2-(Tert-butyldimethylsilyloxymethyl)-4-bromothiazole → 1-[2-(tert-butyldimethylsilanyloxymethyl)thiazol-4-yl]-2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]ethanol

HRID 244481Notes

Reaction equation

HRID 244481 reaction equation
Br[C:2]1[N:3]=[C:4]([CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[S:5][CH:6]=1.[Li]CCCC.[F:21][C:22]([F:42])([F:41])[C:23]([C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)[N:29]=[CH:28]2)=[O:24]>CCOCC>[Si:9]([O:8][CH2:7][C:4]1[S:5][CH:6]=[C:2]([C:23]([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[N:30]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[N:29]=[CH:28]3)([OH:24])[C:22]([F:41])([F:21])[F:42])[N:3]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]

Participants

5

Reactant 3

HCID 167365792-(Tert-butyldimethylsilyloxymethyl)-4-bromothiazoleHCID 579432692,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]ethanoneHCID 178418339Butyllithium

Product 1

HCID 594372131-[2-(tert-butyldimethylsilanyloxymethyl)thiazol-4-yl]-2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]ethanolYield 67%

Reagents, catalysts & solvents 1

HCID 3283Diethyl EtherSolvent2×

Procedure

To a chilled (−78° C.) solution of 4-bromo-2-(tert-butyldimethylsilanyloxymethyl)thiazole (339 mg, 1.10 mmol) (prepared according to a procedure described by Nicolaou et al., Bioorg. Med. Chem. 1999, 7, 665-697) in dry ether (5 mL) was added n-BuLi (440 μL, 2.5 M in hexane, 1.10 mmol). After 2 minutes, a chilled (−78° C.) solution of 2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]ethanone (308 mg, 1.00 mmol) in 5 mL of dry ether added. After 15 minutes, the mixture was warmed to room temperature and quenched with 20 mL of saturated aqueous ammonium chloride and extracted with three 20 mL portions of diethyl ether. The combined organic layers were washed with 20 mL of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on SiO2 (0-30% ethyl acetate in hexanes, gradient) to afford 358 mg (67%) of 1-[2-(tert-butyldimethylsilanyloxymethyl)thiazol-4-yl]-2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]ethanol. MS m/z 538.97 (MH+).

Workup

  1. customprepared
  2. additionadded
  3. waitAfter 15 minutes
  4. customquenched with 20 mL of saturated aqueous ammonium chloride
  5. extractionextracted with three 20 mL portions of diethyl ether
  6. washThe combined organic layers were washed with 20 mL of brine
  7. dry with materialdried over magnesium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customThe residue was chromatographed on SiO2 (0-30% ethyl acetate in hexanes, gradient)

Sources & evidence

ORD record
ord-80341a175b7241b697327e7f1f167228
Source dataset
uspto-grants-2014_02
Patent number
US08658637B2

Reaction notes

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