Abstract:

We report herein the synthesis of impurity B of Flumazenil via demethylation, benzyl protection, cyclization and debenzylation from 7-methoxyl-3,4-dihydro-4-methyl-2H-1,4-benzo-diazepine-2,5(1H)-dione. The structure of impurity B of Flumazenil was confirmed by ¹H NMR, ¹³C NMR and HRMS, and the overall yield was 29.3%. The finding will be helpful for optimizing the synthetic process and quality control of Flumazenil.

Key words: Impurity B of Flumazenil, Flumazenil, Synthesis, Quality control

CLC Number: 

• R916

Supporting:

Synthesis of 8-hydroxy Flumazenil

 

1. Analysis and identification of products

  Melting points were determined on a Büchi Melting Point B-540 apparatus and were uncorrected. ¹H-NMR and ¹³C-NMR spectra were recorded on a Bruker ARX-300 spectrometer, using DMSO-d₆ as solvent and TMS as the internal standard. Coupling constants (J) were expressed in Hz. Mass spectra were obtained on an Agilent 1100 mass spectrometer. High-resolution mass spectra (HRMS) were recorded on a Bruker microTOF-Q. Column chromatography (CC) was performed on silica gel H and analytical TLC on silica gel HF254.

 

1.1  ¹H-NMR spectra of 7-Benzyloxy-3, 4-dihydro-4-methyl-2H-1,4 benzodiazepine-2,5(1H)–dione 

 

 

 

 

1.2   ¹H-NMR and ¹³C-NMR spectra of 8-hydroxy Flumazenil 

 

 

 

 

 

 

 

1.3  High-resolution mass spectra of 8-hydroxy Flumazenil