FIELD OF THE INVENTION
The invention, in general, relates to the field of chemical synthesis of H2 receptor antagonist and more particularly, the present invention provides an improved process for the preparation of 4-[l-hydroxy-4-[4-(hydroxydiphenylmethyl)-l-piperidinyl]-butyl]-a,a-dimethylbenzeneacetic acid (fexofenadine) of Formula I, or its salts thereof
(Formula removed)

BACKGROUND OF THE INVENTION
Fexofenadine of Formula I, is a non-sedative antihistaminic compound and is chemically known as 4-[l-hydroxy-4-[4-(hydroxydiphenylmethyl)-l-piperidinyl]-butyl]-a,a-dimethylbenzeneacetic acid,
(Formula removed)

It is reported to be a specific H2-receptor antagonist that is also devoid of any anticholinergic, antiserotoninergic, and antiadrenergic effects.
Fexofenadine was first disclosed in US Patent 4,284,129. According to the said patent fexofenadine can be prepared by reacting ethyl a,a-dimethylphenyl acetate and 4-chlorobutyryl chloride under Friedel Crafts conditions, condensation of the resulting intermediate with a,a-diphenyl-4-piperidinemethanol to give keto ester intermediate, which on reduction followed by hydrolysis yielded fexofenadine.
In general the methods reported in prior art for the preparation of fexofenadine involves the reduction of ketone group of methyl 4-[4-[4-(hydroxydiphenylmethyl)-l-piperidinyl]-l-oxobutyl]- a,oc-dimethylbenzene acetate of formula II,
(Formula removed)

to prepare hydroxyl compound of formula III, which is further hydrolyzed using base.
(Formula removed)

