1088-11-5

Basic information

• Product Name: Nordazepam
• Synonyms: DESMETHYLDIAZEPAM;7-CHLORO-1,3-DIHYDRO-5-PHENYL-2H-1,4-BENZODIAZEPIN-2-ONE;RO 5-2180;NORDIAZEPAM;1,3-dihydro-7-chloro-5-phenyl-2h-4-benzodiazepin-2-one;1-Demethyldiazepam;2H-1,4-Benzodiazepin-2-one, 1,3-dihydro-7-chloro-5-phenyl-;2H-1,4-Benzodiazepin-2-one, 7-chloro-1,3-dihydro-5-phenyl-
• CAS NO: 1088-11-5
• Molecular Formula: C₁₅H₁₁ClN₂O
• Molecular Weight: 270.71
• EINECS: 214-123-4
• Product Categories: ACTIVE PHARMACEUTICAL INGREDIENTS;Metabolites & Impurities;Neurochemicals;Aromatics;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 1088-11-5.mol
• Article Data: 35

Chemical Properties

• Melting Point: 208-210°C
• Boiling Point: 453.103 °C at 760 mmHg
• Flash Point: 11 °C
• Appearance: white to light tan/
• Density: 1.2576 (rough estimate)
• Vapor Pressure: 2.12E-08mmHg at 25°C
• Refractive Index: 1.6330 (estimate)
• Storage Temp.: 2-8°C
• Solubility: DMSO: >10mg/mL
• PKA: pKa 3.5 12.0 (5%MeOH in H2O t=20 I=0.15) (Uncertain)
• CAS DataBase Reference: Nordazepam(CAS DataBase Reference)
• NIST Chemistry Reference: Nordazepam(1088-11-5)
• EPA Substance Registry System: Nordazepam(1088-11-5)

Safety Data

• Hazard Codes: Xn,T,F
• Statements: 22-39/23/24/25-23/24/25-11
• Safety Statements: 7-16-36/37-45
• RIDADR: 3249
• WGK Germany: 3
• RTECS: DF1750000
• HazardClass: 6.1(b)
• PackingGroup: III
• Hazardous Substances Data: 1088-11-5(Hazardous Substances Data)

Usage

Chemical Properties

Off-White Solid

Originator

Madar,Ravizza, Italy ,1973

Uses

Different sources of media describe the Uses of 1088-11-5 differently. You can refer to the following data:
1. The primary metabolite of diazepam. A ligand for the GABAA receptor benzodiazepine modulatory site. This is a controlled drug precursor therefore a liscence may be required for purchase
2. The primary metabolite of Diazepam. A ligand for the GABAA receptor benzodiazepine modulatory site. Anxiolytic. Controlled substance (depressant).

Definition

ChEBI: A 1,4-benzodiazepinone having phenyl and chloro substituents at positions 5 and 7 respectively; it has anticonvulsant, anxiolytic, muscle relaxant and sedative properties but is used primarily in the treatment of anxiety.

Manufacturing Process

A solution of 3.1 g of (2-benzoyl-4-chlorophenyl-carbamoylmethyl)carbamic acid benzyl ester in 30 cc of 20% hydrobromic acid in glacial acetic acid was stirred for 45 minutes at room temperature. On addition of 175 cc of anhydrous ether, a gummy solid precipitated. After several minutes the ether solution was decanted. The resultant 5-chloro-2-glycylaminobenzophenone was not isolated, but about 155 cc of ether was added to the residue and after chilling in an ice bath, 10% sodium hydroxide was added until the mixture was alkaline. The ether layer was then separated, washed twice with water and dried over sodium sulfate. After filtration, the ether solution was concentrated to dryness in vacuo. The residue was crystallized from benzene to yield 7-chloro-5-phenyl-3H-1,4-benzodiazepin-2(1H)-one.

Therapeutic Function

Tranquilizer

Synthesis Reference(s)

Journal of Heterocyclic Chemistry, 25, p. 459, 1988 DOI: 10.1002/jhet.5570250220The Journal of Organic Chemistry, 26, p. 4936, 1961 DOI: 10.1021/jo01070a038

InChI:InChI=1/C15H11ClN2O/c16-11-6-7-13-12(8-11)15(17-9-14(19)18-13)10-4-2-1-3-5-10/h1-8H,9H2,(H,18,19)

Upstream product

• 719-59-5 5-chloro-2-aminobenzophenone 
• 598-21-0 2-Bromoacetyl bromide 
• 79-04-9 chloroacetyl chloride 
• 4076-50-0 2-amino-4-chlorobenzophenone 
• 5680-79-5 glycine ethyl ester hydrochloride 
• 1350621-35-0 tert-butyl (2-((2-benzoyl-4-chlorophenyl)amino)-2-oxoethyl)carbamate 
• 4530-20-5 BOC-glycine 
• 506-87-6 ammonium carbonate 
• 32580-26-0 2-(2-bromoacetamido)-5-chloro-benzophenone 
• 18091-89-9 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine 
• 439-14-5 diazepam 
• 4016-85-7 5-chloro-2-(chloroacetylamino)benzophenone 
• 100-97-0 hexamethylenetetramine 
• 2147-78-6 N,N'-methylenebis<3-(2-benzoyl-4'-chloro)phenyl>-4-imidazolidinone 

Downstream Products

• 55056-38-7 7-chloro-3-furfurylidene-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one 
• 55056-39-8 7-chloro-5-phenyl-3-thiophen-2-ylmethylene-1,3-dihydro-benzo[e][1,4]diazepin-2-one 
• 2878-73-1 7-chloro-2-methyl-9-phenyl-[1,3]oxazolo[5,4-b]quinoline 
• 39683-90-4 10-chloro-3,11b-diphenyl-7,11b-dihydro-benzo[f][1,2,4]oxadiazolo[4,5-d][1,4]diazepin-6-one 
• 39683-96-0 3-tert-butyl-10-chloro-11b-phenyl-7,11b-dihydro-benzo[f][1,2,4]oxadiazolo[4,5-d][1,4]diazepin-6-one 
• 90503-69-8 7-chloro-5-phenyl-1-<3-(4-phenylpiperazino)propyl>-1,3-dihydro-1,4-benzodiazepin-2-one 
• 59318-11-5 di-morpholin-4-yl-phosphinic acid 7-chloro-5-phenyl-3H-benzo[e][1,4]diazepin-2-yl ester 
• 133473-91-3 α-(7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-ylidene)-α-nitroacetic acid ethyl ester 
• 439-14-5 diazepam 
• 51752-98-8 3-(dimethylaminomethylene)-5-phenyl-7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one 
• 55262-23-2 10-chloro-7,11b-dihydro-11b-phenyl-thiazolo<3,2-d><1,4>benzodiazepine-3,6(2H,5H)-dione 
• 67974-46-3 2-(2-dimethylaminoethylthio)-5-phenyl-7-chloro-3H-1,4-benzodiazepine 
• 5571-65-3 7-chloro-5-phenyl-1,3-dihydro-1-ethyl-2H-1,4-benzodiazepin-2-one 
• 50-00-0 formaldehyd 

Relevant articles and documents

Kinetics of diazepam metabolism in rat hepatic microsomes and hepatocytes and their use in predicting in vivo hepatic clearance

The rates of diazepam (DZ) metabolism to the primary metabolites 3-hydroxydiazepam, 4'-hydroxydiazepam and nordiazepam were studied in vitro using rat hepatic microsomes and hepatocytes. 4'-hydroxydiazepam had the largest intrinsic clearance (V(max)/K(m) ratio, CL(int)) in both microsomes and hepatocytes representing 49 and 70% of total metabolism respectively. Whereas the contribution of 3-hydroxydiazepam was similar in both systems (21-24%), the N-demethylation pathway was greater in microsomes (27%) than hepatocytes (9%). The pharmacokinetics of DZ were determined in vivo using the intraportal route to avoid blood flow limitations due to the high clearance of DZ. No dose dependency was observed in either clearance or steady state volume of distribution, which were estimated to be 38 ml/min/SRW (where SRW is a standard rat weight of 250g) and 1.3 L/SRW respectively. Blood binding of DZ was concentration independent, the unbound fraction being 0.22. Scaling factors were used to relate the in vitro CL(int) to the in vivo unbound clearance. Hepatocytes (123 ml/min/SRW) produced a more realistic prediction for the in vivo value (174ml/min/SRW) than microsomes (41 ml/min/SRW). This situation is believed to arise from the quantitative differences in the three metabolic pathways in the two in vitro systems. It is speculated that end product inhibition is responsible for reduced total metabolism in microsomes whereas hepatocytes operate kinetically in a manner close to in vivo.

Photopotentiation of the GABAA receptor with caged diazepam

As the inhibitory γ-aminobutyric acid–ergic (GABAergic) transmission has a pivotal role in the central nervous system (CNS) and defective forms of its synapses are associated with serious neurological disorders, numerous versions of caged GABA and, more recently, photoswitchable ligands have been developed to investigate such transmission. While the complementary nature of these probes is evident, the mechanisms by which the GABA receptors can be pho-tocontrolled have not been fully exploited. In fact, the ultimate need for specificity is critical for the proper synaptic exploration. No caged allosteric modulators of the GABAA receptor have been reported so far; to introduce such an investigational approach, we exploited the structural motifs of the benzodiazepinic scaffold to develop a pho-tocaged version of diazepam (CD) that was tested on basolateral amygdala (BLa) pyramidal cells in mouse brain slices. CD is devoid of any intrinsic activity toward the GABAA receptor before irradiation. Importantly, CD is a photoreleasable GABAA receptor-positive allosteric modulator that offers a different probing mechanism compared to caged GABA and photoswitchable ligands. CD potenti-ates the inhibitory signaling by prolonging the decay time of postsynaptic GABAergic currents upon photoactivation. Additionally, no effect on presynaptic GABA release was recorded. We developed a photochemical technology to individually study the GABAA receptor, which specifically expands the toolbox available to study GABAergic synapses.

Unexpected Reactivity of N-Acyl-Benzotriazoles with Aromatic Amines in Acidic Medium (ABAA Reaction)

Despite the large number of methods for the synthesis of amides, formation of the amide bond from aromatic amines has always been a challenge for organic chemists due to their weak nucleophile character. We describe here a new efficient method of amide formation from N-Acyl-Benzotriazoles and Aromatic Amines (ABAA reaction) including aniline derivatives, in acidic conditions. This reaction is selective for aromatic amines, since aliphatic amines did not react under the same experimental conditions. Using the ABAA reaction, we have synthesized a series of aromatic amide compounds including labelled enzyme substrates, in excellent yield. The ABAA reaction also allowed the one-pot synthesis of Nordiazepam, which is a precursor of the anxiolytic Diazepam (Valium). This procedure opens new ways of synthesis of amides from aromatic amines, as well as of heterocyclic structures.

Structure-Activity Relationship Studies of Retro-1 Analogues against Shiga Toxin

High-throughput screening has shown that Retro-1 inhibits ricin and Shiga toxins by diminishing their intracellular trafficking via the retrograde route, from early endosomes to the Golgi apparatus. To improve the activity of Retro-1, a structure-activity relationship (SAR) study was undertaken and yielded an analogue with a roughly 70-fold better half-maximal effective concentration (EC50) against Shiga toxin cytotoxicity measured in a cell protein synthesis assay.

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.].