2558-30-7

Basic information

• Product Name: N-DESMETHYLFLUNITRAZEPAM
• Synonyms: DESMETHYLFLUNITRAZEPAM;5-(2-fluorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one;N-DESMETHYLFLUNITRAZEPAM,1.0MG/MLINMETHANOL;5-(2-Fluorphenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-on;N-DESMETHYLFLUNITRAZEPAM (100UG/ML METHANOL);N-DESMETHYLFLUNITRAZEPAM,100/MLINMETHANOL;Ro-05-4435;Ro-5-4435
• CAS NO: 2558-30-7
• Molecular Formula: C₁₅H₁₀FN₃O₃
• Molecular Weight: 299.26
• EINECS: 219-878-3
• Product Categories: Heterocycles;Intermediates & Fine Chemicals;Isotope Labelled Compounds;Metabolites & Impurities;Pharmaceuticals;Heterocycles, Metabolites & Impurities, Pharmaceuticals, Intermediates & Fine Chemicals
• Mol File: 2558-30-7.mol
• Article Data: 5

Chemical Properties

• Melting Point: 210-211 °C
• Boiling Point: 497.6°Cat760mmHg
• Flash Point: 9℃
• Appearance: /
• Density: 1.47g/cm³
• Vapor Pressure: 4.87E-10mmHg at 25°C
• Refractive Index: 1.675
• Storage Temp.: ?20°C
• PKA: 11.17±0.70(Predicted)
• CAS DataBase Reference: N-DESMETHYLFLUNITRAZEPAM(CAS DataBase Reference)
• NIST Chemistry Reference: N-DESMETHYLFLUNITRAZEPAM(2558-30-7)
• EPA Substance Registry System: N-DESMETHYLFLUNITRAZEPAM(2558-30-7)

Safety Data

• Hazard Codes: F,T
• Statements: 11-23/24/25-39/23/24/25
• Safety Statements: 7-16-36/37-45
• RIDADR: UN1230 - class 3 - PG 2 - Methanol, solution
• WGK Germany: 1
• Hazardous Substances Data: 2558-30-7(Hazardous Substances Data)

Usage

Uses

Different sources of media describe the Uses of 2558-30-7 differently. You can refer to the following data:
1. A metabolite of Flunitrazepam (F500700).
2. A labelled metabolite of Flunitrazepam (F500700).

InChI:InChI=1/C15H10FN3O3/c16-12-4-2-1-3-10(12)15-11-7-9(19(21)22)5-6-13(11)18-14(20)8-17-15/h1-7H,8H2,(H,18,20)

Synthetic route

2‑(2‑chloroacetamido)‑5‑nitro‑2′‑fluorobenzophenone → 5-(2-fluorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one (2558-30-7)

Conditions	Yield
With hexamethylenetetramine; ammonium chloride In ethanol for 4h; Reflux;	87%

hexamethylenetetramine (100-97-0) + 2‑(2‑chloroacetamido)‑5‑nitro‑2′‑fluorobenzophenone → 5-(2-fluorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one (2558-30-7) + 3-[2-(2-Fluoro-benzoyl)-4-nitro-phenyl]-imidazolidin-4-one + C33H24F2N6O8

Conditions	Yield
With urotropin hydrochloride In methanol; water Heating;	A 50% B n/a C n/a

2‑(2‑chloroacetamido)‑5‑nitro‑2′‑fluorobenzophenone → 5-(2-fluorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one (2558-30-7) + 3-[2-(2-Fluoro-benzoyl)-4-nitro-phenyl]-imidazolidin-4-one + C33H24F2N6O8

Conditions	Yield
With hexamethylenetetramine; urotropin hydrochloride In methanol; water Heating; Yields of byproduct given;	A 50% B n/a C n/a

2-bromo-2'-(2-fluorobenzoyl)-4'-nitroacetanilide → 5-(2-fluorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one (2558-30-7)

Conditions	Yield
With hexamethylenetetramine; ammonia; toluene-4-sulfonic acid In ethanol; toluene

flunitrazepam (1622-62-4) → 5-(2-fluorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one (2558-30-7)

Conditions	Yield
With human hepatocytes; Williams' Medium E cell culture medium In acetonitrile for 1h; pH=7.4; Enzyme kinetics;

2-amino-5-nitro-2'-fluorobenzophenone (344-80-9) → 5-(2-fluorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one (2558-30-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: dichloromethane / 12 h / 0 - 20 °C 2: hexamethylenetetramine; ammonium chloride / ethanol / 4 h / Reflux View Scheme

5-(2-fluorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one (2558-30-7) → 2-amino-5-nitro-2'-fluorobenzophenone (344-80-9)

Conditions	Yield
With hydrogenchloride In ethanol Heating;

5-(2-fluorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one (2558-30-7) → 7-amino-5-(2-fluoro-phenyl)-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one + 5-(2-fluoro-phenyl)-7-hydroxyamino-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one

Conditions	Yield
With boric acid; sodium phosphate; citric acid; Triton X-100 In N,N-dimethyl-formamide Mechanism; var. pH's; d.c. polarography, cyclic voltammetry, a.c. polarography and differential pulse polarography reduction;

5-(2-fluorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one (2558-30-7) → 2-amino-2'-[o-fluoro-α-(hydroxylimino)benzyl]-4'-nitro-acetanilide

