FIELD OF INVENTION
The present invention relates to one pot synthesis of Fexofenadine and its derivatives of Formula I, without isolating the intermediates, which is optionally converted to the pharmaceutically acceptable salts thereof

BACKGROUND OF THE INVENTION:
Fexofenadine which is chemically known as (i?iS)-2-[4-[l-hydroxy-4-[4-(hydroxy diphenylmethyl)-l-piperidyl]butyl]phenyl]-2-methyl-propanoic acid and is structurally represented as

Fexofenadine is an active metabolite of Terfenadine, which is used in the treatment of chronic idiopathic urticaria and for pediatric use and marketed uilder the trade names ALLEGRA®, TELFAST®, FASTOFEN®, TILFUR® available as capsule oral 60 mg, tablet oral (30mg, 60mg, 180mg) and orally disintegrating tablet 30mg. Fexofenadine like other second and third generation antihistamines does not readily cross

the blood brain barrier and so causes less drowsiness than first generation histamine-receptor antagonists.
Piperidine derivatives having antihistamine properties are disclosed in following U.S patents US 3,806,526, US 3,829,433, US 3,862,173, US 3,878,217, US 3.931.197, US 3,941,795, US 3,946,022, US 3,965,257.
Fexofenadine was first disclosed in 4,254,129 assigned to Richardson-Merrell Inc., this patent discloses a process for preparing Fexofenadine by reacting ethyl a.a-dimethylphenyl acetate and chlorobutyryl chloride under Friedel crafts conditions, condensing the resulting intermediate with a,a-diphenyl-4-piperidinemethanol to give ketoester intermediate, which on reduction followed by'hydrolysis produce Fexofenadine.
US 4,285,958 assigned to Richardson-Merrell Inc., discloses a procedure for preparing Fexofenadine and related compounds by alkylation of substituted piperidine derivative a co-haloalkyl substituted phenyl ketone. Further the co-haloalkyl substituted phenyl ketone is prepared by reacting a- a-dimethyl phenyl acetic acid with a haloalkyl acyl chloride under general conditions of a Friedal-Crafts acylation.
US 5,578,610 assigned to Albany Molecular Research, Inc., provides an inseparable mixture of mono-substituted aromatic region isomers of formula

wherein chlorobutyryl substituent is attached at either if of three aromatic carbons, which are meta or Para to the dimethyl acetate substituent. When the mixture of mono-substituted aromatic regioisomers of the preceding formula is reacted with a piperidine derivative a second mixture of aromatic region isomers is obtained of formula


wherein mono-substituted meta, para mixture of regioisomers are obtained.
US 5,663,412 assigned to AMR Technology Inc., discloses a substantially pure regioisomer of formula

US 6,340,761 assigned to Merrell pharmaceuticals Inc., discloses novel intermediates of formula

US 6,903,232 B2 assigned to Aurobindo Pharma Ltd discloses a novel process to obtain highly pure 4-(cyclopropylcarbonyl)-a,a-dimethyl phenyl acetic acid through crystallization of a mixture of para & meta regioisomers, which is prepared by treating 1-acetoxy-2-methyl-2-phenyl propane in methylene chloride with 4-chlorobutyryl chloride and anhydrous aluminium chloride to obtain a mixture of regioisomers, the mixture of regioisomers are hydrolyzed to. obtain the specific regioisomers of highly pure 4-(cyclopropylcarbonyl)-a,a-dimethyl phenyl acetic acid.

us 2006/0173042 Al discloses a process for preparing cyclopropylketo-a,a-dimethyl phenyl acetic acid; this includes treating 4-(cyclopropyloxomethyl)-2,-2-dimethylphenethyl alcohol with hydroxide of an alkali metal adding oxidizing agent followed by aqueous acidic work up and isolating cyclopropylketo-a,a,-dimetiiyl phenyl acetic acid,
US 2007/0106078 Al disclose a process for preparing' substantially pure Fexofenadine. The process includes reducing methyl 4-[4-[4-hydroxy biphenyl methyl)-1-piperidinyl]-1-0X0 butyl]-a, a dimethyl phenyl acetate with a reducing agent to produce 4-[4-[4-hydroxybiphenylmethyl)-i -piperidinyl]-! -hydroxybutyl3-a,a-dimethylphenyl acetate.
WO2007/049303 A2 assigned to Ind-Swift laboratories discloses a one pot
process for the preparation of highly pure Fexofenadine, comprising reducing completely
methyl 4-[4-[4-(hydroxydiphenylmethyl)-l-piperidinyl]-l-oxobutyl](a,a-dimethyl)
benzene acetate with a reducing agent in situ followed by hydrolysis with base and isolating the highly pure Fexofenadine
The process described in the prior art not suitable from industrial point of view, because the desired para-isomer is not obtained in required purity and requires repeated purifications to remove the unwanted meta isomer impurity and other impurities generated from unreacted ketone, which yields to low yields. Therefore there is an urgent need to develop a simple and cost effective process for the preparation of Fexofenadine in high yields and high purity levels.
OBJECTIVE OF THE INVENTION
The main object of the present invention is to provide an improved, simple, cost effective and industrially advantageous process for the preparation of Fexofenadine and its derivatives with high purity and high yields on commercial scale.

