Potassium Carbonate → 3-(Benzyloxy)-4-bromo-5-((2-(trimethylsilyl)ethoxy)methoxy)benzoic acid

HRID 1027243Notes

Reaction equation

HRID 1027243 reaction equation
[CH3:1][Si:2]([CH3:9])([CH3:8])[CH2:3][CH2:4][O:5][CH2:6]Cl.[CH2:10]([O:17][C:18]1[CH:19]=[C:20]([CH:25]=[C:26]([OH:29])[C:27]=1[Br:28])[C:21]([O:23]C)=[O:22])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>CN(C=O)C.O1CCCC1.CO>[CH2:10]([O:17][C:18]1[CH:19]=[C:20]([CH:25]=[C:26]([O:29][CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:9])([CH3:8])[CH3:1])[C:27]=1[Br:28])[C:21]([OH:23])=[O:22])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1

Participants

7

Reactant 4

HCID 11430Potassium CarbonateHCID 14798Sodium HydroxideHCID 27242712-Chloromethyl 2-(trimethylsilyl)ethyl ether2×HCID 86710603Methyl 3-(benzyloxy)-4-bromo-5-hydroxybenzoate

Product 1

HCID 867106503-(Benzyloxy)-4-bromo-5-((2-(trimethylsilyl)ethoxy)methoxy)benzoic acidYield 88.2%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 21899815MeOH tetrahydrofuranSolvent

Procedure

(2-(Trimethylsilyl)ethoxymethyl chloride (SEM-Cl, 3.10 mL, 17.5 mmol) was added to a mixture of methyl 3-(benzyloxy)-4-bromo-5-hydroxybenzoate (Example 22-1 Step 1, 5.36 g, 15.9 mmol) and potassium carbonate (5.49 g, 39.7 mmol) in DMF (53.0 mL), and the mixture was allowed to stir at room temperature for two days. An additional portion of SEM-Cl (3.10 mL, 17.5 mmol) was added and the mixture stirred an additional 4 hours. The reaction mixture was partitioned between saturated sodium bicarbonate and 1:1 ethyl acetate/diethyl ether. The organic phase was washed with water (5×), brine, dried over MgSO4, and concentrated to a light orange oil. The crude product was dissolved into 2:1 tetrahydrofuran/methanol (100 mL) and aqueous sodium hydroxide solution (2.0 M, 63.6 mL, 127 mmol) was added. The solution was stirred for 1 hour after which time volatiles were removed via rotary evaporation. The remaining solution was acidified to pH 3 by slow addition of concentrated hydrochloric acid, extracted with dichloromethane (1×), then with 1:1 ether/ethyl acetate (4×). The combined extracts were washed with brine, dried over MgSO4 and concentrated to a solid. The crude product was triturated with heptane and dried under vacuum to provide 3-(benzyloxy)-4-bromo-5-((2-(trimethylsilyl)ethoxy)methoxy)benzoic acid (6.36 g) as a white solid. MS (M+1)=453.4. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.28-7.59 (m, 7H) 5.36 (s, 2H) 5.18-5.28 (m, 2H) 3.75-3.90 (m, 2H) 0.92-1.03 (m, 2H) 0.00 (s, 9H).

Workup

  1. stirringthe mixture stirred an additional 4 hours
  2. customThe reaction mixture was partitioned between saturated sodium bicarbonate and 1:1 ethyl acetate/diethyl ether
  3. washThe organic phase was washed with water (5×), brine
  4. dry with materialdried over MgSO4
  5. concentrationconcentrated to a light orange oil
  6. additionwas added
  7. stirringThe solution was stirred for 1 hour after which time volatiles
  8. customwere removed via rotary evaporation
  9. additionThe remaining solution was acidified to pH 3 by slow addition of concentrated hydrochloric acid
  10. extractionextracted with dichloromethane (1×)
  11. washThe combined extracts were washed with brine
  12. dry with materialdried over MgSO4
  13. concentrationconcentrated to a solid
  14. customThe crude product was triturated with heptane
  15. customdried under vacuum

Sources & evidence

ORD record
ord-2ae3b9dc3c1240a0b9caaa7d91cd1d47
Source dataset
uspto-grants-2014_05
Patent number
US08729263B2

Reaction notes

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