methohexital sodium Chemical Properties

CAS DataBase Reference

309-36-4

EPA Substance Registry System

Methohexital sodium (309-36-4)

Safety Information

RIDADR 

3249

HazardClass 

6.1(b)

PackingGroup 

III

methohexital sodium Usage And Synthesis

Description

Methohexital sodium, sodium 5-allyl-1-methyl-5-(1-methyl-2-pentynyl)- barbiturate, The free acid forms colorless crystals, mp 6 0 – 6 4?C. It is prepared by condensing diethyl allyl(1-methyl-2-pentynyl)malonate with N-methylurea .

Originator

Brevital,Lilly,US,1960

Uses

Amobarbital is used as anesthetics for perioperative sedation as well as in the short-term treatment of insomnia, anxiety, psychosis, control of seizures, and alcohol withdrawal. These agents are also exploited in abuse settings. Abuse of barbiturates started in the 1940s as they were liberally given to military personnel stationed in the South Pacific in order to help them cope with harsh conditions. They were called ‘goofballs’ in this context. After World War II, many servicemen needed detoxification and treatment for barbiturate dependence upon returning to the United States. Reported barbiturate abuse peaked in the 1970s, but has since declined with the increased use of other sedatives such as benzodiazepines. Use of certain long-acting barbiturates as anticonvulsants, however, continues. Phenobarbital is currently the most commonly prescribed anticonvulsant in use worldwide. Pentobarbital has been used in the United States for lethal injection during executions. Phenobarbital is also used for the treatment of alcohol withdrawal and compares favorably to other agents including benzodiazepines.

Uses

Anesthetic (intravenous).

Definition

ChEBI: The sodium salt of methohexital.

