Dimethyl Sulfate → (3R,5S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methylpyrrolidin-2-one

HRID 882512Notes

Reaction equation

HRID 882512 reaction equation
[CH2:1]([Li])CCC.C(NC(C)C)(C)C.[C:13]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:18]=[CH:17][C:16]([CH2:19][C@H:20]2[N:24]([C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[C:23](=[O:31])[CH2:22][CH2:21]2)=[CH:15][CH:14]=1.COS(OC)(=O)=O>O1CCCC1.[Cl-].[NH4+]>[C:13]1([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:14]=[CH:15][C:16]([CH2:19][C@H:20]2[N:24]([C:25](=[O:30])[C:26]([CH3:28])([CH3:29])[CH3:27])[C:23](=[O:31])[C@H:22]([CH3:1])[CH2:21]2)=[CH:17][CH:18]=1

Participants

7

Reactant 4

HCID 6497Dimethyl SulfateHCID 7912DiisopropylamineHCID 58160363(S)-5-[(biphenyl-4-yl)methyl]-1-(2,2-dimethylpropionyl)pyrrolidin-2-oneHCID 178418339Butyllithium

Product 1

HCID 66738857(3R,5S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methylpyrrolidin-2-one

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 25517Ammonium ChlorideSolvent

Procedure

0.37 ml of n-butyllithium (1.6 M) was added to a solution of 88 μl diisopropylamine in 1 ml tetrahydrofuran at about 0° C. After about 15 min, 200 mg (S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)pyrrolidin-2-one (1-a, R1=pivaloyl) of example 4 dissolved in 2 ml tetrahydrofuran were added. After about 15 min, 59 μl dimethylsulphate were added. After about 2 hours at about 0° C., the mixture was diluted with ammonium chloride solution, extracted with ethyl acetate and concentrated to dryness (196 mg). According to HNMR analysis, the ratio of diastereoisomers is 83:17 [(3R,5S):(3S,5S)]. The material was purified by chromatography to afford 43 mg (3R,5S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methylpyrrolidin-2-one=1H-NMR (DMSO): (2-a, R1=pivaloyl) 1.07 (3H, d, 1-CH3); 1.29 (9H, s, C(CH3)3); 1.63 (1H, m, 4-CHH); 2.03 (1H, m, 4-CHH); 2.81 (2H, m, 3-CH, 1-CHH); 2.94 (1H, dd, 1-CHH); 4.45 (1H, m, 5-CH); 7.34 (3H, m, aromatic); 7.44 (2H, m, aromatic); 7.61 (4H, m, aromatic). m/z: 350 (MH+, 100%). Spectroscopic data for (2-b, R1=pivaloyl) as Example 5-2.

Workup

  1. additionwere added
  2. waitAfter about 15 min
  3. waitAfter about 2 hours at about 0° C.
  4. extractionextracted with ethyl acetate
  5. concentrationconcentrated to dryness (196 mg)
  6. customThe material was purified by chromatography

Sources & evidence

ORD record
ord-1d92100cda8343b499e9ac73b083cfd1
Source dataset
uspto-grants-2015_03
Patent number
US08993785B2

Reaction notes

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