1,2-Dichloroethane → (R)-2-ethoxy-N-(2-hydroxy-(R)-1-phenylethyl)-3-[4-(2-{4-methanesulfonyloxyphenyl}-ethoxy)phenyl]propanoic amide

HRID 432071Notes

Reaction equation

HRID 432071 reaction equation
[CH2:1]([O:3][CH:4]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][CH:19]=2)=[CH:11][CH:10]=1)[C:5]([OH:7])=O)[CH3:2].C(Cl)CCl.C(N(C(C)C)CC)(C)C.[CH:42]1[CH:47]=[CH:46][C:45]([CH:48]([NH2:51])[CH2:49][OH:50])=[CH:44][CH:43]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl.C(OCC)(=O)C>[CH2:1]([O:3][C@H:4]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][S:25]([CH3:28])(=[O:26])=[O:27])=[CH:22][CH:23]=2)=[CH:13][CH:14]=1)[C:5]([NH:51][C@H:48]([C:45]1[CH:46]=[CH:47][CH:42]=[CH:43][CH:44]=1)[CH2:49][OH:50])=[O:7])[CH3:2]

Participants

8

Reactant 5

HCID 111,2-DichloroethaneHCID 311Citric AcidHCID 81531DiisopropylethylamineHCID 924662-Amino-2-phenylethanolHCID 113387772-Ethoxy-3-[4-(2-{4-[(methanesulfonyl)oxy]phenyl}ethoxy)phenyl]propanoic acid

Product 1

HCID 20670105(R)-2-ethoxy-N-(2-hydroxy-(R)-1-phenylethyl)-3-[4-(2-{4-methanesulfonyloxyphenyl}-ethoxy)phenyl]propanoic amideYield 32.7%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

A solution of 2-ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl} ethoxy)phenyl]propanoic acid (10.5 g; 25.7 mmole) in dry dichloromethane (150 ml) was cooled on an ice-bath and EDC (5.42 g; 28.3 mmole), diisopropylethylamine (4.8 ml; 28.3 mmole) and HOBtxH2O (3.82 g; 28.3 mmole) were added. After 20 minutes the ice-bath was removed and (R)-phenylglycinol (3.88 g; 28.3 mmole) was added. After stirring at room temperature over night dichloromethane (100 ml), citric acid (60 ml, 10%) and ethyl acetate were added and the phases were separated. The organic phase was washed with citric acid (60 ml), sodium bicarbonate (2×60 ml) and brine (60 ml), dried (sodium sulfate), filtered and the solvent evaporated in vacuo. The crude product was crystallized twice in ethyl acetate/heptan to give 4.43 g of (R)-2-ethoxy-N-(2-hydroxy-(R)-1-phenylethyl)-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoic amide. The mother liquids were combined, the solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel using ethyl acetate:heptan (gradient 25 to 100% ethyl acetate) to give 5.14 g (yield 38%) of (S)-2-ethoxy-N-(2-hydroxy-(R)-1-phenylethyl)-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)-phenyl]propanoic amide and 0.51 g (totally 4.94 g, yield 36%) of (R)-2-ethoxy-N-(2-hydroxy-(R)-1-phenylethyl)-3-[4-(2-{4-methanesulfonyloxyphenyl}-ethoxy)phenyl]propanoic amide.

Workup

  1. customAfter 20 minutes the ice-bath was removed
  2. additionwere added
  3. customthe phases were separated
  4. washThe organic phase was washed with citric acid (60 ml), sodium bicarbonate (2×60 ml) and brine (60 ml)
  5. dry with materialdried (sodium sulfate)
  6. filtrationfiltered
  7. customthe solvent evaporated in vacuo
  8. customThe crude product was crystallized twice in ethyl acetate/heptan

Sources & evidence

ORD record
ord-9f9b71ff9a1e431dae135f1e5a8ff44b
Source dataset
uspto-grants-2003_12
Patent number
US06660879B2

Reaction notes

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