Claims:WE CLAIM:
1. Novel amine salts of 2-[4-(cyclopropanecarbonyl)phenyl]-2-methylpropanoic acid having the following structure:

Formula IIIa
2. A process for preparation of the intermediate as claimed in claim 1, which comprises:
a) dissolving crude compound of 2-[4-(cyclopropanecarbonyl)phenyl]-2-methylpropanoic acid (Formula IIa containing meta isomer 10-35 %) in an aromatic hydrocarbon selected from toluene, xylene, benzene or mixture thereof;
b) heating & stirring the reaction mass to 40-45 °C to ensure complete dissolution;
c) adding an organic amine which is selected from dicyclohexylamine, benzylamine, phenyl hydrazine, a,a-Diphenyl-4-piperidinemethanol, 2-(2-methoxyphenoxy) ethyl amine, tris (hydroxymethyl)aminomethane, cyclohexylamine, dibenzylamine, phenylethyl amine, di-n-propyl amine, diisopropyl amine, t-butyl amine, isopropyl amine and a-methyl benzyl amine, 4-methoxy aniline;
d) adding C5-C8 aliphatic hydrocarbon such as cyclohexane, pentane, hexane, heptane, octane and a mixture thereof to the reaction mass of step c;
e) stirring for 3-4 hours for complete crystallization;
f) cooling the reaction mass to 0-5 °C;
g) stirring the reaction;
h) isolating the product by routine filtration; and
i) drying the wet cake at 40-45 °C for 6-8 hours to give 2-[4-(cyclopropane carbonyl)phenyl]-2-methylpropanoic acid amine salt.

3. A novel process for highly pure compound 2-[4-(cyclopropane carbonyl)phenyl]-2-methylpropanoic acid (Formula IIa) which comprises:
a) dissolving 2-[4-(cyclopropanecarbonyl)phenyl]-2-methylpropanoic acid amine salt (Formula IIIa) as claimed in claim 1, in a aliphatic halogenated hydrocarbon such as methylene chloride, chloroform, carbon tetra chloride or mixture thereof followed by addition of water;
b) cooling the reaction mass to 10-20 °C;
c) adjusting the pH of reaction mass to 1.0-2.0 by dilute hydrochloric acid;
d) stirring the reaction mass for 20-30 minutes at 10-20 °C;
e) fine filtration of the reaction mass via hyflow bed to remove formation of unwanted salt;
f) layer separation followed by extraction of aqueous layer using solvent of step a) above; and
g) complete recovery of solvent to get desired highly pure 2-[4-(cyclopropanecarbonyl)phenyl]-2methylpropanoic acid (Formula IIa).
4. A process for the preparation of highly pure 2-methyl-2-[4-(4-chlorobutanoyl) phenyl propanoic acid, which comprises:
a) treatment of amine salt compound of Formula IIIa as claimed in claim 1 with hydrochloric acid in an aliphatic or aromatic halogenated/non halogenated hydrocarbon such as methylene dichloride, chloroform or mixture thereof to get pure free acid analogue, 2-methyl-2-[4-(4-chlorobutanoyl) phenyl propanoic acid in organic layer; and
b) water washing the organic layer of step a) and performing complete recovery of organic layer to get highly pure 2-methyl-2-[4-(4-chlorobutanoyl) phenyl propanoic acid, which is essentially free of any corresponding meta-isomer.

Description:REFERENCE
This application is a Patent of Addition filed under section 54 and rule 13(3) to main patent application number: 1508/DEL/2010 (patent number: 351665) filed on June 28, 2010, the contents of which are being incorporated herein by reference. The invention comprises an improvement in and a modification of the invention claimed in the specification of the main patent applied for.
FIELD OF THE INVENTION
The present 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 & purification of key intermediates of Fexofenadine namely 2-[4-(cyclopropane carbonyl)phenyl]-2-methylpropanoic acid by preparation of its novel amine salts and its subsequent reversal to give highly pure material with negligible respective meta isomer content. The highly pure intermediate thus produced by this novel process is subsequently used in production of highly pure Fexofenadine hydrochloride. This pure intermediate is converted to a,a-Dimethyl-4-[1-oxo-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]phenyl methyl acetate (compound of Formula IV) via a new intermediate of compound of formula III (Scheme I).
