Benzyl chloromethyl ether → HCID 67696645, compound

HRID 343243Notes

Reaction equation

HRID 343243 reaction equation
[O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:4](=[O:34])[CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:45]([O:52][CH2:53]Cl)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>CN(C=O)C.C1COCC1>[CH2:45]([O:52][CH2:53][CH:3]1[C:2](=[O:1])[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:4]1=[O:34])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1

Participants

6

Reactant 3

HCID 137983Benzyl chloromethyl etherHCID 2724254Sodium bis(trimethylsilyl)amideHCID 107900232-(2,4-Dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl) acetamide

Product 1

HCID 67696645HCID 67696645, compoundYield 39.7%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a stirring solution of 1.0 g (2.18 mmol) of 2-(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 Intermediate 4, in 10 mL of DMF at -5° C. is added 2.40 mL (2.40 mmol, 1.1 equiv) of a 1.0M solution of NaN(TMS)2 in THF. The resulting solution is stirred 5 min, and then 530 μL (3.05 mmol, 1.4 equiv) of chloromethyl benzyl ether (80%, tech.) is added neat. The resulting solution is stirred for 1 h at RT then quenched with 5 mL of H2O. The reaction mixture is poured into 100 mL of EtOAc and extracted with H2O (2×80 mL). The organic layer is separated, dried (MgSO4), and the solvents removed in vacuo. Purification by silica gel flash column chromatography using a gradient elution of hexane/EtOAc 4/1 to hexane/EtOAc 1/2 as eluent afforded 500 mg of the title compound as a white solid, along with 320 mg of recovered starting benzodiazepine: mp. 203°-204° C.; 1H NMR (CDCl3, 400 MHz) δ7.37-7.18 (m, 13H), 7.10 (m, 2H), 6.92 (m, 3H), 4.98 (m, 1H), 4.56 (dd, 2H, J=11.8, 22.7), 4.25 (m, 3H), 4.08 (dd, 1H, J=5.0, 9.8), 3.83 (s, 3H), 3.67 (dd, 1H, J=5.0, 7.5), 1.06 (2×d, 6H, J=6.2); low resolution MS (FAB)m/e 578 (MH+), 443, 413, 277, 223; Anal. (C35H35N3O5) Calcd. C, 72.77; H, 6.11; N, 7.27 Found C, 71.62; H, 6.06; N, 7.10.

Workup

  1. stirringThe resulting solution is stirred for 1 h at RT
  2. customthen quenched with 5 mL of H2O
  3. additionThe reaction mixture is poured into 100 mL of EtOAc
  4. extractionextracted with H2O (2×80 mL)
  5. customThe organic layer is separated
  6. dry with materialdried (MgSO4)
  7. customthe solvents removed in vacuo
  8. customPurification by silica gel flash column chromatography
  9. washa gradient elution of hexane/EtOAc 4/1 to hexane/EtOAc 1/2 as eluent

Sources & evidence

ORD record
ord-f7a1abfda9f74ff1be01c01c76f021cd
Source dataset
uspto-grants-1999_01
Patent number
US05859007

Reaction notes

Loading…