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UBC Theses and Dissertations

Synthesis of cycloalkyl analogues of diphenhydramine Chan, Gwendolyn Faye Quen

Abstract

Two series of diphenhydramine analogues have been prepared. In the first series, one phenyl ring in the benzhydryl nucleus has been substituted with a cycloalkyl ring containing three to seven carbon atoms inclusive. In the second series both phenyl rings have been replaced by two rings containing three, five and six carbon atoms. The following amines have been prepared: 2-(α -cyclopropylbenzyloxy)-N,N-dimethylethylamine, 2-(α -cyclobutylbenzyloxy) -N,N-dimethylethylamine, 2-(α-cyclopentylbenzyloxy)-N,N-dimethylethylamine, 2- (α -cyclohexylbenzyloxy) -N, N-dimethylethylamine, 2-(α-cycloheptylbenzyloxy)-N,N-dimethylethylamine, 2-(dicyclopropylmethoxy)-N,N-dimethylethylamine, 2-(dicyclopentylmethoxy)-N,N-dimethylethylamine and 2-(dicyclohexylraethoxy)-N,N,-dimethylethylamine. These compounds have been characterized by their infrared spectra and, where possible, by elemental analyses of the chloroplatinates. The reaction scheme involved a Grignard reaction of the cycloalkylbromide on benzaldehyde to yield the cycloalkyl-phenylcarbinol for the first series, and reaction on ethyl formate to yield the dicycloalkylcarbinol for the second series. Cyclobutylphenylcarbinol was obtained through a Friedel-Crafts reaction of cyclobutanecarboxyl chloride on benzene using aluminum chloride as the catalyst and subsequent reduction of the cyclobutylphenylketone with lithium aluminum hydride. These secondary carbinols were then condensed with 2-dimethylaminoethylbromide hydrobromide in the presence of sodium amide. An alternate condensation reaction in the second series involved reaction of the dicycloalkylmethylbromide with 2-dimethylaminoethanol using sodamide as the condensing agent. The major problems in the syntheses of the carbinols are the presence of carbonyl contaminants in some of the products, particularly in the cycloheptyl and cyclooctyl compounds, and the low yields of addition products obtained. It appears that better results would be achieved if the amount of Grignard reagent in the solution is estimated by a standard method to determine the amount of aldehyde or ester required for the reaction. In the condensation reactions, difficulty was encountered in formation of the sodium derivative. This reaction required a finely-divided form of the condensing agent and sufficient warming time for the reaction to proceed. However, too lengthy a period of heating appears to alter the carbinol molecule so that no product could be obtained. The second phase of the condensation reaction also proceeds slowly, and a sufficient period of refluxing is necessary for the reaction to go to completion. The alternate procedure which was also employed in the second series of compounds did not appear to improve the yields of products. Signature of Examiners

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