FIELD OF THE INVENTION
The present invention relates to an eco-friendly and improved process for the preparation ofpiperidine derivative of formula I, a key intermediate in the preparation of fexofenadine.

(Formula Removed)
BACKGROUND OF THE INVENTION
Fexofenadine, chemically known as 4-[4-[4-(hydroxydiphenylmethyl)-l-piperidinyl]-l-hydroxybutyl]-α,α-dimethylbenzene acetic acid, has following structure formula,
(Formula Removed)
It is an H1 receptor antagonist and an useful antihistamine drug. It is a terfenadine carboxylic acid metabolite and was developed as an alternative to terfenadine, an antihistamine with potentially serious side effects like cardiac toxicity or other contraindications.
Fexofenadine and pharmaceutically acceptable salts were first disclosed in US patent 4,254,129. According to the disclosed process, fexofenadine can be prepared by the reduction of carbonyl functionality of piperidine derivative of formula I,
(Formula Removed)
in the presence of Pt/O/H2 followed by hydrolysis of the resulting ester compound to yield fexofenadine base.
According to synthetic approach reported in this patent, the piperidine derivative of formula I can be prepared starting from ethyl, α,α-dimethylphenyl acetate. The process involves the reaction ethyl, α,α-dimethylphenyl acetate and 4-chlorobutyroyl chloride under Friedel-Crafts conditions to form 4-(4-chlorobutyryl)-α,α-dimethyl benzene acetic acid methyl ester. Then chloride displacement reaction from the Friedel-Crafts product with α,α-diphenyl-4-piperidine-methanol takes place in the solvents like C1-C4 alcohols; ketones such as methylisobutylketone; hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as chlorobenzene or methylene chloride or dimethylformamide and inorganic base to give piperidine derivative of formula I, which is isolated as its hydrochloride salt.
US patent 5,578,610 discloses the process for the preparation of piperidine derivative of formula I by the alkylation reaction of 4-iodobutyryl- α,α-dimethyl benzene acetic acid methyl ester with α,α-diphenyi-4-piperidine-methanol in a suitable solvent that include alcohol, ketone solvents, hydrocarbon solvents, halogenated solvents or dimethylformamide preferably in the presence of a base and optionally in the presence of catalytical amount of the potassium iodide to give the piperidine derivative which is further converted to fexofenadine.
US patent 5,618,940 exemplified the preparation of piperidine derivative of formula I by refluxing 4-(4-chlorobutyryl)- α,α-dimethyl benzene acetic acid methyl ester and
α,α-diphenyl-4-piperidine-methanol in the presence of potassium hydrogen carbonate, potassium iodide in toluene and water for 72 hours. The resulting product is purified by the chromatography method which is very time consuming and cumbersome process.
US patent application 2007/0191428 discloses the process for the preparation of piperidine derivatives of formula I by condensation of 4-chlorobutyryl- α,α-dimethyl benzene acetic acid methyl ester with α,α-diphenyl-4-piperidine-methanol in the presence of potassium carbonate, potassium iodide in methylisobutylketone and dimethylformamide as a solvent.
PCT publication WO 08/012859A2 exemplifies the process for the preparation of piperidine derivative of formula I by condensation of 4-chlorobutyryl- α,α-dimethyl benzene acetic acid methyl ester with α,α-diphenyl-4-piperidine-methanol by using mixture of methylisobutylketone and water as a solvent.
All the prior art processes, involve the use of organic solvent during the condensation of 4-(4-chlorobutyryl)-α,α-dimethyl benzene acetic acid methyl ester with α,α-diphenyl-4-piperidine-methanol for the preparation of piperidine derivative of formula I. We have not found any reference wherein organic solvent has not been used. Use of organic solvent in synthetic reactions also needs the control of the solvent to be shown in the final API like fexofenadine.
In view of the above, the present invention aims to develop an eco-friendly and economically viable process for the synthesis of piperidine derivative of formula I, wherein use of organic solvent is avoided during condensation reaction.
OBJECT OF THE INVENTION
It is the foremost object of the present invention to provide an eco-friendly, and cost-effective process for the preparation of piperidine derivative of formula I, a key intermediate for fexofenadine.
Another object of the invention is to provide a process for the preparation of piperidine derivative of formula I without the use of organic solvents during condensation reaction.
Another object of the invention is to provide a process for the conversion of piperidine derivative of formula I to fexofenadine and pharmaceutically acceptable salts thereof.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides an eco-friendly and cost-effective process for the preparation of piperidine derivative of formula I, an intermediate of fexofenadine,
(Formula Removed)
which comprises the steps of
a). condensing 4-(4-chlorobutyryl)-α,α-dimethyl benzene acetic acid methyl ester of formula II,

