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1H-Pyrazole, 1-methyl- → 1-{(2S,4R)-1-benzyl-4-(t-butyldimethylsilyloxy)-pyrrolidin-2-yl}-1-(1-methylpyrazol-5-yl)methanol

HRID 975678
Notes
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Reaction equation

HRID 975678 reaction equation
[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[N:3]1.C([Li])CCC.[CH2:12]([N:19]1[CH2:23][C@H:22]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:21][C@H:20]1[CH:32]=[O:33])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCCC1.CCCCCC>[CH2:12]([N:19]1[CH2:23][C@H:22]([O:24][Si:25]([C:28]([CH3:29])([CH3:30])[CH3:31])([CH3:27])[CH3:26])[CH2:21][C@H:20]1[CH:32]([C:6]1[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=1)[OH:33])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 3

HCID 702551H-Pyrazole, 1-methyl-HCID 50922891(2S,4R)-1-benzyl-2-formyl-4-(t-butyldimethylsilyloxy)pyrrolidineHCID 178418339Butyllithium

Product 1

HCID 571086521-{(2S,4R)-1-benzyl-4-(t-butyldimethylsilyloxy)-pyrrolidin-2-yl}-1-(1-methylpyrazol-5-yl)methanolYield 87.9%

Reagents, catalysts & solvents 2

HCID 8028
Tetrahydrofuran
Solvent
2×
HCID 8058HexaneSolvent

Procedure

To a solution of 1-methylpyrazole (30.5 g) in tetrahydrofuran (460 ml) was added dropwise n-butyllithium (1.6N) in hexane (250 ml) keeping the temperature below -60° C. The mixture was warmed to 0°-5° C. over 30 minutes, and stirred for 30 minutes, then cooled to -70°~60° C. To the mixture was added a solution of (2S,4R)-1-benzyl-4-(t-butyldimethylsilyloxy)-2-formylpyrrolidine (91.4 g) in tetrahydrofuran (90 ml) keeping the temperature below -60° C. The reaction mixture was warmed to 0°-5° C. over 40 minutes, and stirred for 2 hours. The mixture was quenched with ice water (300 ml) 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 kg, eluting with ethyl acetate-n-hexane (1:1 to 5:1)) to give 1-{(2S,4R)-1-benzyl-4-(t-butyldimethylsilyloxy)-pyrrolidin-2-yl }-1-(1-methylpyrazol-5-yl)methanol (101 g) (as a 2:1 mixture of diastereomer).

Workup

  1. customthe temperature below -60° C
  2. temperatureThe mixture was warmed to 0°-5° C. over 30 minutes
  3. temperaturecooled to -70°~60° C
  4. customthe temperature below -60° C
  5. temperatureThe reaction mixture was warmed to 0°-5° C. over 40 minutes
  6. stirringstirred for 2 hours
  7. customThe mixture was quenched with ice water (300 ml)
  8. customthe organic layer was separated
  9. extractionThe aqueous layer was extracted with ethyl acetate (×2)
  10. washthe combined organic layer was washed with water and brine
  11. dry with materialdried over magnesium sulfate
  12. customevaporated under reduced pressure
  13. customchromatographed on silica gel (3 kg, eluting with ethyl acetate-n-hexane (1:1 to 5:1))

Sources & evidence

ORD record
ord-2df193deb26e471ca40ad50a891ee152
Source dataset
uspto-grants-1997_03
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US05608056

Reaction notes

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