Potassium Carbonate → 6-(4-{[3-(2,6-Dichlorophenyl)-5-isopropylisoxazol-4-yl]methoxy}phenyl)-2-naphthoic acid

HRID 646025Notes

Reaction equation

HRID 646025 reaction equation
[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([C:18]([O:20]C)=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:29][C:30]1[C:31]([C:38]2[C:43]([Cl:44])=[CH:42][CH:41]=[CH:40][C:39]=2[Cl:45])=[N:32][O:33][C:34]=1[CH:35]([CH3:37])[CH3:36].[OH-].[Na+]>CN(C=O)C.CCOC(C)=O.O.C1COCC1.CCO>[Cl:44][C:43]1[CH:42]=[CH:41][CH:40]=[C:39]([Cl:45])[C:38]=1[C:31]1[C:30]([CH2:29][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:17]=[C:16]4[C:15](=[CH:10][CH:9]=3)[CH:14]=[C:13]([C:18]([OH:20])=[O:19])[CH:12]=[CH:11]4)=[CH:4][CH:3]=2)=[C:34]([CH:35]([CH3:37])[CH3:36])[O:33][N:32]=1

Participants

10

Reactant 4

HCID 11430Potassium Carbonate2×HCID 14798Sodium HydroxideHCID 19834505Methyl 6-(4-hydroxyphenyl)-2-naphthoateHCID 592648754-(Chloromethyl)-3-(2,6-dichlorophenyl)-5-isopropylisoxazole2×

Product 1

HCID 247391706-(4-{[3-(2,6-Dichlorophenyl)-5-isopropylisoxazol-4-yl]methoxy}phenyl)-2-naphthoic acidYield 94%

Reagents, catalysts & solvents 5

HCID 702EthanolSolventHCID 962WaterSolventHCID 6228DimethylformamideSolvent2×HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

To solution of methyl 6-(4-hydroxyphenyl)-2-naphthoate (55 mg, 0.20 mmol) in DMF (1.0 mL) was added K2CO3 (68 mg, 0.49 mmol) and 4-(chloromethyl)-3-(2,6-dichlorophenyl)-5-isopropylisoxazole (91 mg, 0.30 mmol) and the mixture was stirred at ambient temperature for 12 hr. Additional 4-(chloromethyl)-3-(2,6-dichlorophenyl)-5-isopropylisoxazole (50 mg, 0.16 mmol) and K2CO3 (68 mg, 0.49 mmol) in DMF (0.5 mL) was added and the mixture stirred at 70° C. for 3 hr. The solution was diluted with 50 mL EtOAc then washed with three 25 mL portions of H2O followed by 25 mL of brine then dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography (12 g of silica gel eluting with 0-40% EtOAc in hexanes over 45 minutes.) Product fractions were pooled and concentrated. To this residue was added EtOH (2.5 mL), THF (1.0 mL), H2O (0.5 mL) and NaOH (35 mg, 0.84 mmol) and the solution was stirred at 60° C. for 12 hr. The solution was concentrated to ˜⅓ volume then added dropwise to 1.0 N HCl (6 mL, aq.) The resulting solids were collected by suction filtration, washed with H2O and dried to give the title compound as an off-white solid (42 mg, 94%.) 1H NMR (DMSO-d6): δ 13.0 (broad s, 1H), 8.57 (s, 1H), 8.18 (s, 1H), 8.12 (d, J=9 Hz, 1H), 8.01 (d, J=9 Hz, 1H), 7.95 (d, J=9 Hz, 1H), 7.85 (d, J=9 Hz, 1H), 7.69 (d, J=8 Hz, 2H), 7.62 (d, J=8 Hz, 2H), 7.59-7.51 (m, 1H), 6.91 (d, J=8 Hz, 2H), 4.87 (s, 2 H), 3.45 (septet, J=7 Hz, 1H), 1.33 (d, J=7 Hz, 6H). ESI-LCMS m/z 532 (M+H)+.

Workup

  1. stirringthe mixture stirred at 70° C. for 3 hr
  2. washthen washed with three 25 mL portions of H2O
  3. dry with materialthen dried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. custompurified by silica gel chromatography (12 g of silica gel eluting with 0-40% EtOAc in hexanes over 45 minutes.) Product fractions
  7. concentrationconcentrated
  8. stirringthe solution was stirred at 60° C. for 12 hr
  9. concentrationThe solution was concentrated
  10. additionthen added dropwise to 1.0 N HCl (6 mL, aq.) The resulting solids
  11. filtrationwere collected by suction filtration
  12. washwashed with H2O
  13. customdried

Sources & evidence

ORD record
ord-1b97e3eebbb94e1c8fb1e49d6647c92b
Source dataset
uspto-grants-2010_04
Patent number
US07705028B2

Reaction notes

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