WO2007049303A2 - An improved process for the preparation of highly pure fexofenadine - Google Patents

An improved process for the preparation of highly pure fexofenadine Download PDF

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Publication number
WO2007049303A2
WO2007049303A2 PCT/IN2006/000423 IN2006000423W WO2007049303A2 WO 2007049303 A2 WO2007049303 A2 WO 2007049303A2 IN 2006000423 W IN2006000423 W IN 2006000423W WO 2007049303 A2 WO2007049303 A2 WO 2007049303A2
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Prior art keywords
formula
fexofenadine
compound
preparation
borohydride
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PCT/IN2006/000423
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French (fr)
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WO2007049303A3 (en
Inventor
Lalit Wadhwa
Satyendra Pal Singh
Gajendra Singh
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Ind-Swift Laboratories Limited
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Publication of WO2007049303A3 publication Critical patent/WO2007049303A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms

Definitions

  • the invention in general, relates to the field of chemical synthesis of H 2 receptor antagonist and more particularly, the present invention provides an improved process for the preparation of 4-[l-hydroxy-4 ⁇ [4-(hydroxydiphenylmethyl)-l-piperidinyl]-butyl]- ⁇ , ⁇ -dimethylbenzeneacetic acid (fexofenadine) of Formula I, or its salts thereof
  • Fexofenadine of Formula I is a non-sedative antihistaminic compound and is chemically kno wn as 4- [ 1 -hydroxy-4- [4-(hydroxydiphenylmethyl)- 1 -piperidinyl] -butyl] - ⁇ , ⁇ - dimethylbenzeneacetic acid,
  • Formula I Il is reported to be a specific H 2 -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 ⁇ , ⁇ -dimethylphenyl acetate and 4- chlorobutyryl chloride under Friedel Crafts conditions, condensation of the resulting intermediate with ⁇ , ⁇ -diphenyl-4-piperidinemethanol to give keto ester intermediate, which on reduction followed by hydrolysis yielded fexofenadine.
  • hydrolysis and reduction are carried out parallel in single step.
  • hydrolysis is performed before reducing the ketone group of compound of formula II and purity of the product is not mentioned.
  • WO 2005/67511 Al discloses a two step process to prepare fexofenadine from compound of formula II, wherein in the first step compound of formula II is reduced to compound of formula III, and in the second step i.e. hydrolysis of compound of formula III is carried out using base and additionally reducing agent is also added during hydrolysis to reduce unreacted keto compound of formula II.
  • the present invention provides a novel one pot method for the preparation of Fexofenadine of formula I, of high purity and in good yield,
  • fexofenadine can be prepared in high yields and high purity from compound of formula II, by treating compound of formula II with reducing agent to reduce keto group to hydroxy compound at temperature 35-7O 0 C and followed by treatment with base to hydrolyze ester group.
  • the invention further advantageously accomplishes both the steps in single step thus reducing the number of process steps, increasing safety and cost-effectiveness.
  • a new process for producing Fexofenadine from compound of formula II by treating it with reducing agent in the presence of alcoholic solvent can be selected from sodium borohydride, potassium borohydride, tetralkyl ammonium borohydride, or zinc borohydride.
  • the reducing agent is sodium borohydride.
  • the solvent may include alcoholic solvent such as methanol, ethanol, denatured spirit, n- propanol, isopropanol, isobutanol, r ⁇ -butanol and f-butanol.
  • the alcoholic solvent may include methanol and ethanol. Mixtures of all of these solvents are also contemplated.
  • HPLC HPLC-High Capacity Liquid Cell Chroxide
  • the reaction mixture When the presence of keto compound of formula II is less than 0.1% in HPLC, the reaction mixture is concentrated by distilling about half of the solvent. The resulting reaction mixture is used as such, for the next step, without the isolation of reduced compound of formula III. The reaction mixture is treated with base at reflux temperature.
  • the base may include one or more of alkali metal hydroxide, amide, alkoxide, alkali metal, or mixtures thereof.
  • the base is alkali metal hydroxide.
  • the alkali metal hydroxide may be lithium hydroxide, sodium hydroxide, or potassium hydroxide.
  • the hydroxide is sodium hydroxide.
  • reaction mixture It is advantageous to reflux the reaction mixture for about 1-2 hours to obtain the reaction product in the high purity and high yield. After refluxing for 1 hour, reaction mixture is cooled and pH is maintained at 6.5-7.0, product is isolated in high yields by cooling and filtration. Crude fexofenadine is purified using ethanol to obtain fexofenadine having purity greater than 99.5% by high performance liquid chromatography.
  • Step-1 Preparation of fexofenadine
  • reaction mass sodium hydroxide solution (7g in 75 ml of water) was added at 60-65 0 C and the resulting reaction mixture was refluxed for 6 hours.
  • the reaction mixture was cooled to 50-55 0 C; pH was adjusted to 6.5-7.0 using dilute hydrochloric acid and stirred at 70-75 0 C for further one hour. Thereafter reaction mixture was cooled to room temperature maintaining pH at 6.5-7.0 and further cooled to 0-5 0 C.
  • the reaction mixture was filtered, washed with water and dried at 60- 65 0 C to obtain 44.3 g of title compound having purity 97.88 % by HPLC.
  • Step-2 Purification of fexofenadine
  • Fexofenadine (43.Og) obtained in Step-1 was slurred in ethanol (95%, 215ml) and was refluxed for 3 hours. Thereafter reaction mixture was cooled to 0-5 0 C, filtered, washed with ethanol and dried at 50-60 0 C to obtain 40.8 g of title compound having purity 99.78 % by HPLC, meta impurity 0.07% and keto impurity is not detected.
  • reaction mixture was cooled to 50-55°C, pH was adjusted to 6.5-7.0 using dilute hydrochloric acid and further stirred at 70-75°C for one hour. Thereafter reaction mass was cooled to room temperature maintaining pH at 6.5-7.0 and further cooled to 0-5°C. The reaction mixture was filtered, washed with water and dried at 60-65°C to obtain 46.7g of title compound which was slurred in ethanol (95%, 233ml) and was refiuxed for 3 hours. Thereafter reaction mixture was cooled to 0-5°C, filtered, washed with ethanol and dried to obtain 44.8 g of title compound having purity 99.79 % by HPLC, meta impurity 0.03% and keto impurity is not detected.

