963-39-3

Basic information

• Product Name: Demoxepam
• Synonyms: 1,3-dihydro-7-chloro-5-phenyl-2h-1,4-benzodiazepin-2-one4-oxide;2H-1,4-Benzodiazepin-2-one, 1,3-dihydro-7-chloro-5-phenyl-, 4-oxide;2H-1,4-Benzodiazepin-2-one, 7-chloro-1,3-dihydro-5-phenyl-, 4-oxide;4-benzodiazepin-2-one,1,3-dihydro-7-chloro-5-phenyl-2h-4-oxide;4-benzodiazepin-2-one,7-chloro-1,3-dihydro-5-phenyl-2h-4-oxide;7-Chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one 4-oxide;7-Chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one-4-oxid;7-Chloro-1,3-dihydro-5-phenyl-2H-1,4-ben-zodiazepin-2-one4-oxide
• CAS NO: 963-39-3
• Molecular Formula: C₁₅H₁₁ClN₂O₂
• Molecular Weight: 286.71304
• EINECS: 213-515-2
• Product Categories: Aromatics;Heterocycles;Intermediates & Fine Chemicals;Metabolites & Impurities;Pharmaceuticals
• Mol File: 963-39-3.mol
• Article Data: 4

Chemical Properties

• Melting Point: 235-236 °C (decomp)
• Flash Point: 2℃
• Appearance: /
• Density: 1.405 g/cm³
• Refractive Index: 1.682
• Storage Temp.: ?20°C
• PKA: pKa 4.5 (Uncertain)
• CAS DataBase Reference: Demoxepam(CAS DataBase Reference)
• NIST Chemistry Reference: Demoxepam(963-39-3)
• EPA Substance Registry System: Demoxepam(963-39-3)

Safety Data

• Hazard Codes: F,Xn
• Statements: 11-20/21/22-36
• Safety Statements: 16-26-36/37
• RIDADR: UN 1648 3 / PGII
• WGK Germany: 3
• Hazardous Substances Data: 963-39-3(Hazardous Substances Data)

Usage

Uses

A major metabolite of Chlordiazepoxide (C327050). A benzodiapine derivative with anticonvulsant properties.

Synthesis Reference(s)

Journal of Heterocyclic Chemistry, 4, p. 647, 1967 DOI: 10.1002/jhet.5570040435The Journal of Organic Chemistry, 26, p. 4936, 1961

InChI:InChI=1/C15H11ClN2O2/c16-11-6-7-13-12(8-11)15(10-4-2-1-3-5-10)18(20)9-14(19)17-13/h1-8H,9H2,(H,17,19)

Synthetic route

diazepam (439-14-5) → desmethyldiazepam (1088-11-5) + oxazepam (604-75-1) + demoxepam (963-39-3) + diazepam 4-oxide (2888-64-4) + temazepam (846-50-4) + 6-chloro-1-methyl-4-phenyl-2(1H)-quinazolinone (20927-53-1)

Conditions	Yield
With dihydrogen peroxide; 1H-imidazole; {5,10,15,20-tetrakis(pentafluorophenyl)porphynato}manganese(III) chloride; ammonium acetate In 1,1,1,3',3',3'-hexafluoro-propanol; water; 4-methyl-1,2,3-trifluorobenzene for 4.83333h; Product distribution / selectivity;	A 4% B 0% C 0% D 5% E 7% F 1%

chlordiazepoxide (58-25-3) → 6-Chloro-4-hydroxy-3-methyl-4-phenyl-3,4-dihydro-quinazoline-2-carbaldehyde oxime + N-nitrosochlordiazepoxide (51715-17-4) + demoxepam (963-39-3)

Conditions	Yield
With hydrogenchloride; sodium nitrite In water at 37℃; for 1h; Product distribution; varying pH; varying amounts of reagents;

Chlordiazepoxide hydrochloride (438-41-5) → demoxepam (963-39-3)

Conditions	Yield
With water at 37℃; for 960h;

methyl isocyanate (624-83-9) + demoxepam (963-39-3) → 10-chloro-1-methyl-11b-phenyl-7,11b-dihydro-1H-benzo[f][1,2,4]oxadiazolo[2,3-d][1,4]diazepine-2,6-dione (49626-81-5)

Conditions	Yield
In tetrahydrofuran

demoxepam (963-39-3) → 8-chloro-9b-phenyl-5,9b-dihydro-benzo[f]oxazirino[2,3-d][1,4]diazepin-4-one (27090-87-5)

Conditions	Yield
In tetrahydrofuran Irradiation;

trifluoroacetic anhydride (407-25-0) + demoxepam (963-39-3) → Trifluoro-acetic acid 7-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl ester

Conditions	Yield
for 1.5h;

demoxepam (963-39-3) → 6-chloro-4-phenyl-2-quinazolinone (4797-43-7)

Conditions	Yield
With sodium hydroxide for 0.5h; Irradiation;
for 0.5h; Irradiation;

demoxepam (963-39-3) → [3-2H2]nordiazepam 4-oxide (181648-03-3)

