N,N-Dimethyl-(3,3-diphenyltetrahydro-2-furyliden)ammonium bromide (3.1.54) is synthesized from diphenylacetic acid ethyl ester, which is reacted with ethylene oxide in the presence of sodium hydroxide, giving 2,2-diphenylbutyrolactone (3.1.51). Reacting this with hydrogen bromide in acetic acid opens the lactone ring, forming 2,2-diphenyl-4-bro-mobutyric acid (3.1.52). This transforms into acid chloride (3.1.53) using thionyl chloride, which cyclizes upon further treatment with an aqueous solution of dimethylamine, thus forming the desired N,N-dimethyl-(3,3-diphenyltetrahydro-2-furyliden)ammonium bromide (3.1.54). Reacting this with 4-(4-chlorphenyl)-4-hydroxypiperidine (3.1.50) gives the desired loperamide (3.1.55) [34-36].
Loperamide is presently used more often as an antidiarrheal drug than as an analgesic, and it is also included in the list of over-the-counter drugs because of its insignificant action on the CNS. It reduces intestinal smooth muscle tone and motility as a result of binding to intestinal opiate receptors. It is used for symptomatic treatment of severe and chronic diarrhea of various origins. The most popular synonym for loperamide is imodium.
Diphenoxylate: Diphenoxylate, ethyl ester of 1-(3-cyano-3,3-diphenylpropyl)-4-phenylpiperidine-4-carboxylic acid (3.1.58), is also a drug of 4-phenylpiperidine series. In practice there are two ways of making it. The first way is by the alkylation of the ethyl ester of 4-phenylpiperidine-4-carboxylic acid (3.1.56) with 2,2-diphenyl-4-bromobutyronitrile, which in turn is synthesized from 1-benzyl-4-phenyl-4-cyanopiperidine. The product undergoes ethanolysis in the presence of acid, followed by benzylation. The second way is a synthesis accomplished by alkylation of diphenylacetonitrile using ethyl ester of 1-(2-chloroethyl)-4-phenylpiperidine-4-carboxylic acid (3.1.57), which is synthesized by reaction of ethyl ester of 4-phenylpiperidine-4-carboxylic acid with /¡-chloroethanol or eth-ylenoxide with the subsequent substitution of hydroxyl group, which results from the opening of the epoxide ring, by chlorine via action of thionyl chloride [37,38].
This drug is a structural analog of meperidine and loperamide; however, it practically duplicates all of the pharmacological properties of loperamide. Being analogous to loperamide, it is mainly used for treating diarrhea. Synonyms for this drug are fentanest, leprofen, and others.
Fentanyl: Fentanyl, 1-phenethyl-4-N-propinoylanilinopiperidine (3.1.63), is an extremely powerful intramuscular and intravenous analgesic. The synthesis of fentanyl is accomplished beginning with 1-benzylpiperidin-4-one (3.1.48), which is condensed with aniline to form the corresponding Schiff base (3.1.59). The double bond in this product is reduced by lithium aluminum hydride, and the resulting 1-benzyl-4-anilinopiperidine (3.1.60) is acylated using propionic acid anhydride. The resulting 1-benzyl-4-N-propinoylanilinopiperidine (3.1.61) undergoes debenzylation using hydrogen and a palladium on carbon catalyst, to give 4-N-propanoylanilinopiperidine (3.1.62), which is N-alkylated by 2-phenylethylchloride, to give fentanyl (3.1.63) [39,40].
Was this article helpful?