The present invention also relates to the purification process for Fexofenadine base (V) as well as Fexofenadine hydrochloride (VI) for generation of highly pure i.e. almost impurity free Fexofenadine hydrochloride of formula VI.

BACKGROUND OF THE INVENTION
Fexofenadine hydrochloride of Formula VI is a non-sedative antihistaminic compound and is chemically known as a,a-Dimethyl-4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl] benzene acetic acid hydrochloride.
It is reported to be a specific H2-receptor antagonist that is also devoid of any anticholinergic, antiseroloninergic 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 Friedal Crafts conditions to give compound of formula II (meta isomer ~35%) which on condensation with [a,a]-diphenyl-4-piperidinemethanol gives compound of formula IV, followed by reduction & hydrolysis to yield Fexofenadine base (compound V). The compound of formula II produced by this process has ~35% of meta isomer which is not possible to remove at this stage. Therefore, an improved process for the preparation/purification of compound of formula II was required. Similarly, there was a need of cost effective process for the preparation as well as purification of compound of formula IV to improve its quality especially removal of meta isomer at commercial scale as per market demand.
Similarly the methods reported in prior art for preparation of fexofenadine involves reduction & hydrolysis of compound of formula IV to give compound of formula V. Generally reduction reaction is carried out at ambient temperature and always results in keto fexofenadine impurity of formula VII in the final API due to unreacted compound of formula IV.
In the patents such as WO 95/31437, US 2004/0077683, WO 2005/67511, preparation of Fexofenadine is reported.
Most of the processes described above are not suitable to get high purity of Fexofenadine hydrochloride at commercial scale due to higher contents of impurities specially keto Fexofenadine, meta keto Fexofenadine & meta-Fexofenadine impurities. Therefore, to achieve highly pure API at commercial scale, an improved process was required to reduce/remove all these impurities. Furthermore, as keto Fexofenadine & meta keto Fexofenadine do not get separated by pharmacopoeial analytical method for HPLC analysis, therefore, there was an urgent need of an improved analytical HPLC method by which both these impurities can be separated along with simultaneous separation of other impurities including meta fexofenadine by single method.
SUMMARY OF THE INVENTION
The present invention discloses a new purification process for intermediate of formula II for removal of meta isomer by preparation of a new amine salt intermediate of formula III & IIIa.
Other objective of the present invention is to develop a novel cost-effective process for preparation & purification of compound of formula II to reduce the impurities especially meta isomer to get high purity of compound IV at commercial scale for industrial use. The present invention also describes the purification process for Fexofenadine hydrochloride for removal of impurities especially keto Fexofenadine, meta keto Fexofenadine & meta Fexofenadine impurities.
DETAILED DESCRIPTION OF THE INVENTION
The first aspect of the present invention is to provide a highly pure compound of formula II by removal of the meta isomer. It ultimately results in controlling the meta isomer in the final API.
The second aspect of the present invention provides a process for highly pure compound of formula II which comprises:
a) treatment of crude compound of formula II (meta isomer ~35%) with caustic in an aliphatic alcohol followed by pH adjustment to 1.0 – 2.0 using hydrochloric acid;
b) extraction of product in an organic solvent;
c) addition of an organic amine;
d) isolation of compound of formula III i.e. 2-methyl-2-[4-(4-chlorobutanoyl)phenyl propanoic acid amine salt by addition of aliphatic hydrocarbon as anti-solvent;
e) treatment of compound of formula III of step (d) with hydrochloric acid in an organic solvent to get pH 1.0-2.0;
f) recovery of the solvent by conventional methods to get the residue;
g) reaction of residue of step (f) with methanolic hydrogen chloride gas; and
h) isolation of pure compound of formula II i.e. 2-methyl-2-[4-(4-chlorobutanoyl) phenyl propanoate by extraction in suitable organic solvent followed by its recovery by conventional methods.
According to another aspect of the present invention, aliphatic alcohols used in above steps are methanol, ethanol, propanol, butanol, or a mixture thereof.
According to yet another aspect of the invention, the organic solvents used in step (b) are aliphatic halogenated hydrocarbon such as methylene chloride, chloroform, carbon tetra chloride, etc., aromatic hydrocarbons such as toluene, xylene, benzene, etc., aliphatic esters such as ethyl acetate, propyl acetate, etc. or a mixture thereof.
