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

HRID 343108Notes

Reaction equation

HRID 343108 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][CH:18]2[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[N:20]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:19]2=[O:51])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:52][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI.CCOC(C)=O>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([CH3:52])[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:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:19]2=[O:51])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

6

Reactant 4

HCID 6328Methyl iodideHCID 8857Ethyl AcetateHCID 2724254Sodium bis(trimethylsilyl)amideHCID 10556460CCK-A Agonist 26

Product 1

HCID 677001112-[3-(1-Benzyl-1H-indazol-3-ylmethyl)-3-methyl-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-(4-methoxy-phenyl) acetamide

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
50 °C

Procedure

To a stirring solution of 200 mg (0.30 mmol) of 2-[3-(1-Benzyl-1H-indazol-3-ylmethyl)-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-(4-methoxy-phenyl) acetamide in 5 mL of DMF is added 0.45 mL (0.45 mmol, 1.5 equiv) of a 1.0M solution of NaN(TMS)2. The resulting solution is stirred 5 min, then 76 mg (0.54 mmol, 1.8 equiv) of methyl iodide is added. The resulting solution is stirred at RT for 1 h then heated to 50° C. for 16 h. The solution is cooled to RT, poured into 40 mL of EtOAc and extracted with H2O (1×40 mL), dried (MgSO4), and the solvent removed in vacuo. Purification of the resulting material by silica gel flash chromatography with hexane/ethyl acetate 3/2 as eluent gave 127 mg of the title compound as an off-white solid, contaminated with starting material, which is inseparable, in a ratio of approximately 1/1: 1H NMR (300 MHz, CDCl3) δ7.86 (d, 1H, J=8.1), 7.33-6.88 (m, 21H), 5.58 (s, 2H), 5.43 (s, 2H), 5.05 (m, 1H), 5.00 (m, 1H), 4.50 (d, 1H), 4.25 (m, 3H), 3.85 (s, 3H), 3.58 (dd, 1H, J=5.1, 16.0), 1. 59 (s, 3H), 1.06 (2×d, 6H, J=6.6); Rf =0.15 in hexane/ethyl acetate 2/1.

Workup

  1. stirringThe resulting solution is stirred at RT for 1 h
  2. temperatureThe solution is cooled to RT
  3. extractionextracted with H2O (1×40 mL)
  4. dry with materialdried (MgSO4)
  5. customthe solvent removed in vacuo
  6. customPurification of the resulting material by silica gel flash chromatography with hexane/ethyl acetate 3/2 as eluent

Sources & evidence

ORD record
ord-c49e151877664c0298f2bc6cecf35574
Source dataset
uspto-grants-1999_01
Patent number
US05859007

Reaction notes

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