ACETOHEXAMIDE Property

Melting point:

188-190° (GB 912789); mp 175-177° (Marshall)

Density 

1.2528 (rough estimate)

refractive index 

1.6930 (estimate)

storage temp. 

Refrigerator

solubility 

DMSO: ~45 mg/mL

form 

solid

pka

4.32±0.10(Predicted)

color 

white

Water Solubility 

0.25g/L(25 ºC)

CAS DataBase Reference

968-81-0

EPA Substance Registry System

Acetohexamide (968-81-0)

Safety

Safety Statements 

36

WGK Germany 

2

RTECS 

YR7350000

Hazardous Substances Data

968-81-0(Hazardous Substances Data)

Toxicity

LD50 oral in rat: > 2gm/kg

Hazard and Precautionary Statements (GHS)

ACETOHEXAMIDE Chemical Properties,Usage,Production

Originator

Dymelor ,Lilly ,US ,1964

Uses

Acetohexamide is a sulfonylurea derivative. Acetohexamide is a hyopglycemic agent with moderate uricosuric activity. Acetohexamide is a first generation medication used in the treatment of diabetes metilus type 2.

Uses

antifungal

Uses

Labelled Acetohexamide, a sulfonylurea derivative. Acetohexamide is a hyopglycemic agent with moderate uricosuric activity. Acetohexamide is a first generation medication used in the treatment of diab etes metilus type 2.

Definition

ChEBI: An N-sulfonylurea that is urea in which a hydrogen attached to one of the nitrogens is replaced by a p-acetylphenylsulfonyl group, while a hydrogen attached to the other nitrogen is replaced by a cyclohexyl group.

Manufacturing Process

Preparation of p-Acetylbenzenesulfonamide: 100 grams of paminoacetophenone were dissolved in a solvent mixture containing 165 ml of 12 N hydrochloric acid and 165 ml of glacial acetic acid. The mixture was cooled with stirring to about 0°C. A solution containing 56.2 grams of sodium nitrite and 175 ml of water was added dropwise with stirring to the acidic solution while maintaining the temperature below 5°C.
After the addition had been completed, the acidic solution containing pacetylphenyldiazonium chloride formed in the above reaction was added dropwise with stirring to a mixture of 530 ml of glacial acetic acid and 530 ml of benzene which had been previously cooled, and the cooled solution saturated with sulfur dioxide and to which had been added 34 g of cupric chloride dihydrate. After the addition had been completed, the reaction mixture was stirred at about 40°C for three hours, and was then poured into 3,000 ml of an ice-water mixture.
The benzene layer containing p-acetylbenzenesulfonyl chloride formed in the above reaction was separated, and the acidic aqueous phase was extracted twice with 250 ml portions of benzene. The benzene layers were combined, the combined extracts were filtered, and the benzene was evaporated from the resulting filtrate in vacuum.
The solid residue comprising p-acetylbenzenesulfonyl chloride was dissolved in 100 ml of dioxane, and the solution was added to 200 ml of 14% aqueous ammonium hydroxide. The resulting solution was stirred overnight at ambient room temperature. The p-acetylbenzenesulfonamide thus prepared was collected by filtration. Recrystallization of the filter cake from aqueous ethanol yielded purified p-acetylbenzenesulfonamide melting at about 176°C to 179°C.
Preparation of N-p-Acetylphenylsulfonyl-N'-Cyclohexylurea: A reaction mixture consisting of 32.7 grams of p-acetylbenzenesulfonamide and 64 grams of anhydrous potassium carbonate in 350 ml of anhydrous acetone was stirred at refluxing temperature for about 1% hours, thus forming the potassium salt of p-acetylbenzenesulfonamide. 30.9 grams of cyclohexylisocyanate were added dropwise to the reaction mixture. Refluxing and stirring were continued during the course of the addition and for an additional 16 hours.
The acetone was removed by evaporation in vacuum, and about 750 ml of water were added to dissolve the resulting residue. The solution was filtered. The potassium salt of N-p-acetylphenylsulfonyl-N'-cyclohexylurea formed in the above reaction, being water-soluble, passed into the filtrate. Acidification of the filtrate with 6 N aqueous hydrochloric acid caused the precipitation of N-p-acetylphenylsulfonyl-N'-cyclohexylurea which was collected by filtration. Recrystallization of the filter cake from 90% aqueous ethanol yielded purified N-p-acetylphenylsulfonyl-N'-cyclohexylurea melting at about 188-190°C.

brand name

Dymelor (Lilly).

Therapeutic Function

Hypoglycemic

General Description

Acetohexamide is 4-acetyl-N-[(cyclohexylamino)carbonyl]benzenesulfonamide; or 1-[(p-acetylphenyl)sulfonyl]-3-cyclohexylurea; or 1-(p-acetylbenzenesulfonyl)-3-cyclohexylurea(generic). Acetohexamide incorporates the nearly optimal(for potency) cyclohexyl moiety in the “right-hand” sideof its molecular structure, but a p-acetyl substituent on the“left-side” benzene ring that decreases lipophilicity and israpidly biotransformed by reduction to an active metabolitethat is cleared relatively rapidly (see preceding discussion) independentlyof any P450s.

General Description

Acetohexamide, 1-[(p-acetylphenyl)sulfonyl]-3-cyclohexylurea (Dymelor), is relatedchemically and pharmacologically to tolbutamide and chlorpropamide.Like the other sulfonylureas, acetohexamidelowers the blood sugar level, primarily by stimulating the releaseof endogenous insulin.

General Description

White fluffy crystalline powder with almost no odor.

Air & Water Reactions

Water insoluble.

Reactivity Profile

An amide. Organic amides/imides react with azo and diazo compounds to generate toxic gases. Flammable gases are formed by the reaction of organic amides/imides with strong reducing agents. Amides are very weak bases (weaker than water). Imides are less basic yet and in fact react with strong bases to form salts. That is, they can react as acids. Mixing amides with dehydrating agents such as P2O5 or SOCl2 generates the corresponding nitrile. The combustion of these compounds generates mixed oxides of nitrogen (NOx).

Fire Hazard

Flash point data for ACETOHEXAMIDE are not available; however, ACETOHEXAMIDE is probably combustible.

Clinical Use

Acetohexamide is metabolized in the liver to a reducedform, the α -hydroxyethyl derivative. This metabolite, themain one in humans, possesses hypoglycemic activity.Acetohexamide is intermediate between tolbutamide andchlorpropamide in potency and duration of effect on bloodsugar levels.

Safety Profile

Human reproductive effects by an unspecified route: stillbirth. Mildly toxic by ingestion. When heated to decomposition it emits very toxic fumes of SO, and NOx,.

Synthesis

Acetohexamide, 1-(p-acetyl phenylsulfonyl)-3-cyclohexylurea (26.2.6), is made in an analogous scheme by reacting p-chlorobenzenesulfonylamide with cyclohexylisocyanate. The necessary p-acetylbenzenesulfonylamide is made by diazotating of p-aminoacetophenone in the presence of sulfur dioxide and copper(II) chloride, forming the sulfonylchloride 26.2.4, which is reacted further with ammonia to give the sulfonamide (26.2.5). Reacting this with cyclohexylisocyanate gives acetohexamide (26.2.6).