28911-01-5

Basic information

• Product Name: Triazolam
• Synonyms: Triazolam CIV (200 mg);Triazolam solution ;8-CHLORO-6-(2-CHLOROPHENYL)-1-METHYL-4H-1,2,4-TRIAZOLO[4,3-A]1,4-BENZODIAZEPINE;TRIAZOLAM;3-a)(1,4)benzodiazepine,8-chloro-6-(o-chlorophenyl)-1-methyl-4h-s-triazolo(;4h-(1,2,4)triazolo(4,3-a)(1,4)benzodiazepine,8-chloro-6-(2-chlorophenyl)-1-m;4H-[1,2,4]Triazolo[4,3-a][1,4]benzodiazepine, 8-chloro-6-(2-chlorophenyl)-1-methyl-;4H-s-Triazolo(4,3-a)(1,4)benzodiazepine, 8-chloro-6-(o-chlorophenyl)-1-methyl-
• CAS NO: 28911-01-5
• Molecular Formula: C₁₇H₁₂Cl₂N₄
• Molecular Weight: 343.21
• EINECS: 249-307-3
• Product Categories: Heterocycles;Metabolites & Impurities;API;Aromatics, Heterocycles, Metabolites & Impurities, Pharmaceuticals, Intermediates & Fine Chemicals;Organics;Intermediates & Fine Chemicals;Pharmaceuticals;Aromatics
• Mol File: 28911-01-5.mol

Chemical Properties

• Melting Point: 209-212°C
• Boiling Point: 499.51°C (rough estimate)
• Flash Point: 11 °C
• Appearance: white crystalline powder
• Density: 1.2835 (rough estimate)
• Vapor Pressure: 1.51E-11mmHg at 25°C
• Refractive Index: 1.6300 (estimate)
• Storage Temp.: 2-8°C
• PKA: pKa 1.52(H2O) (Uncertain);6.5(H2O) (Uncertain)
• Water Solubility: 30mg/L(ambient temperature)
• CAS DataBase Reference: Triazolam(CAS DataBase Reference)
• NIST Chemistry Reference: Triazolam(28911-01-5)
• EPA Substance Registry System: Triazolam(28911-01-5)

Safety Data

• Hazard Codes: F,T
• Statements: 11-23/24/25-36/38-39/23/24/25
• Safety Statements: 22-24/25-26-36-45-36/37-16-7
• RIDADR: 3249
• WGK Germany: 2
• RTECS: XZ5472500
• HazardClass: 6.1(b)
• PackingGroup: III
• Hazardous Substances Data: 28911-01-5(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Triazolam is used as a hypnotic agent for the treatment of insomnia and other sleep disorders. Its ultra-short-acting nature allows for effective sleep induction with minimal residual effects, making it suitable for patients who require rapid sleep onset and do not want to experience significant sedation during the day.
Used in Elderly Care:
Triazolam is used as a sleep aid for elderly patients, as it causes less daytime sedation compared to other benzodiazepines. This makes it a preferred choice for older individuals who may be more sensitive to the sedative effects of medications.
Used in Drug Interaction Studies:
Triazolam is used in research to study the effects of drug interactions on its metabolism. For example, the increase in peak plasma concentration when coadministered with grapefruit juice can provide insights into how certain substances can affect the metabolism and efficacy of medications.
Used in Toxicology and Forensic Science:
Triazolam's potent sedative effects and rapid metabolism make it a subject of interest in toxicology and forensic science. It can be analyzed in biological samples to determine the presence of the drug in cases of overdose, impaired driving, or other situations where the influence of sedatives is a concern.

Originator

Halcion,Upjohn,Switz.,1978

Manufacturing Process

A mixture of 1.0g (0.0031 mol) of 7-chloro-1,3-dihydro-5-(o-chlorophenyl)- 2H-1,4-benzodiazepine-2-thione, 0.8 g (0.0108 mol) of acetic acid hydrazide and 40 ml of 1-butanol was heated at reflux temperature under nitrogen for 24 hours. During the first 5 hours the nitrogen was slowly bubbled through the solution. After cooling and removing the solvent in vacuo, the product was well mixed with water and collected on a filter, giving 0.9 g of orange solid, melting point 210°C to 212°C. This was heated under nitrogen in an oil bath at 250°C and then cooled, The solid was crystallized from ethyl acetate, giving 0.5 g of tan solid of melting point 215°C to 216°C (decomposition). This was dissolved in 25 ml of 2-propanol, filtered, concentrated to10 ml and cooled, yielding 0.46 g (43%) of tan, crystalline 8-chloro-1-methyl-6-(o_x0002_chlorophenyl)-4H-s-triazolo[4,3-a][1,4]-benzodiazepine of melting point 223°C to 225°C.