According to still another aspect of the invention, the organic amine used in step (c) is selected from dicyclohexylamine, benzylamine, phenylhydrazine, a,a-Diphenyl-4-piperidinemethanol, 2-(2-methoxyphenoxy) ethyl amine, tris(hydroxymethyl)aminomethane, cyclohexylamine, dibenzylamine, phenyl ethyl amine, di-n-propyl amine, diisopropyl amine, t-butyl amine, isopropyl amine and a-methyl benzyl amine, 4-methoxy aniline.
According to another aspect of the invention, the anti-solvent used in step (d) is selected from C5-C8 aliphatic hydrocarbon such as pentane, hexane, heptane, octane and a mixture thereof.
According to a new aspect of the present invention, novel compounds of formula III were prepared.
According to another aspect of the invention, the organic solvent used in step (e) is selected from aliphatic halogenated hydrocarbon such as Methylene chloride, chloroform, carbon tetra chloride, etc., aromatic hydrocarbons such as toluene, xylene, benzene, etc., aliphatic esters such as ethyl acetate, propyl acetate, etc. or a mixture thereof.
According to yet another aspect of the invention, the reaction temperature in step (g) is 20-40 ºC.
According to another aspect of the invention, the organic solvent used in step (h) is selected from aliphatic halogenated hydrocarbon such as methylene chloride, chloroform, carbon tetra chloride, etc., aromatic hydrocarbons such as toluene, xylene, benzene, etc., aliphatic esters such as ethyl acetate, propyl acetate, etc., aliphatic ketones such as acetone, methyl isobutyl ketone, etc. or a mixture thereof.
According to yet another aspect of the present invention, a single analytical method for HPLC analysis of simultaneous detection of keto Fexofenadine, meta keto Fexofenadine and meta Fexofenadine which is given below:
Preparation of Buffer
Dissolve about 3.85 gm of ammonium acetate in 1 liter of water. Filter through 0.45 µm or finer porosity membrane filter.
Preparation of Mobile Phase
Prepare a solution of Buffer: methanol in the ratio of 480: 520 (v/v).
Use mobile phase as a diluent.

Chromatographic Parameters
Use a suitable High Performance Liquid Chromatograph (HPLC) with the following parameters:
Column : Waters Novapak phenyl (150mmx3.9mm) 4µ
Flow rate : 1.0 ml/min
Detector : UV at ?=220 nm
Injection volume : 10 µl
Run time : 40 min
Preparation of Standard Reference Solution
Accurately weigh and transfer about 20 mg each of impurity B and fexofenadine to a 100 ml of volumetric flask. Dissolve in methanol by sonication, if necessary, and dilute to volume with methanol. Further take 1 ml of this solution in 100 ml volumetric flask and make up with the diluent.
Preparation of Sample Solution
Accurately weigh and transfer about 100 mg of sample to a 50 ml of volumetric flask. Dissolve in 5 ml of methanol by sonication if necessary and dilute to volume with diluent
Procedure
Inject 10 ul each of blank (diluent) and sample solutions and record the chromatograms.
Examine the blank run chromatograms for any extraneous peaks and disregard any corresponding peaks observed in the chromatogram of the sample solution.

Name of Compound
RT
Fexofenedine HCl (VI) 7.5 min
Impurity A (keto Fexofenadine; VII) 11.7 min
Impurity B (meta Fexofenadine; VIII) 9.4 min
Impurity C (meta keto Fexofenadine; IX) 14.5 min

Calculation
AT DS
% Impurity = ----- x ----- x PF
AS DT
where,
AT : Peak area counts of impurity and the chromatograms of the sample solution
AS : Average peak area counts of standard in the chromatograms of the standard solution as obtained under system suitability
DT : Dilution factor of the sample solution
DS : Dilution factor of the standard solution
PF : Purity Factor

The Fexofenadine hydrochloride & Fexofenadine base used were prepared as per conventional methods.
