The present invention relates to a commercial process for manufacture of the well known antihistaminic drug, fexofenadine.
Fexofenadine which is an important biphenyl methyl piperidine derivative is chemically 4[1-hydroxy-4-[4-(hydroxybiphenylmethyl)-1 -piperidinyl]butyl]-a,a-dimethylbenzeneacetic acid, of structural formula I, as shown in the accompanied drawings. Fexofenadine is used for treating allergic rhinitis, asthama and other allergic disorders, and are effective bronchodilators.
The process outlined in prior art relates to the preparation of anhydrous acid addition salts of fexofenadine, which comprises of reducing the ketone group of carboxylate derivative, 4-[4-[4-(hydroxybiphenylmethyl)-l-piperidinyl]-l-oxobutyl]-α,α-dimethylbenzeneacetate of structural formula II, to corresponding hydroxyl derivative of structural formula III, as shown in the accompanied drawings. This ester with hydroxyl group is treated with base like alkali metal hydroxides to get carboxylic acid derivative (fexofenadine) which is converted to acid addition salt by treating with the inorganic acids.
There are significant drawbacks to these approaches as the penultimate intermediate of structural formula III always results with:
a. 4-[4-[4-(hydroxybiphenylmethyl)-l-piperidinyl]-l-oxobutyl]-a,a-
dimethylbenzeneacetic acid, the impurity referred to as keto analogue of
fexofenadine, of structural formula IV, as shown in the accompanied drawings.
b. Meta-isomer of fexofenadine of structural formula V, as shown in the accompanied
drawings.
The prior art approach was not suitable from commercial point of view because the desired p-isomer of fexofenadine is isolated in less yield. Moreover, the generation of huge quantity of unwanted meta-isomer makes the process uneconomical. The desired products are not obtained in high yields and high purity, thus making the process complicated from the industrial point of view.
The present inventors have discovered that solubility of fexofenadine is very low in polar solvents like alcohols, esters, or mixtures thereof It was observed that during reduction of Methyl 4- [4- [4-(hydroxybiphenyl methyl)-1 -piperidinyl] -1 -oxobutyl] -a,a-dimethylphenyl acetate of formula II, the product precipitates out as soon as 80-90% conversion is achieved.

Once the product is precipitated, it does not allow reaction to go up to completion, and so the starting material always remains unreacted as a contamination, if not reduced in the next step. This contamination led to the impurity formation in the final product, during hydrolysis.
The present invention discloses the method to minimize the impurities by complete reduction of the methyl 4-[4-[4-(hydroxybiphenylmethyl)-l-piperidinyl]-l-oxobutyl]-a,a-dimethyl phenyl acetate during ester hydrolysis stage wherein the product is in dissolved state in the form of a salt, as well as generation of highly pure desired regioisomer of fexofenadine.
Accordingly, the present invention discloses the techniques to minimize the impurity formation and conversion of the formed impurities to useful product, thus making the process economically more viable due to minimization of side product formation. The product has a higher shelf life as it does not have upper limit or threshold quantity of impurities which can affect the quality of the product during storage.
In accordance with the present invention the process of preparation of biphenylmethyl piperidine derivatives i.e., fexofenadine, comprises of reducing methyl 4-[4-[4-(hydroxybiphenyl methyl)-l-piperidinyl]-l-oxobutyl]-α,α-dimethyl phenyl acetate of formula II, by the process described in the US patent No. 5,578,610. The process has been exemplified in Example 1. The reduced product methyl 4-[4-[4-(hydroxybiphenylmethyl)-l-piperidinyl]-l-hydroxybutyl]-a,a-dimethyl phenyl acetate is converted into the salt by adding it to a solution of organic solvent and a base, followed by heating to reflux for about 3-4 hours.
Organic solvent comprises of polar solvents such as lower alkanols.
Lower alkanols include those of primary, secondary and tertiary alcohols having one to six carbon atoms, preferably selected from primary, secondary and tertiary alcohols having one to four carbon atoms such as methanol, ethanol, n-propylalcohol, isopropyl alcohol, isobutanol, n-butanol, t-butanol or mixtures thereof Most preferably ethanol is used.
Base is selected fi-om alkali metal hydroxides, amides, alkoxides, alkali metals, or mixtures thereof
Alkali metal hydroxide is selected fi-om lithium hydroxide, sodium hydroxide, and potassium hydroxide. Among these sodium hydroxide is the most preferred.

Further aspect of the present invention is reducing the salt solution. The process comprises of adding basic aqueous solution of reducing agent followed by refluxing, cooling and washing the residue with organic solvent, water or mixtures thereof to yield substantially pure fexofenadine, having keto analogue less than 0.05%. The organic solvent and the base is same as defined above.
The reducing agent comprises of conventional reducing agents such as sodium borohydride, potassium borohydride, tetralkyl ammonium borohydride, zinc borohydride. Most preferably sodium borohydride
A still further embodiment of the present invention comprises of suspending the fexofenadine formed in the organic solvent, and adding base to dissolve it. The pH of the reaction mixture is adjusted to 6.7-6.8 by adding dilute hydrochloric acid, followed by cooling and filteration to yield highly pure fexofenadine having meta-isomer less than 0.05%
The present invention has been described in terms of its specific embodiments certain modifications and equivalents will be apparent to those skilled in the art and are intended to be limited within the scope of the present invention.
EXAMPLE 1
Methyl 4- [4- [4-(hydroxydiphenylmethyl)-1 -piperidinyl] -1 -oxobutyl] -2,2-dimethylphenylacetate (20 g) was added to methanol (60 ml), at 25-35°C followed by the addition of soUd sodium borohydride (0.81 g) in small portions. The reaction mixture was further stirred at 25-35°C for 2-3 hours and monitored by HPLC, After the reaction was over, it was quenched with acetic acid and cooled to 0-5 °C. The solid was filtered and washed with cold methanol, dried to get about 18-18.5 g Methyl 4-[4-[4-(hydroxybiphenylmethyl)-l-piperidinyl]-l-hydroxybutyl]-a,a-dimethyl phenyl acetate.

