Ethyl oxoacetate → (RS)-[4-(tert-butyl-diphenyl-silanyloxy)-2,6-difluoro-phenyl]-hydroxy-acetic acid ethyl ester

HRID 1247363Notes

Reaction equation

HRID 1247363 reaction equation
[C:1]([Si:5]([O:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[CH2:32]([O:34][C:35](=[O:38])[CH:36]=[O:37])[CH3:33]>C1COCC1>[CH2:32]([O:34][C:35](=[O:38])[CH:36]([C:22]1[C:23]([F:25])=[CH:24][C:19]([O:18][Si:5]([C:1]([CH3:4])([CH3:2])[CH3:3])([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:20][C:21]=1[F:26])[OH:37])[CH3:33]

Participants

5

Reactant 3

HCID 70211Ethyl oxoacetateHCID 21905446Tert-butyl-(3,5-difluoro-phenoxy)-diphenyl-silaneHCID 178418339Butyllithium

Product 1

HCID 69291129(RS)-[4-(tert-butyl-diphenyl-silanyloxy)-2,6-difluoro-phenyl]-hydroxy-acetic acid ethyl esterYield 109.2%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

A well stirred solution under N2 of tert-butyl-(3,5-difluoro-phenoxy)-diphenyl-silane (20.0 g) and N,N,N′,N′-pentamethyldiethylenetriamine (9.9 g) in dry THF (600 ml) was cooled to −75° C. A 1.6 M sol. of BuLi in Hex (35.6 ml) was added via syringe. The reaction mixture was stirred 1 h under cooling (−78° C.). A white precipitate was formed. Glyoxalic acid ethyl ester (50% in Tol, 22.2 g) was added and it was stirred 2 h at −78° C. The cooling bath was removed and the clear solution was left to warm to −10° C. (1 h). After dilution with TBME (500 ml) the mixture was washed with 1 N HCl (2×500 ml) and brine (250 ml), dried over MgSO4 and the solvent was evaporated. The crude product was purified by CC (Hept, then Hept/CH2Cl2 1:4). 27.9 g (60%) of (RS)-[4-(tert-butyl-diphenyl-silanyloxy)-2,6-difluoro-phenyl]-hydroxy-acetic acid ethyl ester were obtained next to 7.3 g (36%) of recovered starting material. Colorless viscous oil. MS 488.4 ([M+NH4]+).

Workup

  1. customA white precipitate was formed
  2. stirringit was stirred 2 h at −78° C
  3. customThe cooling bath was removed
  4. waitthe clear solution was left
  5. temperatureto warm to −10° C. (1 h)
  6. washAfter dilution with TBME (500 ml) the mixture was washed with 1 N HCl (2×500 ml) and brine (250 ml)
  7. dry with materialdried over MgSO4
  8. customthe solvent was evaporated
  9. customThe crude product was purified by CC (Hept

Sources & evidence

ORD record
ord-1b28b29651f9427a8f02ac8054ba4970
Source dataset
uspto-grants-2006_10
Patent number
US07129238B2

Reaction notes

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