4-Methylmorpholine → HCID 69000370, compound

HRID 985389Notes

Reaction equation

HRID 985389 reaction equation
[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:11])[C:7]=1[C:8]([OH:10])=O.S(Cl)(Cl)=O.[CH2:16]([O:18][C:19](=[O:37])[C@@H:20]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1)[CH3:17].CN1CCOCC1>C(Cl)Cl.CN(C=O)C>[C:33]([O:32][C:30]([NH:29][C@@H:20]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:8](=[O:10])[C:7]2[C:6]([Cl:11])=[CH:5][N:4]=[CH:3][C:2]=2[Cl:1])=[CH:24][CH:23]=1)[C:19]([O:18][CH2:16][CH3:17])=[O:37])=[O:31])([CH3:34])([CH3:35])[CH3:36]

Participants

7

Reactant 4

HCID 79724-MethylmorpholineHCID 24386Thionyl ChlorideHCID 6057633,5-Dichloroisonicotinic acidHCID 10638537Ethyl 4-amino-N-(tert-butoxycarbonyl)-L-phenylalaninate

Product 1

HCID 69000370HCID 69000370, compoundYield 108.7%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideCatalystHCID 6344DichloromethaneSolvent3×

Procedure

A slurry of the compound of Intermediate 1 (51.2 g, 0.267 mol) in DCM (195 ml) and thionyl chloride (195 ml, 2.67 mol) was treated with DMF (5 drops) and heated to reflux for 4 h. The reaction was concentrated in vacuo and azeotroped with toluene (2×50 ml) to give a yellow solid which was used without further purification. A solution of ethyl-(S)-3-(4-aminophenyl)-2-(t-butoxycarbonylamino)propanoate (130.8 g, 0.425 mol) in DCM (800 ml) was cooled to 0° and treated with NMM (56.0 ml, 0.51 mol), stirred for 5 minutes and then a solution of the acid chloride (98.3 g, 0.468 mol) in DCM (200 ml) was added dropwise keeping the reaction temperature below 5°. The reaction was stirred for 1 h, quenched with NaHCO3 solution (500 ml), the organic layer separated, washed with NaHCO3 solution (500 ml), 10% citric acid solution (500 ml) and NaHCO3 solution (500 ml), dried (MgSO4) and concentrated in vacuo to give a yellow solid which was recrystallised (EtOAc/hexane) to give the title compound, (140 g, 69%). δH (DMSO d6), 8.8 (2H, s), 7.55 (2H, d, J 8.5 Hz), 7.23 (2H, d, J 8.5 Hz), 4.0 (3H, m), 3.4 (2H, b s), 2.9 (1H, m), 2.8 (1H, m), 1.3 (9H, s), 1.25 (3H, t); m/z (ES+, 70V) 504 (MNa+).

Workup

  1. temperatureheated
  2. temperatureto reflux for 4 h
  3. concentrationThe reaction was concentrated in vacuo
  4. customazeotroped with toluene (2×50 ml)
  5. customto give a yellow solid which
  6. customwas used without further purification
  7. customthe reaction temperature below 5°
  8. stirringThe reaction was stirred for 1 h
  9. customquenched with NaHCO3 solution (500 ml)
  10. customthe organic layer separated
  11. washwashed with NaHCO3 solution (500 ml), 10% citric acid solution (500 ml) and NaHCO3 solution (500 ml)
  12. dry with materialdried (MgSO4)
  13. concentrationconcentrated in vacuo
  14. customto give a yellow solid which
  15. customwas recrystallised (EtOAc/hexane)

Sources & evidence

ORD record
ord-0a48da2425f74f16a9324bab3e46a472
Source dataset
uspto-grants-2005_03
Patent number
US06872719B1

Reaction notes

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