WO2009136412A2

WO2009136412A2 - PROCESS FOR PREPARATION OF 4-[4-(4-(HYDROXYDIPHENYLMETHYL)- 1-PIPERIDINYL]-1-OXOBUTYL]-α,α-DIMETHYLBENZENE ACETIC ACID METHYL ESTER AND USE THEREOF

Info

Publication number: WO2009136412A2
Application number: PCT/IN2009/000250
Authority: WO
Inventors: Siva Ram Prasad Vellanki; Dnyandev Ragho Rane; Narendra Dattatraya Mane; Venkateswar Katragadda; Ramesh Kumar Sabbam; Debashish Datta
Original assignee: Matrix Laboratories Limited
Priority date: 2008-04-25
Filing date: 2009-04-23
Publication date: 2009-11-12
Also published as: WO2009136412A3

Abstract

The present invention provides an improved process for preparing fexofenadine, its pharmaceutically acceptable salts and solvates thereof, the process comprising reacting methyl-4-(4-halo-1-oxobutyl]-α,α-dimethylphenyl acetate with α,α-diphenyl-4-piperidinemethanol in an alkyl nitrile solvent to prepare 4-[4-(4- (hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α,-dimethylbenzene acetic acid alkyl ester, which is further converted into fexofenadine.

Description

PROCESS FOR PREPARATION OF 4-[4-(4-(HYDROXYDIPHENYLMETHYL)-

1-PIPERIDINYL]-I-OXOBUTYL]- α,α-DIMETHYLBENZENE ACETIC ACID

METHYL ESTER AND USE THEREOF

Field of the Invention This invention, in general relates to an improved process for the preparation of 4-

[4-(4-(hydroxydiphenylmethyl)- 1 -piperidinyl]- 1 -oxobutyl]-α,α,-dimethylbenzene acetic acid alkyl ester. In particular, the present invention provides an improved process for preparing fexofenadine, its pharmaceutically acceptable salts and solvates thereof employing said ester. Background of the Invention

Fexofenadine chemically known as 4-[4-[4-(hydroxydiphenylmethyl)-l- piperidinyl]-l-hydroxybutyl]-α,α-dimethylbenzeneacetic acid is an Hl recptor antagonist and is used as an antihistaminic, antiallergic and bronchodilator drug. Fexofenadine is marketed as Allegra® in United States. The antihistaminic activity of fexofenadine and its pharmaceutically acceptable salts was first disclosed in US 4,254,129 (US' 129). US '129 discloses a process for the preparation of fexofenadine by alkylation of a substituted piperidine derivative such as diphenyl-4-piperdinemethanol with ώ-halo alkyl substituted phenyl ketone. This reaction takes about 72 hours to complete, thereby requiring a lot of reactor time. In addition, the reaction is carried out in presence of carbon disulfide which is hazardous and requires more safety precautions for handling during commercial production. The obtained keto ester intermediate is further reduced and hydrolyzed to give fexofenadine.

US 5,750,703 discloses a process for the preparation of fexofenadine by reacting azacylonol with a cyclopropyl ketone derivative of general formula

This process is severely limited by the need to provide a substantially pure cyclopropyl ketone regioisomer to react with azacyclonol. The cyclopropyl ketone derivative is prepared by acylation of an aromatic ester derivative with an acid chloride in the presence of a lewis acid catalyst. The resulting benzyl ester derivative comprises a mixture of regioisomers. The desired para regioisomer is isolated by fractional crystallization of the corresponding cinchonidine salt and involves a number of cumbersome steps, resulting in low yield of the final product. This process involves the use of expensive and toxic cinchonidine salt.

US 6,147,216 discloses an alternate process to obtain enriched para regioisomer, the process involving high vacuum fractional distillation of methyl or ethyl ester of the mixture of isomeric acids followed by repeated fractional crystallization at low temperature. This process is operationally tedious, inefficient and low yielding and therefore, not amenable for industrial scale production.

WO2003/039482A2 discloses novel crystalline forms of fexofenadine base and process for their preparation. The WO'482 patent designates the described polymorphic forms as Form I, Form II, Form III, Form IV, Form V, Form VI, Form VII.

US 2003/0021849 further disclose crystalline forms of fexofenadine hydrochloride, such as solvates with methyl butyl ether (MTBE Form IX), cyclohexane (cyclohexane Form IX), ethyl acetate (Form XIV and Form XV).

