59467-70-8

Basic information

• Product Name: Midazolam
• Synonyms: MIDAZOLAM-D4 MALEATE;5-a)(1,4)benzodiazepine,8-chloro-6-(2-fluorophenyl)-1-methyl-4h-imidazo(;8-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine;Midazolam (base and/or unspecified salts);MidazolamBaseE.P;4H-Imidazo1,5-a1,4benzodiazepine, 8-chloro-6-(2-fluorophenyl)-1-methyl-;MIDAZOLAM,BP,EP;8-Chloro-6-(o-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine
• CAS NO: 59467-70-8
• Molecular Formula: C₁₈H₁₃ClFN₃
• Molecular Weight: 445.86
• EINECS: 261-774-5
• Product Categories: Intermediates & Fine Chemicals;Pharmaceuticals;Aromatics;Heterocycles
• Mol File: 59467-70-8.mol
• Article Data: 14

Chemical Properties

• Melting Point: 161-164°C
• Boiling Point: 496.9 °C at 760 mmHg
• Flash Point: 9 °C
• Appearance: white crystallized powder
• Density: 1.3136 (estimate)
• Vapor Pressure: 5.21E-10mmHg at 25°C
• Storage Temp.: Controlled Substance, -20°C Freezer
• Solubility: Practically insoluble in water, freely soluble in acetone and in ethanol (96 per cent), soluble in methanol.
• PKA: pKa 1.7±0.1;6.15± 0.1 (Uncertain)
• Water Solubility: 54mg/L(24 oC)
• CAS DataBase Reference: Midazolam(CAS DataBase Reference)
• NIST Chemistry Reference: Midazolam(59467-70-8)
• EPA Substance Registry System: Midazolam(59467-70-8)

Safety Data

• Hazard Codes: F,T
• Statements: 11-23/24/25-39/23/24/25
• Safety Statements: 7-16-36/37-45
• RIDADR: 3249
• WGK Germany: 2
• HazardClass: 6.1(b)
• PackingGroup: III
• Hazardous Substances Data: 59467-70-8(Hazardous Substances Data)

Usage

Description

Midazolam is a benzodiazepine, commonly known by its brand names Dormicum, Hypnovel, and Versed. It is characterized by its sedative properties and is used to treat insomnia and seizures. The structure of midazolam undergoes tautomerism, which allows it to exhibit either water or lipid solubility depending on the pH level. This property enables rapid diffusion into the brain when administered. Versed (Roche) is a concentrated preparation available for intramuscular injection, providing rapid absorption compared to diazepam.

Uses

Used in Anesthesia:
Midazolam is used as an anesthetic for its sedative and anticonvulsant properties, helping to induce a state of calm and relaxation during medical procedures.
Used in Anticonvulsant Applications:
Midazolam is employed as an anticonvulsant to control and prevent seizures, particularly in cases of epilepsy or other seizure disorders.
Used in Sedation:
As a sedative, midazolam is used to promote relaxation and reduce anxiety in patients, making it suitable for various medical and dental procedures.
Used in Hypnotic Applications:
Midazolam is used as a hypnotic to help individuals with insomnia fall asleep and stay asleep throughout the night.
Used in Antidepressant Treatment:
Although not explicitly mentioned in the provided materials, midazolam has been reported to be used off-label as an adjunct in the treatment of certain anxiety disorders and depression, due to its anxiolytic and sedative effects.
Used in Clinical Toxicology and Urine Drug Testing:
Midazolam is utilized in GC/MS or LC/MS applications for clinical toxicology and urine drug testing, as well as in pain prescription monitoring and forensic analysis.

Therapeutic Function

Anesthetic

Pharmacokinetics

Midazolam undergoes hepatic oxidative metabolism and has an elimination half-life of 2–4h. The major metabolite is 1-hydroxymidazolam, which is biologically active. Midazolam has been used as a sole hypnotic for TI VA and produces superior procedural amnesia compared with propofol, but CSHT increases significantly when used by continuous infusion, and this delays recovery. Clinical studies demonstrate the inferiority of midazolam in terms of time to onset of desired sedation score, slower recovery, less clear-headedness, and significantly longer period of postoperative amnesia compared with propofol.

Clinical Use

Benzodiazepine: Sedation with amnesia in conjunction with local anaesthesia, premedication, induction Status epilepticus (unlicensed)

Drug interactions

Potentially hazardous interactions with other drugs Antibacterials: concentration increased by erythromycin, clarithromycin and telithromycin (profound sedation); metabolism possibly accelerated by rifampicin. Antidepressants: concentration of oral midazolam possibly reduced by St John’s wort. Antifungals: concentration increased by itraconazole, fluconazole, ketoconazole, posaconazole and voriconazole (prolonged sedative effect). Antipsychotics: increased sedative effects; increased risk of hypotension, bradycardia and respiratory depression when parenteral benzodiazepines are given with IM olanzapine. Antivirals: concentration increased by atazanavir, boceprevir, efavirenz, indinavir, fosamprenavir, ritonavir, saquinavir and telaprevir increase risk of prolonged sedation; avoid with oral midazolam. Ciclosporin: in vitro studies suggested that ciclosporin could inhibit the metabolism of midazolam. However, blood ciclosporin concentrations in patients given ciclosporin to prevent graft rejection were considered too low to result in an interaction. Cobicistat: avoid with oral midazolam. Cytotoxics: concentration increased by crizotinib and nilotinib; concentration reduced by enzalutamide. Sodium oxybate: enhanced effects of sodium oxybate - avoid.