SUMMARY OF THE INVENTION;
The main objective of the present invention is to provide a one-pot synthesis of Fexofenadine and its derivatives, which are optionally converted to pharmaceutically acceptable salts thereof
First objective of the present invention is to provide a one-pot process for the preparation of compound of formula I;

wherein, X represents -CH2, -CHOH, -CO, Ri and R2 represents hydrogen; halogen selected from chloro, bromo, iodo; and a substituted or unsubstituted alkly chain, R3 represents hydrogen, alkly, aryl groups or alkali and alkaline earth metal salts.
starting from the compound of Formula-II:

wherein R4 is an alkyl group

The second objective of the present invention is to provide a one-pot propess for the preparation of compoxmd of formula I;

wherein, 'X' represents -CH2, -CHOH, -CO, R\ and R2 represents hydrogen; halogen selected from chloro, bromo, iodo; and a substituted or unsubstituted alkly chain, R3 represents hydrogen, alkly, aryl groups or alkali and alkaline earth metal salts.
starting from the compound of Formula-Ill:

wherein R4 represents alkyl group; 'w' represents a halogen or a hydroxy group; 'b' represents -CH2, -CHOH or -CO group.
Third objective of the present invention is to provide Fexofenadine and its pharmaceutically acceptable salts in one-pot starting from the intenriediate l-acetoxy-2-methyl-2-phenyl propane.

Fourth objective of the present invention is to provide Fexofenadine and its pharmaceutically acceptable salts in one-pot starting from the intermediate l-acetoxy-2-methyl-2-[4-[4-chloro-1 -oxy-butyl)phenyl]-propane.
DETAILED DESCRIPTION OF THE INVENTION;
The present invention provides one-pot synthesis of Fexofenadine and its derivatives, which are optionally converted to pharmaceutically acceptable salts thereof, which is economical and industrially feasible process.
According to first aspect of the present invention the Fexofenadine and its derivatives are prepared starting from the intermediate l-alkyl-(2-mfcthyl-2-phenyl)propionate compound of formula II,

wherein R4 is an alkyl group
The compoiind of formula II, l-alkyl-(2-methyl-2-phenyl)propionate is subjected to friedal-craft's reaction, which is subsequently followed by the hydrolysis, oxidation and esterification reactions to produce a compound of Formula VI. Without isolating the compound of Formula VI, the reaction mixture is treated with the 4-(a,a-diphenyl)piperidine methanol derivative (condensation reaction) to obtain a compound of formula I. The process is represented shown as in reaction Scheme-I.


Wherein, Ri and Ra represents hydrogen, halogen selected from chloro, bromo, iodo, or a substituted or unsubstituted alkly chain; R3 represents hydrogen, alkly, aryl groups or alkali and alkaline earth metal salts; R4 represents alkyl group; 'w' represents a halogen or a hydroxy group; 'b' represents hydrogen, hydroxy or -CO group; 'X' represents -CH2, -CHOH, -CO group.
According to the one embodiment of the present invention, the Friedal-craft's reaction is carried out using an alkyl chloride or acyl chloride, in presence of a solvent selected from the group of methylene chloride, ethylene chloride or mixtures thereof

