Patent EP 497512 describes derivatives of imidazole, triazole and tetrazole which act on the 5-HT receptor. Notable among them is the compound 3-[2-(dimethylamino)ethyl]-5-(1,2,4-triazol-1-ylmethyl)-indole, of formula (I):

This compound is known by the INN rizatriptan and is marketed as an anti-migraine product.
The aforesaid European patent describes the preparation of rizatriptan by Fischer indole synthesis, using the corresponding phenylhydrazine and an aldehyde. The method described in that patent nevertheless has the following disadvantages: it requires several steps of column purification and has an overall yield of only 11%.
Other processes for preparing rizatriptan were described subsequently.
On the one hand, preparation of the intermediate (4-[1,2,4]triazol-1-1-ylmethyl-phenyl)-hydrazine is optimised by International Patent Application WO 94/02476. Conversion of this intermediate into rizatriptan is carried out by Fisher indole synthesis, in the same way as in the preceding patent. The yield for obtaining intermediate is improved by said process. The end product nevertheless continues to have the disadvantage of requiring a column purification step, so that it is not cost-effective to carry out the process at industrial scale.
As well, International application WO 95/32197 describes a process for preparing the product sought, by palladium-catalysed coupling ring closure of 3-iodine-4-aminobenzyl-triazol with a suitably protected butynol derivative to the corresponding tryptophol followed by conversion of the hydroxyethyl moiety to dimethylaminoethyl. Although this process does not require column purification, it has the disadvantage of using a palladium catalyst which makes the process more expensive, while also using highly toxic reagents such as iodine chloride and highly flammable ones such as n-butyl lithium.
Finally, application WO 98/06725 describes the preparation of 2-silyl protected indoles, by palladium-catalysed cross-coupling reaction of haloanilines with acylsilanes, and preparation of the product sought by deprotection of these intermediates so obtained. This process also has the disadvantage of using a palladium catalyst which makes the process more expensive, while it also uses highly flammable reagents such as n-butyl lithium.
USPTO Backgrounds
USPTO Backgrounds