4-Methylmorpholine → (1-{1-[2-(4'-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-2-oxo-ethylcarbamoyl]-ethyl}-2-oxo-piperidin-3-yl)-carbamic acid methyl ester

HRID 79710Notes

Reaction equation

HRID 79710 reaction equation
[CH3:1][O:2][C:3]([NH:5][CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH:12]([CH3:16])[C:13]([OH:15])=O)[C:7]1=[O:17])=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:49][O:50][C:51](=[O:85])[NH:52][CH:53]([C:57]([N:59]1[CH2:63][CH2:62][CH2:61][CH:60]1[C:64]1[NH:65][C:66]([C:69]2[CH:74]=[CH:73][C:72]([C:75]3[CH:80]=[CH:79][C:78]([C:81](=[O:84])[CH2:82][NH2:83])=[CH:77][CH:76]=3)=[CH:71][CH:70]=2)=[CH:67][N:68]=1)=[O:58])[CH:54]([CH3:56])[CH3:55]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:4])[NH:5][CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH:12]([C:13](=[O:15])[NH:83][CH2:82][C:81]([C:78]2[CH:79]=[CH:80][C:75]([C:72]3[CH:71]=[CH:70][C:69]([C:66]4[NH:65][C:64]([CH:60]5[CH2:61][CH2:62][CH2:63][N:59]5[C:57](=[O:58])[CH:53]([NH:52][C:51]([O:50][CH3:49])=[O:85])[CH:54]([CH3:56])[CH3:55])=[N:68][CH:67]=4)=[CH:74][CH:73]=3)=[CH:76][CH:77]=2)=[O:84])[CH3:16])[C:7]1=[O:17]

Participants

6

Reactant 4

HCID 79724-MethylmorpholineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 66620889[1-(2-{5-[4'-(2-Amino-acetyl)-biphenyl-4-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl esterHCID 666210692-(3-Methoxycarbonylamino-2-oxo-piperidin-1-yl)-propionic acid

Product 1

HCID 66620876(1-{1-[2-(4'-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-2-oxo-ethylcarbamoyl]-ethyl}-2-oxo-piperidin-3-yl)-carbamic acid methyl esterYield 100%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A solution of 2-(3-methoxycarbonylamino-2-oxo-piperidin-1-yl)-propionic acid (48.5 mg, 0.20 mmol), HATU (91 mg, 0.24 mmol), and 4-methylmorpholine (109 μL, 0.99 mmol) in dimethylformamide (5 mL) was stirred at ambient temperature for 5 minutes. [1-(2-{5-[4′-(2-Amino-acetyl)-biphenyl-4-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (100 mg, 0.20 mmol) was added to the reaction mixture. After 40 minutes the solvent was removed under reduced pressure and the resulting residue was taken up in ethyl acetate (10 mL). The resulting mixture contained a solid and was subjected to flash chromatography with eluent of (10% methanol in ethyl acetate) and hexane followed by 30% methanol in DCM. The product-containing fractions were combined and the solvent was removed under reduced pressure to provide (1-{1-[2-(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-2-oxo-ethylcarbamoyl]-ethyl}-2-oxo-piperidin-3-yl)-carbamic acid methyl ester (149 mg, 0.20 mmol, 99%). C38H47N7O8 calculated 729.4 observed [M+1]+ 730.6; rt=1.78 min.

Workup

  1. customAfter 40 minutes the solvent was removed under reduced pressure
  2. customthe solvent was removed under reduced pressure

Sources & evidence

ORD record
ord-1d408630effd44d3bc81f157802fa03d
Source dataset
uspto-grants-2014_09
Patent number
US08841278B2

Reaction notes

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