Midazolam maleate salt Property

Melting point:

114-117° (solvated)

storage temp. 

2-8°C

solubility 

DMSO (Slightly), Methanol (Slightly)

form 

Solid

color 

White to Off-White

Stability:

Hygroscopic

CAS DataBase Reference

59467-94-6(CAS DataBase Reference)

Safety

Hazard Codes 

Xn

Risk Statements 

22

Safety Statements 

36

RIDADR 

3249

WGK Germany 

3

RTECS 

NI2922200

HazardClass 

6.1(b)

PackingGroup 

III

Toxicity

LD50 in male mice (mg/kg): 760 orally; 86 i.v. (Pieri)

Hazard and Precautionary Statements (GHS)

Symbol(GHS)

Signal word

Warning

Hazard statements

H302Harmful if swallowed

Precautionary statements

P201Obtain special instructions before use.

P202Do not handle until all safety precautions have been read and understood.

P260Do not breathe dust/fume/gas/mist/vapours/spray.

P261Avoid breathing dust/fume/gas/mist/vapours/spray.

P263Avoid contact during pregnancy/while nursing.

P264Wash hands thoroughly after handling.

P264Wash skin thouroughly after handling.

P270Do not eat, drink or smoke when using this product.

P271Use only outdoors or in a well-ventilated area.

P281Use personal protective equipment as required.

P301+P312IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.

P304+P340IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.

P308+P313IF exposed or concerned: Get medical advice/attention.

P312Call a POISON CENTER or doctor/physician if you feel unwell.

P330Rinse mouth.

P403+P233Store in a well-ventilated place. Keep container tightly closed.

P405Store locked up.

P501Dispose of contents/container to..…

Midazolam maleate salt Chemical Properties,Usage,Production

Description

Midazolam maleate, 8- chloro-6-(2-fluorophenyl)?1-methyl-4Himidazo-benzodiazepine maleate , is a stable, water-soluble powder. The solubility in water depends on pH:≈85 mg/mL at pH 2.7 and 0.3 mg/mL at pH 7.6. The maleate is subject to reversible ring opening. Below pH4 the ring is open; above pH 4 the cyclic form is present. The anesthetic formulation is a buffered aqueous solution containing 2.5 mg/mL at pH 3.5.

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.

Synthesis

The preparation starts with 7-chloro- 5-(2-fluorophenyl)?1,3-dihydro-2H-1,4- benzodiaze-pinone . For the literature, also see . Midazolam is approximately twice as active as diazepam, causes less pain at the injection site, and has a shorter half-life than diazepam. Side effects: dose-dependent cerebral depression with tranquilization, sedation, and dryness. Reduction in blood pressure, respiratory depression, and cardiovascular effects were slight.