According to the second embodiment of the present invention, the hydrolysis is carried out using a base and a solvent. The base is selected from the group of sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate etc., -
According to other embodiment of the present invention the solvent used in the hydrolysis step is selected from the group of water; aqueous alcohols, alcohols such as methanol, ethanol, propanol, isopropanol or a mixture thereof.
According to the third embodiment of the present invention oxidation is carried using an oxidizing agent in presence of a solvent. The oxidizing agent is selected from the group of potassium permanganate, sodium permanganate or a mixture thereof The solvent used in the oxidation reaction is selected from the group of water, acetone or mixture thereof or mixture thereof
According to the fourth embodiment of the present invention esterification and halogenation are carried out using thionyl chloride, HCl, HBr in alcohols or in combination with other suitable organic solvents selected from the group of methylisobutylketone (MIBK), toluene, xylene, and methylene chloride, or a mixture thereof
According to the fifth embodiment of the present invention condensation is carried out in presence of a base and an aqueous or anhydrous solvent. The base is selected from the group of alkali and alkaline earth metal hydroxide, bicarbonates and carbonates or suitable organic base such as triethyl amine, pyridine and the solvent is selected from the group of water, MIBK, toluene, xylene or a mixture thereof.
According to the second aspect of the present invention the Fexofenadine and its derivatives are prepared starting from the intermediate compound of formula III,


wherein R4 represents alkyl group; 'w' represents a halogen or a hydroxy group; 'b' represents -CH2, -CHOH or -CO group.
The compound of formula III, l-alkyl-(2-methyl-2-(4-
acyl/alkylsubstituted)phenyl) propionate is subjected to hydrolysis, which is subsequently followed by the oxidation and esterification reactions to produce a compound of Formula VI. Without isolating the compoimd of Formula VI, the reaction mixture is treated with the 4-(a,a-diphenyl)piperidine methanol derivative (condensation reaction) to obtain a compound of formula I. The process is represented shown as in reaction Scheme-II.

Wherein, Ri and R2 represents hydrogen, halogen selected from chloro, bromo, iodo, or a substituted or unsubstituted alkly chain; R3 represents hydrogen, alkly, aryl groups or alkali and alkaline earth metal salts; R4 represents alkyl group; 'w' represents a

halogen or a hydroxy group; 'b' represents hydrogen, hydroxy or -CO group; 'X' represents -CH2, -CHOH, -CO group.
According to the first embodiment of the present invention, the hydrolysis is carried out using a base and a solvent. The base is selected from the group of sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate etc.,
According to other embodiment of the present invention the solvent used in the hydrolysis step is selected from the group of water; aqueous alcohols, alcohols such as methanol, ethanol, propanol, isopropanol or a mixture thereof
According to the second embodiment of the present invention oxidation is carried using an oxidizing agent in presence of a solvent. The oxidizing agent is selected from the group of potassium permanganate, sodium permanganate or a mixture thereof The solvent used in the oxidation reaction is selected from the group of water, acetone or mixture thereof
According to the third embodiment of the present invention esterification and halogenation are carried out using thionyl chloride, HCl, HBr in alcohols or in combination with other suitable organic solvents selected from the group of methylisobutylketone (MIBK), toluene, xylene, and methylene chloride, or a mixture thereof
According to the fourth embodiment of the present invention condensation is carried out in presence of a base and an aqueous or anhydrous solvent. The base is selected from the group of alkali and alkaline earth metal hydroxide, bicarbonates and carbonates or suitable organic base such as triethyl amine, pyridine and the solvent is selected from the group of water, MIBK, toluene, xylene or a mixture thereof

According to the main aspect of the present invention the Fexofenadine is prepared in one-pot starting from the intermediate l-acetoxy-2-methyl-2-phenyl propane, which is subjected to Friedal-Craft's reaction, followed by hydrolysis, oxidation and esterification reactions to produce l-acetoxy-2-methyl-2-[4-[4-chloro-l-oxy-butyl)phenyl]-propane, which is further reacted with the 4-(a,a-diphenyl)piperidine methanol to obtain a compound of keto intermediate of the Fexofenadine, which can optionally isolated or further subjected to reduction using a reducing agent selected from he reduction is carried out in presence of sodium borohydride, lithium aluminum hydride, Pd/C, Raney Nickel. Optionally subjecting the obtained compound to hydrolysis to produce Fexofenadine free base, which is optionally converted to its pharmaceutically acceptable salt thereof. The process is represented shown as in reaction Scheme-Ill.


According to the main aspect of the present invention the Fexofenadine is prepared in one-pot starting from the intermediate l-acetoxy-2-methyl-2-[4-[4-cliloro-l-oxy-butyl)phenyl]-propane, which is subjected hydrolysis, followed by oxidation and esterification reactions to produce a compound of, which is further reacted with the 4-(a,a-diphenyl)piperidine methanol to obtain a compound of keto intermediate of the Fexofenadine, which can optionally isolated or further subjected to reduction and

hydrolysis to produce Fexofenadine free base, which is optionally converted to its pharmaceutically acceptable salts thereof. The process is represented shown as in reaction Scheme-IV.

