Tetrahydrofuran → (2-Cyano-5-(isothiazol-4-ylmethoxy)phenoxy]-4-(2-methylphenyl)butanoic acid

HRID 322916Notes

Reaction equation

HRID 322916 reaction equation
O[C@@H:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14])[CH2:3][CH2:4][C:5]([O-:7])=[O:6].[Na+].[H-].[Na+].F[C:19]1[CH:26]=[C:25]([O:27][CH2:28][C:29]2[CH:30]=[N:31][S:32][CH:33]=2)[CH:24]=[CH:23][C:20]=1[C:21]#[N:22].[O:34]1CCCC1>>[C:21]([C:20]1[CH:23]=[CH:24][C:25]([O:27][CH2:28][C:29]2[CH:30]=[N:31][S:32][CH:33]=2)=[CH:26][C:19]=1[O:34][CH:4]([CH2:3][CH2:2][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14])[C:5]([OH:7])=[O:6])#[N:22]

Participants

5

Reactant 4

HCID 8028Tetrahydrofuran2×HCID 24758Sodium hydrideHCID 220102302-Fluoro-4-(isothiazol-4-ylmethoxy)benzonitrileHCID 86756593Sodium (R)-4-Hydroxy-4-(2-methylphenyl)butanoate

Product 1

HCID 23204063(2-Cyano-5-(isothiazol-4-ylmethoxy)phenoxy]-4-(2-methylphenyl)butanoic acid

Conditions

Temperature
50 °C

Procedure

Sodium (R)-4-Hydroxy-4-(2-methylphenyl)butanoate (0.39 g) is added in one portion to a stirred suspension of sodium hydride (0.11 g, 60% dispersion in mineral oil) in tetrahydrofuran (30 mL) and the mixture is stirred at 50° C. for 1 hour. A solution of 2-fluoro-4-(isothiazol-4-ylmethoxy)benzonitrile (0.21 g) in tetrahydrofuran (20 mL) is added and the reaction mixture is stirred at reflux for 16 hours. The reaction mixture is concentrated in vacuo and water is added to the residue. The solution is acidified with 1 N hydrochloric acid and extracted with ethyl acetate (50 mL). The organic phase is washed with water (50 mL), with brine (50 mL), dried over magnesium sulphate and evaporated. The residue is purified by flash chromatography on silica eluting with a mixture of dichloromethane and methanol (19:1 v/v). Fractions homogeneous in the required product are combined and evaporated to give (R)-4-[(2-cyano-5-(isothiazol-4-ylmethoxy)phenoxy]-4-(2-methylphenyl)butanoic acid, (0.02 g) in the form of a yellow oil. [NMR (CDCl3) (300 MHz): -2.2-2.4 (m, 2H), 2.45 (s, 3H), 2.6-2.65 (m), 2.75-2.8 (m,1H), 5.0 (q, 2H), 5.5 (dd,1H), 6.15 (d,1H), 6.5 (dd, 1H), 7.2 (m, 3H), 7.4 (m,1H), 7.45 (d,1H), 8.45 (d, 2H)].

Workup

  1. stirringthe reaction mixture is stirred
  2. temperatureat reflux for 16 hours
  3. concentrationThe reaction mixture is concentrated in vacuo and water
  4. additionis added to the residue
  5. extractionextracted with ethyl acetate (50 mL)
  6. washThe organic phase is washed with water (50 mL), with brine (50 mL)
  7. dry with materialdried over magnesium sulphate
  8. customevaporated
  9. customThe residue is purified by flash chromatography on silica eluting with a mixture of dichloromethane and methanol (19:1 v/v)
  10. customevaporated

Sources & evidence

ORD record
ord-3c1ec38766f64f00a5473449b4cc8d27
Source dataset
uspto-grants-2001_04
Patent number
US06211234B1

Reaction notes

Loading…