Hexachloroethane → 4-[5-[[3-Fluoro-5-(3,4,5,6-tetrahydro-4-methoxypyran-4-yl)-phenoxy]-methyl]-3-phenylisoxazol-4-yl]benzenesulfonamide

HRID 890883Notes

Reaction equation

HRID 890883 reaction equation
[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1.CN(C)CCN(C)C.C([Li])CCC.ClC(Cl)(Cl)C(Cl)(Cl)Cl.ClCC1ON=CC=1.[F:51][C:52]1[CH:53]=[C:54]([OH:66])[CH:55]=[C:56]([C:58]2([O:64][CH3:65])[CH2:63][CH2:62][O:61][CH2:60][CH2:59]2)[CH:57]=1>O1CCCC1.O1CCOCC1.[OH-].[Na+].O>[F:51][C:52]1[CH:53]=[C:54]([CH:55]=[C:56]([C:58]2([O:64][CH3:65])[CH2:59][CH2:60][O:61][CH2:62][CH2:63]2)[CH:57]=1)[O:66][CH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1

Participants

11

Reactant 6

HCID 6214HexachloroethaneHCID 8037N,N,N',N'-TetramethylethylenediamineHCID 119607ValdecoxibHCID 38580135-(Chloromethyl)isoxazole2×HCID 117362763-Fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenolHCID 178418339Butyllithium

Product 1

HCID 129861394-[5-[[3-Fluoro-5-(3,4,5,6-tetrahydro-4-methoxypyran-4-yl)-phenoxy]-methyl]-3-phenylisoxazol-4-yl]benzenesulfonamideYield 67%

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 8028TetrahydrofuranSolventHCID 14798Sodium HydroxideSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
-30 °C

Procedure

A solution of 4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide (1.0 g, 3.2 mmol) and N,N,N′,N′-tetramethylethylenediamine (1.12 g, 9.6 mmol) in tetrahydrofuran (100 mL) was cooled to −78° C. Butyllithium (6 mL, 1.6 M, 9.6 mmol) was then added to this solution. After 30 min, hexachloroethane (2.27 g, 9.6 mmol) was added to the reaction mixture, the reaction mixture was warmed to −30° C., and then quenched with dilute hydrochloric acid. The reaction mixture was extracted with ethyl acetate (100 mL), washed with brine, dried and concentrated to afford a 1:1 mixture of the desired 5-chloromethyl isoxazole product and the starting material as an inseparable mixture, which was carried to the next stage without further purification. The crude 5-chloromethyl isoxazole (0.25 g, 0.718 mmol) was added to a solution of 3-fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenol (Example 8, Step 4) (0.324 g) in dioxane (5 mL) and aqueous sodium hydroxide (1N, 2.86 mL), and the reaction mixture was stirred for 3 days at room temperature. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2×20 mL). The organic layers were combined and washed with water and brine, dried, filtered, and concentrated. The resulting residue was purified by flash column chromatography on silica gel, eluting with 1:2 ethyl acetate in hexane, to give 0.130 g (67%) of 4-[5-[[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxypyran-4-yl)-phenoxy]-methyl]-3-phenylisoxazol-4-yl]benzenesulfonamide as a crystalline solid: 1H NMR (CDCl3/300 MHz) δ 7.93 (d, 2H, J=8.5 Hz), 7.42–7.36 (m, 7H), 6.78–6.54 (m, 3H), 5.15 (s, 2H), 3.79–3.82 (m, 4H), 2.99 (s, 3H), 1.88–1.86 (m, 4H). FABMS m/z=545 (M+Li). HRMS calcd for C28H27N2FO6S 538.1652. Found 539.1652 (M+H).

Workup

  1. customquenched with dilute hydrochloric acid
  2. extractionThe reaction mixture was extracted with ethyl acetate (100 mL)
  3. washwashed with brine
  4. customdried
  5. concentrationconcentrated
  6. customto afford
  7. customthe starting material as an inseparable mixture, which was carried to the next stage without further purification
  8. extractionextracted with ethyl acetate (2×20 mL)
  9. washwashed with water and brine
  10. customdried
  11. filtrationfiltered
  12. concentrationconcentrated
  13. customThe resulting residue was purified by flash column chromatography on silica gel
  14. washeluting with 1:2 ethyl acetate in hexane

Sources & evidence

ORD record
ord-c3122b9ccd5f454790a8372ff24f4fff
Source dataset
uspto-grants-2006_02
Patent number
US06998415B2

Reaction notes

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