Sodium hydride → (RS)-4-{5-[3-(2-carboxyethyl)benzyloxy]-2-cyano-phenoxy}-4-(2-methylphenyl)butanoic acid

HRID 322896Notes

Reaction equation

HRID 322896 reaction equation
[OH:1][CH: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+].[C:18]([C:20]1[CH:42]=[CH:41][C:23]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2CCC(OC(C)(C)C)=O)=[CH:22][C:21]=1F)#[N:19]>O1CCCC1>[C:5]([CH2:4][CH2:3][C:30]1[CH:31]=[C:26]([CH:27]=[CH:28][CH:29]=1)[CH2:25][O:24][C:23]1[CH:41]=[CH:42][C:20]([C:18]#[N:19])=[C:21]([CH:22]=1)[O:1][CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])([OH:7])=[O:6]

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 22010289tert-Butyl 3-[(4-cyano-3-fluoro-phenoxymethyl)phenyl]propionateHCID 23665160Sodium 4-hydroxy-4-(2-methylphenyl)butanoate

Product 1

HCID 22010436(RS)-4-{5-[3-(2-carboxyethyl)benzyloxy]-2-cyano-phenoxy}-4-(2-methylphenyl)butanoic acidYield 60.9%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
60 °C

Procedure

A solution of dry sodium (RS)-4-hydroxy-4-(2-methylphenyl)butanoate (0.18 g) in dry tetrahydrofuran (50 mL) is treated with sodium hydride and stirred at 60° C. for 15 minutes. tert-Butyl 3-[(4-cyano-3-fluoro-phenoxymethyl)phenyl]propionate (0.2 g) is added and the mixture heated at reflux for 4 hours. After standing at room temperature for 18 hours the reaction mixture is filtered. Ethyl acetate (50 mL) and 1 N hydrochloric acid (50 mL) are added to the filtrate and the organic phase is separated. The organic phase is washed with water (10 mL), dried over magnesium sulphate, evaporated and the residue purified by flash chromatography on silica eluting with a mixture of dichloromethane and methanol (95:5 v/v). Fractions homogeneous in the required product are combined and evaporated. The residue is dissolved in ether and the solution washed with 1% sodium bicarbonate solution, 0.5 N hydrochloric acid, water, dried over magnesium sulphate and evaporated. The resulting colourless gum is crystallised from a mixture of cyclohexane and ethyl acetate to give (RS)-4-{5-[3-(2-carboxyethyl)benzyloxy]-2-cyano-phenoxy}-4-(2-methylphenyl)butanoic acid (0.12 g) m.p. 136-137° C. [Elemental analysis:- C,71.4; H,6.23; N,2.91%. Calculated:- C,71.0; H,5.75; N,2.96%].

Workup

  1. temperaturethe mixture heated
  2. temperatureat reflux for 4 hours
  3. waitAfter standing at room temperature for 18 hours
  4. filtrationthe reaction mixture is filtered
  5. additionEthyl acetate (50 mL) and 1 N hydrochloric acid (50 mL) are added to the filtrate
  6. customthe organic phase is separated
  7. washThe organic phase is washed with water (10 mL)
  8. dry with materialdried over magnesium sulphate
  9. customevaporated
  10. customthe residue purified by flash chromatography on silica eluting with a mixture of dichloromethane and methanol (95:5 v/v)
  11. customevaporated
  12. dissolutionThe residue is dissolved in ether
  13. washthe solution washed with 1% sodium bicarbonate solution, 0.5 N hydrochloric acid, water
  14. dry with materialdried over magnesium sulphate
  15. customevaporated
  16. customThe resulting colourless gum is crystallised from a mixture of cyclohexane and ethyl acetate

Sources & evidence

ORD record
ord-bbe82cc5aeba432ba1f307d6ec6b50c1
Source dataset
uspto-grants-2001_04
Patent number
US06211234B1

Reaction notes

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