59467-94-6

Basic information

• Product Name: Midazolam maleate salt
• Synonyms: 5-a)(1,4)benzodiazepine,8-chloro-6-(2-fluorophenyl)-1-methyl-4h-imidazo((z;8-chloro-6-(2-fluorophenyl)-1-methyl-4h-imidazo(1,5-a)(1,4)benzodiazepinemal;dormicum;dormicummaleate;midazolammaleate;ro21-3981/001;MIDAZOLAM MALEATE SALT;8-CHLORO-6-[2-FLUOROPHENYL]-2-METHYL-4H-IMIDAZO[1,5-A]-[1,4]BENZODIAZEPINE MALEATE SALT
• CAS NO: 59467-94-6
• Molecular Formula: C₄H₄O₄*C₁₈H₁₃ClFN₃
• Molecular Weight: 441.84
• EINECS: 261-775-0
• Mol File: 59467-94-6.mol
• Article Data: 4

Chemical Properties

• Melting Point: 114-117° (solvated)
• Boiling Point: 496.9 °C at 760 mmHg
• Flash Point: 254.3 °C
• Appearance: /
• Storage Temp.: 2-8°C
• CAS DataBase Reference: Midazolam maleate salt(CAS DataBase Reference)
• NIST Chemistry Reference: Midazolam maleate salt(59467-94-6)
• EPA Substance Registry System: Midazolam maleate salt(59467-94-6)

Safety Data

• Hazard Codes: Xn
• Statements: 22
• Safety Statements: 36
• RIDADR: 3249
• WGK Germany: 3
• RTECS: NI2922200
• HazardClass: 6.1(b)
• PackingGroup: III
• Hazardous Substances Data: 59467-94-6(Hazardous Substances Data)

Usage

Originator

Dormicum,Roche,Switz.,1982

Uses

Sedative; ligand GABA receptor benzodiazepine modulatory site

Manufacturing Process

Acetic anhydride (7 ml) was added to a solution of 6.16 g of crude 2- aminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepine in 200 ml of methylene chloride. The solution was added to 200 ml of saturated aqueous sodium bicarbonate and the mixture was stirred for 20 minutes. The organic layer was separated, washed with sodium bicarbonate, dried over sodium sulfate and evaporated to leave resinous 2- acetylaminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-lH -l,4- benzodiazepine. This material was heated with 40 g of polyphosphoric acid at 150°C for 10 minutes. The cooled reaction mixture was dissolved in water, made alkaline with ammonia and ice and extracted with methylene chloride. The extracts were dried and evaporated and the residue was chromatographed over 120 g of silica gel using 20% methanol in methylene chloride. The clean fractions were combined and evaporated to yield resinous 8-chloro-3a,4-dihydro-6-(2-fluorophenyl)-1- methyl-4H-imidazo[1,5-a][1,4] - benzodiazepine.A mixture of this material with 500 ml of toluene and 30 g of manganese dioxide was heated to reflux for 1? hours. The manganese dioxide was separated by filtration over Celite. The filtrate was evaporated and the residue was crystallized from ether to yield 8-chloro-6-(2-fluorophenyl)-1-methyl-4Himidazo[1,5-a][1,4]benzodiazepine, melting point 152°C to 154°C. The analytical sample was recrystallized from methylene chloride/hexane.A warm solution of 6.5 g (0.02 mol) of 8-chloro-6-(2-fluorophenyl)-1-methyl- 4H-imidazo[1,5-a] [1,4]-benzodiazepine in 30 ml of ethanol was combined with a warm solution of 2.6 g (0.022 mol) of maleic acid in 20 ml of ethanol. The mixture was diluted with 150 ml of ether and heated on the steam bath for 3 minutes. After cooling, the crystals were collected, washed with ether and dried in vacuo to yield 8-chloro-6-(2-fluorophenyl)-1-methyl-4Himidazo[1.5-a] [1,4]-benzodiazepine maleate, melting point 148°C to 151°C.

Therapeutic Function

Anesthetic

Biochem/physiol Actions

Sedative/Hypnotic; ligand for the GABAA receptor benzodiazepine modulatory site; CYP3A4 substrate.

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 
• 110-16-7 maleic acid 
• 59468-44-9 8-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid 
• 59467-70-8 Midazolam 

Relevant articles and documents

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.

Imidazodiazepines and processes therefor

Novel Imidazobenzodiazepines and their analogs are useful as anticonvulsants, muscle relaxant, anxiolytic and sedative agents. Preferred compounds of this class belong to the imidazo[1,5-a][1,4]diazepine series which may have a very wide variety of organic substituents. An especially preferred genus included within the purview of the invention encompasses a compound of the formula STR1 wherein R1 is hydrogen and lower alkyl preferably methyl; R3 and R5 are hydrogen; R4 is hydrogen, nitro and halogen, most preferably, chlorine, and in a most preferred embodiment when positioned on the fused benzo portion of the imidazobenzodiazepine is in the 8-position thereof, R6 is phenyl or halo, nitro, or lower alkyl-substituted phenyl, preferably, halo, with fluorine being the preferred halogen, the substituted fluoro being positioned in the 2-position of the phenyl moiety and R2 is hydrogen and lower alkyl.