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 72020Notes

Reaction equation

HRID 72020 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-33bda24105354e5ea049496aa8a49b27
Source dataset
uspto-grants-2014_09
Patent number
US08822430B2

Reaction notes

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