Conditions	Yield
With hydroxylamine hydrochloride In pyridine; dichloromethane

Ethyl isocyanoacetate (2999-46-4) + diethyl chlorophosphate (814-49-3) + 5-(2-fluorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one (2558-30-7) → 6-(2-fluoro-phenyl)-8-nitro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxylic acid ethyl ester (69796-86-7)

Conditions	Yield
In tetrahydrofuran; dichloromethane; acetic acid; ethyl acetate

Lawessons reagent (19172-47-5) + 5-(2-fluorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one (2558-30-7) → 7-nitro-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepine-2-thione (68210-63-9)

Conditions	Yield
In N,N,N,N,N,N-hexamethylphosphoric triamide; water

5-(2-fluorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one (2558-30-7) → 2-amino-5-(2-fluorophenyl)-7-nitro-3H-1,4-benzodiazepine

Conditions	Yield
Multi-step reaction with 2 steps 1: N,N,N,N,N,N-hexamethylphosphoric triamide; water 2: ammonium hydroxide / tetrahydrofuran View Scheme

5-(2-fluorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one (2558-30-7) → 6-(2-Fluorophenyl)-8-nitro-4H-imidazo[1,2-a][1,4]benzodiazepine-2 methanol

Conditions	Yield
Multi-step reaction with 3 steps 1: N,N,N,N,N,N-hexamethylphosphoric triamide; water 2: ammonium hydroxide / tetrahydrofuran 3: hydrogenchloride; sodium bicarbonate; sodium carbonate; toluene-4-sulfonic acid / 1,4-dioxane; ethanol; dichloromethane; chloroform; water; ethyl acetate View Scheme

diethyl chlorophosphate (814-49-3) + 5-(2-fluorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one (2558-30-7) → C19H19FN3O6P

Conditions	Yield
Stage #1: 5-(2-fluorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one With potassium tert-butylate In tetrahydrofuran at 0℃; for 0.333333h; Inert atmosphere; Stage #2: diethyl chlorophosphate In tetrahydrofuran at -20 - 0℃; for 0.583333h; Inert atmosphere;

Upstream product

• 100-97-0 hexamethylenetetramine 
• 344-80-9 2-amino-5-nitro-2'-fluorobenzophenone 
• 1622-62-4 flunitrazepam 
• 52130-86-6 2-bromo-2'-(2-fluorobenzoyl)-4'-nitroacetanilide 

Downstream Products

• 68210-63-9 7-nitro-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepine-2-thione 
• 69796-86-7 6-(2-fluoro-phenyl)-8-nitro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxylic acid ethyl ester 
• 344-80-9 2-amino-5-nitro-2'-fluorobenzophenone 

Relevant articles and documents

Improved and scalable methods for the synthesis of midazolam drug and its analogues using isocyanide reagents

Abstract: In this research, two improved and scalable methods for the synthesis of midazolam and its analogues have been described. Midazolam has been synthesized using isocyanide reagents in satisfactory yield. In this methodology, imidazobenzodiazepine intermediates can be easily prepared via an improved process. One-pot condensation of benzodiazepines with mono-anion of tosylmethyl isocyanide or ethyl isocyanoacetate under mild condition led to formation of imidazobenzodiazepine. In the first method, tosylmethyl isocyanide (Tos-MIC) is used and the number of synthetic steps are decreased in comparison to previous report. In the second method, ethyl isocyanoacetate which is commonly used for the synthesis of some imidazobenzodiazepines, is consumed to generate midazolam. The latter, a relatively different method for the synthesis of midazolam analogues has been reported. Graphical abstract: [Figure not available: see fulltext.].

Prediction of metabolic clearance using fresh human hepatocytes: Comparison with cryopreserved hepatocytes and hepatic microsomes for five benzodiazepines

1. Predictions of in vivo intrinsic clearance from cryopreserved human hepatocytes may be systematically low. In the current study, the metabolite kinetics of a series of CYP3A4 substrates (benzodiazepines) in fresh human hepatocytes from five donors, via a major UK supplier, were investigated and compared with those previously reported (by the authors' laboratory) for cryopreserved human hepatocytes and hepatic microsomes. 2. A high incidence of autoactivation (up to tenfold) and heteroactivation (by testosterone, up to 14-fold) among the major pathways was observed. CYP capacity (Vmax) was marginally lower and 'affinity' constants (KM, S50) were marginally greater compared with cryopreserved hepatocytes. 3. Average intrinsic clearance (based on maximal clearance, CLmax) was sevenfold lower than in cryopreserved hepatocytes (reflecting sensitivity of intrinsic clearance estimation in vitro to mechanistic parameter values, particularly those involving atypical kinetics), but scaled intrinsic clearances for fresh (and cryopreserved) hepatocytes were within the range previously determined in hepatic microsomes. 4. There was no evidence from this series of studies that fresh hepatocytes provide quantitatively improved estimates of intrinsic clearance over cryopreserved hepatocytes.

Process for preparing benzodiazepines

1,4-Benzodiazepin-2-ones are prepared via the reaction of a haloacetamidophenyl ketone with hexamethylenetetramine in the presence of ammonia. The 1,4-benzodiazepin-2-ones so prepared are known compounds useful as muscle relaxant and anti-convulsant agents.