According to an aspect of the present invention, a process for highly pure compound 2-[4-(cyclopropanecarbonyl) phenyl]-2-methylpropanoic acid amine salt (formula IIIa-Scheme II) is claimed which comprises:
a) dissolving crude compound of 2-[4-(cyclopropanecarbonyl) phenyl]-2-methylpropanoic acid (Formula IIa containing meta isomer 10-35%) in an aromatic hydrocarbon selected from toluene, xylene, benzene or mixture thereof;
b) heating & stirring the reaction mass to 40-45 °C to ensure complete dissolution;
c) adding an organic amine which is selected from dicyclohexylamine, benzylamine, phenyl hydrazine, a,a-diphenyl-4-piperidinemethanol, 2-(2-methoxyphenoxy) ethyl amine, tris (hydroxymethyl)aminomethane, cyclohexylamine, dibenzylamine, phenylethyl amine, di-n-propyl amine, diisopropyl amine, t-butyl amine, isopropyl amine and a-methyl benzyl amine, 4-methoxy aniline;
d) adding C5-C8 aliphatic hydrocarbon such as cyclohexane, pentane, hexane, heptane, octane and a mixture thereof to the reaction mass of step c;
e) stirring for 3-4 hours for complete crystallization;
f) cooling the reaction mass to 0-5°C;
g) stirring the reaction;
h) isolating the product by routine filtration;
i) drying the wet cake at 40-45 °C for 6-8 hours to give 2-[4-(cyclopropane carbonyl)phenyl]-2-methylpropanoic acid amine salt (Formula IIIa).
According to yet another aspect of current embodiment, 2-[4-(cyclopropane carbonyl)phenyl]-2-methylpropanoic acid amine salt can be optionally purified in toluene/ cyclohexane.
According to another aspect of the present invention a process for highly pure compound 2-[4-(cyclopropane carbonyl)phenyl]-2-methylpropanoic acid (Formula IIa) which comprises:
a) dissolving 2-[4-(cyclopropanecarbonyl)phenyl]-2-methylpropanoic acid amine salt (Formula IIIa) in a aliphatic halogenated hydrocarbon such as methylene chloride, chloroform, carbon tetra chloride or mixture thereof followed by addition of water;
b) cooling the reaction mass to 10-20 °C;
c) adjusting the pH of reaction mass to 1.0-2.0 by dilute hydrochloric acid;
d) stirring the reaction mass for 20-30 minutes at 10-20 °C;
e) fine filtration of the reaction mass via hyflow bed to remove formation of unwanted salt;
f) layer separation followed by extraction of aqueous layer using solvent of step a) above.
g) complete recovery of solvent to get desired highly pure 2-[4-(cyclopropane carbonyl)phenyl]-2methylpropanoic acid (Formula IIa).
This patent of addition is a modification/improvement over the originally filed invention in application number 1508/DEL/2010. In that application, a novel intermediate 2-methyl-2-[4-(4-chloro butanoyl)phenyl propanoic acid dicyclohexylamine salt was claimed which was eventually granted. Now this process described herein which is a patent of addition of 1508/DEL/2010, gives preparation of novel amine salt of 2-[4-(cyclopropane carbonyl)phenyl]-2methylpropanoic acid (Formula IIIa). As per the current invention, this amine salt of formula IIIa (Scheme-II) is converted back to give highly pure IIa (Scheme-II) which is subsequently converted to 2-methyl-2-[4-(4-chloro butanoyl) phenyl methyl propanoate (II of Scheme I) by its treatment with methanolic HCl. The current invention provides better control on yield & quality of Formulas IV or V or Fexofenadine hydrochloride with respect to the process described in application number 1508/DEL/2010 although the basic invention is the same. The process claimed herein is commercially more viable due to ease of operational procedures. Also it may be noted that if meta isomer in either of IIa or II is more then 15% it is not possible to purify it by any other known process in literature.
The above mentioned invention is supported by the following non-limiting examples:

EXAMPLES
Example 1:
Preparation of 2-Methyl-2-[4-(4-chlorobutanoyl) phenyl propanoic acid dicyclohexylamine salt (III)
To 1.0 kg of crude 2-methyl-2-[4-(4-chlorobutanoyl) phenyl methyl propanoate (II) in 6.0 liter of methanol, aqueous caustic solution (0.30 kg) was added and the reaction mass was heated to refluxing. The completion of the reaction was monitored by TLC. After 15-16 hours, methanol was recovered under vacuum to get a viscous semi solid mass. The product was extracted in toluene at (1.0 liter) at acidic pH of about 1.0-2.0 adjusted by HCl (0.65 Liter) followed by washing of organic layer with water. To the toluene layer, dicyclohexylamine was added and 2-methyl-2-[4-(4-chlorobutanoyl) phenyl propanoic acid dicyclohexylamine salt (III) was isolated by adding hexane at 0-10 ºC. The crude compound of formula III was further purified in toluene-hexane to get pure compound of formula III.