While 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 included within the scope of the present invention.
The present invention can be illustrated in one of its embodiment by the following non- limiting examples.

EXAMPLES;
Example -1: One Pot synthesis of Fexofenadine:
200g of l-acetoxy-2-methyl-2-phenyl propane was dissolved in 800ml of methylene chloride, and the reaction mixture was cooled to 0-5° C. To this reaction mass 4-chlorobutyryl chloride (180g) was added drop-wise in l-2hrs at temperature 0-5° C and reaction mass was further stirred at same temperature for 30-60 min, and then reaction mass was further cooled to -5 to -8° C and 390g of aluminum chloride was added maintaining mass temperature below -4° C. After addition of aluminum chloride stirring was continued further at -3 to 0° C for 6-8hrs. After completion of the reaction, reaction mass is decomposed in Ice (2000g) and hydrochloric acid 250-300ml mixture, and layers were separated at 20-30° C. Aqueous layer was extracted with methylene chloride (200-400ml). The combined methylene chloride layer was washed with water. The methylene chloride was distilled, and the crude product was dissolved in methanol 400-500 ml and heated to 40-45° C. At 40-45 ° C sodium hydroxide solution (Dissolve 130 g of sodium hydroxide flakes in 130 ml of water) was added in 2-3hrs. After addition of sodium hydroxide solution, the reaction mass temperature was raised to reflux temperature and maintained for 3-5hrs, then methanol was distilled and crude was dissolved in water, extracted with 600-800ml of toluene and solvent was distilled to obtain a still residue as product. The residue was suspended in 2000ml of about 3%s sodium hydroxide solution and cooled to 20-2$° C. Then to the reaction mas 250-260g of potassium permanganate was added in lot-wise maintaining mass temperature at 20-25° C in 6-10 hrs. Further the reaction mass was heated to 30-35° C for Ihr and pH was adjusted to 10.5-11.0 and added lOg of sodium meta bi sulfite to decompose excess potassium permanganate. The water insoluble in-organics were filtered and washed with water, to the filtrate, toluene was added (500ml) and pH was adjusted to acidic with Hydrochloric acid solution. RM was stirred and layers were separated. Toluene is removed by distillation and crude was dissolved in methanol 340-360ml and further it was cooled to 0-5° C. Then 160g of Thionyl chloride was slowly added maintaining temperature at 0-5° C in 5-lOhrs. RM was stirred at 40-45 ° C for 4-6 hrs and solvent was distilled under low vacuum, and

residue was dissolved in and washed with water 100-200 ml. And toluene was removed under vacuum and crude product was dissolved in 950ml of Methyl isobutyl ketone and further added, water 20-30rtil, Sodium bicarbonate 100-140 g , 4-(a,a-diphenyl)piperidine methanol 140g, and Ig of potassium Iodide and maintained stirring at reflux temperature for a period of 24-36hrs. There after, reaction mass was cooled, filtered in-organics and the filtrate was concentrated under reduced pressure at below 95° C. The crude product was cooled and dissolved in methanol 700ml, and added 15g of sodium borohydride slowly in 2-6hrs at 10-15° C. There, after slowly raised temperature to 30-35° C and added sodium hydroxide solution (Dissolved 57g of sodium hydroxide flakes in 58ml of water) in 30-40 min., then stirred at 60-65° C for a period of 5-6hrs. After completion of reaction a second lot of sodium hydroxide 3.0g and sodium borohydride 3g were added and continued reflux temperature for Ihr. Then reaction mass was cooled and pH was adjusted to 6.5-7.0 with concentrated Hydrochloric acid solution to the obtained Fexofenadine base. The reaction mass is cooled to below 30° C and filtered to obtain 250-300g of wet Fexofenadine. The wet material was added to 700-1000ml of methanol and heated to reflux for l-2hrs, cooled, filtered and washed with methanol to obtain 200-225g of crude Fexofenadine, base, which contained inorganic substances. Again the crude material was suspended in 950-1250ml of hot water stirred for 30-60min and filtered at hot condition washed with water and dried at below 70° C obtained 140-160g of pure Fexofenadine base.
Example - 2: One Pot synthesis of Fexofenadine intermediate (Methyl-2-[4-[4-[4-(hydroxydiphenylinethyl)piperidin-l-yI]butanoyl]phenyl]-2-niethyl propionate)
200g of l-acetoxy-2-methyl-2-phenyl propane was dissolved in 800ml of methylene chloride, and mixture was cooled to 0-5° C. To this mass, 4-chlorobutyryl chloride (180g) was added drop-wise inl-2hrs at temperature 0-5° C. and reaction mass was fiirther stirred at same temperature for 30-60min, and then reaction mass was further cooled to -5 to -8° C and 390g of aluminum chloride was added maintaining mass temperature below -4° C. After addition of aluminum chloride stirring was continued fiirther at -3 to 0° C for 6-8hrs. After completion of the reaction, reaction mass was decomposed in Ice