Abstract

The present invention provides an improved process for the preparation of highly pure 4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-butyl]-α,α-dimethylbenzene acetic acid (fexofenadine) of Formula (I), or its salts thereof.

Description

TITLE OF THE INVENTION
An improved process for the preparation of highly pure Fexofenadine
FIELD OF THE INVENTION
The 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 of 4-[l-hydroxy-4~[4-(hydroxydiphenylmethyl)-l-piperidinyl]-butyl]- α,α-dimethylbenzeneacetic acid (fexofenadine) of Formula I, or its salts thereof
Figure imgf000002_0001
Formula I
BACKGROUND OF THE INVENTION
Fexofenadine of Formula I, is a non-sedative antihistaminic compound and is chemically kno wn as 4- [ 1 -hydroxy-4- [4-(hydroxydiphenylmethyl)- 1 -piperidinyl] -butyl] -α,α- dimethylbenzeneacetic acid,
Figure imgf000002_0002
Formula I Il 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 α,α-dimethylphenyl acetate and 4- chlorobutyryl chloride under Friedel Crafts conditions, condensation of the resulting intermediate with α,α-diphenyl-4-piperidinemethanol to give keto ester intermediate, which on reduction followed by hydrolysis yielded fexofenadine.
In general the methods reported in prior art for the preparation of fexofenadine involves the reduction of ketone group of methyl 4-[4-[4-(hydroxydiphenylmethyl)-l- piperidinyl]-l-oxobutyl]- α,α-dimethylbenzene acetate of formula II,
Figure imgf000003_0001
Formula II to prepare hydroxyl compound of formula III, which is further hydro lyzed using base.
Figure imgf000003_0002
Formula III Generally reaction is carried out at ambient temperature and always results in incompletion of reaction. The unreacted starting keto compound leads to formation of impurities in the final product.
In few references, such as WO 95/31437, US 2004/0077683 etc., hydrolysis and reduction are carried out parallel in single step. In the exemplified methods, hydrolysis is performed before reducing the ketone group of compound of formula II and purity of the product is not mentioned.
Recently WO 2005/67511 Al discloses a two step process to prepare fexofenadine from compound of formula II, wherein in the first step compound of formula II is reduced to compound of formula III, and in the second step i.e. hydrolysis of compound of formula III is carried out using base and additionally reducing agent is also added during hydrolysis to reduce unreacted keto compound of formula II.
Most of the processes described above are not suitable for industrial point of view, because the desired para-isomer is not obtained in required purity and requires repeated purifications to remove unwanted meta isomer impurity and other impurities generated from unreacted ketone compound, leading to low yields. To achieve a high efficiency of the reaction for industrial synthesis of fexofenadine, it is necessary that conversion of ketone compound to hydroxyl compound should go to completion to minimize the formation of impurities and improve the yields.
Therefore there is an urgent need to develop a simple and cost effective process to prepare fexofenadine in high purity and high yield.
SUMMARY OF THE INVENTION
The present invention provides a novel one pot method for the preparation of Fexofenadine of formula I, of high purity and in good yield,
Figure imgf000005_0001
Formula I
by treating methyl 4-[4-[4-(hydroxydiphenylmethyl)-l~piperidinyl]-l-oxobutyl]- α,α- dimethylbenzene acetate of formula II,
Figure imgf000005_0002
Formula II
with reducing agent to reduce completely keto group of compound of formula II to prepare hydroxy compound of formula III,
Figure imgf000005_0003
Formula III at temperature 35-70°C and in situ followed by treatment with base to hydrolyze the ester group.
DETAILED DESCRIPTION OF THE INVENTION
Based on our related art disclosure in the background, the present inventors have conducted extensive experimentation with an intention to overcome the difficulties of producing Fexofenadine in high yields and high purity greater than 99.5%. We have found that fexofenadine can be prepared in high yields and high purity from compound of formula II, by treating compound of formula II with reducing agent to reduce keto group to hydroxy compound at temperature 35-7O0C and followed by treatment with base to hydrolyze ester group. The invention further advantageously accomplishes both the steps in single step thus reducing the number of process steps, increasing safety and cost-effectiveness.
In accordance with the present invention, there is provided a new process for producing Fexofenadine from compound of formula II by treating it with reducing agent in the presence of alcoholic solvent. The reducing agent used can be selected from sodium borohydride, potassium borohydride, tetralkyl ammonium borohydride, or zinc borohydride. In particular, the reducing agent is sodium borohydride.
