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1H-Pyrazole, 4-bromo-1-methyl- → (2S,4R)-1-{1-benzyl-4-(t-butyl-dimethylsilyloxy) pyrrolidin-2-yl}-1-(1-methyl-4-pyrazolyl)methanol

HRID 975669
Notes
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Reaction equation

HRID 975669 reaction equation
Br[C:2]1[CH:3]=[N:4][N:5]([CH3:7])[CH:6]=1.C([Li])CCC.[CH2:13]([N:20]1[CH2:24][C@H:23]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH2:22][C@H:21]1[CH:33]=[O:34])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OCC)C.CCCCCC>[CH2:13]([N:20]1[CH2:24][C@H:23]([O:25][Si:26]([C:29]([CH3:30])([CH3:31])[CH3:32])([CH3:28])[CH3:27])[CH2:22][C@H:21]1[CH:33]([C:2]1[CH:3]=[N:4][N:5]([CH3:7])[CH:6]=1)[OH:34])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 3

HCID 1674331H-Pyrazole, 4-bromo-1-methyl-HCID 50922891(2S,4R)-1-benzyl-2-formyl-4-(t-butyldimethylsilyloxy)pyrrolidineHCID 178418339Butyllithium

Product 1

HCID 54269984(2S,4R)-1-{1-benzyl-4-(t-butyl-dimethylsilyloxy) pyrrolidin-2-yl}-1-(1-methyl-4-pyrazolyl)methanolYield 64.6%

Reagents, catalysts & solvents 2

HCID 3283
Diethyl Ether
Solvent
2×
HCID 8058HexaneSolvent

Procedure

To a solution of 4-bromo-1-methylpyrazole (170.7 g) in diethyl ether (2 l) was added dropwise n-butyllithium (1.6N) in hexane (713 ml) keeping the temperature below -60° C. After stirring for 45 minutes, a solution of (2S,4R)-1-benzyl-4-(t-butyldimethylsilyloxy)-2-formylpyrrolidine (260 g) in diethyl ether (200 ml) was added dropwise. After stirring for 30 minutes, the mixture was warmed to 0°~5° C. over 2.5 hours and stirred for 45 minutes. The reaction mixture was quenched with ice water (1 l) and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (×2), and the combined organic layer was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was column chromatographed on silica gel (3.5 kg, eluting with n-hexane:AcOEt=3:2 to 1:1 to 0:1) to give (2S,4R)-1-{1-benzyl-4-(t-butyldimethyl-silyloxy) pyrrolidin-2-yl}-1-(1-methyl-4-pyrazolyl)methanol (211.2 g) as a 1:1 mixture of diastereomers.

Workup

  1. customthe temperature below -60° C
  2. stirringAfter stirring for 30 minutes
  3. temperaturethe mixture was warmed to 0°~5° C. over 2.5 hours
  4. stirringstirred for 45 minutes
  5. customThe reaction mixture was quenched with ice water (1 l)
  6. customthe organic layer was separated
  7. extractionThe aqueous layer was extracted with ethyl acetate (×2)
  8. washthe combined organic layer was washed with water and brine
  9. dry with materialdried over magnesium sulfate
  10. customevaporated under reduced pressure
  11. customchromatographed on silica gel (3.5 kg, eluting with n-hexane:AcOEt=3:2 to 1:1 to 0:1)

Sources & evidence

ORD record
ord-92a1aec3939f4bb79abb059b39c9aa19
Source dataset
uspto-grants-1997_03
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US05608056

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes