Diazapam Chemical Properties

Melting point:

131.5-134.5°C

Boiling point:

497.4±45.0 °C(Predicted)

Density 

1.2245 (rough estimate)

refractive index 

1.6330 (estimate)

Flash point:

11 °C

storage temp. 

2-8°C

solubility 

45% (w/v) aq 2-hydroxypropyl-β-cyclodextrin: 1.6 mg/mL

form 

A neat solid

pka

3.4(at 25℃)

Water Solubility 

50mg/L(25 ºC)

BCS Class

1

Stability:

Stable. Light-sensitive. Incompatible with strong oxidizing agents.

CAS DataBase Reference

439-14-5(CAS DataBase Reference)

NIST Chemistry Reference

2H-1,4-benzodiazepin-2-one, 7-chloro-1,3-dihydro-1-methyl-5-phenyl-(439-14-5)

IARC

3 (Vol. Sup 7, 66) 1996

EPA Substance Registry System

Diazepam (439-14-5)

Safety Information

Hazard Codes 

Xn,T,F,Xi

Risk Statements 

21/22-39/23/24/25-23/24/25-11-36/37/38

Safety Statements 

36/37-45-36-26-16-7

RIDADR 

UN 2811 6.1/PG 3

WGK Germany 

2

RTECS 

DF1575000

HazardClass 

6.1(b)

PackingGroup 

III

HS Code 

2933910000

Hazardous Substances Data

439-14-5(Hazardous Substances Data)

Toxicity

LD50 oral in rabbit: 328mg/kg

MSDS

• Language:English Provider:7-Chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one
• Language:English Provider:SigmaAldrich

Diazapam Usage And Synthesis

Description

Diazepam is a yellow crystalline powder.Molecular weight = 284.75; Freezing/Meltingpoint = 125-126℃. Insoluble in water.

Chemical Properties

Light Yellow Crystalline Solid

Chemical Properties

Diazepam is a yellow crystalline powder.

Originator

Valium,Roche,Italy,1962

Uses

Anxiolytic; muscle relaxant (skeletal); anticonvulsant. Controlled substance (depressant).

Uses

Diazepam is an anxiolytic; muscle relaxant (skeletal); anticonvulsant. Diazepam is a controlled substance (depressant).

Uses

Anxiolitic; muscle relaxant (skeletal); anticonvulsant. Controlled substance (depressant)

Definition

ChEBI: Diazepam is a 1,4-benzodiazepinone that is 1,3-dihydro-2H-1,4-benzodiazepin-2-one substituted by a chloro group at position 7, a methyl group at position 1 and a phenyl group at position 5. It has a role as a xenobiotic, an environmental contaminant, an anxiolytic drug, an anticonvulsant and a sedative. It is a 1,4-benzodiazepinone and an organochlorine compound.

Manufacturing Process

Into a stirred, cooled (10°-15°C) solution of 26.2 grams (0.1 mol) of 2-amino5-chlorobenzophenone β-oxime in 150 ml of dioxane were introduced in small portions 12.4 grams (0.11 mol) of chloracetyl chloride and an equivalent amount of 3 N sodium hydroxide. The chloracetyl chloride and sodium hydroxide were introduced alternately at such a rate so as to keep the temperature below 15°C and the mixture neutral or slightly alkaline. The reaction was completed after 30 minutes. The mixture was slightly acidified with hydrochloric acid, diluted with water and extracted with ether. The ether extract was dried and concentrated in vacuum. Upon the addition of ether to the oily residue, the product, 2-chloroacetamido-5-chlorobenzophenone βoxime, crystallized in colorless prisms melting at 161°-162°C.
20 ml of 1 N sodium hydroxide were added to a solution of 6.4 grams (20 mmol) of 2chloroacetamido-5-chlorobenzophenone β-oxime. After 15 hours the mixture was diluted with ice cold 1 N sodium hydroxide and extracted with ether. The ether extract was discarded. The alkaline solution was acidified with hydrochloric acid and extracted with methylene chloride. The methylene chloride solution was concentrated to a small volume and then diluted with petroleum ether to obtain 7-chloro-5-phenyl-3H-1,4-benzodiazepin-2(1H)-one 4-oxide.
To a stirred suspension of 10 grams (35 mmol) of 7-chloro-5-phenyl-3H-1,4- benzodiazepin-2(1H)-one 4-oxide in approximately 150 ml of methanol was added in portions an excess of a solution of diazomethane in ether. After about one hour, almost complete solution had occurred and the reaction mixture was filtered. The filtrate was concentrated in vacuum to a small volume and diluted with ether and petroleum ether. The reaction product, 7- chloro-1-methyl-5-phenyl-3H-1,4-benzodiazepin-2(1H)-one 4-oxide, crystallized in colorless prisms. The product was filtered off and recrystallized from acetone, MP 188°-189°C.
A mixture of 3 grams (0.01 mol) of 7-chloro-1-methyl-5-phenyl-3H-1,4- benzodiazepin-2(1H)-one 4-oxide, 30 ml of chloroform and 1 ml of phosphorus trichloride was refluxed for one hour. The reaction mixture was then poured on ice and stirred with an excess of 40% sodium hydroxide solution. The chloroform was then separated, dried with sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in methylene chloride and crystallized by the addition of petroleum ether. The product, 7- chloro-1-methyl-5-phenyl-3H-1,4-benzodiazepin-2(1H)-one, was recrystallized from a mixture of acetone and petroleum ether forming colorless plates melting at 125°-126°C.
The manufacturing procedure above is from US Patent 3,136,815. Purification of diazepam is discussed in US Patent 3,102,116.

brand name

Diastat (Valeant); Dizac (Pharmacia & Upjohn); Q-Pam (Quantum Pharmics); Valium (Roche).

Therapeutic Function

Tranquilizer

Synthesis Reference(s)

Journal of Heterocyclic Chemistry, 5, p. 731, 1968 DOI: 10.1002/jhet.5570050528

General Description

Diazepam is given orally (Valium) or rectally (Diastat) as anadjunctive treatment in patients with generalized tonic–clonicstatus epilepticus (i.e., an acute and potentially fatal seizure)or in patients with refractory epilepsy in combination withother AEDs.For details on diazepam (Valium), see its discussionunder anxiolytics and sedative–hypnotic agents.

General Description

Diazepam, 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepine-2-one .Like chlordiazepoxide, repeated administration of diazepamleads to accumulation of an active nordazepam,which can be detected in the blood for more than 1 weekafter discontinuation of the drug. This drug is a long actingfor the same reason. Diazepam is metabolized to nordazepamby CYP2C19 and CYP3A4. Cimetidine, by inhibitingCYP3A4, decreases the metabolism and clearanceof diazepam. Thus, drugs that affect the activityof CYP2C19 or CYP3A4 may alter diazepam kinetics.Because diazepam clearance is decreased in the elderlyand in patients with hepatic insufficiency, a dosage reductionmay be warranted. It is widely used for several anxietystates and has an additional wide range of uses (e.g., asan anticonvulsant, a premedication in anesthesiology, andin various spastic disorders).

General Description

Off-white to yellow crystalline powder. Practically odorless. Tasteless at first with a bitter aftertaste.

Air & Water Reactions

Hydrolysis occurs in aqueous solutions with a maximum stability around pH 5. . Insoluble in water.

Fire Hazard

Flash point data for Diazapam are not available; however, Diazapam is probably combustible.

Biological Activity

Ligand at the GABA A receptor benzodiazepine modulatory site. Anxiolytic, anticonvulsant and sedative/hypnotic agent.

Pharmacokinetics

The second group of antispastic drugs to be developed were the benzodiazepines, typified by diazepam. Diazepam exerts its skeletal muscle relaxant effect by binding as an agonist at the benzodiazepine receptor of the GABAA receptor complex, which enhances GABA potency to increase chloride conductance. The muscle relaxant properties of classical benzodiazepines, such as diazepam, appear to be mediated mainly by the GABAA α2 and α3 subunits. The result is neuronal hyperpolarization, probably at both supraspinal and spinal sites for spasmolytic activity. Its actions are sufficient to relieve spasticity in patients with lesions affecting the spinal cord and in some patients with cerebral palsy.

Clinical Use

Benzodiazepine:
Perioperative sedation (IV)
Anxiolytic
Muscle relaxant
Status epilepticus

Side effects

Few high-quality clinical trials have evaluated diazepam as a muscle relaxant, but these few suggest that diazepam is no more efficacious than, for example, carisoprodol, cyclobenzaprine, or tizanidine (i.e., efficacy is marginal). Moreover, diazepam produces drowsiness and fatigue in most patients at doses required to significantly reduce muscle tone.

Safety Profile

Poison by ingestion, parenteral, subcutaneous, intravenous, and intraperitoneal routes. Moderately toxic by skin contact. Questionable carcinogen with experimental tumorigenic data. Human systemic effects: dermatitis, effect on inflammation or mediation of inflammation, change in cardiac rate, somnolence, respiratory depression, and other respiratory changes, visual field changes, diplopia (double vision), change in motor activity, muscle contraction or spasticity, ataxia (loss of muscle coordination), an antipsychotic and general anesthetic. Human reproductive effects by ingestion and intravenous routes causing developmental abnormalities of the fetal cardiovascular (circulatory) system and postnatal effects. Experimental teratogenic and reproductive effects. Human mutation data reported. An allergen. A drug for the treatment of anxiety. When heated to decomposition it emits very toxic fumes of Cl and NOx.

Potential Exposure

Those involved in the manufacture,packaging, or consumption of this widely used tranquilizingdrug.

Drug interactions

Potentially hazardous interactions with other drugs
Antibacterials: metabolism enhanced by rifampicin; metabolism inhibited by isoniazid.
Antifungals: concentration increased by fluconazole and voriconazole - risk of prolonged sedation.
Antipsychotics: increased sedative effects; increased risk of hypotension, bradycardia and respiratory depression with parenteral diazepam and IM olanzapine; risk of serious adverse effects in combination with clozapine
Antivirals: concentration possibly increased by ritonavir.
Sodium oxybate: enhanced effects of sodium oxybate - avoid.

First aid

If this chemical gets into the eyes, remove anycontact lenses at once and irrigate immediately for at least15 min, occasionally lifting upper and lower lids. If thisDiazepam 877chemical contacts the skin, remove contaminated clothingand wash immediately with soap and water

Metabolism

Diazepam is rapidly and completely absorbed after oral administration. Maximum peak blood concentration occurs in 2 hours, and elimination is slow, with a half-life of approximately 20 to 50 hours. As with chlordiazepoxide, the major metabolic product of diazepam is N-desmethyldiazepam, which is pharmacologically active and undergoes even slower metabolism than its parent compound. Repeated administration of diazepam or chlordiazepoxide leads to accumulation of N-desmethyldiazepam, which can be detected in the blood for more than 1 week after discontinuation of the drug. Hydroxylation of N-desmethyldiazepam at the 3-position gives the active metabolite oxazepam.

storage

Store at RT

Shipping

UN2811 Toxic solids, organic, n.o.s., Hazard Class: 6.1; Labels: 6.1-Poisonous materials, Technical Name Required. UN3249 Medicine, solid, toxic, n.o.s., Hazard Class: 6.1; Labels: 6.1-Poisonous materials.

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