The solvent may include alcoholic solvent such as methanol, ethanol, denatured spirit, n- propanol, isopropanol, isobutanol, rø-butanol and f-butanol. In particular, the alcoholic solvent may include methanol and ethanol. Mixtures of all of these solvents are also contemplated. The progress of the reaction is monitored by HPLC. It is advantageous to attain complete conversion of keto group to hydroxyl which is achieved by heating the reaction mixture for 1-2 hours at 60-65°C. Complete conversion of keto group to hydϊoxyl means keto compound of formula II should not be present in more than 0.1% ratio by HPLC. When the presence of keto compound of formula II is less than 0.1% in HPLC, the reaction mixture is concentrated by distilling about half of the solvent. The resulting reaction mixture is used as such, for the next step, without the isolation of reduced compound of formula III. The reaction mixture is treated with base at reflux temperature.
The base may include one or more of alkali metal hydroxide, amide, alkoxide, alkali metal, or mixtures thereof. In particular, the base is alkali metal hydroxide. The alkali metal hydroxide may be lithium hydroxide, sodium hydroxide, or potassium hydroxide. In particular, the hydroxide is sodium hydroxide. The reaction can be continued until the content of unreacted hydroxyl compound of formula III is less than 0.5% by HPLC analysis. This degree of conversion usually takes about 6 to 7 hours. After the reaction is completed, the reaction mixture is cooled to 50-55°C and subsequently the pH is adjusted to 6.5-7.0 with a suitable acid such as hydrochloric acid, acetic acid but preferably hydrochloric acid.
It is advantageous to reflux the reaction mixture for about 1-2 hours to obtain the reaction product in the high purity and high yield. After refluxing for 1 hour, reaction mixture is cooled and pH is maintained at 6.5-7.0, product is isolated in high yields by cooling and filtration. Crude fexofenadine is purified using ethanol to obtain fexofenadine having purity greater than 99.5% by high performance liquid chromatography.
The following examples are provided merely to be exemplary of the inventions and are not intended to limit the scope of the invention. Example-I
PREPARATION OF HIGHLY PURE FEXOFENADINE
Step-1: Preparation of fexofenadine
Methyl 4- [4- [4-(hydroxydiphenylmethyl)- 1 -piperidinyl] - 1 -oxobutyl] -α,α-dimethyl benzene acetate (50 g) was added to methanol (500 ml), at 25-35°C followed by the addition of solid sodium borohydride (2.5 g) in small portions. The reaction mixture was stirred at 35-400C for one and half hours and further at 60-65°C for one hour and monitored by HPLC. After completion of reaction (i.e. staring material was 0.04%), methanol (300 ml) was distilled off. To the reaction mass sodium hydroxide solution (7g in 75 ml of water) was added at 60-650C and the resulting reaction mixture was refluxed for 6 hours. The reaction mixture was cooled to 50-550C; pH was adjusted to 6.5-7.0 using dilute hydrochloric acid and stirred at 70-750C for further one hour. Thereafter reaction mixture was cooled to room temperature maintaining pH at 6.5-7.0 and further cooled to 0-50C. The reaction mixture was filtered, washed with water and dried at 60- 650C to obtain 44.3 g of title compound having purity 97.88 % by HPLC.
Step-2: Purification of fexofenadine
Fexofenadine (43.Og) obtained in Step-1 was slurred in ethanol (95%, 215ml) and was refluxed for 3 hours. Thereafter reaction mixture was cooled to 0-50C, filtered, washed with ethanol and dried at 50-600C to obtain 40.8 g of title compound having purity 99.78 % by HPLC, meta impurity 0.07% and keto impurity is not detected.
Example-II
PREPARATION OF HIGHLY PURE FEXOFENADINE
Methyl 4-[4-[4-(hydroxydiphenylmethyl)-l-piperidinyl]-l-oxobutyl]-α5α-dimethyl benzene acetate (50 g) was added to methanol (500 ml), at 25-35°C followed by the addition of solid sodium borohydride (2.5 g) in small portions. The reaction mixture was stirred at 35-40°C for 1 hour and further at 60-65°C for lhour. After completion of reaction, methanol (300 ml) was distilled off. To the reaction mass sodium hydroxide solution (7g in 75 ml of water) was added at 60-65°C and refiuxed for 6 hours. The reaction mixture was cooled to 50-55°C, pH was adjusted to 6.5-7.0 using dilute hydrochloric acid and further stirred at 70-75°C for one hour. Thereafter reaction mass was cooled to room temperature maintaining pH at 6.5-7.0 and further cooled to 0-5°C. The reaction mixture was filtered, washed with water and dried at 60-65°C to obtain 46.7g of title compound which was slurred in ethanol (95%, 233ml) and was refiuxed for 3 hours. Thereafter reaction mixture was cooled to 0-5°C, filtered, washed with ethanol and dried to obtain 44.8 g of title compound having purity 99.79 % by HPLC, meta impurity 0.03% and keto impurity is not detected.

