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

HRID 889199Notes

Reaction equation

HRID 889199 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][NH:60][C:61]([CH:63]1[CH2:68][CH2:67][CH2:66][N:65]([CH2:69][C:70](O)=[O:71])[CH2:64]1)=[O:62].C(N(C(C)C)CC)(C)C>CN(C=O)C.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:70](=[O:71])[CH2:69][N:65]1[CH2:66][CH2:67][CH2:68][CH:63]([C:61]([NH:60][CH3:59])=[O:62])[CH2:64]1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 667593892-(3-(Methylcarbamoyl)piperidin-1-yl)acetic 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 667598411-(2-(2-((2,4-dichloro-3-((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yloxy)methyl)phenyl)(methyl)amino)-2-oxoethylamino)-2-oxoethyl)-N-methylpiperidine-3-carboxamide

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

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 DMF (10 ml) was treated with HBTU (0.48 g, 1.2 mmol), 2-(3-(methylcarbamoyl)piperidin-1-yl)acetic acid (0.20 g, 0.99 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 sticky yellow residue, 0.63 g that was purified by chromatography (silica gel, dichloromethane and methanol gradient) to afford 1-(2-(2-((2,4-dichloro-3-((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yloxy)methyl)phenyl)(methyl)amino)-2-oxoethylamino)-2-oxoethyl)-N-methylpiperidine-3-carboxamide (35) as a white solid, 0.17 g (28%), that was pure by LC/MS (+APCI) m/z 682 (M++1), 1HNMR (400 MHz, CDCl3) δ 8.60 (m, 1H), 7.60 (m, 2H), 7.50 (m, 1H), 7.30 (m, 1H), 7.35 (m, 1H), 7.19 (m, 1H), 7.04 (m, 1H), 6.92 (m, 1H), 6.81 (m, 2H), 6.70 (broad m, 1H), 5.67 (s, 2H), 5.29 (s, 2H), 4.21 (two s, 3H), 4.1 to 1.4 (many multiplets, 19H). 13CNMR (100 MHz, CDCl3) δ 174.4, 170.5, 168.8, 156.8, 156.1, 149.6, 149.0, 138.4, 138.2, 137.0, 136.5, 135.8, 135.3, 130.3, 122.6, 121.7, 120.8, 107.3, 103.1, 67.0, 61.6, 57.5, 56.5, 56.2, 54.3, 53.4, 47.7, 45.4, 41.3, 36.0, 30.9, 26.3, 26.1, 24.5. Anal. Calcd for C33H37Cl2N6O5+0.57CH2Cl2: C, 55.16; H, 5.26; N, 13.41. Found: C, 55.18; H, 5.14; N, 13.35.

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 sticky yellow residue, 0.63 g that
  5. customwas purified by chromatography (silica gel, dichloromethane and methanol gradient)

Sources & evidence

ORD record
ord-b126c29a0866400e8d875034b1cd0d81
Source dataset
uspto-grants-2012_08
Patent number
US08252793B2

Reaction notes

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