Dichloromethane → Methyl {4-[({6-[2-fluoro-4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinyl}(oxo)acetate

HRID 423595Notes

Reaction equation

HRID 423595 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](OC(C)(C)C)=[O:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=1.[C:33]([OH:39])(C(F)(F)F)=[O:34].[CH2:40](Cl)Cl>>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:9])=[O:10])[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:27])[C:33]([O:39][CH3:40])=[O:34])[CH2:22][CH2:21]2)=[CH:14][CH:13]=1

Participants

4

Reactant 3

HCID 6344DichloromethaneHCID 6422Trifluoroacetic acidHCID 249943361,1-Dimethylethyl 4-[({6-[2-fluoro-4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate

Product 1

HCID 24993715Methyl {4-[({6-[2-fluoro-4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinyl}(oxo)acetateYield 77%

Procedure

A solution of 1,1-dimethylethyl 4-[({6-[2-fluoro-4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate (0.15 g, 0.32 mmol) in CH2Cl2 (10 mL) was treated with TFA (0.3 mL). The mixture was stirred at ambient temperature overnight. CH2Cl2 and excess of TFA were removed under reduced pressure. The residue was redissolved in CH2Cl2 (5 mL) and cooled in an ice bath. Diisopropylethylamine (1.5 mL) was added, followed by addition of methyl oxalyl chloride (34 μL, 0.36 mmol). The reaction mixture was allowed to warm up to ambient temperature and stirred overnight, quenched with aqueous NaHCO3 and extracted with EtOAc (50 mL×2). The combined organic extract was washed with brine and dried over Na2SO4, filtered, and the filtrate was concentrated to a viscous brown oil. The crude material was purified by chromatography on a silica gel column eluted with 1:5 acetone/CH2Cl2 to give 0.112 g (77%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.42 (d, 1H, J=2.9 Hz), 8.23 (t, 1H, J=7.8 Hz), 7.85-7.80 (m, 2H), 7.73 (dd, 1H, Ja=10.3 Hz, Jb=1.5 Hz), 7.27 (dd, 1H, Ja=10.8 Hz, Jb=2.9 Hz), 4.65-4.55 (m, 1H), 4.00-3.90 (m, 2H), 3.88 (s, 3H), 3.80-3.70 (m, 1H), 3.25-3.10 (m, 1H), 3.09 (s, 3H), 2.80-2.70 (m, 1H), 2.25-2.10 (m, 1H), 200-1.90 (m, 2H), 1.50-1.35 (m, 2H); LRMS (APCI), m/z 451 (M+H).

Workup

  1. customCH2Cl2 and excess of TFA were removed under reduced pressure
  2. dissolutionThe residue was redissolved in CH2Cl2 (5 mL)
  3. temperaturecooled in an ice bath
  4. additionDiisopropylethylamine (1.5 mL) was added
  5. temperatureto warm up to ambient temperature
  6. stirringstirred overnight
  7. customquenched with aqueous NaHCO3
  8. extractionextracted with EtOAc (50 mL×2)
  9. extractionThe combined organic extract
  10. washwas washed with brine
  11. dry with materialdried over Na2SO4
  12. filtrationfiltered
  13. concentrationthe filtrate was concentrated to a viscous brown oil
  14. customThe crude material was purified by chromatography on a silica gel column
  15. washeluted with 1:5 acetone/CH2Cl2

Sources & evidence

ORD record
ord-b9eb031ff8654ffcaa1b05f8e024e6f9
Source dataset
uspto-grants-2012_01
Patent number
US08101634B2

Reaction notes

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