Sodium hydride → (4R)-tert-butyl 4-((tert-butyldimethylsilyl)oxy)-2-(3-cyano-5-fluorophenyl)pyrrolidine-1-carboxylate

HRID 513012Notes

Reaction equation

HRID 513012 reaction equation
CS(O[CH:6]([C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([C:33]#[N:34])[CH:27]=1)[CH2:7][C@@H:8]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])(=O)=O.[H-].[Na+]>CN(C=O)C>[Si:19]([O:18][C@H:8]1[CH2:9][N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]([C:26]2[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([C:33]#[N:34])[CH:27]=2)[CH2:7]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]

Participants

4

Reactant 2

HCID 24758Sodium hydrideHCID 86704999(3R)-4-((tert-butoxycarbonyl)amino)-3-((tert-butyldimethylsilyl)oxy)-1-(3-cyano-5-fluorophenyl)butyl methanesulfonate

Product 1

HCID 66688415(4R)-tert-butyl 4-((tert-butyldimethylsilyl)oxy)-2-(3-cyano-5-fluorophenyl)pyrrolidine-1-carboxylate

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of (3R)-4-((tert-butoxycarbonyl)amino)-3-((tert-butyldimethylsilyl)oxy)-1-(3-cyano-5-fluorophenyl)butyl methanesulfonate (I-11) (5.3 g, 10.3 mmol) in DMF (30 mL) at 0° C. was added NaH (0.43 mg of a 60% mineral oil dispersion, 10.8 mmol). The reaction was stirred at room temperature for 12 hours. The reaction was quenched with water and extracted with EtOAc, washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography on silica gel with EtOAc/hexanes gradient as eluant to yield (4R)-tert-butyl 4-((tert-butyldimethylsilyl)oxy)-2-(3-cyano-5-fluorophenyl)pyrrolidine-1-carboxylate (I-12). 1H NMR (400 MHz, CDCl3) δ 7.38 (s, 1 H), 7.33-7.20 (m, 1 H), 7.20-7.12 (m, 1 H), 4.90 (dd, J=7.6, 56.2 Hz, 1 H), 4.45-4.39 (m, 1 H), 3.78-3.65 (m, 1 H), 3.52 (dd, J=11.2, 36.8 Hz, 1 H), 2.56-2.41 (m, 1 H), 1.89 (t, J=13.2 Hz, 1 H), 1.47 (s, 4 H), 1.23 (s, 5 H), 0.75 (d, J=7.6 Hz, 9 H), 0.03 (s, 3 H), −0.08 (d, J=10.8 Hz, 3 H). MS m/z 443.2 (M+23)+.

Workup

  1. customThe reaction was quenched with water
  2. extractionextracted with EtOAc
  3. washwashed with brine
  4. dry with materialdried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe crude product was purified by column chromatography on silica gel with EtOAc/hexanes gradient as eluant

Sources & evidence

ORD record
ord-e56816d1fa9745fbb069c0d0304f3aef
Source dataset
uspto-grants-2015_08
Patent number
US09102671B2

Reaction notes

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