28981-97-7

Usage

Uses

Used in Pharmaceutical Industry:
Alprazolam is used as an anxiolytic for the treatment of anxiety disorders and panic attacks. It works by enhancing the effects of a neurotransmitter called GABA in the brain, which helps to produce a calming effect. Alprazolam is known for its potency on a milligram basis, making it a widely prescribed medication for anxiety-related conditions.
Used in Research and Forensic Applications:
Alprazolam, as an analytical reference material, is utilized in research and forensic applications. It is regulated and categorized as a Schedule IV compound in the United States, which indicates its potential for abuse and dependence while also recognizing its accepted medical use.
Used as an Atorvastatin Metabolite:
In the field of pharmaceutical research, Alprazolam is recognized as a metabolite of atorvastatin, a widely prescribed drug for lowering cholesterol levels. This connection highlights the importance of understanding the metabolic pathways and interactions of various drugs in the body.

Originator

Xanax ,Upjohn ,US ,1981

Manufacturing Process

6-Chloro-2-hydrazino-4-phenylquinoline: A stirred mixture of 2,6-dichloro-4- phenylquinoline (2.7 g, 0.01 mol) and hydrazine hydrate (6.8 g) was refluxed under nitrogen for 1 hour and concentrated in vacuum. The residue was suspended in warm water, and the solid was collected by filtration, dried and recrystallized from ethyl acetate-Skelly B hexanes to give 1.81 g (67% yield) of 6-chloro-2-hydrazino-4-phenylquinoline of melting point 156.5-157°C. 7-Chloro-1-methyl-5-phenyl-s-trizolo[4,3-a]quinoline: A stirred mixture of 6- chloro-2-hydrazino-4-phenylquinoline (1.4 g, 0.0052 mol), triethylorthoacetate (0.925 g, 0.0057 mol) and xylene (100 ml) was refluxed, under nitrogen, for 2 hours 40 minutes. During this period the ethanol formed in the reaction was removed by distillation through a short, glass helix-packed column. The mixture was concentrated to dryness in vacuum and the residue was crystallized from methanol-ethyl acetate to give: 1.28 g of 7-chloro-1- methyl-5-phenyl-s-triazolo[4,3-a]quinoline (83.9% yield). The analytical sample was crystallized from methylene chloride:methanol and had a melting point 252.5-253.5°C. 5-Chloro-2-(3-methyl-4H-1,2,4-triazol-4-yl)benzophenone (Oxidation of 7- chloro-1-methyl-5-phenyl-s-trizolo[4,3-a]quinoline): A stirred suspension of 7- chloro-1-methyl-5-phenyl-s-triazolo[4,3-a] quinoline (2,94 g, 0.01 mol) in acetone (110 ml) was cooled in an ice-bath and treated slowly with a solution prepared by adding sodium periodate (2 g) to a stirred suspension of ruthenium dioxide (200 mg) in water (35 ml). The mixture became dark. Additional sodium periodate (8 g) was added during the next 15 minutes. The ice-bath was removed and the mixture was stirred for 45 minutes. Additional sodium periodate (4 g) was added and the mixture was stirred at ambient temperature for 18 hours and filtered. The solid was washed with acetone and the combined filtrate was concentrated in vacuum. The residue was suspended in water and extracted with methylene chloride. The extract was dried over anhydrous potassium carbonate and concentrated. The residue was chromatographed on silica gel (100 g) with 10% methanol and 90% ethyl acetate; 50 ml fractions were collected. The product was eluted in fractions 10-20 and was crystallized from ethyl acetate to give: 0.405 g of melting point 168-169.5°C and 0.291 g of melting point 167.5-169°C (23.4% yield) of 5-chloro-2-(3-methyl-4H-1,2,4-triazol-4-yl)benzophenone. The analytical sample had a melting point of 168°C. 5-Chloro-2-[3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone: A stirred mixture of 5-chloro-2-(3-methyl-4H-1,2,4-triazolo-4- yl)benzophenone, (2.98 g, 0.01 mol) paraformaldehyde (3 g) and xylene (100 ml) was warmed under nitrogen, in a bath maintained at 125°C for 7 hours. The mixture was then concentrated in vacuum. The residue was chromatographed on silica gel (150 g) with 3% methanol-97% chloroform. Fifty ml fractions were collected. The product was eluted in fractions 20-44. The fractions were concentrated and the residue was crystallized from ethanol-ethyl acetate to give: 1.64 g of melting point 138-142°C; 0.316 g of melting point 138.5-141°C; 0.431 g of melting point 139-141°C (72.8% yield) of 5-chloro-2-[3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazol-4- yl]benzophenone. The analytical sample had a melting point of 138-139°C. 5-Chloro-2-[3-(bromomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]-benzophenone: A solution of 5-chloro-2-[3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazol-4-yl]- benzophenone (328 mg, 0.001 mol) in dry, hydrocarbon-stabilized chloroform (5 ml) was cooled in an ice-bath and treated with phosphorus tribromide (0.1 ml). The colorless solution was kept in the ice-bath for 55 minutes, at ambient temperature (22-24°C), for 5 hours. The resulting yellow solution was poured into a mixture of ice and dilute sodium bicarbonate. This mixture was extracted with chloroform. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was crystallized from methylene chloride-ethyl acetate to give: 0.285 g of melting point 200- 240°C (decomposition) and 0.030 g of melting point 200-220°C (decomposition) of 5-chloro-2-[3-(bromomethyl)-5-methyl-4H-1,2,4-triazol-4- yl]benzophenone. The analytical sample had a melting point of 200-240°C. 8-Chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine: A stirred suspension of 5-chloro-2-[3-(bromomethyl)-5-methyl-4H-1,2,4-triazol- 4-yl]-benzophenone (391 mg, 0.001 mol) in tetrahydrofuran (15 ml) was cooled in an ice-bath and treated with a saturated solution of ammonia in methanol (12.5 ml). The resulting solution was allowed to warm to ambient temperature and stand for 24 hours. It was then concentrated in vacuum. The residue was suspended in water, treated with a little sodium bicarbonate and extracted with methylene chloride. The extract was washed with brine, dried with anhydrous potassium carbonate and concentrated. The residue was crystallized from methylene chloride-ethyl acetate to give 0.220 g of crude product of melting point 227-228.5°C. Recrystallization of this material from ethyl acetate gave 0.142 g of melting point 228-229.5°C of 8-chloro-1- methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.

