Diisopropylamine → 4-(3-((2-((2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)(methyl)amino)-2-oxoethyl)amino)-3-oxopropyl)-N-(2-methoxyethyl)benzamide

HRID 889171Notes

Reaction equation

[NH2:1][CH2:2][C:3]([N:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([CH2:14][O:15][C:16]2[C:24]3[N:23]=[C:22]([O:25][CH3:26])[N:21]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[C:20]=3[CH:19]=[CH:18][CH:17]=2)[C:8]=1[Cl:34])[CH3:6])=[O:4].[CH3:35][O:36][CH2:37][CH2:38][NH:39][C:40]([C:42]1[CH:47]=[CH:46][C:45]([CH2:48][CH2:49][C:50](O)=[O:51])=[CH:44][CH:43]=1)=[O:41].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(NC(C)C)(C)C>CN(C=O)C.O>[Cl:34][C:8]1[C:9]([CH2:14][O:15][C:16]2[C:24]3[N:23]=[C:22]([O:25][CH3:26])[N:21]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[C:20]=3[CH:19]=[CH:18][CH:17]=2)=[C:10]([Cl:13])[CH:11]=[CH:12][C:7]=1[N:5]([CH3:6])[C:3](=[O:4])[CH2:2][NH:1][C:50](=[O:51])[CH2:49][CH2:48][C:45]1[CH:46]=[CH:47][C:42]([C:40]([NH:39][CH2:38][CH2:37][O:36][CH3:35])=[O:41])=[CH:43][CH:44]=1

Participants

Conditions

Temperature: 23 °C

Procedure

A solution of (E)-benzyl 3-(4((2-methoxyethyl)carbamoyl)phenyl)acrylate (1.0 g, 3.38 mmol) in ethanol (50 ml) is hydrogenated over 10% Pd/C (100 mg) at 50 psi for 24 h. The catalyst is removed by filteration and the solvent removed under vacuum to give 3-(4-((2-methoxyethyl)carbamoyl)phenyl)propanoic acid as a clear oil that solidifies on standing. MS (ESI) 251 (M+), 1H NMR (CDCl3); 1.24 (t, 3H, J=6.8 Hz), 2.686 (t, 2H, J=7.2 Hz), 3.00 (t, 2H, J=7.2 Hz), 3.39 (s, 3H), 3.57 (t, 2H, J=5.2 Hz), 3.63 (t, 2H, J=5.2 Hz), 3.69-3.74 (m, 1H), 7.27 (d, 2H, J=8.4 Hz), 7.73 (d, 2H, J=8.4 Hz). A mixture of 2-amino-N-(2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)-N-methylacetamide (400 mg, 0.8 mmol), 3-(4-((2-methoxyethyl)carbamoyl)phenyl)propanoic acid (251 mg, 1.0 mmol) and TBTU (O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate) (321 mg, 1.0 mmol) and diisopropyl amine (0.42 ml) are dissolved in DMF (20 mL) and stirred for 12 h at 23° C. The mixture was poured into water and extracted with ethyl acetate (3×, 50 mL). The ethyl acetate layer is washed with saturated sodium bicarbonate, 1 N HCl then dried over sodium sulfate and concentrated to give a tan oil. The oil was purified by silica gel chromatography using 10% methanol in dichloromethane with 0.1% NH4OH as eluant to give 4-(3-((2-((2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)(methyl)amino)-2-oxoethyl)amino)-3-oxopropyl)-N-(2-methoxyethyl)benzamide (1) as a tan solid, 250 mg (43%). MS (ESI) 733 (M+); 1H NMR (CDCl3) 2.53 (d, 2H, J=6.8 Hz), 2.89 (d, 2H, J=6.8 Hz), 3.23 (s, 3H), 3.37 (s, 3H), 3.54-3.55 (m, 2H), 3.56-3.62 (m, 2H), 4.21 (s, 3H), 5.29-5.28 (m, 2H), 5.67 (s, 2H), 6.31-6.37 (m, 1H), 6.42-6.55 (m, 1H), 6.75-6.85 (m, 2H), 6.89-6.92 (m, 1H), 7.02-7.08 (m, 1H), 7.15-7.28 (m, 6H), 7.45-7.46 (m, 1H), 7.51-7.59 (m, 1H), 7.67-7.69 (m, 1H), 8.55-8.58 (m, 1H).

Workup

extractionextracted with ethyl acetate (3×, 50 mL)
washThe ethyl acetate layer is washed with saturated sodium bicarbonate, 1 N HCl
dry with materialthen dried over sodium sulfate
concentrationconcentrated
customto give a tan oil
customThe oil was purified by silica gel chromatography

Sources & evidence

ORD record: ord-b25479fa48ab4046888683b2438f0cd1
Source dataset: uspto-grants-2012_08
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08252793B2

Reaction notes

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