FIELD OF THE INVENTION

The present invention relates to a process for the preparation of a,a-dimethyl-4-[4-[4-(hydroxydiphenylmethyl)-l-piperidinyl]-l-oxobutyl]phenyl acetic acid alkyl ester of

BACKGROUND OF THE INVENTION

a,a-Dimethyl-4-[4-[4-(hydroxydiphenylmethyl)-1 -piperidinyl]-1 -oxobutyl]phenyl acetic acid alkyl ester of Formula I, is an intermediate and precursor in the preparation of Fexofenadine Hydrochloride of Formula II. Fexofenadine is a second-generation antihistamine drug, without side effects, used in the treatment of allergy symptoms, related to histamine release. Histamine is a mediator of inflammation, antigen response and cellular injury, derived from the decarboxylation of the histidine, by the enzyme L-histidine decarboxylase. Histamine antagonists block release of histamine through inhibition of Hi histamine receptors, especially found on skin, bronchus. Fexofenadine is chemically known as a,a-Dimethyl-4-[l-hydroxy-4-[4-(hydroxyl diphenylmethyl)-l-piperidinyl]butyl]benzene acetic acid and is being marketed as hydrochloride salt under the brand name Allegra® as an oral tablet and oral suspension.

Fexofenadine is the carboxylic acid derivative of Terfenadine, which is the major metabolite, but without the cardiac toxicity than its parent compound. US Patent 4,254,129 discloses a process for 4-[4-[4-(hydroxydiphenylmethyl)-l-piperidinyl]-l-oxobutyl]phenyl acetic acid ethyl ester by reacting a,a-dimethyl phenylacetic acid ethyl esters with 4-halobutyryl halide in presence of a base and in presence of catalytic amount of potassium iodide, which is obtained as oily residue. The obtained oily residue is treated with hydrochloric acid to obtain 4-[4-[4-(hydroxydiphenylmethyl)-l-piperidinyl]-l-oxobutyl]phenyl acetic acid ethyl ester hydrochloride. The present inventors observed that 4-[4-[4-(hydroxydiphenylmethyl)-l-piperidinyl]-l-oxobutyl]phenyl acetic acid ethyl ester obtained as oil is difficult to handle and store. Further, the converted hydrochloride salt from oil has impurities / by-products (about 85 % (by HPLC)), which carried over to the finished product and results in impure Fexofenadine Hydrochloride (about 98 % (by HPLC)).

WO 2008/012859 Al discloses a process by reacting a,a-dimethyl phenylacetic acid methyl ester with 4-halobutyryl chloride in presence of sodium bicarbonate and methylisobutylketone to yield 4-[4-[4-(hydroxydiphenylmethyl)-l-piperidyl]-l-oxobutyl]-a,a-dimethylbenzeneacetic acid methyl ester. However, the present inventors repeated and found that the 4-[4-[4-(hydroxydiphenylmethyl)-l-piperidyl]-l-oxobutyl]-a,a-dimethylbenzeneacetic acid methyl ester is obtained as a oily residue and not as a solid. To overcome the prior-art problems the present inventors have now developed a process for the preparation of a,a-dimethyl-4-[4-[4-(hydroxydiphenyl methyl)-l-piperidinyl]-l-oxobutyl]phenyl acetic acid alkyl ester, which is highly pure, easy to handle, easy to store, industrially and commercially feasible.

OBJECTIVE OF THE INVENTION

The objective of the present invention is to provide a process for preparing a,cc-dimethyl-4-[4-[4-(hydroxydiphenylmethyl)-l-piperidinyl]-l-oxobutyl]phenyl acetic acid alkyl ester, which is industrially and commercially feasible. Yet another objective of the invention is to provide a,a-dimethyl-4-[4-[4-(hydroxydiphenyl methyl)-l-piperidinyl]-l-oxobutyl]phenyl acetic acid alkyl ester in a solid form. Yet another objective of the invention is to provide a,a-dimethyl-4-[4-[4-(hydroxydiphenyl methyl)-l-piperidinyl]-l-oxobutyl]phenyl acetic acid alkyl ester has a purity greater than about 97%. Yet another objective of the invention is to provide Fexofenadine Hydrochloride, has a purity greater than about 99%.