Therapeutic Function

Tranquilizer

InChI:InChI=1/C17H13ClN4/c1-11-20-21-16-10-19-17(12-5-3-2-4-6-12)14-9-13(18)7-8-15(14)22(11)16/h2-9H,10H2,1H3

Upstream product

• 38150-28-6 2-(3-bromomethyl-5-methyl-[1,2,4]triazol-4-yl)-5-chloro-benzophenone 
• 1068-57-1 acetic acid hydrazide 
• 819793-73-2 7-chloro-2-(N-nitrosomethylamino)-5-phenyl-3H-1,4-benzodiazepine 
• 693-98-1 2-methylimidazole 
• 124-42-5 acetamidine hydrochloride 
• 18091-89-9 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine 
• 2208-07-3 ethyl acetimidate hydrochloride 
• 144-55-8 sodium hydrogencarbonate 
• 27046-54-4 1-acetyl-7-chloro-5-phenyl-1H-benzo[e][1,4]-diazepin-2(3H)-one 
• 719-59-5 5-chloro-2-aminobenzophenone 
• 41212-87-7 7-chloro-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one ethylidenehydrazone 
• 1088-11-5 desmethyldiazepam 
• 30858-38-9 2-(α-aminoethylidene)hydrazino-7-chloro-5-phenyl-3H-1,4-benzodiazepine 
• 59077-20-2 5-chloro-2-[3-(hydroxyamino-methyl)-5-methyl-[1,2,4]triazol-4-yl]-benzophenone 

Downstream Products

• 42915-42-4 2-chloro-6-methyl-13a-phenyl-9H,13aH-benzo[f]thiazolo[3,2-d][1,2,4]triazolo[4,3-a][1,4]diazepin-11-one 
• 71616-90-5 1-methyl-4-<(dimethylamino)methyl>-6-phenyl-8-chloro-4H-s-triazolo-<4,3-a><1,4>benzodiazepine 
• 121899-12-5 (8-Chloro-1-methyl-6-phenyl-6H-2,3,5,10b-tetraaza-benzo[e]azulen-6-ylmethyl)-dimethyl-amine 
• 85966-74-1 ({2-[3-(aminomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]-5-chlorophenyl}(phenyl)methanone) 
• 30896-65-2 8-chloro-1-methyl-6-phenyl-4H-s-triazolo<4,3-a><1,4>benzodiazepine 5-oxide 
• 36916-14-0 10-chloro-6-methyl-11b-phenyl-3H,11bH-oxazirino<3,2-d>-s-triazolo<4,3-a><1,4>benzodiazepine 
• 38150-35-5 8-chloro-1-methyl-6-phenyl-4H-s-triazolo<4,3-a><1,4>benzodiazepine-4-carboxylic acid ethyl ester 
• 36916-19-5 5-chloro-2-(3-methyl-4H-1,2,4-triazol-4-yl)benzophenone 
• 37115-32-5 adinazolam 
• 37952-14-0 2-(8-chloro-6-phenyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-1-yl)-ethanol 
• 60218-33-9 8-chloro-1-<2-(dimethylamino)ethyl>-6-phenyl-4H-s-triazolo<4,3-a><1,4>benzodiazepine p-toluenesulfonate 
• 72874-68-1 8-chloro-1-[2-(diethylamino)ethyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine 
• 37115-43-8 8-chloro-1-hydroxymethyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine 
• 1246182-55-7 C₇H₆O₄*C₁₇H₁₃ClN₄ 

