Methyl iodide → HCID 10770092, compound

HRID 343205Notes

Reaction equation

HRID 343205 reaction equation
[C: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])=[CH:9]1)(OC(C)(C)C)=O.[CH3:52][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI>CN(C=O)C.C1COCC1>[CH3:1][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]([CH3:39])[CH3:40])[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:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:19]2=[O:51])=[CH:9]1

Participants

6

Reactant 3

HCID 6328Methyl iodideHCID 2724254Sodium bis(trimethylsilyl)amideHCID 67696894HCID 67696894, compound

Product 1

HCID 10770092HCID 10770092, compound

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
50 °C

Procedure

To a stirring solution of 295 mg (0.43 mmol) of 2-[3-(N-BOC-indol-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, prepared as in Example 23, in 10 mL of DMF at 0° C. is added 690 μL (0.69 mmol, 1.6 equiv) of a 1.0M solution of NaN(TMS)2 in THF. The resulting solution is stirred 10 min, then 53 μL (0.86 mmol, 2.0 equiv) of methyl iodide is added. The reaction mixture is stirred 2 h at RT and then heated to 50° C. for 14 h, then quenched with 1 mL H2O. The reaction mixture is diluted with 40 mL EtOAc and washed with 40 mL H2O. The organic layer is dried (MgSO4) and the solvents removed in vacuo. The crude material is then resubjected to the same conditions as stated above to ensure complete alkylation. The crude material is then dissolved in 10 mL of 4N HCl in dioxane and the reaction mixture is stirred 6 h at RT. The reaction mixture is diluted with 40 mL of EtOAc and extracted with NaHCO3 (1×30 mL) and H2O (1×30 mL). The organic layer is dried (MgSO4) and the solvents removed in vacuo. The resulting crude oil is purified via reverse phase MPLC using a C-18 column and 65% acetonitrile/35% H2O as eluent followed by lyophilization to afford 51 mg of 2-[3-(N-methyl-indol-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 as a white amorphous solid. 1H NMR (DMSO-d6, 300 MHz) δ7.61-6.88 (m, 18H), 4.86 (m,1H), 4.28 (m, 2H), 3.80 (s, 3H), 3.74 (s, 3H), 2.71 (dd, 2H, J=14.9, 35.4), 1.25 (s, 3H), 1.00 (m, 6H); low resolution MS (FAB)m/e 615 (MH+), 614 (M+).

Workup

  1. stirringThe reaction mixture is stirred 2 h at RT
  2. customquenched with 1 mL H2O
  3. additionThe reaction mixture is diluted with 40 mL EtOAc
  4. washwashed with 40 mL H2O
  5. dry with materialThe organic layer is dried (MgSO4)
  6. customthe solvents removed in vacuo
  7. dissolutionThe crude material is then dissolved in 10 mL of 4N HCl in dioxane
  8. stirringthe reaction mixture is stirred 6 h at RT
  9. additionThe reaction mixture is diluted with 40 mL of EtOAc
  10. extractionextracted with NaHCO3 (1×30 mL) and H2O (1×30 mL)
  11. dry with materialThe organic layer is dried (MgSO4)
  12. customthe solvents removed in vacuo
  13. customThe resulting crude oil is purified via reverse phase MPLC

Sources & evidence

ORD record
ord-dbd4d493a8ff47e69f4e5d127f843302
Source dataset
uspto-grants-1999_01
Patent number
US05859007

Reaction notes

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