SUMMARY OF THE INVENTION

The present invention provides a process for preparing a,a-dimethyl-4-[4-[4-(hydroxyl diphenylmethyl)-l-piperidinyl]-l-oxobutyl]phenyl acetic acid alkyl ester of Formula I, which comprises:

a) dissolving a,a-dimethyl-4-[4-[4-(hydroxydiphenylmethyl)-l-piperidinyl]-l-oxobutyl]phenyl acetic acid alkyl ester hydrochloride in a solvent;

b) adding a base; and

c) isolating the a,a-dimethyl-4-[4-[4-(hydroxydiphenylmethyl)-l-piperidinyl]-l-oxobutyl] phenyl acetic acid alkyl ester.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a process for preparing a,a-dimethyl-4-[4-[4-(hydroxydiphenylmethyl)-l-piperidinyl]-l-oxobutyl]phenyl acetic acid alkyl ester of Formula I, by dissolving a,a-dimethyl-4-[4-[4-(hydroxydiphenylmethyl)-l-piperidinyl]-l-oxobutyl] phenyl acetic acid alkyl ester hydrochloride salt in a solvent in presence of a base at a temperature ranging from 20 - 30°C, preferably at 25°C. In yet another aspect of the present invention, a,a-dimethyl-4-[4-[4-(hydroxyl diphenyl methyl)-l-piperidinyl]-l-oxobutyl] phenyl acetic acid alkyl ester is obtained in the form of hydrate solvate. In yet another aspect of the present invention, a,a-dimethyl-4-[4-[4-(hydroxydiphenyl methyl)- l-piperidinyl]-l-oxobutyl] phenyl acetic acid alkyl ester is obtained in the form of monohydrate solvate. In yet another aspect of the present invention base is selected from group comprising of sodium hydroxide, potassium hydroxide, lithium hydroxide, ammonia and the like.

In yet another aspect of the present invention, the solvent is selected from group comprising of ethyl acetate, methyl acetate, methanol, ethanol, acetone, methyl isobutyl ketone, water and mixtures thereof. In yet another aspect of the present invention, cc,a-dimethyl-4-[4-[4-(hydroxydiphenylmethyl)-l-piperidinyl]-l-oxobutyl]phenyl acetic acid alkyl ester free base obtained is highly pure compared to the oily residue and hydrochloride salt known in the prior-art, which increases & enables the control of impurities in final Fexofenadine Hydrochloride, having high purity greater than 99.9 %. The process of the present invention is feasible commercially and simple on industrial scale. In yet another aspect of the present invention, a,oc-dimethyl-4-[4-[4-(hydroxydiphenylmethyl)-l-piperidinyl]-l-oxobutyl]phenyl acetic acid alkyl ester is prepared by the following process or by using the process described in the prior-art.

a,a-dimethyl-4-[4-[4-(hydroxydiphenylmethyl)-1 -piperidinyl]-1 -oxobutyl]phenyl acetic acid, alkyl ester is prepared by reacting Methyl 4-(4-chloro-l-oxobutyl)-a,a-dimethylphenylacetate with azacyclonol in presence of potassium bicarbonate and solvent selected from group comprising of methyl isobutyl ketone, toluene, xylene and the like; at a temperature ranging from 25-30°C. The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

EXAMPLE 1 Preparation of methyl 4-(4-chloro-l-oxobutyl)-a,a-dimethylphenylacetate 4-(Cyclopropylcarbonyl)-a,a-dimethylphenylacetic acid (15 g, 0.065 mml) and 70 g (0.29 mml) of 15% w/w hydrogen chloride solution in methanol were heated at 40-45 °C for 4 h. Thereafter, the reaction mass was concentrated under reduced pressure at below 40-45°C to remove methanol/hydrogen chloride. The residue was cooled to 20-25°C and dissolved in DM water (40 ml) and toluene (30ml). Stirred the reaction mass for about 10 min and separated the organic layer. The organic layer was washed with DM water(10 ml) and concentrated under reduced pressure at below 35-65°C to remove toluene. This oily residue containing methyl 4-(4-Chloro-l-oxobutyl)-a,a-dimethylphenylacetate was taken as such for the next step. Yield: 18 g (Viscous oily mass) Chromatographic purity (by HPLC): 95%