(2000g) and hydrochloric acid 250-300ml mixture, and layers were separated at 20-30° C. Aqueous layer was extracted with methylene chloride (200-400ml). The combined methylene chloride, layer was washed with water. The methylene chloride was distilled, and the crude product was dissolved in methanol 400-500 ml and heated to 40-45° C. At 40-45 " C sodium hydroxide solution (Dissolve 130 g of sodium hydroxide flakes in 130 ml of water) was added in 2-3hrs. After addition of sodium hydroxide solution, the reaction mass temperature was raised to reflux temperature and maintained for 3-5hrs, then methanol was distilled and crude was dissolved in water, extracted with 600-800ml toluene and toluene was distilled to obtained still residue as product. The residue was suspended in 2000ml of about 3% sodium hydroxide solution and cooled to 20-25° C. Then to the reaction mass 250-260g of Potassium permanganate was added in lot-wise maintaining mass temperature at 20-25° C in 6-10 hrs. Further the reaction mass was heated to 30-35° C for Ihr and pH was adjusted, to 10.5-11.0 and added lOg of sodium meta bi sulfite to decompose excess potassium permanganate. The water insoluble in¬organics were filtered and washed with water, to the filtrate, toluene was added (500ml) and pH was adjusted to acidic with Hydrochloric acid solution. Reaction mixture was stirred and layers were separated. Toluene was removed by distillation and crude was dissolved in methanol 340-360ml and further it was .cooled to 0-5° C. Then 160g of thionyl chloride was slowly added, maintaining temperature at 0-5° C in 5-lOhrs. Reaction Mixture was stirred at 40-45 ° C for 4-6hrs and solvent was distilled under low vacuum, and residue was dissolved in 500ml of toluene and washed with water 100-200 ml. And toluene was removed under vacuum and crude product was'dissolved in 950ml of methyl isobutyl ketone and further added, water 20-30ml, Sodium bicarbonate 100-140 g , 4-(a,a-diphenyl)piperidine methanol 140g, and Ig of potassiimi Iodide and maintained stirring at reflux teniperature for a period of 24-36hrs. There after, reaction mass was cooled, filtered in-organics and the filtrate was concentrated under reduced pressure at below 95° C. The crude product was cooled and dissolved in aqueous alcohols 950ml at 60-85° C and charged activated carbon 5-lOg, filtered and washed with aqueous alcohol, combined filtrate was cooled to 0-5° C, filtered, washed with aqueous alcohol and dried yielded 140-160g.(purity about 85%) of methyl-2-[4-[4-[4-(hydroxydiphenylmethyl)piperidin-l -yl]butanoyl]-phenyl]-2-methyl propionate. The

