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A New Route for the Synthesis of Ozagrel Hydrochloride

(E)-3-[4-(1H-Imidazol-1-ylmethyl)phenyl]-2-propenoic acid hydrochloride (ozagrel hydrochloride) is a highly selective inhibitor of thromboxane A2 (TXA2). The beneficial effects of TXA2 inhibition by ozagrel include improved motor coordination after experimental stroke and antihypertensive effects in spontaneously hypertensive rats. Since 1988, ozagrel hydrochloride has been marketed as an antithrombotic drug in Japan.1 Therefore, the development of an efficient synthetic method is of great interest. The reported preparations of ozagrel hydrochloride involve the reaction of alkyl 4bromomethylcinnamate with N-acetylimidazole2 or with imidazole.3 However, both the methods are costly as the result of either the price of the starting material in the case of Nacetylimidazole procedure and the low yield (34%) of the reaction in the imidazole method. We now describe a new cost efficient synthetic route to prepare ozagrel hydrochloride using low-priced reagents, under mild reaction conditions and in high overall yield. Ozagrel hydrochloride was obtained through a three-step sequence starting from commercially available p-tolualdehyde by bromination with elemental bromine to afford 4(bromomethyl)benzaldehyde 2 in 88% yield. Although bromine was selected as the brominating agent because of its lower price in China, the reaction works equally well (90% yield) by bromination with NBS which had to be used in the bromination of alkyl bromethylcinnamate because the use of bromine lead to reaction at the double bond.4 The subsequent substitution of 2 with imidazole proceeded smoothly in 92% yield to give 4-(1H-imidazol1-ylmethyl)benzaldehyde (3) in the presence of potassium carbonate instead of the much stronger base NaH.3 The final condensation of 3 with malonic acid5 in toluene followed by treatment with hydrochloric acid successfully provided ozagrel hydrochloride in 87% yield. The overall yields of ozagrel hydrochloride using bromine and NBS from 1 are 70% and 72%, respectively. Although intermediates 2 and 3 were purified by chromatography in this article, in a larger scale preparation (30 g), the crude materials are sufficiently pure to be used in the