Toluene → (3S,5R)-5-Biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methyl-2-oxo-pyrrolidine-3-carboxylic acid ethyl ester

HRID 1500451Notes

Reaction equation

HRID 1500451 reaction equation
[C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]2N(CN3CCCC3)[C:11](=[O:19])[CH2:10][CH2:9]2)=[CH:3][CH:2]=1.[CH3:26][Si]([N-][Si](C)(C)C)(C)C.[K+].Cl[C:37]([O:39][CH2:40][CH3:41])=[O:38].[CH3:42][O:43]S([O:47][CH3:48])(=O)=O.[Cl-].[NH4+:50].[C:51]1([CH3:57])[CH:56]=CC=C[CH:52]=1>C(OCC)(=O)C.O>[CH2:40]([O:39][C:37]([C@:10]1([CH3:26])[CH2:9][C@@H:8]([CH2:7][C:4]2[CH:3]=[CH:2][C:1]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:6][CH:5]=2)[N:50]([C:48](=[O:47])[C:51]([CH3:57])([CH3:56])[CH3:52])[C:11]1=[O:19])=[O:38])[CH3:41].[CH2:40]([O:39][C:37]([C@@:10]1([CH3:26])[CH2:9][C@@H:8]([CH2:7][C:4]2[CH:3]=[CH:2][C:1]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:6][CH:5]=2)[N:50]([C:42](=[O:43])[C:51]([CH3:52])([CH3:56])[CH3:57])[C:11]1=[O:19])=[O:38])[CH3:41]

Participants

10

Reactant 6

HCID 1140TolueneHCID 6497Dimethyl SulfateHCID 10928Ethyl chloroformateHCID 25517Ammonium ChlorideHCID 3251421Potassium bis(trimethylsilyl)amideHCID 59318460(S)-5-biphenyl-4-ylmethyl-1-pyrrolidin-1-ylmethylpyrrolidin-2-one

Product 2

HCID 66738823(3S,5R)-5-Biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methyl-2-oxo-pyrrolidine-3-carboxylic acid ethyl esterHCID 66739130(3R,5R)-5-Biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)3-methyl-2-oxo-pyrrolidine-3-carboxylic acid ethyl ester

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
-2.5 °C

Procedure

2.0 g (S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)pyrrolidin-2-one (1-a, R1=pivaloyl) in 7.5 ml toluene is added to 26.2 ml potassium bis(trimethylsilyl)amide (0.5 M in toluene) at −10° C. After 1 h, 568 μl ethyl chloroformate is added and the mixture is stirred for 1.5 h at −5 to 0° C. 733 μl Dimethylsulfate are then added and the mixture is stirred at room temperature for 1.5 h. 8 ml saturated ammonium chloride solution are then added, along with 10 ml water and 20 ml ethyl acetate. The aqueous phase is extracted with ethyl acetate and the combined organic phases are then washed with brine, dried (MgSO4) and concentrated in vacuo. According to HNMR analysis the ratio of diastereoisomers is 62:38. The residue is purified by column chromatography, eluting with ethyl acetate/heptane (1:12) to afford (3R,5R)-5-Biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methyl-2-oxo-pyrrolidine-3-carboxylic acid ethyl ester (R1=Piv; R10=OEt; R11=Me) and (3S,5R)-5-Biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methyl-2-oxo-pyrrolidine-3-carboxylic acid ethyl ester (R1=Piv; R10=OEt; R11=Me). Fractions containing both diastereoisomers are combined. According to HNMR analysis the ratio of diastereoisomers is 62:38. 1H NMR (CDCl3) Major diastereomer: 1.11 (3H), 1.17 (9H), 1.23 (3H), 1.62 (1H), 2.26 (2H), 2.95 (1H), 4.07 (2H), 4.30 (1H), 7.03-7.37 (9H). 1H NMR (CDCl3) Minor diastereomer: 0.99 (3H), 1.16 (9H), 1.25 (3H), 1.51 (1H), 2.20 (2H), 3.13 (1H), 3.91 (2H), 4.34 (1H), 7.03-7.37 (9H). Data for mixture of diastereoisomers.

Workup

  1. stirringthe mixture is stirred at room temperature for 1.5 h
  2. extractionThe aqueous phase is extracted with ethyl acetate
  3. washthe combined organic phases are then washed with brine
  4. dry with materialdried (MgSO4)
  5. concentrationconcentrated in vacuo
  6. customThe residue is purified by column chromatography
  7. washeluting with ethyl acetate/heptane (1:12)

Sources & evidence

ORD record
ord-2df61f84eede4b06b4817214d800b092
Source dataset
uspto-grants-2015_12
Patent number
US09206116B2

Reaction notes

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