Therapeutic Function

Hypnotic

World Health Organization (WHO)

Triazolam, a benzodiazepine derivative with sedative and hypnotic activity, was introduced in 1978 for themanagement of insomnia. It is controlled under Schedule IV of the 1971 Convention of Psychotropic Substances. Concern regarding the psychotropic effects of triazolam was first raised in the Netherlands in 1979 when Triazolam was suspended for sale and subsequently withdrawn by the Committee for the Evaluation of Medicines on the basis of reports of a reversible complex of symptoms including paranoia, depersonalization, nightmares, suicidal tendency and hyperaesthesia in patients receiving the drug. The basis for this decision was later successfully contested by the manufacturer and the drug was reregistered in early 1990 with a revised product information. However, concern was regenerated elsewhere that higher doses are associated with an unacceptable incidence of unwanted effects and the manufacturer has eventually withdrawn 0.5 mg tablets on a worldwide basis. In 1991 the issue of the safety of triazolam was again reopened by reports of retrograde amnesia and depression among patients taking the decreased recommended dosages. The product information has been revised by the United States FDA to include more rigorous cautions regarding dosage. In the Member States of the European Communities the products have been suspended pending further review by the EC Committee on Proprietary Medicinal Products.

InChI:InChI=1/C17H12Cl2N4/c1-10-21-22-16-9-20-17(12-4-2-3-5-14(12)19)13-8-11(18)6-7-15(13)23(10)16/h2-8H,9H2,1H3

Upstream product

• 1068-57-1 acetic acid hydrazide 
• 59467-72-0 7-chloro-5-(2-chlorophenyl)-2-(N-nitrosomethylamino)-3H-1,4-benzodiazepine 
• 2894-71-5 7-chloro-1,3-dihydro-5-(o-chlorophenyl)-2H-1,4-benzodiazepine-2-thione 
• 71-36-3 butan-1-ol 
• 144-55-8 sodium hydrogencarbonate 
• 54196-62-2 5-chloro-2-(3-hydroxymethyl-5-methyl-4H-1,2,4-triazol-4-yl)-2'-chlorobenzophenone 
• 2894-67-9 delorazepam 
• 54196-63-3 N-<<4-(2-Benzoyl-4-chlorophenyl)-5-methyl-4H-1,2,4-triazol-3-yl>-methyl>phthalimide 
• 54196-64-4 N-<<4-<4-Chloro-2-(2-chlorobenzoyl)phenyl>-5-methyl-4H-1,2,4-triazol-3-yl>methyl>phthalimide 
• 108209-90-1 Methanone 

Downstream Products

• 121899-08-9 1-methyl-4-<(dimethylamino)methyl>-8-chloro-6-(o-chlorophenyl)-4H-s-triazolo<4,3-a><1,4>benzodiazepine 
• 108209-90-1 Methanone 
• 54305-10-1 8-Chloro-6-(2-chloro-phenyl)-1-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene 
• 65686-11-5 4-Hydroxytriazolam 
• 37115-45-0 1'-hydroxytriazolam 
• 53257-72-0 {2-[8-chloro-6-(2-chloro-phenyl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-1-yl]-ethyl}-dimethyl-amine 
• 60700-35-8 N-{2-[8-chloro-6-(2-chloro-phenyl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-1-yl]-ethyl}-phthalimide 
• 72874-62-5 1-(2-aminoethyl)-8-chloro-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine 

Relevant articles and documents

IMPROVED PROCESS FOR PREPARATION OF TRIAZOL-BENZODIAZEPINE DERIVATIVES

An improved process for preparation of triazol-benzodiazepine derivatives, such as alprazolam, triazolam, brotizolam and etizolam, is presented. The process comprises a cyclization reaction of compound Formula B in toluene with catalytic amount of p-toluene sulphonic acid to obtain the triazol-benzodiazepine derivative of Formula C: wherein R is, and X is hydrogen or halogen.