EXAMPLE 2 Preparation of a,a-dimethyl-4-[4-[4-(hydroxydiphenylmethyl)-l-piperidinyl]-l-oxobutyl] phenyl acetic acid methyl ester hydrochloride Methyl 4-(4-chloro-l-oxobutyl)-a,a-dimethylphenylacetate (15 g, 0.053 mml) was added to the mixture containing azacyclonol (10 g, 0.037 mml) and methyl isobutyl ketone (50 ml) at 20-25°C under nitrogen atmosphere. To the reaction mass potassium bicarbonate (20.5 g, 0.21 mml) followed by DM water (0.5 g) were added at 26-28°C. The obtained reaction mass was heated to 96-98°C and stirred for 22 h. The reaction mass was cooled to 25-30°C, filtered and washed the salts with methyl isobutyl ketone (20 ml, 25-30°C). Thereafter, the reaction mass was concentrated under reduced pressure at 65-70°C to remove methyl isobutyl ketone. The residue was dissolved in ethyl acetate (20 ml) and continued distillation under reduced pressure (-20 mm Hg) at 65-70°C. The obtained residue was cooled to 10-15°C and dissolved in ethyl acetate (100 ml). Hydrogen chloride solution in ethyl acetate(15% w/w, 9.6 g) was added slowly till product was precipitated out. Stirred the reaction mass for 1 hr at 10-15°C and filtered the product. The product was washed with ethyl acetate (3x10 ml, 10°C) and dried the product under reduced pressure (-20 mm Hg) at 45±5°C to yield a,a- dimethyl-4-[4-[4-(hydroxydiphenylmethyl)-1 -piperidinyl]-1 -oxobutyl]phenyl acetic acid methyl ester hydrochloride. Yield: 17 g Chromatographic purity (by HPLC): 85%

EXAMPLE 3 Preparation of a,a-dimethyl-4-[4-[4-(hydroxydiphenylmethyl)-l-piperidinyI]-l-oxobutyl] phenyl acetic acid methyl ester monohydrate a,a-dimethyl-4-[4-[4-(hydroxydiphenylmethyl)-l-piperidinyl]-l-oxobutyl]phenyl acetic acid methyl ester hydrochloride (15 g, 0.0273 mml) was suspended in a mixture of ethyl acetate (75 ml) and DM water (30 ml) at 25-30°C. To the reaction mass sodium hydroxide solution (1 g, 0.025 mml sodium hydroxide dissolved in DM water 10 ml) was added for 10 min at 25-28°C and stirred the contents for 2 h at 25-30GC. Thereafter, the reaction mass was cooled to 15-20°C and stirred for 1 h at 15-20°C. Filtered the product, washed with DM water (2 x 15 ml) at 15-20°C and dried the product under reduced pressure (-20 mm Hg) at 30±5°C to yield a,a-dimethyl-4-[4-[4-(hydroxyl diphenylmethyl)-l-piperidinyl]-1-oxobutyl] phenyl acetic acid methyl ester monohydrate Yield: 12 g Chromatographic purity (by HPLC): 97.5% Water content: 4% *H NMR (500 MHz, DMSO-d6): 1.22,1.43 & 1.74 (3m, 6H,), 1.47 (s, 6H,), 1.93, 2.31 & 2.96 {3t, 6H,), 2.44 (m, 1H,), 2.87 (dd, 2H,), 3.58 (s, 3H), 5.23 (brs, 1H,), 7.08-7.90 (m, 14H,)

