Citric Acid → (2S,3R)-3-([(1S)-2,2-Dimethyl-1-([(1R)-1-phenylethyl]aminocarbonyl)propyl]aminocarbonyl)-2ethoxy-6-(3-fluoro-4-phenoxyphenyl)hexanoic acid

HRID 1700983Notes

Reaction equation

HRID 1700983 reaction equation
O.[OH-].[Li+].[CH3:4][C:5]([CH3:48])([CH3:47])[C@H:6]([NH:18][C:19]([C@H:21]([CH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[C:35]([F:46])[CH:34]=1)[C@H:22]([O:27][CH2:28][CH3:29])[C:23]([O:25]C)=[O:24])=[O:20])[C:7]([NH:9][C@@H:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11])=[O:8].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[CH3:48][C:5]([CH3:4])([CH3:47])[C@H:6]([NH:18][C:19]([C@H:21]([CH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[C:35]([F:46])[CH:34]=1)[C@H:22]([O:27][CH2:28][CH3:29])[C:23]([OH:25])=[O:24])=[O:20])[C:7]([NH:9][C@@H:10]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH3:11])=[O:8]

Participants

6

Reactant 4

HCID 311Citric AcidHCID 962WaterHCID 168937Lithium hydroxide, monohydrateHCID 57064299methyl (2S,3R)-3-({[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]amino}carbonyl)-2-ethoxy-6-(3-fluoro-4-phenoxyphenyl)hexanoate

Product 1

HCID 22950018(2S,3R)-3-([(1S)-2,2-Dimethyl-1-([(1R)-1-phenylethyl]aminocarbonyl)propyl]aminocarbonyl)-2ethoxy-6-(3-fluoro-4-phenoxyphenyl)hexanoic acidYield 18.1%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

Lithium hydroxide hydrate (116 mg, 2.83 mmol) was added to a solution of methyl (2S,3R)-3-({[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]amino}carbonyl)-2-ethoxy-6-(3-fluoro-4-phenoxyphenyl)hexanoate (368 mg, 0.566 mmol) in methanol:water=10:1 (5 mL) and the mixture was stirred at room temperature for 2 h. The solution was neutralised with 5% aqueous citric acid and concentrated under reduced pressure. The residue was partitioned between ethyl acetate (100 mL) and 5% aqueous citric acid (20 mL), washed with saturated aqueous sodium chloride (20 mL), dried MgSO4), and concentrated under reduced pressure. Purification by flash chromatography (eluting with dichloromethane:methanol=20:1 to 10:1) gave the title compound (62 mg, 18%) as a colourless glass, and some mixed fractions. These were combined and repurified by flash chromatography (eluting with ethyl acetate:hexane:acetic acid=33:66:1 to 50:50:1) to give the title compound (37 mg, 11%), as a white solid.

Workup

  1. concentrationconcentrated under reduced pressure
  2. customThe residue was partitioned between ethyl acetate (100 mL) and 5% aqueous citric acid (20 mL)
  3. washwashed with saturated aqueous sodium chloride (20 mL), dried MgSO4), and
  4. concentrationconcentrated under reduced pressure
  5. customPurification
  6. washby flash chromatography (eluting with dichloromethane:methanol=20:1 to 10:1)

Sources & evidence

ORD record
ord-430eb4ab388c4d1bb00ef5df9301dfa8
Source dataset
uspto-grants-2002_02
Patent number
US06350907B1

Reaction notes

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