PROCESS FOR PREPARATION OF TRIAZOL-BENZODIAZEPINE DERIVATIVES

An improved process for preparation of triazol-benzodiazepine derivatives, such as alprazolam, triazolam, brotizolam and etizolam, is presented. The process comprises a cyclization reaction of compound Formula B in toluene with catalytic amount of p-toluene sulphonic acid to obtain the triazol-benzodiazepine derivative of Formula C: wherein R is, and X is hydrogen or halogen.

1,4-Benzodiazepine N-nitrosoamidines: Useful intermediates in the synthesis of tricyclic benzodiazepines

1,4-Benzodiazepine N-nitrosoamidines have been used as scaffolds for the preparation of different tricyclic derivatives. Replacement of the N-nitrosoamidine moiety through treatment with the nucleophiles acetylhydrazine, aminoacetaldehyde dimethylacetal and 1-amino-2-propanol, followed by an acid-catalyzed cyclization step, afforded triazolo and imidazobenzodiazepines 1, 6, and 7, respectively, in good yields. When acetylhydrazine is used as a nucleophile, the overall process provides an alternative route to alprazolam (1b) and triazolam (1c), respectively.

Cyclodextrin complexes of benzodiazepines

Methods for enhancing the complexation efficiency of a drug with cyclodextrin and for enhancing the availability of a drug following administration of a cyclodextrin-drug complex.

Certain PAF antagonist/antihistamine combinations and methods

Methods and compositions are disclosed employing combinations of antihistamines with certain diaryl tetrahydrofuran, diaryl tetrahydrothiophene, triazolobenzodiazepine or thienotriazolodiazepine PAF--antagonist compounds in the treatment of allergic reactions.

Phosphorylation of cyclic amides

Compounds of the general formula STR1 are reacted with a strong base followed by a phosphorylating agent, such as dicyclicaminophosphinic halide or bis-di-lower alkylaminophosphinic halide to produce an imine of the formula STR2 wherein R is dicyclicaminophosphinyloxy or bis-di-lower alkylaminophosphinyloxy. R represents a leaving group which will undergo nucleophilic displacement with nitrogen, oxygen, sulfur and carbon containing nucleophiles, that is, nucleophiles which have, as a reactive site, a nitrogen, oxygen, sulfur or carbon atom, such that, when the cyclic imine undergoes nucleophilic displacement, there is formed C--N, C--O, C--S and C--C bonds between the carbon atom of the cyclic imine and the nucleophilic group. The end products may be utilized as intermediates in the production of pharmaceutically valuable compounds and, in some instances, are pharmaceutically valuable compounds per se.

Kinetics and mechanism of the equilibrium reaction of triazolam in aqueous solution

The equilibrium kinetics of triazolam in aqueous solution was investigated in the pH range of 1-11 at body temperature. The quantitative study indicated that it forms equilibrium mixtures consisting of ring-opened and closed forms with the composition being dependent on pH. The equilibrium constants of the two species in the pH range studied were determined by GLC method. The apparent first-order rate constants were estimated from the decreasing or increasing absorbance of the mixture in solutions. The forward-reaction rate constant (k(f)) showed a bell-shaped k(f)-pH profile with a rate maximum at pH 4.59, which indicates not only that the carbinolamine intermediate forms during equilibrium reaction, but that the rate-determining step of the reaction differs for the acidic and basic side of the rate maximum. The reverse-reaction rate constant decreased with increasing pH and could not be estimated in the pH region >5.65. Theoretical curves for both forward and reverse reactions satisfactorily fit the observed data. The pKa values of triazolam and its opened-form amine were estimated to be 1.52 and 6.50, respectively.

Novel synthesis of the pharmacologically important 1-substituted-6-phenyl-4H-s-triazolo[4,3-α][1,4]benzodiazepines

Several 6-phenyl-4H-s-triazolo[4,3-α][1,4]benzodiazepines have useful biological activity both in experimental animals and in man. This manuscript describes a novel synthesis of these compounds from intermediates that do not have a pre-formed benzodiazepine ring system.