impure material of methyl-2-[4-[4-[4-(hydroxydiphenylmethyl)piperidin-l-yl]butanoyl] phenyl]-2-methyl propionate was again recrystallized in aqueous alcohol Yielded 130-145g of pure methyl-2-[4-[4-[4-(hydroxydiphenylmethyl)piperidin-l-yl]butanoyl] phenyl]-2-methyl propionate.
Example - 3: One pot preparation of Methyl-4-(4-chIoro-l-oxobutyl)-2,2-dimethyI phenyl acetate.
200g of l-acetoxy-2-methyl-2-phenyl propane was dissolved in 800ml of methylene chloride, and mixture was cooled to 0-5° C. To this mass, 4-chlorobutyryl chloride (180g) -was added drop-wise inl-2hrs at temperature 0-5° C. and reaction mass was further stirred at same temperature for 30-60 min, and then reaction mass was further cooled to -5 to -8° C and 390g of aluminum chloride was added maintaining mass temperature below -4° C. After addition of aluminum chloride stirring was continued further at -3 to 0° C for 6-8hrs. After completion of the reaction, reaction mass was decomposed in Ice (2000g) and hydrochloric acid 250-300ml mixture, and layers were separated at 20-30° C. Aqueous layer was extracted with methylene chloride {200-400ml). The combined methylene chloride layer was washed with water. The methylene chloride was distilled, and the crude product was dissolved in methanol 400-500 ml and heated to 40-45° C. At 40-45 ° C sodiimi hydroxide solution (Dissolve 130 g of sodium hydroxide flakes in 130 ml of water) was added in 2-3 hrs. After addition of sodium hydroxide solution, the reaction mass temperature was raised to reflux temperature and maintained for 3-5hrs, then methanol was distilled and crude was dissolved in water, extracted with 600-800ml of solvent was distilled to obtained still residue as product. The residue was suspended in 2000ml of about 3% sodium hydroxide solutiori and cooled to 20-25° C. Then to the reaction mass 250-260 g of potassium permanganate was added in lot-wise maintaining mass temperature at 20-25° C in 6-10 hrs. Further the reaction mass was heated to 30-35° C for Ihr and pH was adjusted to 10.5-11.0 and added lOg of sodium metabisulfite to decompose excess potassiimi permanganate. The water insoluble in-organics were filtered and washed with water, to the filtrate, toluene was added (500ml) and pH was adjusted to acidic with Hydrochloric acid solution. Reaction mixture was stirred and

layers were separated. Toluene was removed by distillation and crude was dissolved in methanol 340-360 ml and further it was cooled to 0-5° C. Then 160g of Thionyl chloride was slowly added, maintaining temperature at 0-5° C in 5-lOhrs. Reaction mixture was stirred at 40-45 ° C for 4-6hrs and solvent was distilled under low vacuum, and residue was dissolved in 50.0 ml of toluene is added and washed with water 100-200 ml, followed by dilute sodium bicarbonate. The toluene was removed under vacuum distillation to * obtained 160-170 g of methyl-4-(4-chloro-l-oxobutyl)-2,2-dimethylphenyl acetate.
Example - 4: One Pot synthesis of Fexofenadine:
300 g of l-Acetoxy-2-methyl-2-[4-[4-chloro-l-oxy-butyl)phenyl]propane was dissolved in methanol 400-500 ml and heated to 40-45° C. At 40-45 ° C sodium hydroxide solution (Dissolve 130 g of sodium hydroxide flakes in 130 ml of water) was added in 2-3hrs. The reaction mass temperature was raised to reflux temperature and maintamed for 3-5hrs, then methanol was distilled and concentrated crude was dissolved in water, extracted with 600-800ml of toluene and the toluene was distilled to obtained still residue as product. The residue was suspended in 2000ml of about 3%sodium hydroxide solution and cooled to 20-25° C. Then to the reaction mass 250-260g of Potassium permanganate was added in lot-wise maintaining mass temperature at 20-25° C in 6-10 hrs. Further the reaction mass was heated to 30-35° C for Ihr and pH w adjusted to 10.5-11.0 and added lOg of sodium metabisulfite to decompose excess potassium permanganate. The water insoluble in-organics were filtered and washed with water, to the filtrate, toluene was added (500ml) and pH was adjusted to acidic with Hydrochloric acid solution. Reaction mixture was stirred and layers were separated. Toluene was removed by distillation and crude was dissolved in methanol 340-360ml and further it was cooled to 0-5° C. Then 160g of Thionyl chloride was slowly added maintaining temperature at 0-5° C in 5-lOhrs. Reaction mixture was stirred at 40-45 ° C for 4-6hrs and solvent was distilled under low vacuum, and residue was dissolved in 500ml of toluene and washed with water 100-200 ml. And toluene was removed under vacuum and crude product was dissolved in 950ml of methyl isobutyl ketone and further added, water 20-30ml, Sodium bicarbonate 100-140 g , 4-(a,a-diphenyl)piperidine methanol 140g, and Ig of potassium iodide and

