Benzyl chloroformate → (S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acid benzyl ester

HRID 1500436Notes

Reaction equation

HRID 1500436 reaction equation
[C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]2[NH:12][C:11](=[O:13])[CH2:10][CH2:9]2)=[CH:3][CH:2]=1.C([Li])CCC.Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>C1COCC1.CCCCCC>[CH2:29]([O:28][C:26]([N:12]1[C:11](=[O:13])[CH2:10][CH2:9][C@H:8]1[CH2:7][C:4]1[CH:3]=[CH:2][C:1]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:6][CH:5]=1)=[O:27])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1

Participants

6

Reactant 3

HCID 10387Benzyl chloroformateHCID 58160438(S)-5-[(Biphenyl-4-yl)methyl]pyrrolidin-2-oneHCID 178418339Butyllithium

Product 1

HCID 59318446(S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acid benzyl ester

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8058HexaneSolvent

Conditions

Temperature
-78 °C

Procedure

1 g (4 mmol) (S)-5-biphenyl-4-ylmethylpyrrolidin-2-one (1-a, R1=H) is dissolved in 10 ml dry THF and cooled to −78° C. After the addition of 2.76 ml butyl lithium in hexane (1.59 M), the yellow solution is stirred at −78° C. for 30 min. Subsequently, 676 l (820 mg, 4.8 mmol) benzyl chloroformate (Cbz-Cl) is added and stirring is continued at −78° C. for 2 h. The reaction is then quenched by addition of 12 ml saturated NH4Cl solution followed by 10 ml water and then extracted with 2×40 ml isopropyl acetate. The layers are separated and the organic layer is dried over MgSO4, filtered and evaporated. The resulting residue (1.73 g) is purified on column chromatography (dichloromethane:methanol=99.5:0.5) to give (S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acid benzyl ester (1-a, R1=Cbz) as off-white solid. NMR (400 MHz, DMSO-d6, /ppm): 7.66 (m, 2H); 7.60 (m, 2H); 7.51-7.34 (m, 8H); 7.26 (d, J=8.2, 2 H); 5.28 (s, 2H); 4.37 (m, 1H); 3.05 (dd, J=3.3, 13.1, 1 H); 2.88 (dd, J=9.0, 13.1, 1 H); 2.45 (m, 1H); 2.28 (m, 1H); 2.01 (m, 1H); 1.77 (m, 1H). MS (ESI, m/e) 386 [M+H]+, 788 [2M+NH4+]. IR (solution in CH2Cl2, /cm−1): 3092; 2957; 1756; 1705; 1488; 1396; 1304; 1287; 1231; 1139; 1043; 952; 750.

Workup

  1. stirringstirring
  2. waitis continued at −78° C. for 2 h
  3. customThe reaction is then quenched by addition of 12 ml saturated NH4Cl solution
  4. extractionextracted with 2×40 ml isopropyl acetate
  5. customThe layers are separated
  6. dry with materialthe organic layer is dried over MgSO4
  7. filtrationfiltered
  8. customevaporated
  9. customThe resulting residue (1.73 g) is purified on column chromatography (dichloromethane:methanol=99.5:0.5)

Sources & evidence

ORD record
ord-9499cd57635b46669c60033294ce38ac
Source dataset
uspto-grants-2015_12
Patent number
US09206116B2

Reaction notes

Loading…