FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of pure 2-[4-(4-chloro-butyryl) phemTJ-2-methyl propionic acid of Formula I,
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Formula I
which is an important intermediate in the preparation of Fexofenadine. The present invention particularly relates to a process that results in the production of pure 2-[4-(4-choloro-butyryl) phenyl]-2-methyl propionic acid and to the use of this compound as an intermediate for the preparation of an antihistaminic agent. Fexofenadine.
BACKGROUND OF THE INVENTION
Formula II
Fexofenadine of Formula II, is a terfenadine carboxylic acid metabolite and is
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chemically known as 4-[4-[4-hydroxydiphenylmethy)-1 -piperidinyl]-1 -hydroxybutyl]-a,a-dimethyl phenyl acetic acid. It is reported to be a specific HO -receptor antagonist that is also devoid of any anticholinergic. antiserotoninergic and antiadrenergic effects
The antihistaminic activity of fcxofenadine was first disclosed in LJS Patent 4,254,129. In this patent, fexofenadine of Formula II, is prepared by alkylation of a substituted piperidine derivative of Formula III.
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Formula 111
with an w-haloalkyl substituted phenyl ketone of Formula IV
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wherein X is a halogen atom, such as, chlorine, bromine or iodine, and R is an alkyl moiety of 1 to 6 carbon atoms and is straight or branched, followed by reduction of the ketone group and subsequent base hydrolysis.
Preparation of compounds of Formula TV is achieved by reacting a.a dimethylphenylacetic acid alkyl esters with 4- halobutyryl halide under general
conditions of Friedel-Crafts acylation. US Patent 4,254.129 describes the preparation of ethyl 4-(4-chJoro-l-oxobutyl)- a,a-dimethylphenylacetate by reaction of 4-chlorobutyryl chloride, aluminum chloride and ethyl a,a.-dimethylphenylacetate in carbon clisulphide
However, the described reaction results in almost inseparable mixture of monosubstituted aromatic para and meta regioisomers of the Formula V where unwanted meta isomer prevails to about 65%.
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European patent application EP 0 648 759 Al discloses a process, which has proved to be more selective in the formation of para isomer. In this process, Friedel-Crafts acylation has been carried out on the derivative of Formula VI
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Formula VT
with 4-chlorobutyryl chloride as the acylating agent in carbon disulfide in the presence of aluminum chloride and the corresponding para acylated product has been obtained that contains about 10% of meta isomer. The presence of meta isomer at this stage results in an unacceptable level of meta isomer in terfenacline carboxylate and it is difficult to achieve pharmaceutically pure product from such a mixture.
In view of this, the object of the present invention is to provide an efficient process for the preparation of pure 2-[4-(4-choloro-butyryl) phenyl]-2-inethyl propionic acid of Formula I.
SUMMARY OF THE INVENTION
The present relates to an simple and efficient process for the preparation of pure 2-[4-(4-choloro-butyryl) phcnyl]-2-methyl propionic acid of Formula I.
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Formula 1
wherein the amount of meta isomer is reduced to less than 1%.
DETAILED DESCRIPTION OF THE INVENTION
One aspect of the present invention relates to a process for the preparation of 2-[4-choloro-butyryl) phenyl]-2-methyl propionic acid of formula I.
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Formula I
with less than 1% of meta impurity. Specifically, the reaction involves the condensation of l-acetoxy-2-methyl-2-pheriylpropane. of Formula VI.
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Formula VI
with 4-chlorobutyryl chloride of formula VII,
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Formula-VII
in methylene chloride in the presence of anhydrous aluminium chloride to obtain a mixture of regioisomers, namely methyl 2-[4-(4-chloro-butyry1) phenyl]-2-methyI propanoate of Formula VTII.
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FoniHila VIII
that contains greater than 80% of para isomer.
The compound of formula VIII. is hydrolyzcd using acidic reaction conditions which are well, known in the prior art and arc effective to produce a mixture of regioisomers namely 2-[4-(4-choloro-butyryl) phenylJ-2-methyl propanol of Formula IX.
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The compound of formula IX is further oxidized using potassium permanganate and acetic acid in the presence of acetone to prepare a compound of formula X, having rneta isomer about 10%.
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Formula X
.In one aspect of the present invention, the removal of mcta isomer from the compound of formula X is carried out by slurring the compound of formula X in an organic solvent at ambient temperature.
Specifically the purification by slurring is carried out in an organic solvent such as cyclohexane, hexane. heptane, isopropyl ether and preferably cyclohexane is used. In particular, purification is carried out by slurring compound of formula X in an organic solvent at ambient temperature. The reaction mixture can be stirred for 30 minutes to 2 hours. Usually 1 to 10 parts by volume of solvent can be used. Thereafter the reaction solution is cooled to below 15°C and preferably between 10-15°C. The reaction mixture is stirred at this temperature for 2 hours. The pure product is isolated by the methods known in prior art such as filtration.
In another aspect of the present invention, the selective crystallization of above mixture of para and meta isomers of formula X is carried out to prepare pure 2-[4-(4-choloro-butyryl) phenyI]-2-methyl propionic acid of Formula 1.
Specifically the selective crystallization is carried out in an organic solvent such as cyclohexane. hexane. heptane, isopropyl ether and preferably cyclohexane is used.
In particular, selective crystallization is carried out by preparing a solution of a compound of formula X in an organic solvent at reflux temperature. The reaction mixture can be stirred for 30 minutes to 2 hours. Usually 5 to 10 parts by volume of solvent can be used. It is advantageous to use solvent sufficient to dissolve the compound at reflux.
Thereafter solvent is distilled out till 2 parts by volume left in the reaction mixture and reaction solution is cooled below 15°C and preferably between 10-15°C. The reaction mixture is stirred at this temperature for 2 hours. The pure product is isolated by the methods known in prior art such as filtration. Specifically the selective crystallization is carried out using about 10 parts by volume of cyclohexane. The pure compound of formula T is obtained wherein meta isomer is reduced to less than 1%.
In another aspect of the present invention, there is provided a pure compound of formula I, which can be used to prepare fexofenadine having meta isomer impurity within limits.
Formula III
The pure compound of formula I is condensed with substituted piperidine derivative of Formula ITT.
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under the reaction conditions known in prior art to prepare a compound of formula XII.
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Formula XIF
which is reduced using sodium borohydride to prepare pure fexotenadine of formula II having meta isomer less than 0.1%.
The main advantages of the present invention are:
• Increased product purity.
• The reaction does not involve larger reaction volumes.
• Good yield with improved quality.
• Consistency in obtaining the quality product.
• Simple and commercially viable.
The present invention is further illustrated by the following examples which are provided merely to be exemplary of the inventions and is not intended to limit the scope of the invention. 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.
Examples
Example-1
Preparation of crude 2-[4-(4-choloro-butyryl) phcnyll-2-mcthvl propionic acid
2-[4-(4-Chloro-butyry]) phenyl]-2-methyl propanol (154 g) was dissolved in acetone (462 ml) at 25-30°C. Demineralized water (385 ml) and glacial acetic acid (76.8 ml) were added. Potassium permanganate (178.4 g) was added in small lots in 3-4 hours maintaining the temperature at 15-20°C. Stirring was continued for 4 hour at 20-25°C. The reaction mass was filtered through hyflo and the residue was washed with toluene (693 ml) and demineralized water (616 ml). To the filtrate, hydrochloric acid (46.2 ml) was added followed by 15% sodium metabisulfite solution (308 ml). The layers were separated and the aqueous layer was extracted with toluene (154 ml). The combined organic extracts were extracted with 20% potassium carbonate solution twice (308 ml). The aqueous extract was washed twice with methylcne chloride. Thereafter methylene chloride (230 ml) was added to aqueous layer and the reaction mass was acidified with hydrochloric acid. The layers were separated and the aqueous layer was extracted with methylene chloride (77 ml). The combined organic layer was dried over sodium sulfate and methylene chloride was distilled out completely to obtain 119.4 g of crude product having purity 90.36% by HPLC and meta isomer is 9.63%.
ExampIe-2
Preparation of pure 2-[4-(4-choloro-biityryl) phenyl]-2-methyi propionic acid
To the product obtained above, cyclohexane (230 ml) was added. The reaction mixture was stirred for 30 minutes at ambient temperature, cooled to 10-15°C and further stirred for 2 hours. The reaction mixture was filtered and washed with
cyclohexane (154 ml) to get 95 g of the title compound as a white solid having purity 98.93% by HPLC and meta isomer is 0.89%.
Example-3
Preparation of pure 2-|4-(4-choloro-hutyryi) phenyll-2-methyl pronionic acid
To the product (lOg) obtained in Example 1, cyclohexane (100 ml) was added. The reaction mixture was heated to reflux temperature to get a clear solution. The volume of reaction mixture was reduced to 20 ml and stirred for 30 minutes at ambient temperature. The reaction mixture was cooled to 10-15°C, stirred for 2 hours, filtered and washed with cyclohexane (10 ml) to obtain 8 g of the title compound as a white solid having purity 98.80% by HPLC and meta isomer is 0.87%.