EXAMPLE 2
Methyl 4-[4-[4-(hydroxybiphenylmethyl)-1 -piperidinyl]-1 -hydroxybutyl]-a,a-dimethyl phenyl acetate (200 g) obtained in Example 1 was added to a mixture of ethanol (95%, 600 ml), and sodium hydroxide (23.2 g), and heated to reflux for about 3-4 hours. The reaction mixture was cooled to 50°C and added a solution of sodium borohydride (0.8 g) and sodium hydroxide (0.8 g) in water (10 ml). The reaction mixture was again heated to reflux for about 1 hour and cooled to 8-10°C, the product was filtered and washed with water and ethanol (95%). The material was dried to give 162 g of substantially pure product having keto analogue less than 0.05%.
EXAMPLE 3
Methyl 4-[4-[4-(hydroxybiphenylmethyl)-l-piperidinyl]-l-hydroxybutyl]-a,a-dimethyl phenyl acetate (200 g) obtained in Example 1 was added to a mixture of ethanol (95%, 600 ml), and sodium hydroxide (23.2 g), and heated to reflux for about 3-4 hours. The reaction mixture was cooled to 50°C and added a solution of sodium borohydride (0.8 g) and sodium hydroxide (0.8 g) in water (10 ml). The reaction mixture was again heated to reflux for about 1 hour and cooled to 8-10°C, the product was filtered and washed with water and ethanol (95%).
The wet product was suspended in ethanol (95%, 800 ml) and dissolved by adding a solution of sodium hydroxide (12.9 g) in water (12.9 ml). The solution was heated to 50°C and the pH adjusted to 6.7 - 6.8 by adding 1:1 dilute hydrochloric acid. The product was isolated by cooling and filtration. The product was further dried to yield highly pure fexofenadine, having meta-isomer less than 0.05%.

WE CLAIM:
1 A process for preparing highly pure biphenylmethyl piperidine derivative of structural formula I, as shown in the accompanied drawings comprising the step of complete reduction of methyl 4-[4-[4-(hydroxybiphenylmethyl)-l-piperidinyl]-l-hydroxy butyl]-a,a-dimethylphenyl acetate of structural formula III, as shown in the accompanied drawings wherein the starting compound is in the form of a salt.
2 The process of claim 1 wherein the said salt is prepared by adding methyl 4-[4-[4-(hydroxybiphenylmethyl)-1 -piperidinyl] -1 -hydroxybutyl] -a,a-dimethylphenyl acetate to a solution of an organic solvent and a base.
3 The process of claim 2 wherein organic solvent comprises of lower alkanols.
4 The process of claim 3 wherein lower alkanols comprises of primary, secondary and tertiary alcohols having 1 to 6 carbon atoms.
5 The process of claim 4 wherein lower alkanols comprises of primary, secondary and tertiary alcohols having 1 to 4 carbon atoms.
6 The process of claim 5 wherein lower alkanols is selected from methanol, ethanol, n-propyl alcohol, isopropyl alcohol, isobutanol, n-butanol, t-butanol, or mixtures thereof
7 The process of claim 6 wherein the lower alkanol used is ethanol.
8 The process of claim 2 wherein base is selected from alkali metal hydroxides, amides, alkoxides, alkali metals, or mixtures thereof
9 The process of claim 8 wherein alkali metal hydroxide comprises of lithium hydroxide, sodium hydroxide, potassium hydroxide, or mixtures thereof.
10 The process of claim 9 wherein the alkali metal hydroxide used is sodium hydroxide to give sodium salt of methyl 4-[4-[4-(hydroxybiphenylmethyl)-l-piperidinyl]-1-hydroxybutyl] -a,a-dimethylphenyl acetate.

11 The process of claim 1 wherein reduction is carried out by adding the basic aqueous solution of reducing agent, followed by refluxing, cooling and washing the residue with the said organic solvent, water or mixtures thereof
12 The process of claim 11 wherein reducing agents are selected from the conventional reducing agents, such as sodium borohydride, potassium borohydride, tetralkyl ammonium borohydride, zinc borohydride, and the like.
13 The process of claim 12 wherein the reducing agent used is sodium borohydride.
14 The process of claim 11 further comprises of suspending the residue in the organic solvent followed by adding the said hydroxide of alkali metal, water or mixtures thereof, and heating.
15 The process of claim 14 further comprises of adjusting the pH to 6.7-6.8, followed by cooling, filtration and drying the residue to obtain highly pure fexofenadine having keto analogue and meta isomer less than 0.05%.
16 The process for the preparation of biphenylmethyl derivative of structural formula I as shown in the accompanied drawings, substantially as herein described and exemplified by the examples.