The processes disclosed above involve prolonged reaction time and use of toxic and hazardous ingredients that are difficult to handle during commercial production. In addition, the processes require a large number of tedious purification steps to obtain pure para regioisomer, thereby making the process uneconomical and not amenable for commercial scale production.

Therefore, there is a need to provide a highly efficient, high yielding and economical process for industrial production of fexofenadine, pharmaceutically acceptable salts and solvates thereof. Objects and Summary of the Invention

It is a principal object of the present invention to provide an improved process for the preparation of 4-[4-(4-(hydroxydiphenylmethyl)-l-piperidinyl]-l-oxobutyl]-α,α,- dimethylbenzene acetic acid alkyl ester.

It is another object of the present invention to provide a highly efficient, high yielding economical and industrially viable process for preparing fexofenadine, its pharmaceutically acceptable salts and solvates thereof, wherein the process involves minimum steps and less time.

It is another object of the present invention to provide a simple and commercially viable process for preparing fexofenadine, its pharmaceutically acceptable salts and solvates thereof wherein the process employs the solvents which are environmental friendly, safe and easy to handle.

It is yet another object of the present invention to provide a novel crystalline solvate of fexofenadine.

It is still another object of the present invention to provide a process for the preparation of the novel crystalline solvate of fexofenadine.

It is still another object of the present invention to provide a process for the preparation of fexofenadine from the novel crystalline solvate of fexofenadine.

The above and other objects of the present invention are further attained and supported by the following embodiments described herein. However, the scope of the invention is not restricted to the described embodiments herein after.

In accordance with a preferred embodiment of the present invention, there is provided a simple and commercially viable process for preparing 4-[4-(4- (hydroxydiphenylmethyl)-l-piperidinyl]-l-oxobutyl]-α,α,-dimethylbenzene acetic acid alkyl ester of Formula I wherein alkyl is Ci to C₄ alkyl, preferably methyl or ethyl, wherein the process comprises reacting methyl-4-(4-halo-l-butyl]-α,α-dimethylphenyl acetate with α,α-diphenyl-4-piperidinemethanol (azacyclonol) in presence of an alkyl nitrile solvent.

In accordance with another preferred embodiment of the present invention, there is provided an improved process for preparing fexofenadine and its pharmaceutically acceptable salts, the process comprisng reacting methyl -4-(4-halo-l -butyl] -α,α- dimethylphenyl acetate with α,α-diphenyl-4-piperidinemethanol (azacyclonol) in alkyl nitrile solvent to prepare 4-[4-(4-(hydroxydiphenylmethyl)-l-piperidinyl]-l-oxobutyl]- α,α,-dimethylbenzene acetic acid methyl ester, further hydrolysis and reduction of the resultant 4-[4-(4-(hydroxydiphenylmethyl)-l-piperidinyl]-l-oxobutyl]-α,α,- dimethylbenzene acetic acid methyl ester to obtain fexofenadine base. In accordance with yet another embodiment of the present invention, there is provided a novel solvate of fexofenadine, wherein said solvate form is prepared by dissolving fexofenadine in dimethyl formamide, cooling the resultant mixture and isolating the crystalline fexofenadine dimethyl formamide solvate. In accordance with still another embodiment of the present invention, there is provided a process for the preparation of fexofenadine, wherein the process comprises dissolving fexofenadine dimethylformamide solvate in a solvent and isolating the fexofenadine, wherein the solvent is water, alcohol or mixtures thereof.

Brief Description of the Drawings Further objects of the present invention together with additional features contributing thereto and advantages accruing there from will be apparent from the following description of preferred embodiments of the invention which are shown in the accompanying drawing figures, wherein:

Figure 1 depicts the X-ray powder diffraction pattern of fexofenadine dimethyl formamide solvate.

Figure 2 depicts the differential scanning calorimetric pattern of fexofenadine dimethylformamide solvate.