Manufacturing Process

Preparation of 3-Hexyne-2-ol: A solution of ethyl magnesium bromide was prepared by the reaction of 229 g of ethyl bromide and 48.6 g of magnesium in 750 ml of anhydrous ether. To the ether solution was then added with stirring a solution of 108 g of ethyl acetylene in 250 ml of cold anhydrous ether. The addition required approximately 3 hours, and the mixture was stirred and refluxed for a further period of 3? hours. Thereafter there was added to the reaction mixture a solution of 88 g of freshly distilled acetaldehyde in 170 ml of anhydrous ether, over a period of about 45 minutes and at a temperature in the range of about -10° to 0°C.
The resulting reaction mixture was poured over about 1 kg of crushed ice, and neutralized with 10% aqueous hydrochloric acid. The organic phase of the resulting mixture was separated, and the aqueous phase was extracted 3 times with 250 ml portions of ether. The combined organic phase and ether washings were washed twice with water and dried over anhydrous potassium carbonate. The dried ether solution was fractionally distilled, and the 3- hexyne-2-ol formed in the reaction was collected as a fraction boiling at about 79° to 80°C at the pressure of 60 mm of mercury.
Preparation of 2-Bromo-3-Hexyne: A solution of 138 g of 3-hexyne-2-ol and 9 g of pyridine in 138 ml of anhydrous ether was treated with 175 g of phosphorus tribromide, added dropwise over a period of about 20 minutes at a temperature of about -10°C. The reaction mixture was permitted to come to room temperature while stirring for about 3 hours, and was then heated to refluxing for about 1 hour. After cooling, the reaction mixture was poured over about 50 g of crushed ice. A two-phase system formed, and the ether layer was separated, washed with dilute sodium bicarbonate solution, dried over anhydrous potassium carbonate and fractionally distilled. The 2-bromo-3- hexyne formed in the reaction was collected at 75°C at the pressure of 50 mm of mercury.
Preparation of Diethyl (1-Methyl-2-Pentynyl) Malonate: To a solution of 28.6 g of sodium in 430 ml of absolute ethanol were added 200 g of diethyl malonate. About half of the alcohol was removed by distillation in vacuo, and thereafter a solution of 200 g of 2bromo-3-hexyne in 100 ml of anhydrous ether was added slowly to the reaction mixture.
The heat of reaction brought about refluxing during the addition of the 2- bromo-3-hexyne, and when the addition was complete the reaction mixture was heated to refluxing for a further period of 30 minutes. A sufficient amount of water was then added to the reaction mixture to dissolve the sodium bromide which had formed, and the only organic layer was separated, washed with water and dried over anhydrous magnesium sulfate. The dried organic layer was then fractionally distilled under reduced pressure, and the diethyl (1-methyl-2-pentynyl) malonate formed in the reaction was collected at about 117° to 120°C at the pressure of 2 mm of mercury.
Preparation of Diethyl Allyl (1-Methyl-2-Pentynyl) Malonate: A solution of 12.1 g of sodium in 182 ml of absolute ethanol was prepared, and thereto were added 126.6 g of diethyl (1-methyl-2-pentynyl) malonate. Most of the ethanol was then distilled off under reduced pressure, and the residue was cooled and 63.5 g of allyl bromide were slowly added thereto. After completion of the addition, the mixture was refluxed for about 1 hour. The reaction mixture was cooled, treated with about 100 ml of water, and the oily organic layer which formed was removed, washed with water and dried over anhydrous magnesium sulfate. The dried oily organic material was fractionally distilled in vacuo, and diethyl allyl (1-methyl-2-pentynyl) malonate boiling at 105° to 107°C at the pressure of 1 mm of mercury was recovered.
Preparation of 1-Methyl-5-Allyl-5-(1-Methyl-2-Pentynyl) Barbituric Acid: A solution of 23.8 g of sodium in 360 ml of absolute alcohol was prepared and thereto were added 38.3 g of methyl urea and 96.8 g of diethyl allyl (1- methyl-2-pentynyl) malonate. The mixture was refluxed for about 20 hours, cooled, and the ethanol was removed by distillation in vacuo. The residue was dissolved in about 300 ml of water and the aqueous solution was washed with ether, and the washings were discarded. The aqueous solution was then acidified with acetic acid, and extracted with three 150 ml of portions of ether.
The combined ether extracts were washed with 5% aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and fractionally distilled in vacuo. The fraction boiling at about 145 to 150°C at the pressure of 0.5 mm of mercury, weighing 61 g and consisting of 1-methyl-5-allyl-5-(1- methyl-2-pentynyl) barbituric acid, was collected. The only distillate was substantially pure, and could be used as such in pharmaceutical preparation or a salt could be prepared therefrom according to the procedures disclosed hereinafter. On standing, the oil crystallized. The crystalline 1-methyl-5-allyl5-(1-methyl-2-pentynyl) barbituric acid melted at about 60° to 64°C after recrystallization from dilute ethanol.
Preparation of Sodium 1-Methyl-5-Allyl-5-(1-Methyl-2-Pentynyl) Barbiturate: A solution of 61 g of 1-methyl-5-allyl-5-(1-methyl-2-pentynyl) barbituric acid in 100 ml of ether was extracted with 465 ml of 2% aqueous sodium hydroxide solution. The aqueous extract was washed with successive 75 ml and 50 ml portions of ether. The pH of the aqueous solution was adjusted to 11.7, using 5% aqueous sodium hydroxide solution. 5 g of decolorizing carbon were added to the solution with stirring; the mixture was permitted to stand for 20 minutes at room temperature, and the carbon was removed by filtration. A solution containing 4 g of sodium carbonate in 25 ml of water was added to the aqueous solution, and the mixture was filtered sterile through a porcelain filter candle of 02 porosity into sterile bottles. The aqueous solution was then dried from the frozen state, whereupon a sterile residue of sodium 1-methyl-5-allyl-5-(1-methyl-2-pentynyl) barbiturate, weighing about 62 g was obtained.

brand name

Brevital Sodium (King).

Therapeutic Function

Anesthetic

General Description

White powder.

Air & Water Reactions

Water soluble.

Reactivity Profile

Solutions of methohexital sodium are incompatible with silicone and acid. .

Fire Hazard

Flash point data are not available for methohexital sodium, but methohexital sodium is probably combustible.

Clinical Use

Methohexital sodium is a short-acting anesthetic administered intravenously. It is very potent and has the shortest duration of action among the barbiturates used. A disturbing factor is that rather frequently it causes hiccups directly after injection. Patients are reported to recover rapidly from anesthesia. Abuse can lead to addiction.

Safety Profile

Poison by intravenous and implant routes. Human systemic effects by intravenous route: blood pressure lowering, gastrointestinal effects, and allergc dermatitis. An FDA proprietary drug. Cazltion: Excessive use may lead to addction or habituation. Allergenic effects by intravenous route. When heated to decomposition it emits toxic fumes of Na2O and NOx. See also BARBITURATES.

Veterinary Drugs and Treatments

Methohexital is sometimes used in small animals as an ultrashort acting anesthetic agent, but, propofol has largely supplanted methohexital’s use in small animals. However, because it is not dependent on redistribution to fat to reverse its effect, it may be useful in canine sight hound breeds. Because methohexital can induce anesthesia very rapidly, it may also be useful when general anesthesia must be administered to a patient with a full stomach, as an ET tube may be placed rapidly before aspiration of vomitus can occur.

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