Cyclomethycaine

Surfacaine,Lilly,US,1948

Cyclomethycaine is also used in topical anesthesia on the skin or mucous membranes for cuts, bites, and also for urological examinations. A common synonym of this drug is surfacaine.

ChEBI: Cyclomethycaine is a benzoate ester.

7.4 g of sodium are dissolved in 250 cc of isoamyl alcohol, 53 g of ethyl phydroxybenzoate are added and the mixture is heated to refluxing temperature for about 15 minutes. To the cooled mixture, 65 g of cyclohexyl bromide are added and the mixture is refluxed for about 3 hours. The isoamyl alcohol is removed by evaporation in vacuo and the residue is extracted with 10% aqueous sodium hydroxide solution to remove the unreacted ethyl phydroxybenzoate.
The alkali-insoluble residue comprising ethyl p-cyclohexyloxybenzoate is hydrolyzed by refluxing with 10% sodium hydroxide solution for about 3 hours. The alkaline reaction mixture is acidified with hydrochloric acid whereupon p-cyclohexyloxybenzoic acid precipitates. The precipitate is separated by filtration, washed with water and dried. It melts at about 178° to 180°C. Yield: about 7%.
62 g of p-cyclohexyloxybenozic acid and 49.5g of 3-(2'-methylpiperidino)- propyl chloride are dissolved in 300 cc of dry isopropanol and the mixture refluxed for about 12 hours. About half of the isopropanol is then distilled off and the residual solution cooled to about 0°C. 3(2'-methylpiperidino)-propyl p-cyclohexyloxybenzoate hydrochloride precipitates as a white crystalline compound. It is filtered off, washed once with ether and recrystallized from isopropanol.
3(2'-Methylpiperidino)-propyl p-cyclohexyloxybenzoate hydrochloride thus prepared melted at about 178° to 180°C. Analysis showed the presence of 8.88% chlorine as compared with the calculated value of 8.96%.

Surfacaine (Lilly).

Local anesthetic

Cyclomethycaine, the ethyl ester of 3-(2-methylpiperidino)propyl-ocyclohexyloxybenzoic acid (2.3.4), is synthesized according to the figure below. Alkylation of 2-methylpiperidine with 3-chlorpropanol-1 gives 3-(2-methylpiperidino)propanol-1 (2.3.2), whose hydroxyl group is substituted by chlorine using thionyl chloride. The resulting 3-(2-methylpiperidino)propylchloride-1 (2.3.3) is further reacted with 4-cyclohexyloxybenzoic acid, which gives cyclomethycaine [27,28].