4-Methylmorpholine → methyl N-[(1S)-1-[[(1S,2S)-1-benzyl-2-hydroxy-3-[[[(2S,3S)-2-(methoxycarbonylamino)-3-methyl-pentanoyl]amino]-[(4-pyrazin-2-ylphenyl)methyl]amino]propyl]carbamoyl]-2-methyl-propyl]carbamate

HRID 380228Notes

Reaction equation

HRID 380228 reaction equation
[CH3:1][O:2][C:3]([NH:5][C@H:6]([C:11]([OH:13])=O)[C@H:7]([CH2:9][CH3:10])[CH3:8])=[O:4].[B-](F)(F)(F)F.CN(C(ON1C(=O)C=CC=C1)=[N+](C)C)C.Cl.[N:35]1[CH:40]=[CH:39][N:38]=[CH:37][C:36]=1[C:41]1[CH:46]=[CH:45][C:44]([CH2:47][N:48]([NH2:72])[CH2:49][C@H:50]([OH:71])[C@@H:51]([NH:59][C:60](=[O:70])[C@H:61]([CH:67]([CH3:69])[CH3:68])[NH:62][C:63]([O:65][CH3:66])=[O:64])[CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[CH:43][CH:42]=1.CN1CCOCC1>CN(C=O)C.C(OCC)(=O)C.O1CCOCC1.O>[N:35]1[CH:40]=[CH:39][N:38]=[CH:37][C:36]=1[C:41]1[CH:42]=[CH:43][C:44]([CH2:47][N:48]([NH:72][C:11](=[O:13])[C@H:6]([C@H:7]([CH2:9][CH3:10])[CH3:8])[NH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:49][C@H:50]([OH:71])[C@@H:51]([NH:59][C:60](=[O:70])[C@H:61]([CH:67]([CH3:69])[CH3:68])[NH:62][C:63]([O:65][CH3:66])=[O:64])[CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[CH:45][CH:46]=1

Participants

9

Reactant 4

HCID 79724-MethylmorpholineHCID 2733204O-(2-Oxo-1(2H)-pyridyl)-N,N,N',N'-tetramethyluronium TetrafluoroborateHCID 28378062L-Isoleucine, N-(methoxycarbonyl)-HCID 665779391-[4-(pyrazin-2-yl)-phenyl]-4(S)-hydroxy-2-amino-5(S)-N-(N-methoxycarbonyl-(L)-valyl)amino-6-phenyl-2-azahexane hydrochloride

Product 1

HCID 467983methyl N-[(1S)-1-[[(1S,2S)-1-benzyl-2-hydroxy-3-[[[(2S,3S)-2-(methoxycarbonylamino)-3-methyl-pentanoyl]amino]-[(4-pyrazin-2-ylphenyl)methyl]amino]propyl]carbamoyl]-2-methyl-propyl]carbamate

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 6228DimethylformamideSolvent2×HCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Procedure

142 mg (0.75 mmol) of N-methoxycarbonyl-(L)-iso-leucine and 223 mg (0.75 mmol) of TPTU in 3 ml of DMF are stirred at room temperature for 10 min and then a solution of 473 mg (0.75 mmol) of 1-[4-(pyrazin-2-yl)-phenyl]-4(S)-hydroxy-2-amino-5(S)-N-(N-methoxycarbonyl-(L)-valyl)amino-6-phenyl-2-azahexane hydrochloride (Example 40g) and 0.33 ml of NMM in 3 ml of DMF is added. The mixture is stirred at room temperature overnight. Working up is carried out by the slow, dropwise addition of the reaction mixture to 100 ml of water, stirring at room temperature for 20 min and isolation of the resulting precipitate by filtration. The precipitate is washed with water and taken up in methylene chloride; the organic phase is washed in succession with water, sat. sodium hydrogen carbonate solution/water 1:1, water and brine. After removal of the solvent, the residue is digested in ether, with the title compound being obtained in the form of a colourless powder. The compound can be lyophilised from dioxane. TLC: Rf=0.28 (ethyl acetate). HPLC20-100: tRet=13.78. FAB MS(M+H)+=692.

Workup

  1. stirringstirring at room temperature for 20 min
  2. filtrationisolation of the resulting precipitate by filtration
  3. washThe precipitate is washed with water
  4. washthe organic phase is washed in succession with water, sat. sodium hydrogen carbonate solution/water 1:1, water and brine
  5. customAfter removal of the solvent
  6. custombeing obtained in the form of a colourless powder

Sources & evidence

ORD record
ord-0fb5ca8fb76843f3be2d1dd64f70aac3
Source dataset
uspto-grants-2001_10
Patent number
US06300519B1

Reaction notes

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