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

HRID 343218Notes

Reaction equation

HRID 343218 reaction equation
[CH:1]([N:4]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)[C:5](=[O:37])[CH2:6][N:7]1[C:13](=[O:14])[CH:12]([CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH3:25])[N:17]=2)[C:11](=[O:26])[N:10]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:9]2[CH:33]=[CH:34][CH:35]=[CH:36][C:8]1=2)([CH3:3])[CH3:2].[CH3:46][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI>CN(C=O)C.C1COCC1>[CH:1]([N:4]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)[C:5](=[O:37])[CH2:6][N:7]1[C:13](=[O:14])[C:12]([CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH3:25])[N:17]=2)([CH3:46])[C:11](=[O:26])[N:10]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:9]2[CH:33]=[CH:34][CH:35]=[CH:36][C:8]1=2)([CH3:2])[CH3:3]

Participants

6

Reactant 3

HCID 6328Methyl iodideHCID 2724254Sodium bis(trimethylsilyl)amideHCID 10555571N-Isopropyl-N-(4-methoxy-phenyl)-2-[3-(1-methyl-1H-indazol-3-ylmethyl)-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]acetamide

Product 1

HCID 10793883N-Isopropyl-N-(4-methoxy-phenyl)-2-[3-(1-methyl-1H-indazol-3-ylmethyl)-3-methyl-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]acetamide

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
50 °C

Procedure

To a stirring solution of 165 mg (0.27 mmol) of N-Isopropyl-N-(4-methoxy-phenyl)-2-[3-(1-methyl-1H-indazol-3-ylmethyl)-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]acetamide, prepared as in Example 49, in 5 mL of DMF at 0° C. is added 0.82 mL (0.82 mmol, 3.0 equiv) of a 1.0M solution of NaN(TMS)2 in THF. The resulting solution is stirred 5 min, and 51 μL (0.82 mmol, 3.0 equiv) of methyl iodide is added. The resulting solution is stirred for 4 h at RT, warmed to 50° C. for 16 h, and then quenched with 5 mL of H2O. The reaction mixture is poured into 50 mL of Et2O and extracted with H2O (2×50 mL). The organic layer is separated, dried (MgSO4), and the solvents removed in vacuo. Purification by silica gel MPLC on an Si60 column using hexane/EtOAc 4/3 as eluent followed by lyophilization in acetonitrile/H2O afforded 124 mg of the title compound as a white amorphous solid: 1H NMR (DMSO-d6, 300 MHz) δ7.48-6.95 (m, 16H), 6.71 (d, 1H, J=7.3), 4.78 (m, 1H), 4.21 (s, br, 2H), 3.95 (s, 3H), 3.74 (s, 3H), 2.79 (d, 2H, J=5.9), 1.20 (s, 3H), 0.93 (m, 6H); low resolution MS (FAB)m/e 616 (MH+).

Workup

  1. stirringThe resulting solution is stirred for 4 h at RT
  2. customquenched with 5 mL of H2O
  3. additionThe reaction mixture is poured into 50 mL of Et2O
  4. extractionextracted with H2O (2×50 mL)
  5. customThe organic layer is separated
  6. dry with materialdried (MgSO4)
  7. customthe solvents removed in vacuo
  8. customPurification by silica gel MPLC on an Si60 column

Sources & evidence

ORD record
ord-db33b39625fe48d185a9f1fc1797c79f
Source dataset
uspto-grants-1999_01
Patent number
US05859007

Reaction notes

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