Lithium Hexamethyldisilazide → tert-butyl (2R,5R)-2-[2-(2-{[N-(methoxycarbonyl)-beta-phenyl-L-phenylalanyl]amino}phenyl)ethyl]-5-[(1Z)-3-phenylprop-1-en-1-yl]morpholine-4-carboxylate

HRID 629723Notes

Reaction equation

HRID 629723 reaction equation
[PH4+].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:12]([C@H:14]1[N:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][C@@H:17]([CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[NH:35][C:36](=[O:56])[C@H:37]([CH:43]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)C2C=CC=CC=2)[NH:38][C:39]([O:41][CH3:42])=[O:40])[O:16][CH2:15]1)=O>C1COCC1>[CH3:42][O:41][C:39]([NH:38][C@H:37]([C:36]([NH:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH2:28][CH2:27][C@H:17]1[O:16][CH2:15][C@@H:14](/[CH:12]=[CH:27]\[CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18]1)=[O:56])[CH:43]([C:53]1[CH:52]=[CH:51][CH:50]=[CH:55][CH:54]=1)[C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)=[O:40]

Participants

5

Reactant 3

HCID 2733832Lithium HexamethyldisilazideHCID 5460504PhosphoniumHCID 86726317tert-butyl (2R,5S)-5-formyl-2-[2-(2-{[N-(methoxycarbonyl)-b-phenyl-L-phenylalanyl]amino}phenyl)ethyl]morpholine-4-carboxylate

Product 1

HCID 86726325tert-butyl (2R,5R)-2-[2-(2-{[N-(methoxycarbonyl)-beta-phenyl-L-phenylalanyl]amino}phenyl)ethyl]-5-[(1Z)-3-phenylprop-1-en-1-yl]morpholine-4-carboxylate

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
-78 °C

Procedure

To a cold (0° C.) suspension of phosphonium salt triphenyl(2-phenylethyl)phosphonium iodide (2.5 eq) in THF (0.1M) was added dropwise a solution of 1M lithium bis(trimethylsilyl)amide (3 eq) in THF. The reaction mixture was stirred at that temperature for 30 min then cooled to −78° C. A solution of tert-butyl (2R,5S)-5-formyl-2-[2-(2-{[N-(methoxycarbonyl)-β-phenyl-L-phenylalanyl]amino}phenyl)ethyl]morpholine-4-carboxylate (1 eq) in THF (1M) was added dropwise. The reaction mixture was stirred at that temperature for 30 min then allowed to warm to rt for 30 min, quenched with water and the organic layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by automated silica gel flash chromatography system eluted with a gradient 0% to 70% of EtOAc/Hex to afford the desired compound.

Workup

  1. stirringThe reaction mixture was stirred at that temperature for 30 min
  2. temperatureto warm to rt for 30 min
  3. customquenched with water
  4. extractionthe organic layer was extracted twice with EtOAc
  5. washThe combined organic layers were washed with brine
  6. dry with materialdried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe residue was purified by automated silica gel flash chromatography system
  10. washeluted with a gradient 0% to 70% of EtOAc/Hex

Sources & evidence

ORD record
ord-8a8cc7e993944049a8985912c54bbd36
Source dataset
uspto-grants-2016_04
Patent number
US09315475B2

Reaction notes

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