maintained stirring at reflux temperature for a period of 24-36hrs. Thereafter the reaction mass was cooled, filtered in-organics and the filtrate was concentrated under reduced pressure at below 95° C. The crude product was cooled and dissolved in methanol 700ml, and added 15g of sodium borohydride slowly in 2-6hrs at 10-15° C. There, after slowly raised temperature to 30-35° C and added sodium hydroxide solution (Dissolved 57g of sodium hydroxide flakes in 58ml of water) in 30-40min., then stirred at 60-65° C for a period of 5-6hrs.- After completion of reaction a second lot of sodium hydroxide 3.0g and sodium borohydride 3g were added and continued reflux temperature for Ihr. Then reaction mass was cooled and pH was adjusted to 6.5-7.0 with concentrated Hydrochloric acid solution to obtained Fexofenadine base. Cooling the mass to below 30° C and filtration, obtain 250-300g of wet Fexofenadine. The wet material was added to 700-1000ml of methanol and heated to reflux for l-2hrs, cooled, filtered and washed with methanol to obtain 200-225g of crude Fexofenadine base, which were contained inorganic substances. Again crude material was suspended in 950-1250ml of hot water stirred for 30-60min and filtered at hot condition washed vvdth water and dried at below 70° C obtained 140-160g of pure Fexofenadine base.
Example - 5: One Pot synthesis of Fexofenadine intermediate (Preparation of Methyl-2-[4-[4-[4-(hydroxydiphenyImethyl)piperidin-l-yl]butanoyl]phenyl]-2-methyl propionate.
300 g of l-Acetoxy-2-methyl-2-[4-[4-chloro-l-oxy-butyl)phenyl]-propane was dissolved
in methanol 400-500 ml and heated to 40-45° C. At 40-45 ° C sodium hydroxide solution
(Dissolve 130 g of sodium hydroxide flakes in 130 ml of water) was added in 2-3hrs.
After addition of sodiimi hydroxide solution, the reaction mass temperature was raised to
reflux temperature and maintained for 3-5hrs, then methanol was distilled and crude was
dissolved in water, extracted with 600-800ml of solvent toluene and toluene was distilled
to obtain tiie still residue as product. The residue was suspended in 2000ml of about 3%
sodium hydroxide solution and cooled to 20-25° C. Then to the reaction mass 250-260g
of Potassium permanganate was added in lot-wise maintaining mass temperature at 20-
25° C in 6-10 hrs. Further the reaction mass was heated to 30-35° C for Ihr and pH was '

I*
adjusted to 10.5-11.0 and added lOg of sodium meta bi sulfite to decompose excess potassium permanganate. The water insoluble in-organics were filtered and washed with water, to the filtrate, toluene was added (500ml) and pH was adjusted to acidic with Hydrochloric acid solution. Reaction mixture was stirred and layers were separated. Toluene was removed by distillation and crude was dissolved in methanol 340-360ml and further it was cooled to 0-5° C. Then 160g of thionyl chloride was slowly added, maintaining temperature at 0-5° C in 5-lOhrs. Reaction mixture was stirred at 40-45 ° C for 4-6hrs and solvent was distilled under low vacuum, and residue was dissolved in 500ml of toluene and washed with water 100-200 ml. And toluene was removed under vacuum and crude product was dissolved in 950ml of methyl isobutyl ketone and further added, water 20-30ml, sodium bicarbonate 100-140 g, 4-(a,a-diphenyl)piperidine methanol 140g, and Ig of potassium iodide and maintained stirring at reflux temperature for a period of 24-36 hrs. There after, reaction mass was cooled, filtered in-organics and the filtrate was concentrated under reduced pressure at below 95° C. The crude product was cooled and dissolved in aqueous alcohols 950ml at 60-85° C and charged activated carbon 5-1 Og, filtered and washed with aqueous alcohol, combined filtrate was cooled to 0-5° C, filtered, washed with aqueous alcohol and dried yielded 140-160g.(purity about 85%) of methyl-2-[4-[4-[4-(hydK)xydiphenylmethyl)piperidin-l-yl]butanoyl]-phenyl]-2-methyl propionate. The impure material of methyl-2-[4-[4-[4-(hydroxydiphenylmethyl) piperidin-1 -yl]butanoyl]-phenyl]-2-methyl propionate was again recrystallized in aqueous alcohol yielded 130-145g of pure methyl-2-[4-[4-[4-(hydroxydiphenylmethyl) piperidin-l-yl]butanoyl]-phenyl]-2-methyl propionate.