Claims

WE CLAIM
1. An improved one pot process for the preparation of highly pure Fexofenadine of formula I or a salt thereof,
Figure imgf000010_0001
Formula I
the process comprising reducing completely methyl 4-[4-[4-(hydroxydiphenyl- methyl)-l-piperidinyl]-l-oxobutyl]- α,α-dimethylbenzene acetate of formula II,
Figure imgf000010_0002
Formula II with a reducing agent at temperature 35-700C to prepare a compound of formula III,
Figure imgf000010_0003
Formula III in situ followed by hydrolysis with base and isolating the highly pure Fexofenadine of formula I or a salt thereof.
2. The process according to claim 1, wherein reducing agent is sodium borohydride, potassium borohydride, tetralkyl ammonium borohydride, and zinc borohydride.
3. The process according to claim 2, wherein reducing agent is sodium borohydride.
4. The process according to claim 1, wherein the reduced product is not isolated
5. The process according to claim 1, wherein the base comprises one or more of alkali metal hydroxide, amide, alkoxide, alkali metal, or mixtures thereof.
6. The process of claim 5, wherein the alkali metal hydroxide is lithium hydroxide sodium hydroxide, and potassium hydroxide
PCT/IN2006/000423 2005-10-28 2006-10-26 An improved process for the preparation of highly pure fexofenadine WO2007049303A2 (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2105134A1 (en) * 2008-03-24 2009-09-30 Ranbaxy Laboratories Limited Stable amorphous fexofenadine hydrochloride
US7671071B2 (en) 2002-06-10 2010-03-02 Teva Pharmaceutical Industries Ltd. Polymorphic Form XVI of fexofenadine hydrochloride

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4254129A (en) * 1979-04-10 1981-03-03 Richardson-Merrell Inc. Piperidine derivatives
WO2004067511A1 (en) * 2003-01-31 2004-08-12 Ranbaxy Laboratories Limited Process for the preparation of fexofenadine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4254129A (en) * 1979-04-10 1981-03-03 Richardson-Merrell Inc. Piperidine derivatives
WO2004067511A1 (en) * 2003-01-31 2004-08-12 Ranbaxy Laboratories Limited Process for the preparation of fexofenadine

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7671071B2 (en) 2002-06-10 2010-03-02 Teva Pharmaceutical Industries Ltd. Polymorphic Form XVI of fexofenadine hydrochloride
EP2105134A1 (en) * 2008-03-24 2009-09-30 Ranbaxy Laboratories Limited Stable amorphous fexofenadine hydrochloride

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