Figure 3 depicts the thermogravimetric analysis (TGA) of fexofenadine dimethylformamide solvate Detailed Description of the Invention

While this specification concludes with claims particularly pointing out and distinctly claiming that, which is regarded as the invention, it is anticipated that the invention can be more readily understood through reading the following detailed description of the invention and study of the included examples. The present invention discloses an improved process for the preparation of intermediate 4-[4-(4-(hydroxydiphenylmethyl)- 1 -piperidinyl]- 1 -oxobutyl]-α,α,- dimethylbenzene acetic acid alkyl ester of Formula I used for the preparation of 4-[4-[4- (hydroxydiphenylmethyl)-l -piperidinyl]- l-hydroxy]-α,α-dimethylbenzeneacetic acid (fexofenadine), the process comprising reacting alkyl-4-(4-halo-l-oxobutyI]-α,α- dimethylphenyl acetate of Formula II with α,α-diphenyl-4-piperidinemethanol (azacyclonol) in presence of an alkyl nitrile solvent to give 4-[4-(4- (hydroxydiphenylmethyl)- 1 -piperidinyl]- 1 -oxobutyl]-α,α,-dimethylbenzene acetic acid methyl ester, wherein halo is a halogen such as chloro, bromo or iodo and R is Ci - C₄ alkyl, preferably methyl or ethyl as shown in the following scheme:

Formula II Azacyclonol Formula I

The above reaction is carried out in the presence of a base and optionally in the presence of potassium iodide.

The alkyl nitrile solvent employed is selected from acetonitrile, propionitrile, butyronitrile, iso-butyronitrile, preferably acetonitrile. The alkyl nitrile solvent employed in the reaction results in completion of reaction in about 20 hours as compared to about

72 hours mentioned in conventional methods thereby reducing the reaction time and reactor occupancy time.

Moreover, the alkyl nitriles can be distilled off easily from the reaction mixture in comparison to the coventional methods that employ hazardous materials such as toluene making the process tedious, the process involving water washing followed by distillation. Furthermore, the yield of the alkylated product is increased by about 5%. High yield and reduced reaction time results in decrease in quantity of the impurities generated thereby making the process economical for commercial production. In an exemplary process of the present invention, a mixture of α,α-diphenyl-4- piperidinemethanol and methyl-4-(4-halo-l-oxobutyl]-α,α-dimethylphenyl acetate in presence of base and potassium iodide are stirred in acetonitrile at 78-80 ⁰C and refluxed for 10-15 hrs. After completion of the reaction, the mixture was cooled to 25-30 ⁰C. The mixture was filtered and concentrated to remove the acetonitrile at 40-45° C to obtain 4- [4-(4-(hydroxydiphenylmethyl)- 1 -piperidinyl]- 1 -oxobutyl]-α,α,-dimethylbenzene acetic acid methyl ester. The bases employed in the reaction are selected from inorganic bases such as sodium bicarbonate, potassium carbonate, or potassium bicarbonate, or organic bases, such as, a trialkylamine, for example, triethylamine or pyridine.

The substituted piperidine derivative and the ώ-halo alkyl substituted phenyl ketone used are prepared by employing conventional methods. The 4-[4-(4-(hydroxydiphenylmethyl)- 1 -piperidinyl]- 1 -oxobutyl]-α,α,- dimethylbenzene acetic acid methyl ester prepared by the process of the present invention is converted in a number of steps to fexofenadine base, its pharmaceutically acceptable salts and solvates thereof.

The present invention also provides a novel crystalline fexofenadine dimethyl formamide solvate and a process for the preparation of the same from fexofenadine base. The dimethyl formamide solvate is desolvated to give fexofenadine. The fexofenadine so obtained is converted to its hydrochloride salt by conventional method. Powder X-ray Diffraction (PXRD)

The solvate form of the present invention is characterized by their X-ray powder diffraction pattern. The X-ray diffraction patterns of said solvate of the invention was measured on PANalytical, X'Pert PRO powder diffractometer equipped with goniometer of θ/θ configuration and X'Celerator detector. The Cu-anode X-ray tube was operated at 4OkV and 3OmA. The experiments were conducted over the 2Θ range of 2.0°-50.0°, 0.030° step size and 50 seconds step time. Differential Scanning Calorimetry (DSC)

The DSC measurements were carried out on Mettler Toledo 822 Star^e and TA

QlOOO of TA instruments. The experiments were performed at a heating rate of 10.0

°C/min over a temperature range of 30°C-300°C purging with nitrogen at a flow rate of

150 ml/min and 50ml/min. Standard aluminum crucibles covered by lids with three pin holes were used.