Yield = 1.0 kg (HPLC purity = 99.24 %; Meta isomer not detected)
Example 2:
Preparation of pure 2-methyl-2-[4-(4-chlorobutanoyl) phenyl methyl propanoate (II)
To a solution/suspension of 1.0 kg of 2-methyl-2-[4-(4-chlorobutanoyl) phenyl propanoic acid dicyclohexylamine salt (III) in methylene chloride (5.0 liter), water (4.0 liter) was added. The reaction mass was stirred & its pH was adjusted to 1.0-2.0 by aqueous hydrochloric acid (0.25 liter). The organic layer was separated followed by its washing with water. Complete recovery of solvent was done. The residue was reacted with methanolic hydrogen chloride gas at 20-40 ºC followed by complete recovery of methanol and extraction of resulting product with methylene chloride (5.0 liter). Complete recovery of solvent was done to get highly pure 2-methyl-2-[4-(4-chlorobutanoyl) phenyl methyl propanoate (II).
Yield 0.50 kg (HPLC purity >98%; Meta isomer Not detected)
Example 3:
Preparation of a,a-Dimethyl-4-[1-oxo-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl] phenyl methyl acetate (IV)
A solution/suspension of pure 2-methyl-2-[4-(4-chlorobutanoyl) phenyl methyl propanoate (100g) in acetone (100ml) & water (300ml) was reacted with a, a-diphenyl-4-piperidinomethanol (85g) in the presence of potassium bicarbonate (54g), potassium iodide (0.55g) at 60-70 ºC. The completion of reaction was monitored by HPLC. After 24 hours, solvent & water were recovered under vacuum to give viscous solid mass. Then ethanol (100ml) was added to it and the resulting solid was filtered and dried at 40-50 ºC to get compound of formula IV.
Yield 135 g (HPLC purity >95 %)
Example 4:
Purification of a,a-Dimethyl-4-[1-oxo-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl] phenyl methyl acetate (IV)
a,a-Dimethyl-4-[1-oxo-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]Phenyl methyl acetate (100g) was dissolved in 1.0 Liter of ethanol at 40-50 ºC followed by carbon treatment. The resulting filtered ethanol layer was cooled to 0-5 ºC. The material, thus crystallized, was filtered and dried at 40-50 ºC to get pure compound IV.
Yield = 90 g (HPLC purity = 99.42 %; Meta isomer < 0.20%)
Example 5:
Purification of a,a-Dimethyl-4-[1-oxo-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl] phenyl methyl acetate (IV)
a,a-Dimethyl-4-[1-oxo-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]Phenyl methyl acetate (100g) was dissolved in 0.50 Liter of acetone at 40-50 ºC followed by carbon treatment. The resulting filtered ethanol layer was cooled to 0-5 ºC. The material, thus crystallized, was filtered and dried at 40-50 ºC to get pure compound IV.
Yield = 85 g (HPLC purity = 99.11%; Meta isomer not detected)
Example 6:
Purification of a,a-Dimethyl-4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl] benzene acetic acid (V)
To a suspension of a,a-Dimethyl-4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl] benzene acetic acid (100g) in methanol (300ml), N,N-dimethylformamide (100ml) was added to get a clear solution. The resulting solution was cooled to 0-5 ºC and the solid, thus crystallize, was filtered and dried at 50-60 ºC to get pure fexofenadine base i.e. a,a-Dimethyl-4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl] benzene acetic acid (V).
