Triethylamine → methyl (2S,3R,5E)-3-({[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]amino}carbonyl)-2-ethoxy-6-(3-fluoro-4-phenoxyphenyl)hex-5-enoate

HRID 1700981Notes

Reaction equation

HRID 1700981 reaction equation
CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH3:23][C:24]([CH3:53])([CH3:52])[C@H:25]([NH:37][C:38]([C@H:40]([CH2:49][CH:50]=[CH2:51])[C@H:41]([O:46][CH2:47][CH3:48])[C:42]([O:44][CH3:45])=[O:43])=[O:39])[C:26]([NH:28][C@@H:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:30])=[O:27].[F:54][C:55]1[CH:56]=[C:57](Br)[CH:58]=[CH:59][C:60]=1[O:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:53][C:24]([CH3:23])([CH3:52])[C@H:25]([NH:37][C:38]([C@H:40]([CH2:49]/[CH:50]=[CH:51]/[C:57]1[CH:58]=[CH:59][C:60]([O:61][C:62]2[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=2)=[C:55]([F:54])[CH:56]=1)[C@H:41]([O:46][CH2:47][CH3:48])[C:42]([O:44][CH3:45])=[O:43])=[O:39])[C:26]([NH:28][C@@H:29]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH3:30])=[O:27]

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 80271Tri-o-tolylphosphineHCID 227363164-Bromo-2-fluoro-1-phenoxybenzeneHCID 86757820methyl (2S,3R)-3-({[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]amino}carbonyl)-2-ethoxy-hex-5-enoate

Product 1

HCID 86757821methyl (2S,3R,5E)-3-({[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]amino}carbonyl)-2-ethoxy-6-(3-fluoro-4-phenoxyphenyl)hex-5-enoateYield 69%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 6342AcetonitrileSolvent2×

Procedure

A mixture of palladium acetate (12 mg, 0.05 mmol) and tri-(2-methylphenyl)phosphine (30 mg, 0.10 mmol) in anhydrous acetonitrile (1 mL) was sonicated at room temperature for 1 min until a creamy-coloured suspension formed. This suspension was added via Pasteur pipette to a stirred solution of methyl (2S,3R)-3-({[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]amino}carbonyl)-2-ethoxy-hex-5-enoate (415 mg, 0.96 mmol), 3-fluoro-4-phenoxy-bromobenzene (Preparation 10)(400 mg, 1.50 mmol), and triethylamine (280 μL, 2.0 mmol) in anhydrous acetonitrile (1 mL) under nitrogen. The mixture was purged with nitrogen, then heated at reflux for 16 h. After being cooled, the mixture was poured into ethyl acetate (70 mL) and washed with 5% aqueous citric acid (20 mL), saturated aqueous sodium chloride (50 mL), dried (MgSO4), and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution with dichloromethane:ethyl acetate) to give mainly methyl (2S,3R,5E)-3-({[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]amino}carbonyl)-2-ethoxy-6-(3-fluoro-4-phenoxyphenyl)hex-5-enoate as a pale yellow foam (359 mg, 69%). 1H nmr suggested that two alkene isomers, the (5Z) and (4E) were also present. The mixture of alkenes was taken onto the next step (see c, below).

Workup

  1. customwas sonicated at room temperature for 1 min until a creamy-coloured suspension
  2. customformed
  3. customThe mixture was purged with nitrogen
  4. temperatureheated
  5. temperatureat reflux for 16 h
  6. temperatureAfter being cooled
  7. additionthe mixture was poured into ethyl acetate (70 mL)
  8. washwashed with 5% aqueous citric acid (20 mL), saturated aqueous sodium chloride (50 mL)
  9. dry with materialdried (MgSO4)
  10. concentrationconcentrated under reduced pressure
  11. customThe residue was purified by flash chromatography (gradient elution with dichloromethane:ethyl acetate)

Sources & evidence

ORD record
ord-c4ab64b7a40d44bd8782c380fd925dc6
Source dataset
uspto-grants-2002_02
Patent number
US06350907B1

Reaction notes

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