clometacin

Originator

Clometacin,Roussel-Uclaf

Uses

Clometacin is an antalgic drug that binds to human serum albumin (HSA) and inhibits the binding of indomethacin, warfarin, clofibrate and salicylic acid to HSA.

Definition

ChEBI: Clometacin is a N-acylindole.

Manufacturing Process

Preparation of 1-carboxymethyl-2-methyl-3-p-chlorobenzoyl-6-methoxy-indole STEP A: 1-(2'-Nitro-4'-methoxyphenyl)-2-methyl-2-nitroethylene 15.0 g of 2-nitro-4-methoxybenzaldehyde (Boon, Soc., 1949 Suppl., p. 230) were introduced into a mixture of 75 ml of acetic acid, 9.5 ml of nitroethane and 6.5 gm of ammonium acetate and the resulting mixture was heated to reflux and held there for 2 h. After cooling the mixture to room temperature, the mixture was added to ice water and the precipitate formed was recovered by vacuum filtration. The precipitate was washed with water and twice crystallized from ethanol and treated with carbon black to obtain 9.6 gm of 1- (2'-nitro-4'-methoxyphenyl)-2-methyl-2-nitroethylene having a melting point of 111°C.
STEP B: 2-Methyl-6-rnethoxyindole
32 g of 1-(2'-nitro-4'-methoxyphenyl)-2-methyl-2-nitroethylene and 3.2 g of palladized charcoal con training 18% palladium were introduced into a mixture of 320 ml of ethyl acetate, 48 ml of ethanol and 240 ml of acetic acid and after a purge with nitrogen then with hydrogen, the mixture was agitated under a hydrogen atmosphere. The reaction temperature was allowed to rise to 50°C and was held at that temperature by cooling. 18.2 L of hydrogen were absorbed in 3 h after which the reaction mixture was purged with nitrogen and the catalyst was removed by filtration. The reaction mixture was concentrated to dryness under reduced pressure and the residue was
dissolved in methylene chloride. The methylene chloride solution was washed with an aqueous solution of sodium bicarbonate, with water, was dried and concentrated to dryness under reduced pressure. The residue was crystallized from petroleum ether (boiling point 65-75°C) and the resulting product was dissolved in ether. The ether solution was filtered over alumina and 6.4 g of 2- methyl-6-methoxy-indole having a melting point of 104°C were obtained there from.
STEP C: 2-Methyl-3-p-chlorobenzoyl-6-methoxyindole
9 g of 2-methyl-6-methoxy-indole were added to a suspension of 20.6 g of N, N-dimethyl-p-chlorobenzamide and 6.4 ml of phosphorus oxychloride. The interior reaction temperature obtained was brought to 60°C and rapidly rose to 115°C, the temperature was reduced and held for 2 h at 85°C. The temperature was then reduced to 50°C and the reaction mixture was added to water and then 400 ml of ethanol were added thereto. The reaction mixture was adjusted to a pH of 10 by the addition of sodium hydroxide solution and
Preparation of 1-carboxymethyl-2-methyl-3-p-chlorobenzoyl-6-methoxy-indole STEP A: 1-(2'-Nitro-4'-methoxyphenyl)-2-methyl-2-nitroethyl
ene 15.0 g of 2-nitro-4-methoxybenzaldehyde (Boon, Soc., 1949 Suppl., p. 230) were introduced into a mixture of 75 ml of acetic acid, 9.5 ml of nitroethane and 6.5 gm of ammonium acetate and the resulting mixture was heated to reflux and held there for 2 h. After cooling the mixture to room temperature, the mixture was added to ice water and the precipitate formed was recovered by vacuum filtration. The precipitate was washed with water and twice crystallized from ethanol and treated with carbon black to obtain 9.6 gm of 1- (2'-nitro-4'-methoxyphenyl)-2-methyl-2-nitroethylene having a melting point of 111°C.
STEP B: 2-Methyl-6-rnethoxyindole