Thermogravimetric Analysis (TGA)

TGA was recorded on out using the instrument Mettler Toledo TGA/SDTA 85 l^e and TA Q5000 of TA instruments. The experiments were performed at a heating rate of 10.0 °C/min over a temperature range of 30°C-300°C purging with nitrogen at a flow rate of 20 ml/min and 25 ml/min. The crystalline fexofendine dimethylformamide solvate is characterized by powder X-ray diffraction pattern as depicted in Figure 1 having peaks at 5.67, 8.73, 8.98,

11.41, 12.07, 12.98, 13.75, 14.27, 15.71, 16.22, 16.90, 17.40, 17.85, 18.55, 19.58, 20.25, 21.76, 22.46, 22.90, 23.77, 24.58, 25.73, 26.95, 28.30, 31.25, 33.72, 34.81, 35.48, 35, 48,

39.77, 44.42 (±) 0.2 2Θ.

The crystalline fexofenadine dimethylformamide solvate is further characterized by differential scanning calorimetry pattern with a sharp endothermic peak at 165.82 ⁰C as depicted in Figure 2. The crystalline fexofenadine dimethylformamide solvate contains about 12-14% w/w of dimethylformamide as analyzed by weight loss in TGA depicted in

Figure 3.

The present invention further provides a process for the preparation of crystalline dimethyl formamide solvate, the exemplary process comprising stirring 4-[4-[4- (hydroxydiphenylmethyl)-l -piperidinyl]-l -hydroxy]-α,α-dimethylbenzeneacetic acid (fexofenadine) in N,N-dimethylformamide at ambient temperature to obtain a dispersion and subsequently heating the dispersion up to 150 ⁰C and maintaining the temperature for 15-20 minutes to obtain a solution. The solution is filtered and filtrate cooled under stirring. The solid obtained is filtered, washed with dimethylformamide and dried under vacuum. The crystalline fexofenadine dimethylformamide solvate according to the present invention has a purity of more than about 99.5 % w/w as measured by high performance thin layer chromatorgraphy.

The crystalline fexofenadine dimethylformamide solvate is further converted to fexofenadine and its pharmaceutically acceptable salts by employing conventional methods.

Desolvation of fexofenadine dimethylformamide solvate is achieved in water, alcohol and mixtures thereof. The alcohols employed for desolvation include but not limited to methanol, ethanol, isopropanol, butanol.

In an exemplary process, desolvation of fexofenadine dimethylformamide solvate is achieved by dissolving the solvate in DM water or the above said alcohols or mixtures thereof and the resultant mixture was stirred for about 2 hrs. The obtained solid was filtered, washed with DM water and dried for 24 hrs at 65-70⁰C.

The following non-limiting examples illustrate specific embodiments of the present invention. They are, not intended to be limiting the scope of present invention in any way.

Example-1

Preparation of 4-f4-(4-(hvdroxydiphenylmethvD- 1 -piperidinyl]- 1 -oxobutyl]-α,α,- dimethylbenzene acetic acid methyl ester

A mixture of α,α-diphenyl-4-piperidinemethanol (7.5 g) and methyl-4-(4-chloro- l-oxobutyl]-α,α-dimethylphenyl acetate (10.0 g) in presence of 0.10 g potassium bicarbonate (1 1.0 g, 0.1 1 moles) and catalytic amount of potassium iodide (0.10 g) in 50 ml of acetonitrile was stirred at 78-80 ⁰C for 10-15 hours. Subsequently the mixture was cooled to 25-30 ⁰C and filtered. The acetonitrile was removed under vacuum at 40-45°C to obtain a residue. To the residue methanol (30 ml) was added and the mixture stirred at 5-1O⁰C followed by addition of sodium borohydride solution (0.4 g in methanol). The mixture was further stirred at 20-25°C for 3 h, cooled to 5-10 ⁰C and again stirred for 1 h. The suspension was filtered and washed with chilled methanol (10 ml). The solid obtained was dried under vacuum to obtain 4-[4-(4-(hydroxydiphenylmethyl)-l -piperidinyl]- 1- oxobutyl]-α,α,-dimethylbenzene acetic acid methyl ester. The 4-[4-(4- (hydroxydiphenylmethyl)-l -piperidinyl]- l-oxobutyl]-α,α,-dimethylbenzene acetic acid methyl ester is subsequently converted to fexofenadine by employing conventional methods.