Relevant academic research and scientific papers

Kinetics and equilibrium of the reversible alprazolam ring-opening reaction

Alprazolam underwent a facile 1,4-benzodiazepine ring-opening reaction in an acidic aqueous solution to form a benzophenone compound. The reaction was demonstrated by means of UV, IR, and 1H- and 13C-NMR spectroscopy. Its reverse cyclization reaction to alprazolam occurred when an acidic solution was neutralized. Both the ring-opening and the cyclization rate constants were obtained from the overall rate constant measured at 25° over a pH range of 0.5-8.0; the latter was measured by monitoring the UV spectral change of the reaction. Although the equilibrium was favored for the benzophenone compound in acidic solutions, it was possible to directly measure the cyclization rate at three acidic pH values by providing a sink condition for the product, alprazolam, using a biphasic reaction system. The bell-shaped cyclization rate pH profile was interpreted in terms of a change in the rate-determining step. The pH profile of the ring-opening rate showed an inflection point indicating a different reactivity of mono- and dicationic alprazolam. The apparent equilibrium between alprazolam and the benzophenone compound at a given pH was estimated from the rate constants for the ring-opening and cyclization reactions. The results agree with the apparent pK(α) measured by a conventional UV spectrophotometry and a titration technique. The pK(α) of monocationic alprazolam, the reactive species for the covalent hydration, was determined from the pH dependence of the initial absorbance when an alprazolam solution is acidified.

Electrochemical synthesis of 1,2,4-triazole-fused heterocycles

A reagent-free intramolecular dehydrogenative C-N cross-coupling reaction has been developed under mild electrolytic conditions. In this atom- and step-economical one-pot process, valuable 1,2,4-triazolo[4,3-a]pyridines and related heterocyclic compounds could be synthesized efficiently from commercially available aliphatic or (hetero)aromatic aldehydes and 2-hydrazinopyridines. Various functional groups are compatible with this metal- and oxidant-free protocol which can be carried out on a gram scale easily. This novel method was applied to the synthesis of one of the top-selling drugs Xanax and late stage functionalization for generating chemical diversity in biologically relevant lead molecules.

New and mild method for the synthesis of alprazolam and diazepam and computational study of their binding mode to GABAA receptor

A new method for the synthesis of 8-chloro-1-methyl-6-phenyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine (alprazolam) and 7-chloro-1-methyl-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one (diazepam) from 2-amino-5-chloro benzophenone was described under mild conditions. Most of the synthetic steps were carried out under solvent-free conditions, and the products were obtained in high yield and purity. The products were characterized by comparison of physical properties with authentic samples and also by IR, 1H NMR and 13C NMR. Three-dimensional (3D) model of GABAA was constructed using X-ray crystal structure of homopentameric caenorhabditis elegans glutamate-gated chloride channel (GluCl) (3RHW) at 3.3?? as the template based on sequence comparison and homology modeling method. The homology modeling and MD simulation studies predicted the 3D structure of receptor in a water environment. The resulted conformation of the receptor was used for docking of the alprazolam and diazepam. Docking studies indicated many important interactions of the drugs with the receptor. Furthermore, the complex of GABA with drugs was used in MD simulation to realize the conformation changes of the complex.

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.

Alprazolam inclusion complexes and pharmaceutical composition thereof

A pharmaceutical composition an inclusion complex and methods for treating patients and preparing said complex disclosed for transmucosal delivery comprising an inclusion complex of (a) alprazolam and (b) a water soluble 2-hydroxypropyl-beta-cyclodextrin, and a pharmaceutically acceptable carrier therefor, wherein all the alprazolam is present in ring-closed form.

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.

Neuroprotective agents and methods related thereto

Neuroprotective agents are disclosed having the following structure: wherein R1, R2, R3, R4and R5are as defined herein. Such compounds have utility in the treatment of conditions which benefit from administration of neuroprotective agents generally, including treatment of central and peripheral nervous condition as well as for promoting nerve cell differentiation. Methods of treating such conditions are also disclosed, as are pharmaceutical compositions containing one or more of the compounds of this invention.

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.