Yield = 90 g (HPLC purity =99.97%; Keto isomer = 0.007 %; Meta isomer not detected)
Example 7:
Purification of a,a-Dimethyl-4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl] benzene acetic acid hydrochloride (VI)
To a solution of a,a-Dimethyl-4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl] benzene acetic acid hydrochloride (100g) in methanol (500ml), aqueous caustic solution (30 %) was added and reaction mass was heated up to 50-55 ºC, followed by the addition of sodium borohydride (2 g) & the reaction mass was refluxed for 1.0 hour at 65-70 ºC. The reaction mass was cooled to 50-55 ºC again and its pH was adjusted to 6.4-6.6 by dilute hydrochloric acid. The resulting mass was cooled to 0-5 ºC and stirred for 2-3 hours followed by filtration to get a wet cake. To this wet cake, methanol (300 ml) & N,N-dimethylformamide (100ml) was added and the mixture was refluxed at 70-80 ºC for 1 hour. The reaction mass was then cooled to 0-5 ºC to re-crystallize the material. The material formed was filtered & finally dried to give pure a,a-Dimethyl-4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl] benzene acetic acid (V). The suspension of pure compound of formula V thus obtained, in water (160ml) was reacted with aqueous caustic solution to get clear solution which was converted into fexofenadine hydrochloride hydrate by adding aqueous HCl. The solid, thus obtained, was filtered & dried to get fexofenadine hydrochloride hydrate. It was recrystallized in isopropyl alcohol (300 ml) & ethyl acetate (700 ml) followed by filtration and drying at 60-70 ºC to get anhydrous fexofenadine hydrochloride of formula VI.
Yield = 90g (HPLC purity 99.95%; Keto Isomer = 0.02 %; Meta isomer not detected; Assay = 99.95 %)
Example 8:
Preparation of 2-[4-(cyclopropanecarbonyl)phenyl]-2-methylpropanoic acid dicyclohexylamine salt (IIIa-Scheme II)
1.0 kg of crude 2-[4-(cyclopropanecarbonyl)phenyl]-2-methylpropanoic acid (IIa with meta isomer 10-35%) was stirred in 1.0 liter of toluene till dissolution followed by addition of 1.36 Liter of N,N-Dicyclohexylamine and 2.0 Liter of cyclohexane. The reaction mass was stirred for 3-4 hours followed by cooling of reaction mass to 0-5°C. The reaction mass was further stirred to get the desired product, 2-[4-(cyclopropanecarbonyl)phenyl]-2-methylpropanoic acid dicyclohexylamine salt (IIIa) which was isolated by routine filtration at 0-5ºC followed by drying at 40-45°C for 6-8 hours.
Yield = 1.65 kg (HPLC purity = 99.84 %; Meta isomer not detected)
Example 9:
Purification of 2-[4-(cyclopropanecarbonyl)phenyl]-2-methylpropanoic acid dicyclohexylamine salt (IIIa-Scheme II)
To 1.0 kg of 2-[4-(cyclopropanecarbonyl)phenyl]-2-methylpropanoic acid dicyclohexylamine salt (IIIa) added 3.0 Liter of toluene & stirred with heating to 50-60 °C to ensure proper dissolution. After dissolution 3.0 Liter of cyclohexane was added followed by its stirring for 45-60 minutes at 50-60 °C. Further, the reaction mass was cooled to 0-5 °C to ensure proper crystallization. The reaction mass was filtered to get highly pure 2-[4-(cyclopropanecarbonyl)phenyl]-2-methylpropanoic acid dicyclohexylamine salt (IIIa) by drying at 40-45 °C for 6-8 hours.
Yield 0.65 kg (HPLC purity >99.70%; Meta isomer Not detected)
Example 10:
Preparation of purified 2-[4-(cyclopropanecarbonyl)phenyl]-2-methylpropanoic acid (IIa-Scheme II)
1.0 Kg of 2-[4-(cyclopropanecarbonyl)phenyl]-2-methylpropanoic acid dicyclohexylamine salt (IIIa) was dissolved in methylene chloride (5.0 Liter) & water (300ml) followed by addition of water (4.0 Liter) under stirring. The reaction mass was cooled to 10-20 °C followed by its pH adjustment with a hydrochloric acid (0.28 Liter). The reaction mass was stirred followed by removal of undesired salt formation by fine filtration using hyflow bed. The filtrate was collected and its layer separation was done. The aqueous layer was extracted with methylene chloride (2.0 Liter). The reaction mass containing desired product in methylene chloride was obtained by performing complete recovery under vacuum to give desired highly pure 2-[4-(cyclopropanecarbonyl)phenyl]-2-methylpropanoic acid.