(Formula Removed)
with α,α-diphenyl-4-piperidine-methanol of formula III,
(Formula Removed)
in the presence of base in water;
b). isolating the compound of formula I there from; and
c). optionally, purifying the compound of formula I using a suitable solvent.
According to another embodiment, present invention provides a process for the preparation of fexofenadine, which comprises the steps of:
a), condensing 4-(4-chlorobutyryl)-α,α-dimethyl benzene acetic acid methyl ester of formula II,
(Formula Removed)
with α,α-diphenyl-4-piperidine-methanol of formula III,
(Formula Removed)
in the presence of base in water; b). isolating the compound of formula I therefrom; c). optionally, purifying the compound of formula I using a suitable solvent; and
d). converting the compound of formula I to fexofenadine and pharmaceutically acceptable salts thereof.
DETAILED DESCRIPTION OF THE INVENTION
The process of present invention is economically viable, eco-friendly and industrially advantageous for the preparation of piperidine derivative of formula I,
(Formula Removed)
a key intermediate useful for the synthesis of fexofenadine and pharmaceutically acceptable salts thereof.
According to one embodiment, present invention provides a process for the preparation of piperidine derivative of fonnula I, by the condensation of compound of formula II, with α,α-diphenyl-4-piperidine-methanol of formula III without using organic solvent.
Specifically, the process involves the reaction of the compound of formula II with α,α-diphenyl-4-piperidine-methanol of formula III in the presence of base and water as solvent. Base employed for reaction can be inorganic base which include alkali or alkaline metal hydroxide, alkoxide, carbonates, bicarbonates, hydride and combination thereof. Preferably, the base can be selected from the potassium
carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate and the like or combination thereof. It is optional to add a catalytic amount of potassium iodide to the reaction mixture, as it initiates the reaction. The reaction can be carried out at a temperature of ambient temperature to 95 °C for few minutes to few hours, preferably a temperature of 68°C till the completion of the reaction. Reaction completion can be monitored by the suitable chromatographic techniques such as high-pressure liquid chromatography (HPLC), thin layer chromatography (TLC) and the like. Usually, the reaction undergoes completion in 20 to 48 hours. After the completion of the reaction, water is removed from the reaction by the use of suitable techniques such as decantation, distillation and the like to give piperidine derivative of formula I. The isolation of the desired product is quite easy as only water is used as solvent for the reaction.
The piperidine derivative of formula I, thus obtained, can be purified using any suitable purification procedure to enhance the purity of the compound or to reduce the presence of undersired impurities in the compound. Any suitable purification method such as, for example, crystallization, derivatisation, slurry wash, salt preparation or combination of these procedures can be employed. The solvents used for the purification can be selected form water, C1-6 alcohols such as methanol, ethanol, denatured spirit; ketone such as acetone; nitriles such as acetonitrile; and the like or mixture thereof in suitable proportion.
Specifically, the piperidine derivative of formula I in a suitable solvent is stirred at a temperature of 0 °C to 75 °C for few minutes to several hours. Preferably, the reaction mixture is heated to a temperature of 60 to 75°C for 30 minutes to 3 hours. Thereafter, the crystallization of the purified piperidine derivative of formula is initiated by the suitable method such as cooling; preferably reaction mixture is cooled to a temperature below room temperature and preferably below 10°C. The resulting product may be separated from the reaction mixture by known techniques such as decantation, filtration or centrifugation; any other suitable technique can be employed.
In another alternate way, the piperidine derivative of formula I can be purified by employing sluixy wash with a suitable solvent. Specifically, the piperidine derivative of formula I, is stirred in water at ambient temperature to remove the impurities such as inorganic salts which are soluble in water. The resulting product is removed may be separated from the reaction mixture by known techniques such as decantation, filtration or centrifugation; any other suitable technique can be employed.
The piperidine derivative of formula I, thus obtained by the process of present invention can be converted to the fexofenadine by the process known in the art. The piperidine derivative of formula I can be reduced followed by hydrolysis of the resulting ester moiety or vice versa.
The starting compound of fomiula II, can be procured from the market or can be prepared by the prior art methods.
The major advantage of the present invention resides in the use of water as solvent for the condensation reaction. The use of water as a solvent has several added advantages for the commercial synthesis of any pharmaceutically compound such as fexofenadine. One of the advantages is that it avoids the use of organic solvent and special care for their handling. The other advantage observed is that use of water results in the formation of piperidine derivative with minimum amount of the undesired impurities, either impurities are present in acceptable amounts or absent. The use of water as a solvent for organic reaction offers several "green chemistry" benefits and significant rate enhancement is observed in water as compared to organic solvents.
Although, the following examples illustrate the practice of the present invention in some of its embodiments, the examples should not be construed as limiting the scope of the invention. Other embodiments will be apparent to one skilled in the art from consideration of the specification and examples.
Example 1: Preparation of 4-[4-[4-(hydroxydiphenyl methyl)-l-piperidinyl]-l-oxobutyl]-α,α-dimethyl benzene acetate
α,α-Diphenyl-4-piperidine-methanol (46g) and 4-(4-chlorobutyryl)-α,α-dimethyl benzene acetic acid methyl ester (50g) were added to a mixture of sodium carbonate (25g), potassium iodide (0.25g) and demineralized water (100ml) and the reaction mass was heated to 65-70°C and stirred at same temperature for 24 hours. After the completion of the reaction (monitored by HPLC), reaction mixture was cooled to ambient temperature. Thereafter, water was removed from the reaction mixture by decantation followed by the addition of denatured spirit (62.5ml) and stirred for 1 hour at 65-70°C. Then reaction mixture was cooled to ambient temperature and further to 2-6°C. The reaction mixture was centrifuged. The resulting product was washed with mixture of denatured spirit (7 ml): water (3 ml) and dried to give 61.20g of the title compound having purity 91.73%.
Example 2: Preparation of 4-{4-[4-(hydroxydiphenyl methyl)-l-piperidinyl]-l-oxobutyl]-α,α-dimethyl benzene acetate
α,α-Diphenyl-4-piperidine-methanol (92g) and 4-(4-chlorobutyryl)-α,α-dimethyl benzene acetic acid methyl ester (100g) were added to a mixture of sodium carbonate (50g), potassium iodide (0.5g) and demineralized water (200ml) and the reaction mass was heated to 65-70°C and stirred at same temperature for 24 hours.. After the completion of the reaction (monitored by HPLC), water was distilled out under vacuum and denatured spirit (125ml) was added to the resulting residue. The reaction mixture was stirred for 1 hour at 65-70°C and then cooled' to ambient temperature. Thereafter, reaction mixture was cooled to 0-5°C for 3 hours. The reaction mixture was centrifuged. The product, thus obtained, was washed with denatured spirit (10ml) and dried for 4 hours. Demineralized water (500ml) was added to the resulting product, stirred for 2 hours at ambient temperature, centrifuged, washed with demineralized water (100ml) and dried to give 120 g of the title compound having purity 95.0% by HPLC.

