4-Methylmorpholine → 2,5,6,10,13-Pentaazatetradecanedioic acid, 3-(1,1-dimethylethyl)-8-hydroxy-12-(1-methylethyl)-4,11-dioxo-9-(phenylmethyl)-6-((4-(2-thiazolyl)phenyl)methyl)-, dimethyl ester, (3S,8S,9S,12S)-

HRID 1276979Notes

Reaction equation

HRID 1276979 reaction equation
[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]([NH2:37])[CH2:14][C@H:15]([OH:36])[C@@H:16]([NH:24][C:25](=[O:35])[C@H:26]([CH:32]([CH3:34])[CH3:33])[NH:27][C:28]([O:30][CH3:31])=[O:29])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:8][CH:7]=1.CN1CCOCC1.[CH3:45][O:46][C:47]([NH:49][C@H:50]([C:55](O)=[O:56])[C:51]([CH3:54])([CH3:53])[CH3:52])=[O:48].[B-](F)(F)(F)F.CN(C(ON1C(=O)C=CC=C1)=[N+](C)C)C>CN(C=O)C.C(OCC)(=O)C.O>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]([CH2:12][N:13]([NH:37][C:55](=[O:56])[C@H:50]([C:51]([CH3:53])([CH3:52])[CH3:54])[NH:49][C:47]([O:46][CH3:45])=[O:48])[CH2:14][C@H:15]([OH:36])[C@@H:16]([NH:24][C:25](=[O:35])[C@H:26]([CH:32]([CH3:34])[CH3:33])[NH:27][C:28]([O:30][CH3:31])=[O:29])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:10][CH:11]=1

Participants

8

Reactant 4

HCID 79724-MethylmorpholineHCID 2733204O-(2-Oxo-1(2H)-pyridyl)-N,N,N',N'-tetramethyluronium TetrafluoroborateHCID 106974131-[4-(Thiazol-2-yl)-phenyl]-4(S)-hydroxy-2-amino-5(S)-N-(N-methoxycarbonyl-(L)-valyl)amino6-phenyl-2-azahexaneHCID 11263950N-(Methoxycarbonyl)-L-tert-leucine

Product 1

HCID 4696622,5,6,10,13-Pentaazatetradecanedioic acid, 3-(1,1-dimethylethyl)-8-hydroxy-12-(1-methylethyl)-4,11-dioxo-9-(phenylmethyl)-6-((4-(2-thiazolyl)phenyl)methyl)-, dimethyl ester, (3S,8S,9S,12S)-

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

Under an argon atmosphere, 294 mg of 1-[4-(thiazol-2-yl)-phenyl]-4(S)-hydroxy-2-amino-5(S)-N-(N-methoxycarbonyl-(L)-valyl)amino-6-phenyl-2-azahexane and 165 μl (1.5 mmol) of NMM in 4.8 ml of DMF are added to 113.5 mg (0.60 mmol) of N-methoxycarbonyl-(L)-tert-leucine (Example 2e) and 149 mg (0.50 mmol) of TPTU in 2.5 ml of DMFat 0° C. and the mixture is stirred at room temperature for 18 hours. Water and ethyl acetate are added; the aqueous phase is separated off and extracted a further 2× with ethyl acetate. The organic phases are washed 2× with water, sat. NaHCO3 solution, water and brine, dried (Na2SO4) and concentrated by evaporation. Column chromatography (SiO2 ; methylene chloride/THF 4:1) and precipitation with hexane from a concentrated solution in methylene chloride yield the title compound: HPLC20-100 : tRet =14.5; FAB MS (M+H)+ =697.

Workup

  1. customthe aqueous phase is separated off
  2. extractionextracted a further 2× with ethyl acetate
  3. washThe organic phases are washed 2× with water, sat. NaHCO3 solution, water and brine
  4. dry with materialdried (Na2SO4)
  5. concentrationconcentrated by evaporation
  6. customColumn chromatography (SiO2 ; methylene chloride/THF 4:1) and precipitation with hexane from a concentrated solution in methylene chloride

Sources & evidence

ORD record
ord-bd2158bcff7f40aaa51215728cd4d48b
Source dataset
uspto-grants-2000_12
Patent number
US06166004

Reaction notes

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