32 g of 1-(2'-nitro-4'-methoxyphenyl)-2-methyl-2-nitroethylene and 3.2 g of palladized charcoal con training 18% palladium were introduced into a mixture of 320 ml of ethyl acetate, 48 ml of ethanol and 240 ml of acetic acid and after a purge with nitrogen then with hydrogen, the mixture was agitated under a hydrogen atmosphere. The reaction temperature was allowed to rise to 50°C and was held at that temperature by cooling. 18.2 L of hydrogen were absorbed in 3 h after which the reaction mixture was purged with nitrogen and the catalyst was removed by filtration. The reaction mixture was concentrated to dryness under reduced pressure and the residue was dissolved in methylene chloride. The methylene chloride solution was washed with an aqueous solution of sodium bicarbonate, with water, was dried and concentrated to dryness under reduced pressure. The residue was crystallized from petroleum ether (boiling point 65-75°C) and the resulting product was dissolved in ether. The ether solution was filtered over alumina and 6.4 g of 2- methyl-6-methoxy-indole having a melting point of 104°C were obtained there from. STEP C: 2-Methyl-3-p-chlorobenzoyl-6-methoxyindole 9 g of 2-methyl-6-methoxy-indole were added to a suspension of 20.6 g of N, N-dimethyl-p-chlorobenzamide and 6.4 ml of phosphorus oxychloride. The interior reaction temperature obtained was brought to 60°C and rapidly rose to 115°C, the temperature was reduced and held for 2 h at 85°C. The temperature was then reduced to 50°C and the reaction mixture was added to water and then 400 ml of ethanol were added thereto. The reaction mixture was adjusted to a pH of 10 by the addition of sodium hydroxide solution and
Step D: Methyl ester of 1-carboxymethyl-2-methyl-3-p-chlorobenzoyl-6- methoxyindole 20 ml of dimethylformamide were added to 0.32 g of a 50% suspension of sodium hydride in oil and then a solution of 2 g of 2-methyl-3-pchlorobenzoyl-6-methoxy-indole in 20 ml of dimethylformamide was added thereto. After hydrogen evolution ceased, a solution of 1 g of methyl monochloroacetate in 5 ml of dimethylformamide was added and the reaction mixture was stirred overnight at room temperature. The mixture was evaporated to dryness and the residue was taken up in water and vacuum filtered. The crystals were washed with water and dried in vacuum at 60°C to obtain 2.5 g of product which was purified by recrystallization from hot and cold methanol to give 1.9 g of the methyl ester of 1-carboxymethyl-2-methyl- 3-p-chloro-benzoyl-6-methoxy-indole having a melting point of 148-149°C as yellow crystals.
STEP E: 1-Carboxymethyl-2-methyl-3-p-chlorobenzoyl-6-methoxy-indole 2.25 g of potassium hydroxide were dissolved in 100 ml of methanol and 5 ml of water and then 7.45 g of the methylester of 1-carboxymethyl-2- methylchlorobenzoyl-6-methoxy-indole were added thereto. The mixture was heated at reflux for 1 h and then was concentrated to dryness. The residue was taken up in 70 ml of boiling water and the solution was filtered while hot. The filtrate was cooled to 20°C and acidified to a pH of 1 by the addition of 30 ml of 2 N hydrochloric acid. The precipitate was recovered by vacuum filtration and was washed with water, then methanol and finally ether and was dried at 70°C. The resulting 6.3 g of product was purified by recrystallization from ethanol to obtain 3.7 g of 1-carboxymethyl-2-methyl-3-p-chloro-benzoyl- 6-methoxyindole having a melting point of 242°C.

Therapeutic Function

Analgesic, Antiinflammatory

World Health Organization (WHO)

Clometacin, an analogue of indometacin, was introduced on the market in 1971. Subsequently several cases of severe - in some cases fatal - hepatitis were reported, which led in 1987 to the withdrawal of a high-dosage tablet formulation, while the indications for a lower dosage tablet were restricted and duration of the treatment was limited. Eventually all tablet formulations were removed from the market. Clometacin is not widely registered in other countries.