WE CLAIM:
1. A process for the preparation of piperidine derivative of formula I,

(Formula Removed)
which comprises the steps of:
a), condensing 4-(4-chlorobutyryl)-α,α-dimethyl benzene acetic acid methyl ester of formula II,

(Formula Removed)
with α,α-diphenyl-4-piperidine-methanol of formula III,

(Formula Removed)
in the presence of base in water; b). isolating the compound of formula I there from; and
c). optionally, purifying the compound of formula I using a suitable solvent.
2. The process according to claim 1, wherein in step a) base is inorganic base which includes alkali or alkaline metal hydroxide, alkoxide, carbonates, bicarbonates, hydride and the like or combination thereof.
3. The process according to claim 2, wherein base is selected from sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like or combination thereof.
4. The process according to claim 2, wherein base is selected from sodium carbonate or potassium carbonate.
5. The process according to claim 1, wherein step c) solvent is selected from water, C1-6 alcohols such as methanol, ethanol, denatured spirit; water, C^ alcohols such as methanol, ethanol, denatured spirit; ketone such as acetone; nitriles such as acetonitrile; and the like or mixture thereof in suitable proportion.
6. The process according to claim 1, wherein step c) piperidine derivative is purified by crystallization with denatured spirit or mixture thereof with water.
7. The process according to claim 1, wherein step c) piperidine derivative is purified by slurry wash in water.
8. A process for the preparation of fexofenadine, which comprises the steps of:
a), condensing 4-(4-chlorobutyryl)-a,a-dimethyl benzene acetic acid methyl ester of formula II,
(Formula Removed)
with α,α-diphenyl-4-piperidine-methanol of formula III,

(Formula Removed)
in the presence of base in water;
b). isolating the compound of formula I therefrom;
c). optionally, purifying the compound of formula I using a suitable solvent; and
d). converting the compound of formula I to fexofenadine and pharmaceutically acceptable salts thereof.
9. The process according to claim 8, wherein in step a) base is inorganic base which includes alkali or alkaline metal hydroxide, alkoxide, carbonates, bicarbonates, hydride and the like or combination thereof.
10. The process according to claim 8, wherein step c) solvent is selected from water, C1-6 alcohols such as methanol, ethanol, denatured spirit; water, C1-6 alcohols such as methanol, ethanol, denatured spirit; ketone such as acetone; nitriles such as acetonitrile; and the like or mixture thereof in suitable proportion.