Diisopropylethylamine → (4,4,4-Trifluoro-1-{2-[5-(4'-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl]-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-butyl)-carbamic acid methyl ester

HRID 1185926Notes

Reaction equation

HRID 1185926 reaction equation
[CH3:1][O:2][C:3](=[O:46])[NH:4][CH:5]([C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH:15]1[C:19]1[NH:20][C:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][C:33]([C:36]4[NH:37][C:38]([CH:41]5[CH2:45][CH2:44][CH2:43][NH:42]5)=[N:39][CH:40]=4)=[CH:32][CH:31]=3)=[CH:26][CH:25]=2)=[CH:22][N:23]=1)=[O:13])[CH2:6][CH2:7][C:8]([F:11])([F:10])[F:9].[CH3:47][O:48][C:49]([NH:51][CH:52]([CH:56]([CH3:58])[CH3:57])[C:53](O)=[O:54])=[O:50].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:46])[NH:4][CH:5]([C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH:15]1[C:19]1[NH:20][C:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]3[CH:35]=[CH:34][C:33]([C:36]4[NH:37][C:38]([CH:41]5[CH2:45][CH2:44][CH2:43][N:42]5[C:53](=[O:54])[CH:52]([NH:51][C:49]([O:48][CH3:47])=[O:50])[CH:56]([CH3:58])[CH3:57])=[N:39][CH:40]=4)=[CH:32][CH:31]=3)=[CH:28][CH:29]=2)=[CH:22][N:23]=1)=[O:13])[CH2:6][CH2:7][C:8]([F:9])([F:11])[F:10]

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 138211012-((Methoxycarbonyl)amino)-3-methylbutanoic acidHCID 66621118[4,4,4-Trifluoro-1-(2-{5-[4'-(2-pyrrolidin-2-yl-3H-imidazol-4-yl)-biphenyl-4-yl]-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl)-butyl]-carbamic acid methyl ester

Product 1

HCID 66621108(4,4,4-Trifluoro-1-{2-[5-(4'-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl]-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-butyl)-carbamic acid methyl esterYield 47%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Procedure

To a solution of crude [4,4,4-Trifluoro-1-(2-{5-[4′-(2-pyrrolidin-2-yl-3H-imidazol-4-yl)-biphenyl-4-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-butyl]-carbamic acid methyl ester (125 mg, 0.20 mmol) in dimethylformamide (0.6 mL) was added a solution of 2-methoxycarbonylamino-3-methyl-butyric acid (38 mg, 0.22 mmol) and HATU (82 mg, 0.22 mmol) in dimethylformamide (0.6 mL). Diisopropylethylamine (70 μL, 0.40 mmol) was then added and the reaction was stirred at room temperature for 16 hours. The solution was concentrated and purified by preparative reverse phase HPLC (Gemini, 15 to 50% ACN/H2O+0.1% HCO2H) to yield (4,4,4-trifluoro-1-{2-[5-(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-butyl)-carbamic acid methyl ester (73 mg, 47%). LCMS-ESI+: calculated for C40H47F3N8O6: 792.85; observed [M+1]+: 794.33. 1H-NMR: 400 MHz, (CD3OD) δ: 7.82-7.70 (m, 4H), 7.68-7.63 (m, 4H), 7.32-7.31 (m, 2H), 5.20-5.16 (m, 2H), 4.56-4.51 (m, 1H), 4.26-4.22 (m, 1H), 4.04-3.96 (m, 1H), 3.91-3.84 (m, 2H), 3.67 (s, 3H), 3.66 (s, 3H), 3.51-3.46 (m, 1H), 2.38-1.96 (m, 12H), 1.90-1.78 (m, 1H), 1.01-0.89 (m, 6H) ppm.

Workup

  1. concentrationThe solution was concentrated
  2. custompurified by preparative reverse phase HPLC (Gemini, 15 to 50% ACN/H2O+0.1% HCO2H)

Sources & evidence

ORD record
ord-a9e2639b1b1f4946a66d0342593aa151
Source dataset
uspto-grants-2014_03
Patent number
US08669234B2

Reaction notes

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