Citric Acid → 2-[3(S)-(tert-butoxycarbonyl)amino-5(S)-(p-tert-butyl-benzyl)-2(S)-hydroxy-6-methyl-heptyl]-N-butyl-acrylamide

HRID 744772Notes

Reaction equation

HRID 744772 reaction equation
[CH2:1]([NH:5][C:6](=[O:10])[C:7]([CH3:9])=[CH2:8])[CH2:2][CH2:3][CH3:4].C([Li])CCC.C(O[C@@:21]([NH2:42])([C:24](=C=O)[C@H:25]([CH:37]([CH3:39])[CH3:38])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=1)[CH:22]=[O:23])(C)(C)C.C(O)(=O)[CH2:44][C:45]([CH2:50]C(O)=O)([C:47](O)=O)[OH:46].[O:56]1CCC[CH2:57]1>CCCCCC.CC(C)[O-].CC(C)[O-].CC(C)[O-].Cl[Ti+3].C(OCC)C.O>[CH2:1]([NH:5][C:6](=[O:10])[C:7](=[CH2:9])[CH2:8][C@H:22]([OH:23])[C@@H:21]([NH:42][C:57]([O:46][C:45]([CH3:44])([CH3:47])[CH3:50])=[O:56])[CH2:24][C@@H:25]([CH:37]([CH3:39])[CH3:38])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=1)[CH2:2][CH2:3][CH3:4]

Participants

10

Reactant 5

HCID 311Citric AcidHCID 8028Tetrahydrofuran2×HCID 9855497N-ButylmethacrylamideHCID 866064382(S)tert-butoxy-carbonyl-amino-4(S)-isopropyl-5-(p-tert-butylphenyl)-pentanalHCID 178418339Butyllithium

Product 1

HCID 545017412-[3(S)-(tert-butoxycarbonyl)amino-5(S)-(p-tert-butyl-benzyl)-2(S)-hydroxy-6-methyl-heptyl]-N-butyl-acrylamide

Reagents, catalysts & solvents 4

HCID 11673339ChlorotitaniumtriisopropoxideCatalystHCID 962WaterSolventHCID 3283Diethyl EtherSolventHCID 8058HexaneSolvent2×

Conditions

Temperature
0 °C

Procedure

695 mg of methacrylic acid butylamide are dissolved in 30 ml of tetrahydrofuran and, at -75° C., 6.2 ml of 1.6M n-butyllithium in hexane are added thereto. The reaction mixture is stirred for 30 minutes at 0° C. and then, at -75° C., 9.8 ml of 1M chlorotitanium triisopropoxide in hexane are added thereto. The mixture is stirred for a further 15 minutes at -75° C. and then, at the same temperature, a solution of 924 mg of 2(S)-tert-butoxy-carbonyl-amino-4(S)-isopropyl-5-(p-tert-butyl-phenyl)-pentanal in 10 ml of tetrahydrofuran is added dropwise thereto. The reaction mixture is then stirred further for 15 minutes at -75° C. and for 70 minutes at 0° C. and then, in succession, 15 ml of 10% aqueous citric acid solution, water and diethyl ether are added thereto. The product is extracted repeatedly with diethyl ether. The diastereoisomeric mixture is separated by FC (700 g of silica gel, eluant: dichloromethane/diethyl ether=9:1). The title compound is obtained: diastereoisomer I: Rf (dichloromethane/diethyl ether=9:1)=0.21; diastereoisomer II:

Workup

  1. stirringThe mixture is stirred for a further 15 minutes at -75° C.
  2. stirringThe reaction mixture is then stirred further for 15 minutes at -75° C. and for 70 minutes at 0° C.
  3. extractionThe product is extracted repeatedly with diethyl ether
  4. customThe diastereoisomeric mixture is separated by FC (700 g of silica gel, eluant: dichloromethane/diethyl ether=9:1)

Sources & evidence

ORD record
ord-3c1b8f333ea247d38f5fb2d3b581eade
Source dataset
uspto-grants-1996_09
Patent number
US05559111

Reaction notes

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