FLUNITRAZEPAM Property

Melting point:

166-167°; mp 170-172°

Boiling point:

540.9±50.0 °C(Predicted)

Density 

1.3720 (estimate)

Flash point:

11 °C

storage temp. 

2-8°C

solubility 

45% (w/v) aq 2-hydroxypropyl-β-cyclodextrin: 1 mg/mL

pka

pKa 1.8 (Uncertain)

form 

A neat solid

EPA Substance Registry System

2H-1,4-Benzodiazepin-2-one, 5-(2-fluorophenyl)-1,3-dihydro-1-methyl-7-nitro- (1622-62-4)

Safety

Hazard Codes 

Xn,T,F

Risk Statements 

22-36-39/23/24/25-23/24/25-11

Safety Statements 

7-16-36/37-45-36-26

RIDADR 

UN 1230 3/PG 2

WGK Germany 

2

RTECS 

DF2385000

HazardClass 

6.1(b)

PackingGroup 

III

Hazardous Substances Data

1622-62-4(Hazardous Substances Data)

Hazard and Precautionary Statements (GHS)

Symbol(GHS)

Signal word

Warning

Hazard statements

H302Harmful if swallowed

H319Causes serious eye irritation

Precautionary statements

P305+P351+P338IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continuerinsing.

FLUNITRAZEPAM Chemical Properties,Usage,Production

Chemical Properties

White or yellowish, crystalline powder.

Originator

Roipnol,Roche,Italy,1976

Uses

antitussive

Uses

Flunitrazepam is used as an hypnotic. This is a controlled substance (depressant).

Definition

ChEBI: Flunitrazepam is a 1,4-benzodiazepinone that is nitrazepam substituted by a methyl group at position 1 and by a fluoro group at position 2'. It is a potent hypnotic, sedative, and amnestic drug used to treat chronic insomnia. It has a role as a sedative, a GABAA receptor agonist and an anxiolytic drug. It is a 1,4-benzodiazepinone, a C-nitro compound and a member of monofluorobenzenes.

