(+)-Methoxyphenylacetic acid → (2S)-methoxyphenyl acetic acid (1S)-2-(t-butoxycarbonyl-methylamino)-1-(4-fluorophenyl)ethyl ester

HRID 1351266Notes

Reaction equation

HRID 1351266 reaction equation
[C:1]([O:5][C:6](=[O:19])[N:7]([CH2:9][CH:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[OH:11])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:20][O:21][C@@H:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23](O)=[O:24].CCCCCC.C(OCC)(=O)C>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)C>[C:1]([O:5][C:6]([N:7]([CH3:8])[CH2:9][C@@H:10]([O:11][C:23](=[O:24])[C@@H:22]([O:21][CH3:20])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)=[O:19])([CH3:4])([CH3:2])[CH3:3]

Participants

7

Reactant 3

HCID 643325(+)-Methoxyphenylacetic acidHCID 21226206Ethyl acetate hexaneHCID 69414015tert-butyl N-[2-(4-fluorophenyl)-2-hydroxyethyl]-N-methylcarbamate

Product 1

HCID 86600988(2S)-methoxyphenyl acetic acid (1S)-2-(t-butoxycarbonyl-methylamino)-1-(4-fluorophenyl)ethyl ester

Reagents, catalysts & solvents 3

HCID 142844-(Dimethylamino)pyridineCatalystHCID 3283Diethyl EtherSolventHCID 6344DichloromethaneSolvent

Procedure

To a solution of [2-(4-fluorophenyl)-2-hydroxyethyl]methyl-carbamic acid t-butyl ester (the compound of Preparation Example 32) (8.46 g) and (S)-(+)-α-methoxyphenyl acetic acid (5.74 g) in dichloromethane (60 mL) was added 4-dimethylaminopyridine (0.19 g) and N,N-dicyclohexylcarbodiimide (7.7 g) on an ice bath. The solution was stirred for 3.5 hours while being slowly warmed to room temperature. When the reaction solution was developed with silica gel TLC (hexane/ethyl acetate=4:1), two products could be identified. After diluting with diethyl ether, the insoluble matter was removed by Celite filtration. The residue that was obtained upon removing the solvent by evaporation was purified by silica gel column chromatography (hexane/ethyl acetate), the (S, S) isomer (the compound that demonstrates a high Rf value in TLC) (3.60g) was obtained from the low polarity elution portion. The NMR suggested that it was a mixture of rotamers. The three-dimensional structure was determined from the NMR data by applying the Mosher method.

Workup

  1. customthe insoluble matter was removed by Celite filtration
  2. customThe residue that was obtained
  3. customupon removing the solvent
  4. customby evaporation
  5. customwas purified by silica gel column chromatography (hexane/ethyl acetate)
  6. customwas obtained from the low polarity elution portion
  7. additiona mixture of rotamers

Sources & evidence

ORD record
ord-e9ea71faac714e19838c884e1ce9c438
Source dataset
uspto-grants-2007_05
Patent number
US07217723B2

Reaction notes

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