Butibufen

Description

Butibufen is a new phenylalkanoic antiinflammatory/analgesic useful in the treatment of rheumatologic conditions. In a study of patients with osteoarthritis, the onset of action of butibufen was faster with less frequent and milder side effects than indomethacin.

Chemical Properties

White to Off-White Solid

Originator

Juste (Spain)

Uses

Anti-inflammatory.

Definition

ChEBI: Butibufen is a monoterpenoid.

Manufacturing Process

1st method:
4-Isobutylphenylbenzyl chloride was prepared by passing a stream of hydrogen chloride into a suspension of p-bromoaldehyde and anhydrous zinc chloride in isobutylbenzene. A mixture of 137 g (0.75 mol) of 4-isobutylbenzyl chloride thus prepared, 44.1 g (0.90 mol) of sodium cyanide, 216 g of 99% ethanol, and 81.3 g of water was heated refluxed for 6 hours. The mixture became reddish-black in color. From this mixture, 215 ml of ethanol and water was then distilled and the residue was filtered. The solids that were separated by filtration were washed with 100 ml of diethyl ether and the ether washings were combined with the original filtrate, to which 800 ml of water was then added. The organic phase was then separated from the aqueous phase, washed with five 400 ml portions of water and dried over anhydrous sodium sulfate. The ether was evaporated from the dried organic phase by vacuum distillation and the residue which distilled between 130°C and 132°C at a pressure of 7 mm of mercury was collected. The yields of 4-isobutylbenzene cyanide 100-113 g.
To a solution of 6.7 g of sodium amide in 100 ml of anhydrous diethyl ether was added dropwise 26 g of 4-isobutylbenzene cyanide while the mixture was stirred and heated under gentle reflux. After all of the 4-isobutylbenzene cyanide had been added, the mixture was heated under gentle reflux for 15 min, after which 23.4 g of ethyl iodide was slowly added dropwise thereto from the dropping funnel. After completion of the addition of the ethyl iodide, the mixture was heated under gentle reflux for an initial period of 15 min, after which it was diluted with an equal volume of water and shaken. The two layers that formed were separated and the aqueous layer was then extracted with two 50 ml portions of diethyl ether. The ether extracts were combined and then washed with two 80 ml portions of water and dried over anhydrous magnesium sulfate. The dried ether extract was then distilled at a subatmospheric pressure. In this manner, 25 g of a clear transparent uncolored liquid having a boiling point of 118-122°C at a pressure of 1mm of mercury, which consisted of 2-(4-isobutylphenyl)butyronitrile, was collected. This yield was equivalent to 83% of the theoretical.
A mixture of 40 g (0.2 mol) of 2-(4-isobutylphenyl)butyronitrile and 78 ml of a freshly prepared solution of sodium hydroxide that was prepared by dissolving 28 g of sodium hydroxide in 25 ml of distilled water and the volume of which was brought to 100 ml by addition thereto of methanol, was heated under gentle reflux in a flask provided with a stirrer and reflux condenser while the mixture was stirred during a period of 9 hours. From the mixture the methanol and a portion of the water were distilled and the mixture was then cooled, the crystals began to separate. The mixture was then diluted with 150 ml of water and extracted with two 25 ml portions of diethyl ether. The remaining aqueous solution containing the sodium salt of 2-(4- isobutylphenyl)butyric acid was then saturated with sodium chloride until the salt started to precipitate. The solution was then cooled to 5°C and the precipitated salt was separated by filtration, recrystallized from isopropanol, and dried in a vacuum desiccator at a pressure of 1 mm of mercury until it had attained a constant weight. In this manner, 32 g of sodium 2-(4- isobutylphenyl)butyrate having a melting point of 188-191°C, which is equivalent to a yield of 67% of the theoretical, was obtained.
Dilute hydrochloric acid (19% by weight of hydrogen chloride) was slowly added to a cold solution of 25 g of the sodium 2-(4-isobutylphenyl)butyrate thus prepared in 100 ml of water until the solution corresponded to pH of 1.0. The oil which precipitated was then allowed to solidify to a white solid by standing in a refrigerator. The white solid was then separated by filtration, dried, and recrystallized from petroleum ether. It had a melting point of 50- 52°C, and its elementary analysis corresponded to the 2-(4- isobutylphenyl)butyric acid.
2nd method:
5.0 g of small pellets of sodium metal were added slowly with stirring to 150 ml of absolute ethanol, while a current of nitrogen gas was passed there through so as to blanket the solution from the atmosphere. After all of the sodium metal had been dissolved and while the solution was maintained at a temperature of 50°C, a solution of 52 g of ethyl 2-(4- isobutylphenyl)cyanoacetate in 50 ml of absolute ethanol was added dropwise while the mixture was stirred. Subsequently, 81 g of ethyl iodide was gradually added to the mixture with stirring, after which the introduction of nitrogen gas into the mixture was discontinued and the mixture was heated for a period of 2.5 hours under gentle reflux. Thereafter, the ethanol and excess ethyl iodide were distilled from the mixture and the residue was then diluted with three times its volume of water and shaken therewith. The 2-(4- isobutylphenyl)-2-(ethoxycarbonyl)butyronitrile was then extracted from the mixture with three 50 ml portions of diethyl ether, the extracts were combined, washed with a 20% aqueous solution of sodium bisulfate and dried over anhydrous magnesium sulfate. The ether was then expelled from the extract by distillation and the residue was distilled at a subatmospheric pressure, yielding 45 g of a fraction containing 2-(4-isobutylphenyl)-2- (ethoxycarbonyl)butyronitrile having a boiling point of 150-155°C/3 mm of mercury (78% of the theoretical yield).
In a 2-liter flask provided with a stirrer and reflux condenser a solution of 129 g of 2-(4-isobutylphenyl)-2-(ethyoxycarbonyl)butyronitrile in 980 ml of a 20% solution of potassium hydroxide in methanol was heated with stirring at 40°C for a period of 1 hour. The mixture was then heated under gentle reflux with stirring for an additional period of 3 hours, during which a white solid precipitated. This mixture was then poured into 1.5 liters of water and acidified with an aqueous solution of hydrochloric acid (concentrated hydrochloric acid diluted with an equal volume of water) to a hydrogen ion concentration corresponding to a pH of 2.5, while carbon dioxide was evolved therefrom. The aqueous mixture was then extracted with diethyl ether. The extracts were washed successively with a saturated solution of sodium bicarbonate and water, dried over anhydrous magnesium sulfate, and distilled at a subatmospheric pressure, to yield 86.5 g of a fraction consisting of 2-(4- isobutylphenyl)butyronitrile having a boiling point of 124-128°C at a pressure of 1.5 mm of mercury, which is equivalent to approximately 0.43 mol and a yield of 91% of the theoretical based on the original 2-(4-isobutylphenyl)-2- (ethoxycarbonyl)butyronitrile.
The 2-(4-isobutylphenyl)butyronitrile was converted to sodium 2-(4- isobutylphenyl)butyrate and subsequently to 2-(4-isobutylphenyl)butyric acid in the same manner as described in Method 1 hereinbefore.

brand name

Butilopan

Therapeutic Function

Antiinflammatory, Analgesic