Example 2 Preparation of Fexofenadine N. N-dimethylformamide solvate

Fexofenadine (lOOgms) was dissolved in N-N-dimethyl formamide (1900 ml) at room temperature. The resultant mixture was heated to 85-90 ⁰C and stirred for 15-20 minutes at the same temperature. The hot solution was filtered through micron filter and washed with 100 ml of N, N-dimethylformamide. The filtrate was cooled under stirring at 0-5⁰C for 60 minutes. Finally the obtained cake was washed with 200 ml of N₅N- dimethylformamide at 0-5 ⁰C and dried under vacuum.

Example 3

Desolvation of Fexofenadine dimethyl formamide solvate Fexofenadine N, N-dimethylformamide solvate was added to DM water (100 ml) and the resultant mixture was stirred for about 2 hrs. The solid was filtered and washed with DM water (20 ml). The obtained solid was dried under vacuum at 65-70⁰C for 24 hrs.

Example-4

Preparation of Fexofenadine hydrochloride

Fexofenadine dimethyl formamide solvate obtained from the ExampIe-2 (100 g) was slowly added to methanol (300 ml). The reaction mixture was cooled and Cone. Hydrochloric acid (20 g) was added. Reaction was stirred for 15-30 min. Solid was filtered, washed with water and dried to yield Fexofenadine hydrochloride.

Certain modifications and improvements of the disclosed invention will occur to those skilled in the art without departing from the scope of invention, which is limited only by the appended claims.

Claims

We Claim:

1. An improved process for preparing 4-[4-(4-(hydroxydiphenylmethy I)-I- piperidinyl]-l-oxobutyl]-α,α,-dimethylbenzene acetic acid alkyl ester of Formula I

Formula I comprising reacting alkyl-4-(4-halo-l-oxobutyl]-α,α-dimethylphenyl acetate of Formula II

Formula II with azacyclonol in the presence of alkyl nitrile solvent, wherein R is selected from Ci to C₄ alkyl, preferably methyl or ethyl.

2. The process according to claim 1, wherein the alkyl nitrile solvent is selected from a group comprising acetonitrile, propionitrile, butyronitrile, iso- butyronitrile or mixtures thereof.

3. The process according to claim 1, wherein the process further comprising converting 4-[4-(4-(hydroxydiphenylmethyl)- 1 -piperidinyl]- 1 -oxobutyl]-α,α,- dimethylbenzene acetic acid alkyl ester into fexofenadine and its pharmaceutically acceptable salts thereof.

4. The process according to claim 3, wherein the process further comprising converting the fexofenadine to fexofenadine dimethyl formamide solvate.

5. A crystalline fexofenadine dimethyl formamide solvate.

6. The solvate according to claim 5, wherein said dimethyl formamide solvate is characterized by an X-ray powder diffraction pattern having peaks at about 5.67, 8.73, 8.98, 1 1.41, 12.07, 12.98, 13.75, 14.27, 15.71, 16.22, 16.90, 17.40, 17.85, 19.58; 20.25, 21.76, 22.46, 23.77, 24.58 (±) 0.2 2Θ.

7. The solvate according to claim 5, wherein said dimethyl formamide solvate is having a substantially similar X-ray powder diffraction pattern as depicted in Figurel.

8. The solvate according to claim 5, wherein said dimethyl formamide solvate is characterized by a differential scanning calorimetry (DSC) as depicted in Figure 2.

9. The solvate according to claim 5, wherein the fexofenadine dimethyl formamide solvate is characterized by thermogravimetric analysis as depicted in Figure 3.

10. A process for preparing crystalline fexofenadine dimethylformamide solvate, the process comprising: (a) dissolving fexofenadine in dimethylformamide;

(b) cooling resultant mixture; and

(c) isolating the crystalline fexofenadine dimethylformamide solvate.

11. A process for the preparation of fexofenadine, the process comprising: a) dissolving fexofenadine dimethylformamide solvate in a solvent; and b) isolating the fexofenadine.

12. The process according to claim 11 wherein the solvent is selected from alcohol, water or mixtures thereof.

13. The process according to claim 12, wherein the alcohol is selected from methanol, ethanol, isopropanol, and butanol.

14. The process according to claim 10, wherein the process further comprising converting the fexofenadine dimethylformamide solvate to fexofenadine hydrochloride by using source of HCl.

15. The process according to claim 14, wherein fexofenadine dimethylformamide solvate is converted to fexofenadine hydrochloride in an alcoholic solvent.