EXAMPLE 4 Preparation of a,a-dimethyl-4-[4-[4-(hydroxydiphenylmethyl)-l-piperidinyl]-l-oxobutyl] phenyl acetic acid methyl ester monohydrate a,a-dimethyl-4-[4-[4-(hydroxydiphenylmethyl)-1 -piperidinyl]-1 -oxobutyl] phenyl acetic acid methyl ester hydrochloride (20 g, 0.0304 mml) was suspended in a mixture of ethyl acetate (100 ml) and DM water (40 ml) at 25-30°C. To the reaction mass potassium hydroxide solution (6 g, 0.107 mml potassium hydroxide dissolved in DM water 20 ml) was added for 10 min at 25-28°C and stirred the contents for 2 h at 25-30°C. Thereafter, the reaction mass was cooled to 15-20°C and stirred for 1 h at 15-20°C. Filtered the product, and washed with DM water (2 x 20 ml) at 15-20°C and dried the product under reduced pressure (~20 mm Hg) at 30±5°C to yield a,oc-dimethyl-4-[4-[4-(hydroxydiphenylmethyl)-l -piperidinyl]-1 -oxobutyl] phenyl acetic acid methyl ester monohydrate. Yield: 15 g Chromatographic purity (by HPLC): 98.27% Water content: 3.6% *H NMR (500 MHz, DMSO-d6): 1.22,1.43 & 1.74 (3m, 6H,), 1.47 (s, 6H,), 1.93, 2.31 & 2.96 (3t, 6H,), 2.44 (m, 1H,), 2.87 (dd, 2H,), 3.58 (s, 3H), 5.23 (brs, 1H,), 7.08-7.90 (m, 14H,)

EXAMPLE 5 Preparation of a,a-dimethyl-4-[4-[4-(hydroxydiphenylmethyl)-l-piperidinyl]-l-oxobutyl] phenyl acetic acid methyl ester monohydrate a,a-dimethyl-4-[4-[4-(hydroxydiphenylmethyl)-l-piperidinyl]-l-oxobutyl]phenyl acetic acid methyl ester hydrochloride (20 g, 0.0304 mml) was suspended in a mixture of ethyl acetate (100 ml) and DM water (40 ml) at 25-30°C. To the reaction mass aqueous ammonia (10 ml, 0.088 mml) was added for 10 min at 25-28°C and stirred the contents for 2 h at 25-30°C. Thereafter, the reaction mass was cooled to 15-20°C and stirred for 1 h at 15-20°C. Filtered the product, washed with DM water (2 x 20 ml) at 15-20°C and dried the product under reduced pressure (-20 mm Hg) at 30±5°C. a,cc- dimethyl-4-[4-[4-(hydroxyldiphenylmethyl)-l-piperidinyl]-l-oxobutyl] phenyl acetic acid methyl ester monohydrate. Yield: 15 g Chromatographic purity (by HPLC): 98.08% Water content: 3.8%% JH NMR (500 MHz, DMSO-d6): 1.22, 1.43 & 1.74 (3m, 6H,), 1.47 (s, 6H,), 1.93,2.31 & 2.96 (3t, 6H,), 2.44 (m, 1H,), 2.87 (dd, 2H,), 3.58 (s, 3H), 5.23 (brs, 1H,), 7.08-7.90 (m, 14H,)

EXAMPLE 6 Preparation of a,a-dimethyl-4-[4-[4-(hydroxydiphenylmethyl)-l-piperidinyl]-l-oxobutyl] phenyl acetic acid methyl ester monohydrate a,a-dimethyl-4-[4-[4-(hydroxydiphenylmethyl)-l-piperidinyl]-l-oxobutyl]phenyl acetic acid methyl ester hydrochloride (15 g, 0.0273 mml) was dissolved in methanol (105 ml) at 25-30°C. To the reaction mass sodium hydroxide (1 g, 0.025 mml) was added and stirred for 2 h at 25-30°C, then added DM water (150 ml) at 25-30°C for 20 min and stirred for 2 h at 25-30°C. Thereafter, the reaction mass was cooled to 15-20°C and stirred for 1 h at 25-30°C. Filtered the product, washed with DM water (2x15 ml) at 15-20°C and dried the product under reduced pressure (-20 mm Hg) at 30±5°C to yield a,a-dimethyl-4-[4-[4-(hydroxydiphenylmethyl)-l-piperidinyl]-l-oxobutyl]phenyl acetic acid methyl ester monohydrate. Yield: 13 g Chromatographic purity (by HPLC): 97% Water content: 3.8% rH NMR (500 MHz, DMSO-d6): 1.22, 1.43 & 1.74 (3m, 6H,), 1.47 (s, 6H,), 1.93, 2.31 & 2.96 (3t, 6H,), 2.44 (m, 1H,), 2.87 (dd, 2H,), 3.58 (s, 3H), 5.19 (brs, 1H, ),7.08-7.90 (m, 14H)

