Diisopropylethylamine → methyl 4-(3-(2-((2,4-dichloro-3-((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yloxy)methyl)phenyl)(methyl)amino)-2-oxoethylamino)-3-oxopropyl)benzoate

HRID 889201Notes

Reaction equation

HRID 889201 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].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:59][O:60][C:61]([C:63]1[CH:68]=[CH:67][C:66]([CH2:69][CH2:70][C:71](O)=[O:72])=[CH:65][CH:64]=1)=[O:62].C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1.C(OCC)(=O)C>[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:71](=[O:72])[CH2:70][CH2:69][C:66]1[CH:67]=[CH:68][C:63]([C:61]([O:60][CH3:59])=[O:62])=[CH:64][CH:65]=1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 227166883-(4-(Methoxycarbonyl)phenyl)propanoic acidHCID 667603852-amino-N-(2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)-N-methylacetamide

Product 1

HCID 66759939methyl 4-(3-(2-((2,4-dichloro-3-((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yloxy)methyl)phenyl)(methyl)amino)-2-oxoethylamino)-3-oxopropyl)benzoate

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolventHCID 13387N-methyl-2-pyrrolidoneSolvent

Procedure

A solution 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 (0.45 g, 0.9 mmol) in anhydrous NMP (12 ml) was treated with HBTU (0.48 g, 1.2 mmol), 3-(4-(methoxycarbonyl)phenyl)propanoic acid (0.22 g, 1.08 mmol) and diisopropylethyl amine (0.47 mL, 2.7 mmol) with stirring at room temperature overnight. To the reaction was added ethyl acetate (100 mL) and the mixture was washed with aqueous saturated sodium bicarbonate (100 mL×3). The organic layer was dried over magnesium sulfate, filtered and evaporated to a yellow residue, 0.59 g that was purified by chromatography (silica gel, ethyl acetate and methanol gradient) to afford methyl 4-(3-(2-((2,4-dichloro-3-((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yloxy)methyl)phenyl)(methyl)amino)-2-oxoethylamino)-3-oxopropyl)benzoate (37) as a white solid, 0.18 g (29%), LC/MS (+APCI) m/z 690 (M++1) and 704 (M++1), 1HNMR (400 MHz, CDCl3) δ 8.60 (m, 1H), 7.92 (m, 2 H), 7.60 (m, 1H), 7.49 (m, 1H), 7.29 (m, 1H), 7.19 (m, 1H), 7.02 (m, 1H), 6.91 (m, 1H), 6.82 (m, 2H), 6.35 (m, 1H), 5.67 (s, 2H), 5.28 (s, 2H), 4.21 (s, 3H), 3.89 (s, 3H), 4.1 to 2.5 (many multiplets, 10H). 13CNMR (100 MHz, CDCl3) δ 171.4, 168.2, 156.1, 149.6, 149.0, 146.2, 138.4, 138.1, 137.0, 135.8, 135.3, 130.2, 129.9, 128.4, 128.2, 122.6, 121.7, 120.8, 107.3, 103.0, 67.0, 57.5, 51.9, 47.7, 41.9, 37.4, 35.9, 31.4

Workup

  1. washthe mixture was washed with aqueous saturated sodium bicarbonate (100 mL×3)
  2. dry with materialThe organic layer was dried over magnesium sulfate
  3. filtrationfiltered
  4. customevaporated to a yellow residue, 0.59 g that
  5. customwas purified by chromatography (silica gel, ethyl acetate and methanol gradient)

Sources & evidence

ORD record
ord-5f02aa32b8ba4ee882414979dc872832
Source dataset
uspto-grants-2012_08
Patent number
US08252793B2

Reaction notes

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