WE CLAIM:
1). A one-pot process for the preparation of compound of formula I:

wherein, X represents -CHOH, -CO, Ri and. R2 represents hydrogen; halogen selected from chloro, bromo, iodo; and a substituted or unsubstituted alkly chain, R3 represents hydrogen, alkly, aryl groups or alkali and alkaline earth metal salts starting from the compound of Formula-II:

wherein R4 is an alkyl group. 2). A one-pot process for the preparation of compound of formula I:


wherein, X represents, -CH2, -CHOH, -CO, Rj and R2 represents hydrogen; halogen selected from chloro, bromo, iodo; and a substituted or unsubstituted alkly chain, R3 represents hydrogen, alkly, aryl groups or alkali and alkaline earth metal salts
starting from the compound of Formula-Ill:

wherein R4 represents alkyl group; 'w' represents a halogen or a hydroxy group. 3) The process according to claim 1 and 2, reacting a compound of formula IX,

with a reducing agent to obtain a Methyl-2-[4-[4-[4-(hydroxydiphenylmethyl) piperidin-l-yl]butanoyl]phenyl]-2-methyl propionate, which is isolated and further

converted to Fexofenadine or optionally with out isolating the said intermediate methyl-2-[4-[4-[4-(hydroxydiphenylmethyl) piperidin-1 -yl]butanoyl]phenyl]-2-methyl propionate converted to Fexofenadine of formula

4) A one-pot synthesis of Fexofenadine base and its pharmaceutically acceptle salts, which comprises:
a) subjecting l-acetoxy-2-methyl-2-phenyl propane to Friedal-crafts reaction to obtain an intermediate of formula

without isolating, subjecting the l-acetoxy-2-methyl-2-[4-[4-chloro-l-oxy-butyl)phenylJ-propane, to hydrolysis followed by the oxidation, esterification and condensation with 4-(a,a-diphenyl)piperidine methanol to obtain 2-[4-[l-oxo-4-[4-(hydroxydiphenyhnethyl)-1 -piperidyl]butyl]phenyl]-2-methyl-propanoic acid alkyl ester;
further subjecting 2-[4-[l-oxo-4-[4-(hydroxydiphenylmethyi)-l-piperidyl3butyl] phenyl]-2-methyl-propanoic acid alkyl ester to reduction followed by hydrolysis in presence of a base insitu in the reaction mixture to produce Fexofenadine;

b) optionally converting the Fexofenadine base to its pharmaceutically acceptable salts and hydrates thereof.
5) A one-pot synthesis of Fexofenadine base and its pharmaceutically acceptable salts,
which comprises:
a) subjecting l-acetoxy-2-methyl-2-[4-[4-chloro-l-oxy-butyl)phenyl]-propane to
hydrolysis followed by the oxidation, esterification and condensation with 4-
(a,a-diphenyl)piperidine methanol to obtain 2-[4-[l-oxo-4-[4-
(hydroxydiphenylmethyl)-1 -piperidyl]butyl]phenyl]-2-methyl-propanoic acid
alkyl ester;
further subjecting 2-[4-[l-oxo-4-[4-(hydroxydiphenylmethyl)-l-piperidyl]butyl] phenyl]-2-methyl-propanoic acid alkyl ester to reduction followed by hydrolysis in presence of a base insitu in the reaction mixture to produce Fexofenadine;
b) optionally, converting the Fexofenadine base to its pharmaceutically acceptable
salts and hydrates thereof.
6) The process according to claim 1 to 5, the friedal crafts reaction is carried out in presence of methylene chloride, ethylene chloride or mixtures thereof.
7) The process according to claim 1 to 5, the hydrolysis is carried out in presence of base selected from the group of sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and a solvent selected from water; aqueous alcohols, alcohols such as methanol, ethanol, propanol, isopropanol or a mixture thereof
8) The process according to claim 1 to 5, oxidation is carried out in presence of a oxidizing agent selected from the group of potassium permanganate, sodium permanganate or a mixture thereof and a solvent selected from the group of water, acetone or mixture thereof

9) The process according to the claim 1 to 5, esterification and halogenation is carried out
in presence of thionyl chloride,- HCl, HBr in alcohols or in combination with other
suitable organic solvents thereof.
10) The process according to the claim 1 to 5, condensation is carried out in presence of a
base selected from the group of alkali and alkaline earth metal hydroxide, bicarbonates
and carbonates or suitable organic base such as triethyl amine, pyridine and the aqueous
or anhych-ous solvent is selected from the group of water, MIBK, toluene, xylene or a
mixture thereof.
11) The process according to claim 3, 4 and 5, the reduction is carried out in presence of
sodium borohydride, lithium aluminimi hydride, Pd/C, Raney Nickel.