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A Simple and Convenient Synthesis of Triprolidine

Triprolidine (3)1 is an anti-histamine drug belonging to 1,1-diaryl-2-propyleneamine class1 having trade names ActidilTM and MyodilTM. It is a very popular first-generation antihistamine used for coughs and colds. In combination with pseudo-ephedrine, it is being sold under the brand name ActifedTM. Recently Bolser,2 Pratter, and Abouzgheib3 reported that for coughs associated with the common cold, first-generation anti-histamine decongestants would be more effective than newer nonsedative antihistamines. This observation together with continuous demand for first-generation anti-histamines prompted us to search for nonhazardous commercially viable alternate synthesis of triprolidine. The carbon-carbon double bond in propyleneamines such as Acrivastine,4–7 Pyrrobutamine,8,9 Triprolidine, Zimeldine10 have been built by dehydration of corresponding alcohols11–14 or by the Wittig method.15 n-Butyllithium has been employed in both the Wittig condensation and in the preparation of the tertiary alcohol (Scheme 1) at around −70◦C. However, large-scale preparations of these compounds employ the dehydration method rather than the Wittig method because no efficient method was available for preparation of the intermediates such as 2-(N,N-dialkylaminoethyl)triphenylphosphonium bromides and 2-aroylpyridines. Having developed commercially viable methods for the preparation of 2-(p-toloyl)pyridine (1)16 and 2-(N-pyrrolidinoethyl)triphenylphosphonium bromide (2)17 we now report the preparation of triprolidine (3) without the use of n-butyllithium. The existing industrial scale preparation of triprolidine11–14 involves the condensation of 2-bromopyridine with β-pyrrolidino-4-methylpropiophenone using alkyllithium at around −70◦C followed by dehydration using sulfuric acid between 140