p-Toluenesulfonic acid monohydrate → HCID 69069089, compound

HRID 1822029Notes

Reaction equation

HRID 1822029 reaction equation
C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[Cl:30])[CH:16]=2)[CH2:10][CH:9]1[CH3:32])=O)(C)(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:30][C:24]1[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:23]=1[C:22]([NH:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH:11]2[CH2:12][CH2:13][NH:8][CH:9]([CH3:32])[CH2:10]2)[CH:16]=1)=[O:31]

Participants

4

Reactant 2

HCID 521998p-Toluenesulfonic acid monohydrateHCID 69070654HCID 69070654, compound

Product 1

HCID 69069089HCID 69069089, compoundYield 55%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

Combine 4-[3-(2-chloro-4-fluoro-benzoylamino)-phenoxy]-2-methyl-piperidine-1-carboxylic acid tert-butyl ester cis isomer 1 (Preparation 78, 0.60 g, 1.31 mmol), toluene (20 mL), and p-toluenesulfonic acid monohydrate (2.5 g, 13.1 mmol), stir, and heat at 100° C. After 1 hr., cool to ambient temperature. Concentrate the reaction mixture. Partition the residue between ethyl acetate (100 mL) and 1M aqueous sodium hydroxide solution (50 mL). Separate the organic layer, wash with 1M aqueous sodium hydroxide solution (2×50 mL), wash with aqueous NaCl solution (50 mL), dry over sodium sulfate, filter and concentrate. Purify residue by silica gel flash chromatography eluting with 10% (2M ammonia/methanol) in dichloromethane to obtain the title compound (0.26 g, 55%). Mass spectrum: Obs. m/z 363.1289; Calc. m/z 363.1275; Analysis calculated for C19H21C12FN2O2.0.9H2O: C, 54.92; H, 5.53; N, 6.74. Found: C, 54.90; H, 5.36; N, 6.55. 1H NMR (CDCl3) of free base: 7.9 (bs, 1H), 7.8 (m, 1H), 7.4 (s, 1H), 7.2 (m, 3H), 7.1 (m, 2H), 6.7 (dd, 1H), 4.3 (m, 1H), 3.2 (m, 1H), 2.75 (m, 2H), 2.15 (m, 2H), 1.45 (m, 2H), 1.1 (d, 3H).

Workup

  1. temperature, cool to ambient temperature
  2. concentrationConcentrate the reaction mixture
  3. customPartition the residue between ethyl acetate (100 mL) and 1M aqueous sodium hydroxide solution (50 mL)
  4. customSeparate the organic layer
  5. washwash with 1M aqueous sodium hydroxide solution (2×50 mL)
  6. washwash with aqueous NaCl solution (50 mL)
  7. dry with materialdry over sodium sulfate
  8. filtrationfilter
  9. concentrationconcentrate
  10. washPurify residue by silica gel flash chromatography eluting with 10% (2M ammonia/methanol) in dichloromethane

Sources & evidence

ORD record
ord-93475ccb611144dabe16f897744ff78e
Source dataset
uspto-grants-2009_10
Patent number
US07608629B2

Reaction notes

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