Manufacturing Process

A mixture of 176 grams of orthofluorobenzoyl chloride and 64 grams of parachloroaniline was stirred and heated to 180°C, at which temperature 87 grams of zinc chloride was introduced, the temperature raised to 200° to 205°C and maintained there for 40 minutes. The golden colored melt was quenched by the careful addition of 500 ml of 3 N hydrochloric acid and the resulting mixture refluxed for 5 minutes. The acid solution was decanted and the process repeated three times to remove all orthofluorobenzoic acid. The grey granular residue was dissolved in 300 ml of 75% (v/v) sulfuric acid and refluxed for 40 minutes to complete hydrolysis. The hot solution was poured over 1 kg of ice and diluted to 2 liters with water. The organic material was extracted with four 300 ml portions of methylene chloride, and the combined extracts subsequently washed with two 500 ml portions of 3 N hydrochloric acid to remove traces of para-chloroaniline, three 500 ml portions of 5 N sodium hydroxide solution to remove orthofluorobenzoic acid, and finally two 200 ml portions of saturated brine solution.
The combined methylene chloride extracts were dried over anhydrous sodium sulfate and the solvent removed to give the crude 2-amino-5-chloro-2'- fluorobenzophenone which upon recrystallization from methanol formed yellow needles melting at 94° to 95°C.
50.0 grams of 2-amino-5-chloro-2'-fluorobenzophenone in 300 cc of tetrahydrofuran was hydrogenated at atmospheric pressure in the presence of 10 grams of charcoal (Norite), 30.0 grams of potassium acetate and 2.5 cc of a 20% palladous chloride solution (20% by weight of palladium). After an initiation period varying from 10 minutes to an hour, hydrogen uptake was rapid and stopped completely after the absorption of the theoretical amount.
Filtration of the catalyst over a Hyflo pad and removal of the solvent left a yellow crystal line residue. The crude mixture of ketone and potassium acetate was partitioned between methylene chloride (300 cc) and water (1 liter). The layers were separated and the water layer washed with methylene chloride (3 x 50 cc). The organic layers were combined, washed with 3 N sodium hydroxide solution (2 x 50 cc), water (3 x 100 cc), dried over anhydrous sodium sulfate and filtered. The solvent was removed and the product recrystallized from ethanol to give 2-amino-2'-fluorobenzophenone as yellow prisms melting at 126° to 128°C.
A solution of 21.5 grams of 2-amino-2'-fluorobenzophenone in 500 cc of ether was treated with 20 cc of a 20% (v/v) solution of bromoacetyl bromide in ether. The mixture was shaken and allowed to stand for 5 minutes and then washed with water (20 cc). The process was repeated five times. The final solution was washed thoroughly with water (5 x 500 cc) and concentrated to 100 cc. The crystals were filtered and recrystallized from methanol to give 2- bromacetamido-2'-fluorobenzophenone as white needles melting at 117° to 118.5°C.
A solution of 23.7 grams of 2-bromoacetamido-2'-fluorobenzophenone in tetrahydrofuran (100 cc) was added to liquid ammonia (approximately 500 cc) and allowed to evaporate overnight. The residue was treated with water (1 liter) and the crystals filtered off and refluxed in toluene (100 cc) for 30 minutes. The mixture was treated with decolorizing carbon (Norite) and filtered over Hyflo. The solution was concentrated to a small volume (25 cc) cooled, diluted with 20 cc of ether and allowed to stand. The product was recrystallized from acetone/hexane to give 5-(2-fluorophenyl)-3H-1,4- benzodiazepin-2(1H)-one as white needles melting at 180° to 181°C.
23.8 grams of 5-(2-fluorophenyl)-3H-1,4-benzodiazepin-2(1H)-one was dissolved in 50 cc of concentrated sulfuric acid at 0°C. To the resulting mixture there was then added dropwise with stirring a solution of 7.1 grams of potassium nitrate in 20 cc of concentrated sulfuric acid. The mixture was stirred for 2? hours at 0°C and then diluted with 300 grams of ice. The resulting solution was made alkaline with concentrated ammonium hydroxide solution, keeping the temperature at 0°C. The formed suspension was extracted thoroughly with methylene chloride (6 x 100 cc). The organic layers were combined, washed with saturated brine solution, dried over anhydrous sodium sulfate and filtered. Removal of the solvent yielded a brown gum which was taken up in a small amount of methylene chloride and filtered through a pad of grade I alumina. The alumina was eluted with methylene chloride, the solvent removed, and the residue crystallized from acetone/hexane to yield 7-nitro-5-(2-fluorophenyl)-3H-1,4-benzodiazepin- 2(1H)-oneas white needles melting at 210° to 211°C.
23.8 grams of 5-(2-fluorophenyl)-3H-1,4-benzodiazepin-2(1H)-one was dissolved in 50 cc of concentrated sulfuric acid at 0°C. To the resulting
20.2 grams of the abovementioned 7-nitro-5-(2-fluorophenyl)-3H-1,4- benzodiazepin-2(1H)-one was dissolved in 60 cc of N,N-dimethyl formamide to which was then added 3.49 grams of a 50% suspension of sodium hydride in heavy mineral oil. The mixture was allowed to stir for 15 minutes in the cold, 11.2 grams of methyl iodide was added and the solution was stirred for a further 20 minutes. Solvent was removed under reduced pressure to give an oil which was partitioned between water and methylene chloride (1 liter/300 cc), the water layer was extracted with methylene chloride (5 x 200 cc), the organic layers combined and washed with water (2 x 100 cc), 3N hydrochloric acid (1

brand name

Rohypnol (Roche, Puerto Rico);Darkene;Flumipam;Hipnosedon;Hiposedon;Hypnodorm;Hypnosedon;Libelins;Noviel;Primun;Riopnol;Rohipnol;Rohpinol;Rohpnol;Valseram.

Therapeutic Function

Hypnotic

World Health Organization (WHO)

Flunitrazepam, a benzodiazepine derivative with sedative and hypnotic activity, was introduced in 1974 for the management of anxiety. Although it is subject to international control under Schedule IV of the 1971 Convention on Psychotropic Substances, its potential for abuse by drug addicts has led at least two countries (Germany and Turkey) to apply controls equivalent to those of Schedule II. (Reference: (UNCPS4) United Nations Convention on Psychotropic Substances (IV), , , 1971)

Biochem/physiol Actions

Hypnotic; anxiolytic; ligand for the GABAA receptor benzodiazepine modulatory site.