EXAMPLE 7 Preparation of a,a-dimethy 1-4-[4-[4-(hydroxydiphenylmethy 1)-1 -piperidiny 1] -1 -oxobutyl] phenyl acetic acid methyl ester monohydrate 4-(Cyclopropylcarbonyl)-a,a-dimethylphenylacetic acid (70 g, 0.302 mml) was suspended in methanol (70 ml) at 25-30°C. To the reaction mass thionyl chloride (40 g, 0.336 mml) was added at 25-40°C.Thereafter, temperature of reaction was raised to 40-45°C and stirring was continued for 7 hr. Thereafter, the reaction mass was concentrated at 40-45°C under reduced pressure (40-50 mm Hg) to remove methanol /thionyl chloride. The residue was cooled to 25-30°C then added methyl isobutyl ketone (400 ml) and DM water (350 ml). There after pH was adjusted to 6.5 to 7.5 with -8% w/w aqueous sodium bicarbonate solution (25 ml) and stirred the reaction mass for 10 min, separated the organic layer. To the organic layer azacyclonol (66 g, 0.247 mml), potassium iodide (2 g, 0.012 mml), DM water (5 ml) and potassium bicarbonate (36 g, 0.36 mml) were added at 20-25°C. Reaction mass was heated upto 96-98°C and continued stirring at 96-98°C for 22 h. Thereafter reaction mass was cooled to 25-30°C, water (50 ml) was added and stirred reaction mass for 1 h. The product was filtered and washed with water (3x10 ml, 28°C).

The above filtered wet oxo compound was dissolved in mixture of ethyl acetate (500ml) and DM water (200 ml) at 26-28°C. The pH of the reaction mass was adjusted to 2.0 at 26-28°C with 1: 1 v/v aqueous hydrochloric acid (~ 50 ml) and stirred for 15 min. Thereafter the organic layer separated, DM water (200 ml) and -10 % w/w aqueous sodium hydroxide solution (85 ml) were added, stirred the reaction mass for 2 h at 25-30°C and cooled to 15-20°C. The product was filtered and washed with DM water (2 x 20 ml) at 15-20°C. The product was filtered under reduced pressure (-20 mm Hg) at 30±5°C to yield a,a-dimethyl-4-[4-[4-(hydroxydiphenylmethyl)-l-piperidinyl]- 1-oxobutyl] phenyl acetic acid methyl ester monohydrate. Yield: 80 g Chromatographic purity (by HPLC): 98.84% Water content: 3.7% *H NMR (500 MHz, DMSO-d6): 1.22,1.43 & 1.74 (3m, 6H,), 1.47 (s, 6H,), 1.93, 2.31 & 2.96 (3t, 6H,), 2.44 (m, 1H,), 2.87 (dd, 2H,), 3.58 (s, 3H), 5.23 (brs, 1H,), 7.08-7.90 (m, 14H,)

EXAMPLE 8 Preparation of Fexofenadine Hydrochloride from Oxo compound monohydrate

