Toluene → N-Benzylnormechlorethamine

Participants

Reaction Steps

Heretofore, 1-benzyl-4-cyano-4-phenylpiperidine hydrochloride was produced commercially by first refluxing benzyl chloride in toluene with bis(2-hydroxyethyl)amine at about 105° C. to 115° C. for no less than 24 hour preferably 48 hours, and then in a second step adding thionyl chloride to the resulting N,N-bis(2-hydroxyethyl)benzylamine in toluene, quenching the reaction mixture with water followed by addition of aqueous sodium hydroxide solution, separating the toluene layer and azeotroping it to dryness to obtain a toluene solution containing about 70% yield (based on benzyl chloride) of N,N-bis(2-chloroethyl)benzylamine, and then in a third step treating portionwise a toluene solution of the latter and phenylacetonitrile with sodamide, quenching the reaction mixture with water, separating the toluene solution, distilling off in vacuo the toluene, dissolving the residual oil in methanol, acidifying the methanol solution with concentrated hydrochloric acid, collecting the precipitate, washing it with cold methanol and drying it to produce about a 57% yield [based on benzyl chloride] of 1-benzyl-4-cyano-4-phenylpiperidine hydrochloride. Analysis of the reaction mixture resulting from the first step of this preparation by gas chromatography/mass spectrography (GC/MS) revealed the presence of three major peaks in the ratio by weight of 53:13:16 (I:II:III) found to be respectively the desired intermediate, N,N-bis(2-hydroxyethyl)benzylamine (I) and two by-products, identified as N,N-dibenzyl-N-(2-hydroxyethyl)amine (II) and N-benzyl-N-(2-benzyloxyethyl)-N-(2-hydroxyethyl)amine (III). Comparable analysis of the second step of this preparation revealed the presence of another by-product, namely N-benzylmorpholine (about 5-10%). Virtual elimination of the formation of these three by-products is accomplished by the improved process of the invention.

Provenance & Evidence