Conditions	Yield
With deuteriated sodium hydroxide In deuteromethanol for 8h; Heating;	0.92 g

demoxepam (963-39-3) → <3-2H>oxazepam

Conditions	Yield
Multi-step reaction with 3 steps 1: 0.92 g / NaOD / CH3OD / 8 h / Heating 2: 1 g / 3 h / Heating 3: 0.49 g / NaOD / CH3OD / 0.5 h / Ambient temperature View Scheme

demoxepam (963-39-3) → 3,3-dideuterio-7-chloro-1-methyl-5-phenyl-1H-benzo[e][1,4]diazepine-2(3H)-one

Conditions	Yield
Multi-step reaction with 3 steps 1: 0.92 g / NaOD / CH3OD / 8 h / Heating 2: 0.79 g / PCl3 / CHCl3 / 3 h / Heating 3: 1.) 4M NaOD / 1.) CH3CN, 5 min, 2.) CH3CN, RT, 5 h View Scheme

demoxepam (963-39-3) → [3-2H]oxazepam 3-acetate (181648-04-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: 0.92 g / NaOD / CH3OD / 8 h / Heating 2: 1 g / 3 h / Heating View Scheme

demoxepam (963-39-3) → <3-2H2>nordiazepam (51278-96-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: 0.92 g / NaOD / CH3OD / 8 h / Heating 2: 0.79 g / PCl3 / CHCl3 / 3 h / Heating View Scheme

demoxepam (963-39-3) → 7-chloro-3-fluoro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one-3d

Conditions	Yield
Multi-step reaction with 5 steps 1: 1.5 h 2: aq. 5 percent sodium bicarbonate / ethanol / 18 h / 25 °C 3: 82 percent / diethylaminosulfur trifluoride / CH2Cl2 / 1.) -70 deg C, 2.) to -10 deg C, 25 min 4: 50 percent / sodium hydride / tetrahydrofuran / 3 h / 25 °C 5: 26 g / 2 N NaOD, deuterium oxide / dimethylformamide View Scheme

demoxepam (963-39-3) → oxazepam (604-75-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1.5 h 2: aq. 5 percent sodium bicarbonate / ethanol / 18 h / 25 °C View Scheme

demoxepam (963-39-3) → 1-allyl-7-chloro-3-fluoro-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one (62659-56-7)

Conditions	Yield
Multi-step reaction with 4 steps 1: 1.5 h 2: aq. 5 percent sodium bicarbonate / ethanol / 18 h / 25 °C 3: 82 percent / diethylaminosulfur trifluoride / CH2Cl2 / 1.) -70 deg C, 2.) to -10 deg C, 25 min 4: 64 percent / sodium hydride / tetrahydrofuran / 2 h / 25 °C View Scheme

demoxepam (963-39-3) → 7-chloro-3-fluoro-2-oxo-5-phenyl-2,3-dihydro-benzo[e][1,4]diazepine-1-carboxylic acid methylamide (62659-61-4)

Conditions	Yield
Multi-step reaction with 4 steps 1: 1.5 h 2: aq. 5 percent sodium bicarbonate / ethanol / 18 h / 25 °C 3: 82 percent / diethylaminosulfur trifluoride / CH2Cl2 / 1.) -70 deg C, 2.) to -10 deg C, 25 min 4: 56 percent / benzene / 48 h / Heating View Scheme

demoxepam (963-39-3) → 7-chloro-3-fluoro-2-oxo-5-phenyl-2,3-dihydro-benzo[e][1,4]diazepine-1-carboxylic acid ethylamide (62659-62-5)

Conditions	Yield
Multi-step reaction with 4 steps 1: 1.5 h 2: aq. 5 percent sodium bicarbonate / ethanol / 18 h / 25 °C 3: 82 percent / diethylaminosulfur trifluoride / CH2Cl2 / 1.) -70 deg C, 2.) to -10 deg C, 25 min 4: 54 percent / benzene / 48 h / Heating View Scheme

demoxepam (963-39-3) → 3-fluoro-5-phenyl-7-chloro-2,3-dihydro-1H-1,4-benzodiazepin-2-one (60628-57-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: 1.5 h 2: aq. 5 percent sodium bicarbonate / ethanol / 18 h / 25 °C 3: 82 percent / diethylaminosulfur trifluoride / CH2Cl2 / 1.) -70 deg C, 2.) to -10 deg C, 25 min View Scheme
With SbCl5; HF

demoxepam (963-39-3) → 3-fluoro-1,3-dihydro-1-methyl-7-chloro-5-phenyl-2H-1,4-benzodiazepin-2-one (60628-55-9)

