3-Bromopyridine → 2-[3-(1-Benzyl-1H-indazol-3-ylmethyl)-3-methoxy-2,4-dioxo-5-pyridin-3-yl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-(4-methoxy-phenyl)-acetamide

HRID 343128Notes

Reaction equation

HRID 343128 reaction equation
[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][C:18]2([O:46][CH3:47])[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:38]([CH3:40])[CH3:39])[C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)=[O:28])[C:22]3[CH:41]=[CH:42][CH:43]=[CH:44][C:21]=3[NH:20][C:19]2=[O:45])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[K+].Br[C:54]1[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=1>CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][C:18]2([O:46][CH3:47])[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:38]([CH3:40])[CH3:39])[C:30]3[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)=[O:28])[C:22]3[CH:41]=[CH:42][CH:43]=[CH:44][C:21]=3[N:20]([C:54]3[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=3)[C:19]2=[O:45])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

5

Reactant 3

HCID 122863-Bromopyridine2×HCID 517044Potassium AcetateHCID 67696854HCID 67696854, compound

Product 1

HCID 676968152-[3-(1-Benzyl-1H-indazol-3-ylmethyl)-3-methoxy-2,4-dioxo-5-pyridin-3-yl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-(4-methoxy-phenyl)-acetamideYield 70.5%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
120 °C

Procedure

To a stirring suspension of 570 mg (0.90 mmol) of 2-[3-(1-Benzyl-1H-indazol-3-ylmethyl)-3-methoxy-2,4-dioxo-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-(4-methoxy-phenyl)-acetamide, prepared as in Part A, and 172 mg (2.71 mmol, 3.0 equiv) of Cu0 powder in 10 mL of DMF is added 117 mg (1.80 mmol, 2.0 equiv of potassium acetate, followed by 285 mg (1.80 mmol, 2.0 equiv) of 3-bromopyridine). The resulting mixture is heated to 120° C. for 4 h, then an additional 285 mg of 3-bromopyridine is added and the reaction heated to 120° C. for an additional 15 h. The reaction mixture is then cooled to RT and filtered through a pad of Celite to remove the Cu0 powder. The reaction mixture is then poured into 100 mL of EtOAc-Et2O (1:1) and extracted with H2O (2×100 mL), dried (MgSO4), and the solvent removed in vacuo. Purification of the crude material by silica gel flash column chromatography using hexane/EtOAc 1/1 as eluent afforded 450 mg of the title compound as a light tan solid: mp 223°-224° C.; 1H NMR (CDCl3, 400 MHz) δ8.47 (d, 1H, J=3.8), 8.31 (s, br, 1H), 8.04 (d, 1H, J=8.2), 7.51 (d, 1H, J=7.3), 7.38 (d, 1H, J=7.7), 7.31-6.93 (m, 15H), 6.64 (d, 1H, J=7.5), 5.52 (s, 2H), 5.04 (m, 1H), 4.46 (d, 1H, J=15.9), 4.26 (d, 1H, J=15.8), 4.00 (m, 2H), 3.84 (s, 3H), 3.15 (s, 3H), 1.11 (2×d, 6H, J=6.7); low resolution MS (FAB)m/e 709 (MH+), 293, 265; Anal. (C42H40N6O5) Calcd. C, 71.17; H, 5.69; N, 11.86; Found C, 70.90; H, 5.74; N, 11.65.

Workup

  1. temperaturethe reaction heated to 120° C. for an additional 15 h
  2. temperatureThe reaction mixture is then cooled to RT
  3. filtrationfiltered through a pad of Celite
  4. customto remove the Cu0 powder
  5. additionThe reaction mixture is then poured into 100 mL of EtOAc-Et2O (1:1)
  6. extractionextracted with H2O (2×100 mL)
  7. dry with materialdried (MgSO4)
  8. customthe solvent removed in vacuo
  9. customPurification of the crude material by silica gel flash column chromatography

Sources & evidence

ORD record
ord-23a1885b0597422488a79c483e04c639
Source dataset
uspto-grants-1999_01
Patent number
US05859007

Reaction notes

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