Generally reaction is carried out at ambient temperature and always results in incompletion of reaction. The unreacted starting keto compound leads to formation of impurities in the final product.
In few references, such as WO 95/31437, US 2004/0077683 etc., hydrolysis and reduction are carried out parallel in single step. In the exemplified methods, hydrolysis is performed before reducing the ketone group of compound of formula II and purity of the product is not mentioned.
Recently WO 2005/67511 Al discloses a two step process to prepare fexofenadine from compound of formula II, wherein in the first step compound of formula II is reduced to compound of formula III, and in the second step i.e. hydrolysis of compound of formula III is carried out using base and additionally reducing agent is also added during hydrolysis to reduce unreacted keto compound of formula II.
Most of the processes described above are not suitable for industrial point of view, because the desired para-isomer is not obtained in required purity and requires repeated purifications to remove unwanted meta isomer impurity and other impurities generated from unreacted ketone compound, leading to low yields. To achieve a high efficiency of the reaction for industrial synthesis of fexofenadine, it is necessary that conversion of ketone compound to hydroxyl compound should go to completion to minimize the formation of impurities and improve the yields.
Therefore there is an urgent need to develop a simple and cost effective process to prepare fexofenadine in high purity and high yield.
SUMMARY OF THE INVENTION
The present invention provides a novel one pot method for the preparation of
Fexofenadine of high purity (>99.5%) and in good yield (84-95%) by treating methyl 4-
[4-[4-(hydroxydiphenylmethyl)-l-piperidinyl]-l-oxobutyl]- a,a-dimethylbenzene
acetate of formula II with reducing agent to reduce completely keto group of compound of formula II to prepare hydroxy compound of formula III at temperature 35-70°C and in situ followed by treatment with base to hydrolyze the ester group.
DETAILED DESCRIPTION OF THE INVENTION
Based on our related art disclosure in the background, the present inventors have conducted extensive experimentation with an intention to overcome the difficulties of producing Fexofenadine in high yields and high purity. We have found that fexofenadine can be prepared in high yields and high purity from compound of formula II, by treating compound of formula II with reducing agent to reduce keto group to hydroxy compound at temperature 35-70°C and followed by treatment with base to hydrolyze ester group. The invention further advantageously accomplishes both the steps in single pot thus reducing the number of process steps, increasing safety and cost-effectiveness.
In accordance with the present invention, there is provided a new process for producing Fexofenadine from compound of formula II by treating it with reducing agent in the presence of alcoholic solvent. The reducing agent used can be selected from sodium borohydride, potassium borohydride, tetralkyl ammonium borohydride, or zinc borohydride. In particular, the reducing agent is sodium borohydride. The solvent may include alcoholic solvent such as methanol, ethanol, denatured spirit, n-propanol, isopropanol, isobutanol, n-butanol and t-butanol. In particular, the alcoholic solvent may include methanol and ethanol. Mixtures of all of these solvents are also
contemplated. The progress of the reaction is monitored by HPLC. It is advantageous to attain complete conversion of keto group to hydroxyl which is achieved by heating the reaction mixture for 1-2 hours at 60-65 °C.
Complete conversion of keto group to hydroxyl means keto compound of formula II should not be present in more than 0.1% ratio by HPLC. When the presence of keto compound of formula II is less than 0.1% in HPLC, the reaction mixture is concentrated by distilling about half of the solvent. The resulting reaction mixture is used as such, for the next step, without the isolation of reduced compound of formula III. The reaction mixture is treated with base at reflux temperature. The base may include one or more of alkali metal hydroxide, amide, alkoxide, alkali metal, or mixtures thereof. In particular, the base is alkali metal hydroxide. The alkali metal hydroxide may be lithium hydroxide, sodium hydroxide, or potassium hydroxide. In particular, the hydroxide is sodium hydroxide. The reaction can be continued until the content of unreacted hydroxyl compound of formula III is less than 0.5% by HPLC analysis. This degree of conversion usually takes about 6 to 7 hours. After the reaction is completed, the reaction mixture is cooled to 50-55°C and subsequently the pH is adjusted to 6.5-7.0 with a suitable acid such as hydrochloric acid, acetic acid but preferably hydrochloric acid. It is advantageous to reflux the reaction mixture for about 1-2 hours to obtain the reaction product in the high purity and high yield. After refluxing for 1 hour, reaction mixture is cooled and pH is maintained at 6.5-7.0, product is isolated in high yields by cooling and filtration. Crude fexofenadine is purified using ethanol to obtain fexofenadine having purity greater than 99.5% by high performance liquid chromatography.
The following examples are provided merely to be exemplary of the inventions and are not intended to limit the scope of the invention.
Example-I
PREPARATION OF HIGHLY PURE FEXOFENADINE
Step-1
Preparation of fexofenadine
Methyl 4-[4-[4-(hydroxydiphenylmethyl)-1 -piperidinyl]-1 -oxobutyl]-a,oc-dimethyl benzene acetate (50 g) was added to methanol (500 ml), at 25-35°C followed by the addition of solid sodium borohydride (2.5 g) in small portions. The reaction mixture was stirred at 35-40°C for one and half hours and further at 60-65°C for one hour and monitored by HPLC. After completion of reaction (i.e. staring material was 0.04%), methanol (300 ml) was distilled off. To the reaction mass sodium hydroxide solution (7g in 75 ml of water) was added at 60-65°C and the resulting reaction mixture was refluxed for 6 hours. The reaction mixture was cooled to 50-55°C; pH was adjusted to 6.5-7.0 using dilute hydrochloric acid and stirred at 70-75°C for further one hour. Thereafter reaction mixture was cooled to room temperature maintaining pH at 6.5-7.0 and further cooled to 0-5°C. The reaction mixture was filtered, washed with water and dried at 60-65°C to obtain 44.3 g of title compound having purity 97.88 % by HPLC.
Step-2
Purification of fexofenadine
Fexofenadine (43. Og) obtained in Step-1 was slurred in ethanol (95%, 215ml) and was refluxed for 3 hours. Thereafter reaction mixture was cooled to 0-5°C, filtered, washed with ethanol and dried at 50-60°C to obtain 40.8 g of title compound having purity 99.78 % by HPLC, meta impurity 0.07% and keto impurity is not detected.
ExampIe-II
PREPARATION OF HIGHLY PURE FEXOFENADINE
Methyl 4-[4-[4-(hydroxydiphenylmethyl)-1 -piperidinyl]-1 -oxobutyl]-oc,a-dimethyl benzene acetate (50 g) was added to methanol (500 ml), at 25-35°C followed by the addition of solid sodium borohydride (2.5 g) in small portions. The reaction mixture was stirred at 35-40°C for 1 hour and further at 60-65°C for lhour. After completion of reaction, methanol (300 ml) was distilled off. To the reaction mass sodium hydroxide solution (7g in 75 ml of water) was added at 60-65°C and refluxed for 6 hours. The reaction mixture was cooled to 50-55°C, pH was adjusted to 6.5-7.0 using dilute hydrochloric acid and further stirred at 70-75 °C for one hour. Thereafter reaction mass was cooled to room temperature maintaining pH at 6.5-7.0 and further cooled to 0-5°C. The reaction mixture was filtered, washed with water and dried at 60-65°C to obtain 46.7g of title compound which was slurred in ethanol (95%, 233ml) and was refluxed for 3 hours. Thereafter reaction mixture was cooled to 0-5°C, filtered, washed with ethanol and dried to obtain 44.8 g of title compound having purity 99.79 % by HPLC, meta impurity 0.03% and keto impurity is not detected.

WE CLAIM
1. An improved one pot process for the preparation of highly pure Fexofenadine of formula I or a salt thereof,
(Formula removed)

the process comprising reducing completely methyl 4-[4-[4-(hydroxydiphenyl-methyl)-l-piperidinyl]-l-oxobutyl]- a,a-dimethylbenzene acetate of formula II,
(Formula removed)

with a reducing agent at temperature 35-70°C to prepare a compound of formula HI,
(Formula removed)

in situ followed by hydrolysis with base and isolating the highly pure Fexofenadine of formula I or a salt thereof.
The process according to claim 1, wherein reducing agent is sodium borohydride, potassium borohydride, tetralkyl ammonium borohydride, and zinc borohydride.
The process according to claim 2, wherein reducing agent is sodium borohydride.
The process according to claim 1, wherein the reduced product is not isolated
The process according to claim 1, wherein the base comprises one or more of alkali metal hydroxide, amide, alkoxide, alkali metal, or mixtures thereof.
The process of claim 5, wherein the alkali metal hydroxide is lithium hydroxide, sodium hydroxide, and potassium hydroxide