 (m, 2H), 2.15-2.00 (m, 1H), 1.95-1.85 (m, 2H), 1.40-1.20 (m, 8H); LRMS (ESI), m/z 451 (M+H).

Workup

  1. temperatureThe mixture was then cooled to 0° C. in an ice bath
  2. temperatureto warm to ambient temperature
  3. stirringstirred overnight
  4. washwashed with water and brine
  5. dry with materialdried over Na2SO4
  6. filtrationfiltered
  7. concentrationthe filtrate was concentrated
  8. customto give the crude product as a light brown solid
  9. customThe crude product was purified by chromatography on a silica gel column
  10. washeluted with 25% EtOAc/CH2Cl2

Sources & evidence

ORD record
ord-88e10afa34704dce81b40239ee9a423d
Source dataset
uspto-grants-2012_01
Patent number
US08101634B2

Reaction notes

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