Process for preparing fexofenadine

This application is being filed under Rule 1.371 as a National Stage Application of pending International Application No. PCT/IT2007/000525 filed Jul. 25, 2007, which claims priority to the following parent application: Italian Patent Application No. MI2006A001492, filed Jul. 27, 2006. Both International Application No. PCT/IT2007/000525 and Italian Patent Application No. MI2006A001492 are hereby incorporated by reference herein in their entirety.

Process for preparing fexofenadine comprising the hydrolysis of 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidyl]-1-oxobutyl]-α,α-dimethylbenzeneacetic acid-alkyl ester to 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidyl]-1-oxobutyl]-α,α-dimethylbenzeneacetic acid which is catalytically hydrogenated as fexofenadine carboxylate salt.

Summary of Advantageous Embodiments of the Invention

The present invention concerns a process for preparing fexofenadine, the formula (I) of which is shown below:

The process provides for the hydrolysis of 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidyl]-1-oxobutyl]-α,α-dimethylbenzeneacetic acid-alkyl ester, shown below as formula (II),

where R is an alkyl group, in a mixture of water and optionally an organic solvent, in the presence of a base by obtaining the carboxylate salt of 4-[4-[4-(hydroxidiphenylmethyl)-1-piperidyl]-1-oxobutyl]-α,α-dimethylbenzeneacetic acid, shown below as formula (III),

where M+ is the cation of the carboxylate salt (or, in other words, the cation of the base used for the hydrolysis), which is directly reduced as carboxylate in a basic environment with hydrogen in the presence of a suitable catalyst to give the carboxylate of fexofenadine, which is precipitated by neutralisation of the solution.

The processes of preparing fexofenadine starting from the compound of formula II reported in the literature describe as a preferred method of ketone group reduction the reduction with sodium borohydride as, for example, described in U.S. Pat. No. 4,254,129. This reaction may be carried out before or after the ester hydrolysis. The methods of catalytic reduction mentioned are described as less efficient. These reactions are conducted in organic solvents on the compound of Formula II or its relative acid. Under these conditions, the reaction yields have proven to be quite low because of the formation of an impurity caused by the complete hydrogenolysis and the loss of one or both oxygens at benzyl position and which makes up about 32% of the product deriving from the hydrogenolysis.

In the new process, the compound of FORMULA II

where R is an alkyl group, preferably a C 1 -C 4 alkyl group, still more preferably methyl, is dissolved or suspended in a mixture of organic solvent and water, in the presence of a base, or in water and base only, and hydrolysed under stirring at a temperature comprised between 0° C. and the reflux temperature of the mixture. The organic solvent is preferably a polar solvent, normally of a protic type, preferably a C 1 -C 4 alcohol, still more preferably methanol. The base is preferably of an inorganic nature, such as, for example, the hydroxide of an alkaline or alkaline-earth metal, still more preferably NaOH.

Said organic solvent, when used, is present in ratios in the range of 0.25-16 volumes in relation to water; or said mixture of water and organic solvent is preferably present in 6-7 volumes in relation to compound II; the base, in turn, is preferably used in molar excess in relation to the compound of formula II, preferably with a molar ratio from 3 to 5.

The compound of FORMULA III is obtained from this reaction

where M+ is the cation of the carboxylate salt, preferably Na + .

A suitable metallic-type hydrogenation catalyst is added to the system thus obtained, preferably selected from suitably supported palladium, platinum, or ruthenium (preferably palladium on carbon) and is hydrogenated at a temperature between 0° C. and the boiling point of the solvent at a pressure in the range of 1-100 bar, preferably 1-10 bar.

Fexofenadine, FORMULA I, is obtained from the hydrogenation reaction

which is then precipitated by neutralising the base present in solution with an acid, preferably acetic acid.

The examples which follow are purely illustrative and non limiting of the invention.