Yield 0.50 Kg (HPLC Purity > 99.85% & Meta Isomer < Not detected)
Example 11:
Preparation of 2-[4-(cyclopropanecarbonyl)phenyl]-2-methylpropanoic acid cyclohexylamine salt (IIIa-Scheme II)
1.0 kg of crude 2-[4-(cyclopropanecarbonyl)phenyl]-2-methylpropanoic acid (IIa with meta isomer 10-35%) was stirred in 1.0 Liter of toluene till dissolution followed by addition of 1.26 Liter of cyclohexylamine and 2.0 liter cyclohexane. The reaction mass was stirred for 3-4 hours followed by cooling of reaction mass to 0-5 °C. Further, the reaction mass was stirred to get the desired product, 2-[4-(cyclopropanecarbonyl)phenyl]-2-methylpropanoic acid cyclohexylamine salt (IIIa) which was isolated by routine filtration at 0-5 ºC followed by drying at 40-45 °C for 6-8 hours.
Yield = 1.40 kg (HPLC purity = 99.54 %; Meta isomer not detected)

Example 12:
Preparation of Purified 2-[4-(cyclopropanecarbonyl)phenyl]-2-methylpropanoic acid (IIa-Scheme II)
1.0 kg of 2-[4-(cyclopropanecarbonyl)phenyl]-2-methylpropanoic acid cyclohexylamine salt (IIIa) was dissolved in methylene chloride (5.0 Liter) & water (300 ml) followed by addition of water (4.0 Liter) under stirring. The reaction mass was cooled to 10-20 °C followed by its pH adjustment with a hydrochloric acid (0.28 Liter). The reaction mass was stirred followed by removal of undesired salt formation by fine filtration using hyflow bed. The filtrate was collected and its layer separation was done. The aqueous layer was extracted with methylene chloride (2.0 Liter). The reaction mass containing desired product in methylene chloride was obtained by performing complete recovery under vacuum to give the desired highly pure 2-[4-(cyclopropanecarbonyl)phenyl]-2-methylpropanoic acid.
Example 13:
Preparation of 2-[4-(cyclopropanecarbonyl)phenyl]-2-methylpropanoic acid t-butylamine salt (IIIa-Scheme II)
1.0 kg of crude 2-[4-(cyclopropanecarbonyl)phenyl]-2-methylpropanoic acid (IIa with meta isomer 10-35%) was stirred in 1.0 liter of toluene till dissolution followed by addition of 1.20 liter of t-butylamine and 2.0 liter cyclohexane. The reaction mass was stirred for 3-4 hours followed by cooling of reaction mass to 0-5 °C. The reaction mass was further stirred to get the desired product 2-[4-(cyclopropanecarbonyl)phenyl]-2-methylpropanoic acid t-butylamine salt (IIIa) which was isolated by routine filtration at 0-5 ºC followed by drying at 40-45 °C for 6-8 hours.
Yield = 1.42 kg (HPLC purity = 99.44 %; Meta isomer not detected)
Example 14:
Preparation of purified 2-[4-(cyclopropanecarbonyl)phenyl]-2-methylpropanoic acid (IIa-Scheme II)
1.0 kg of 2-[4-(cyclopropanecarbonyl)phenyl]-2-methylpropanoic acid t-butylamine salt (IIIa) was dissolved in methylene chloride (5.0 Liter) & water (300ml) followed by addition of water (4.0 Liter) under stirring. The reaction mass was cooled to 10-20 °C followed by its pH adjustment with a hydrochloric acid (0.28 Liter). The reaction mass was stirred followed by removal of undesired salt formation by fine filtration using hyflow bed. The filtrate was collected and its layer separation was done. The aqueous layer was extracted with methylene chloride (2.0 Liter). The reaction mass containing desired product in methylene chloride was obtained by performing complete recovery under vacuum to give desired highly pure 2-[4-(cyclopropanecarbonyl)phenyl]-2-methylpropanoic acid.
Advantages
1. Novel Fexofenadine intermediate amine salts of formula IIIa.
2. Present invention is capable of producing almost impurity free Fexofenadine hydrochloride. The importance of the claimed invention lies in the fact that it provides the best method of control on meta isomers of all Formulas II, IIa, IV, V & VI which is otherwise very difficult to remove.
3. Novel purification processes for Fexofenadine Intermediates of formulas II, IIa & IV to get high purity and very less meta isomer (almost not detected) can be produced by following the processes reported in the present invention.
4. The processes reported in present invention are equally effective at commercial scale.
5. The process claimed herein is commercially more viable due to the ease of operational procedures. Also, it may be noted that if meta isomer in either of Formula IIa or II is more than 15% it is not possible to purify it by any other known process in literature but this method is repeatedly able to do the same at commercial scale. It also gives better control on other impurities such as Formulas VII & VIII as well.