WE CLAIM
Formula 1
which comprises slurring a mixture of para and meta compound of formula X.
1. A process for the preparation of pure 2-[4-(4-ch1oro-hutyryl)phenyl]-2-methyl propionic acid of formula 1.
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in an organic solvent at ambient temperature, stirring and cooling the reaction mass, isolating pure compound of formula I.
2. A process according to claim I, wherein the organic solvent is selected from
cyclohexane, hexane, heptane and isopropyl ether.
3. A process according to claim 1. wherein the organic solvent is cyclohexane.
4. A process according to claim 1. wherein the reaction mixture is cooled to beknv
15°C.

which comprises dissolving a mixture of para and meta compound of formula X.
5. A process according to claim 1, wherein the amount of meta impurity in final
product is reduced to less than 1%.
6. A process for the preparation of pure 2-[4-(4-chloro-butyryr)phenyl]-2-methyl
propionic acid of formula I,
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Formula X
in an organic solvent at reflux temperature, distilling out the solvent.
cooling the reaction mass to 10-15°C and stirred, isolating pure compound of formula I.
7. A process according to claim 6, wherein the organic solvent is selected from
cyclohexane. hexane, heptane and isopropyl ether.
8. A process according to claim 6. wherein the organic solvent is cyclohexane.

9. A process according to claim 6. wherein the amount of meta impurity in final
product is reduced to less than 1%.
10. A process for the preparation of fexofenadine of Formula TT or a pharmaceutically
acceptable salt thereof.
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Formula II
the process comprising esterification of pure 2-[4-(4-chToro-butyryl)phenyl]-2-methyl propionic acid of Formula I, prepared by the process of claim 1, using methanolic hydrochloricle followed by condensation with azacyclonol. and reducing the resulting keto derivative.