Step-a: Preparation of a,o>dimethyl-4-[4-[4-(hydroxydiphenylmethyl)-l-piperidinyl]-l-hydroxybutyl] phenylacetic acid methyl ester a, «-dimethyl-4-[4-[4-(hydroxydiphenylmethyl)-1 -piperidinyl]-1 -oxobutyl]phenyl acetic acid methyl ester monohydrate (15 g, 0.028 mml) was dissolved in methanol (100 ml) at 20-25°C and stirred for 5-10 min. To the reaction mass sodium hydroxide (1 g, 0.025 mml) was added followed by sodium borohydride (1.30 g, 0.034 mml) at 25-30°C in small lots and stirred the reaction mass at 26-28°C for 3 hr. Thereafter, the reaction mass was cooled to ~15-20°C and DM water (50 ml), acetic acid (0.3 ml) were added slowly. The obtained reaction mass was cooled to 18-20°C and stirred for 20 min. Filtered the product and washed with DM water (15 ml, 18-20°C). Suspended the wet cake in DM water (50 ml) at 25-30°C and stirred for 30 min. Filtered, washed with DM water (150 ml) and dried the product under reduced pressure (20-50 mm Hg) at 40-45°C to yield a,a-dimethyl-4-[4-[4-(hydroxydiphenylmethyl)-l-piperidinyl]-l-hydroxy-butyl] phenylacetic acid methyl ester. Yield: 12.75g Chromatographic purity (by HPLC): 99%

Step-b: Preparation of Fexofenadine Hydrochloride a,a-dimethyl-4-[4-[4-(hydroxydiphenylmethyl)-l-piperidinyl]-l-hydroxybutyl] phenyl acetic acid methyl ester (10 g, 0.019 mml) was dissolved in ethanol (50 ml) under nitrogen atmosphere and added aqueous sodium hydroxide solution at 20-30°C. Raised the temperature of the reaction mass to 75-80°C and stirred for 5 hrs at 75-80°C. Thereafter, the reaction mass was cooled to 25-28°C and carbon (0.5 g) was added at 35-40°C. The obtained reaction mass was stirred for 30 min, filtered and washed the bed with ethanol (20 ml). The reaction mass was concentrated under reduced pressure (100-20 mm Hg) at 65-70°C to remove ethanol till an oily residue was obtained. The obtained residue was cooled to 25-28°C, added DM water (100 ml) and stirred to get a clear solution. To the reaction mass ethyl acetate (70 ml) was added and stirred at 20-25°C for 30 min. Separated the aqueous layer and keep the aqueous layer at 25-30°C. To the aqueous layer ethanol (50 ml), followed by 35% w/v aqueous hydrochloric acid (-8.5 ml) were added slowly over a period of 45-50 min at 30-35°C. Stirred the reaction mass at 30-35°C for 2 h, cooled the reaction mass to 0-5°C and again stirred for 1 h. Filtered the product, washed with chilled DM water (2 x 10 ml, 0-5°C) and dried under reduced pressure (20-50 mm Hg) at 45-50°C to yield Fexofenadine Hydrochloride. Yield: lOg Chromatographic purity (by HPLC): 99.93% lH NMR (500 MHz, DMSO-d6): 1.19-1.53 (m, 14H), 1.81,2.22 & 2.82 (3m, 6H), 2.45 (m, 1H), 4.47 (t, 1H), 5.65 (brs, 1H), 5.22 (brs, 1H), 7.08-7.51 (m, 14H).

REFERENCE EXAMPLE Preparation of Fexofenadine Hydrochloride from Oxo compound hydrochloride

Step-a: Preparation of a,a-dimethyl-4-[4-[4-(hydroxydiphenylmethyl)-l-piperidinyl]-! hydroxybutyl] phenylacetic acid methyl ester a, a-dimethyl-4-[4-[4-(hydroxydiphenylmethyl)-1 -piperidinyl]-1 -oxobutyl] phenylacetic acid methyl ester hydrochloride (15 g, 0.027 mml) was dissolved in methanol (100 ml) at 20-25°C and stirred for 5-10 min. To the reaction mass sodium hydroxide (1.2 g, 0.03 mml) was added followed by sodium borohydride (1.5 g, 0.039 mml) at 25-30°C in small lots and stirred the reaction mass at 26-28°C for 3 hr. Thereafter, the reaction mass was cooled to ~15-20°C and then DM water (50 ml), acetic acid (0.3 ml) were added slowly. The obtained reaction mass was cooled to 18-20°C and stirred for 20 min. Filtered the product and washed with DM water (15 ml, 18-20°C). Suspended the wet cake in DM water (50 ml) at 25-30°C and stirred for 30 min. Filtered, washed with DM water (150 ml) and dried the product under reduced pressure (20-50 mmHg) at 40-45°C to yield a,a-dimethyl-4-[4-[4-(hydroxydiphenylmethyl)-l -piperidinyl] -1-hydroxy-butyl] phenyl acetic acid methyl ester. Yield: lOg Chromatographic purity (by HPLC): 96%