Metabolism

Metabolised in the liver via the cytochrome P450 isoenzyme CYP3A4. The major metabolite, alpha hydroxymidazolam has some activity; its half-life is less than 1 hour. Midazolam metabolites are excreted in the urine, mainly as glucuronide conjugates.

InChI:InChI=1/C18H13ClFN3.C4H4O4/c1-11-21-9-13-10-22-18(14-4-2-3-5-16(14)20)15-8-12(19)6-7-17(15)23(11)13;5-3(6)1-2-4(7)8/h2-9H,10H2,1H3;1-2H,(H,5,6)(H,7,8)/b;2-1-

Upstream product

• 75-07-0 acetaldehyde 
• 64740-64-3 7-chloro-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepine-2-carboxaldoxime 
• 59467-63-9 7-chloro-5-(2-fluorophenyl)-2-nitromethylene-1,3-dihydro-2H-1,4-benzodiazepine 
• 59468-83-6 8-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine 5-oxide 
• 110-16-7 maleic acid 
• 1584-62-9 2?(2?bromoacetamido)?5?chloro?2'?fluorobenzophenone 
• 59468-46-1 8?chloro-6?(2?fluorophenyl)?4H?imidazo[1,5?a][1,4]benzodiazepine?3?carboxylic acid 
• 69585-93-9 ethyl 8?chloro?6?(2?fluorophenyl)?4H?imidazo[1,5?a][1,4]benzodiazepine?3?carboxylate 
• 59468-56-3 Desmethylmidazolam 
• 74-88-4 methyl iodide 
• 784-38-3 2-amino-5-chloro-2'-fluorobenzophenone 
• 59467-69-5 8-chloro-6-(2-fluoro-phenyl)-1-methyl-3a,4-dihydro-3H-benzo[f]imidazo[1,5-a][1,4]diazepine 
• 59467-64-0 (7-chloro-5-(2-fluorophenyl)-2,3-dihydro-1H-benzo[e][1,4]diazepin-2-yl)methanamine 
• 59468-44-9 8-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid 

Downstream Products

• 308243-61-0 3-[8-chloro-6-(2-fluoro-phenyl)-1-methyl-4H-2,5,10b-triaza-benzo[e]azulen-4-yl]-propionic acid tert-butyl ester 
• 59468-85-8 4-hydroxymidazolam 
• 59468-90-5 1-hydroxymidazolam 
• 59468-83-6 8-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine 5-oxide 
• 59467-94-6 midazolam maleate 
• 59467-96-8 8-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine dihydrochloride 
• 59467-96-8 midazolam hydrochloride 
• 59469-38-4 2-Chloro-13a-(2-fluorophenyl)-12,13a-dihydro-6-methyl-9H,11H-imidazo[1,5-a]oxazolo[3,2-d][1,4]benzodiazepine 
• 59468-73-4 5-aminomethyl-1-[4-chloro-2-(2-fluorobenzoyl)phenyl]-2-methyl-imidazole dihydrochloride 
• 59469-04-4 8-chloro-6-(2-fluoro-phenyl)-1,5-dimethyl-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine 
• 59469-05-5 5-allyl-8-chloro-6-(2-fluoro-phenyl)-1-methyl-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine 
• 59469-02-2 8-chloro-6-(2-fluoro-phenyl)-1-methyl-5-nitroso-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine 
• 59469-06-6 5-acetyl-8-chloro-6-(2-fluoro-phenyl)-1-methyl-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine 
• 59469-01-1 8-chloro-6-(2-fluoro-phenyl)-1-methyl-5-(toluene-4-sulfonyl)-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine 

Relevant articles and documents

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.].

Benzodiazepines method for the preparation of compound

The invention relates to a method for preparing benzodiazepine compounds, and discloses a method for preparing 8-R2-6-(2-R1-phenyl)-1-methyl-3a,4-dihydro-3H-imidazo[1,5-a][1,4] benzodiazepine (midbody II) and 8-R2-6-(2-R1-phenyl)-1-methyl-4H-imidazo[1,5-a][1,4] benzodiazepine (product III), wherein R is hydrogen, fluorine, chlorine, bromine or iodine; R2 is fluorine, chlorine, bromine or iodine. The midbody II is prepared from 7-R2-5-(2-R1-phenyl)-2-aminomethyl-2,3-dihydro-1H-[1,4] benzodiazepine and triethyl orthoacetate as raw materials through ultrasonic reaction; the product III is prepared by performing enzyme dehydrogenation on the midbody II. By adopting the technical scheme of the invention, the dehydrogenation reaction selectivity is improved, and the reaction yield is improved.

Process for the synthesis of 4H-imidazo[1,5-a][1,4]benzodiazepines, in particular midazolam and salts thereof

The present invention refers to a process for the preparation of 4H-imidazo[1,5-a] [1,4]benzodiazepines, in particular Midazolam, through an efficient and selective decarboxylation reaction of the derivative compound of the 5-aminomethyl-1-phenyl-1H-imidazole-4-carboxylic acid of formula (II) avoiding the formation of the 6H-imidazo[1,5-a][1,4]benzodiazepines by-products and the ensuing process for the isomerisation of a 4H-imidazo[1,5-a][1,4]benzodiazepine product.