Conditions	Yield
Multi-step reaction with 4 steps 1: 1.5 h 2: aq. 5 percent sodium bicarbonate / ethanol / 18 h / 25 °C 3: 82 percent / diethylaminosulfur trifluoride / CH2Cl2 / 1.) -70 deg C, 2.) to -10 deg C, 25 min 4: 50 percent / sodium hydride / tetrahydrofuran / 3 h / 25 °C View Scheme

demoxepam (963-39-3) → 10-chloro-1-methyl-2,6-dioxo-11b-phenyl-1,5,6,11b-tetrahydro-2H-benzo[f][1,2,4]oxadiazolo[2,3-d][1,4]diazepine-7-carboxylic acid methylamide (49626-82-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: tetrahydrofuran 2: tetrahydrofuran View Scheme

Re(CO)2(P(C6H5)3)2Cl (35796-29-3) + demoxepam (963-39-3) → Re(CO)2(P(C6H5)3)2(C15H10ClN2O2) (206127-02-8)

Conditions	Yield
With NEt3 In ethanol; dichloromethane addn. of 2 equiv. of ligand soln. (in EtOH) to Re-complex soln. (in CH2Cl2/EtOH=2:1), refluxing with few drops of NEt3 for 3 h; concn., crystn. on EtOH addn., filtration, washing (H2O, EtOH, Et2O), recrystn. (CH2Cl2/EtOH); elem. anal.;

Tc(CO)2(P(C6H5)3)2Cl + demoxepam (963-39-3) → Tc(CO)2(P(C6H5)3)2(C15H10ClN2O2)

Conditions	Yield
With NEt3 In ethanol; dichloromethane addn. of 2 equiv. of ligand soln. (in EtOH) to Tc-complex soln. (in CH2Cl2/EtOH=2:1), refluxing with few drops of NEt3 for 3 h; concn., crystn. on EtOH addn., filtration, washing (H2O, EtOH, Et2O), recrystn. (CH2Cl2/EtOH); elem. anal.;

Upstream product

• 438-41-5 Chlordiazepoxide hydrochloride 
• 439-14-5 diazepam 
• 58-25-3 chlordiazepoxide 

Downstream Products

• 206127-02-8 Re(CO)2(P(C₆H₅)3)2(C₁₅H₁₀ClN₂O₂) 
• 60628-55-9 3-fluoro-1,3-dihydro-1-methyl-7-chloro-5-phenyl-2H-1,4-benzodiazepin-2-one 
• 60628-57-1 3-fluoro-5-phenyl-7-chloro-2,3-dihydro-1H-1,4-benzodiazepin-2-one 
• 62659-62-5 7-chloro-3-fluoro-2-oxo-5-phenyl-2,3-dihydro-benzo[e][1,4]diazepine-1-carboxylic acid ethylamide 
• 62659-61-4 7-chloro-3-fluoro-2-oxo-5-phenyl-2,3-dihydro-benzo[e][1,4]diazepine-1-carboxylic acid methylamide 
• 62659-56-7 1-allyl-7-chloro-3-fluoro-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one 
• 604-75-1 oxazepam 
• 181648-03-3 [3-2H₂]nordiazepam 4-oxide 
• 27090-87-5 8-chloro-9b-phenyl-5,9b-dihydro-benzo[f]oxazirino[2,3-d][1,4]diazepin-4-one 
• 49626-81-5 10-chloro-1-methyl-11b-phenyl-7,11b-dihydro-1H-benzo[f][1,2,4]oxadiazolo[2,3-d][1,4]diazepine-2,6-dione 
• 4797-43-7 6-chloro-4-phenyl-2-quinazolinone 
• 181648-04-4 [3-2H]oxazepam 3-acetate 

Relevant articles and documents

The rapid hydrolysis of chlordiazepoxide to demoxepam may affect the outcome of chronic osmotic minipump studies

Background: In chronic studies, the classical benzodiazepine chlordiazepoxide (CDP) is often the preferred drug because, unlike other benzodiazepines, it is soluble in water. However, rapid CDP hydrolysis in solution has been described. This would diminish plasma levels in chronic minipump studies and introduce the corelease of active compounds. Methods: Therefore, the present study aimed to explore the putative hydrolysis of CDP in aqueous solution over time and to identify the hydrolysis products. Moreover, we aimed to characterize the hydrolysis products for their in vitro ( 3H-flunitrazepam binding and oocyte electrophysiology) and in vivo (stress-induced hyperthermia paradigm) GABAA receptor potency. Results: CDP in solution hydrolyzed to the ketone structure demoxepam which was confirmed using mass spectrometry. The hydrolysis was concentration dependent (first-order kinetics) and temperature dependent. CDP exerted greater potency compared to demoxepam in vitro (increased activity at GABAA receptors containing α1 subunits) and in vivo (stress-induced hyperthermia), although 3H-flunitrazepam binding was comparable. Conclusions: The classical benzodiazepine CDP is rapidly hydrolyzed in solution to the active compound demoxepam which possesses a reduced activity at the GABAA receptor. Chronic studies that use CDP in aqueous solution should thus be interpreted with caution. It is therefore important to consider drug stability in chronic minipump applications.

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HPLC analysis of the nitrosation products of chlordiazepoxide

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