Step-b: Preparation of Fexofenadine Hydrochloride a,a-dimethyl-4-[4-[4-(hydroxydiphenylmethyl)-1 -piperidinyl]-1 -hydroxybutyl]phenyl acetic acid methyl ester (10 g, 0.019 mml) was dissolved in ethanol (50 ml) under nitrogen atmosphere and then added aqueous sodium hydroxide solution at 20-3 0°C. Raised the temperature of the reaction mass to 75-80°C and stirred for 5 hrs at 75-80°C. Thereafter, the reaction mass was cooled to 25-28°C and then added carbon (0.5 g) at 35-40°C. The obtained reaction mass was stirred for 30 min, filtered and washed the bed with ethanol (20 ml). The reaction mass was concentrated under reduced pressure (100-20 mm Hg) at 65-70°C to remove ethanol till an oily residue was obtained. The obtained residue was cooled to 25-28°C, then added DM water (100 ml) and stirred to get a clear solution. To the reaction mass ethyl acetate (70 ml) was added and stirred at 20-25°C for 30 min. Separated the aqueous layer and keep the aqueous layer at 25-30°C. To the aqueous layer ethanol (50 ml) followed by 35% w/v aqueous hydrochloric acid (-8.5 ml) were added slowly over a period of 45-50 min at 30-35°C. Stirred the reaction mass at 30-35°C for 2 h, cooled the reaction mass to 0-5°C and again stirred for 1 h. Filtered the product, washed with chilled DM water (2 x 10 ml, 0-5 °C) and dried under reduced pressure (20-50 mm Hg) at 45-50°C to yield Fexofenadine Hydrochloride. Yield: 8.8 g Chromatographic purity (by HPLC): 98%.

We Claim:

1. A process for preparing a,a-dimethyl-4-[4-[4-(hydroxyl diphenylmethyl)-l-piperidinyl]-l-oxobutyl]phenyl acetic acid alkyl ester of Formula I, wherein R is Ci_6 alkyl which comprises:

a) dissolving a,a-dimethyl-4-[4-[4-(hydroxydiphenylmethyl)-l-piperidinyl]-l-oxobutyl]phenyl acetic acid alkyl ester hydrochloride in a solvent;

b) adding a base; and

c) isolating the a,a-dimethyl-4-[4-[4-(hydroxydiphenylmethyl)-l-piperidinyl]-l- oxobutyl] phenyl acetic acid alkyl ester.

2. The process according to claim 1, wherein the base is selected from the group comprising of sodium hydroxide, potassium hydroxide, lithium hydroxide, ammonia and the like.

3. The process according to claim 1, wherein the solvent is selected from the group comprising of ethyl acetate, methyl acetate, methanol, ethanol, acetone, methyl isobutyl ketone, water and mixtures thereof.

4. The process according to claim 1, wherein a,oc-dimethyl-4-[4-[4-(hydroxydiphenyl methyl)-1- piperidinyl]-l-oxobutyl]phenyl acetic acid alkyl ester isolated in the form of monohydrate solvate.

5. The process according to claim 1, wherein a,a-dimethyl-4-[4-[4-(hydroxydiphenylmethyl)-l-piperidinyl]-l-oxobutyl]phenyl acetic acid alkyl ester has a purity greater than about 97%.

6. The process according to claim 1, wherein a,a-dimethyl-4-[4-[4-(hydroxydiphenylmethyl)-l-piperidinyl]-l-oxobutyl] phenyl acetic acid alkyl ester is converted into Fexofenadine or its pharmaceutical acceptable salts thereof.