Patent Watch

March 5, 2012

Make triazoles by cyclizing hydrazones. A. M. Naik and co-inventors disclose a process for producing compounds that are used for treating anxiety and depression. Examples of these drugs are alprazolam (2a) and triazolam (2b). One step in the synthesis of these and similar compounds involves a cyclization reaction that forms triazole rings from acetyl hydrazones.

The inventors reviewed existing methods for making these compounds. One gives a low yield of crude product that is difficult to purify. Another uses an expensive catalyst and MeC(OEt)3, which is difficult to handle on an industrial scale because of its flammability. In the inventors’ cyclization step, the reaction is carried out by heating a mixture of hydrazone 1a or 1b and toluene to reflux in the presence of p-toluenesulfonic acid (TsOH) and removing water with a Dean–Stark apparatus. The products are isolated in crude form and crystallized from i-PrOH to give 2a in 80% yield or 2b in 77% yield.

The patent’s claims also cover the application of the process to the synthesis of brotizolam (3a) and etizolam (3b), but no examples are given. The inventors claim to provide a facile cyclization of hydrazones that uses readily available and nonhazardous reagents. Although toluene is much less expensive than MeC(OEt)3, it is equally flammable. (Centaur Chemicals Private Ltd. [Mumbai, India]. US Patent 8,106,189, Jan. 31, 2012; Keith Turner)

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