WO2013021343A1 - Process for the optical resolution of () -3- (2 -benzyloxy- 5 - bromophenyl) - 3 - phenylpropionic - Google Patents

Process for the optical resolution of () -3- (2 -benzyloxy- 5 - bromophenyl) - 3 - phenylpropionic Download PDF

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Publication number
WO2013021343A1
WO2013021343A1 PCT/IB2012/054015 IB2012054015W WO2013021343A1 WO 2013021343 A1 WO2013021343 A1 WO 2013021343A1 IB 2012054015 W IB2012054015 W IB 2012054015W WO 2013021343 A1 WO2013021343 A1 WO 2013021343A1
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Prior art keywords
bromophenyl
benzyloxy
formula
phenylpropionic acid
hydroxyindane
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PCT/IB2012/054015
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French (fr)
Inventor
Shravan Kumar SINGH
Shyam Sunder Verma
Sourav HANDIQUE
Seema Ahuja
Kaptan Singh
Mohan Prasad
Sudershan Kumar Arora
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Ranbaxy Laboratories Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/42—Separation; Purification; Stabilisation; Use of additives
    • C07C51/487—Separation; Purification; Stabilisation; Use of additives by treatment giving rise to chemical modification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the present invention relates to a process for the preparation of fesoterodine and its salts.
  • Fesoterodine of Formula I is used to treat overactive bladder and is available as the fumarate salt. Fesoterodine rapidly de-esterifies to its active metabolite in the body, (R)-2- (3-diisopropylamino-l-phenylpropyl)-4-hydroxymethyl-phenol, which is a muscarinic receptor antagonist. Fesoterodine fumarate is chemically known as isobutyric acid 2-((R)- 3-diisopropylammonium- 1 -phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrogen fumarate.
  • U.S. Patent No. 7,384,980 provides a process for the preparation of fesoterodine and its salts which involves the resolution of ( ⁇ )-3-(2-benzyloxy-5-bromophenyl)-3- phenylpropionic acid of Formula II with ephedrine hemihydrate in absolute ethanol at 0°C to obtain ephedrinium salt of R-(-)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionic acid. This salt is recrystallized twice with boiling ethanol to obtain 97.6% e.e.
  • Ephedrine being a controlled substance, is difficult to obtain making the acquisition of ephedrine for use as a resolving agent a very complicated and time consuming process.
  • the present inventors have developed an advantageous process for the preparation of fesoterodine and its salts without the use of any narcotic resolving agent, such as, for example, ephedrine.
  • the present invention provides a simple, cost-effective and efficient process for the preparation of fesoterodine and its salts.
  • An aspect of the present invention provides a process for the resolution of ( ⁇ )-3-(2- benzyloxy-5-bromophenyl)-3-phenylpropionic acid of Formula II, comprising:
  • the compound, ( ⁇ )-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionic acid of Formula II is treated with (lR,2S)-(+)-cis-l-amino-2-hydroxyindane.
  • the reaction is carried out in the presence of an alcoholic solvent such as, for example, methanol, ethanol n-propanol, iso-propanol, butanol, pentanol, or a mixture thereof.
  • the reaction may be carried out at a temperature of about 5°C to about 100°C; preferably at about 15°C to about 70°C.
  • the reaction may be carried out for about 0.5 hour to about 100 hours;
  • the reaction may be facilitated by stirring the reaction mixture.
  • the salt of R-(-)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionic acid (lR,2S)-(+)-cis-l-amino-2-hydroxyindane so obtained may be isolated from the reaction mixture by treatment with an antisolvent, extraction, precipitation, filtration, solvent evaporation, or a combination of these techniques.
  • the purification of the salt of R-(-)-3-(2-benzyloxy-5-bromophenyl)-3- phenylpropionic acid (lR,2S)-(+)-cis- l-amino-2-hydroxyindane may be carried using an alcoholic solvent; preferably, methanol, ethanol, n-propanol, iso-propanol, butanol, pentanol, or a mixture thereof.
  • the purification may be carried out at a temperature of about 5°C to about 100°C; preferably at about 15°C to 70°C.
  • the purification may be carried out for about 0.5 hour to about 100 hours; preferably for about 0.5 hour to about 20 hours.
  • the purification may be facilitated by stirring the reaction mixture.
  • the purified salt of R-(-)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionic acid (1R, 2S)-(+)-cis-l-amino-2-hydroxyindane may be reacted with an organic acid or inorganic acid.
  • the organic acid may be acetic acid, tetra fluoro acetic acid or perchloric acid.
  • the inorganic acid may be hydrochloric acid or sulfuric acid.
  • the reaction may be carried out in presence of a chlorinated solvent, such as, for example, dichloromethane, chloroform, carbon tetrachloride, or a mixture thereof.
  • the R-(-)-3-(2-benzyloxy-5- bromophenyl)-3-phenylpropionic acid of Formula III is isolated from the reaction mixture by treatment with an antisolvent, extraction, precipitation, filtration, solvent evaporation, or a combination thereof.
  • the present method of synthesizing fesoterodine and its salts may further include exposing the compound of Formula III to thionyl chloride under suitable conditions to provide a compound of Formula IV.
  • Suitable conditions for obtaining the compound of Formula IV may include carrying out the reaction in N,N-dimethylformamide.
  • the reaction may be carried out at a temperature of about 30°C to about 120°C; preferably at about 45°C to about 60°C, for about 0.5 hour to about 24 hours; preferably for about 4 hours to about 7 hours.
  • the compound of Formula IV may be isolated from the reaction mixture by treatment with an antisolvent, extraction, precipitation, filtration, solvent evaporation, or a combination thereof.
  • the compound of Formula IV may further be treated with diisopropylamine under suitable conditions to provide a compound of Formula V.
  • Suitable conditions for obtaining the compound of Formula V include carrying out the reaction in a hydrocarbon solvent.
  • the hydrocarbon solvent may be selected from the group consisting of cycloheptane, cyclohexane, toluene and xylene.
  • the reaction may be carried out at a temperature of about 0°C to about 60°C; preferably at about 0°C to about 40°C, for about 1 hour to about 24 hours.
  • the compound of Formula V may be isolated from the reaction mixture by treatment with an antisolvent, extraction, precipitation, filtration, solvent evaporation, or a combination thereof.
  • the compound of Formula V may be reduced under suitable conditions to provide a compound of Formula VI.
  • Suitable conditions for obtaining the compound of Formula VI may include carrying out the reduction with metal hydride.
  • the metal hydride may be selected from the group consisting of sodium borohydride, lithium borohydride and diisobutylaluminum hydride.
  • the reduction may be carried out in ether solvent.
  • the ether solvent may include preferably diethyl ether, dimethyl ether, tetrahydrofuran, dioxane, or a mixture thereof.
  • the reaction may be carried out at a temperature of about 20°C to about 120°C; preferably at about 30°C to about 80°C, for about 1 hour to about 24 hours.
  • the compound of Formula VI may be isolated from the reaction mixture by treatment with an antisolvent, extraction, precipitation, filtration, solvent evaporation, or a combination thereof.
  • the compound of Formula VI may be exposed to ethyl halide and magnesium in the presence of solid carbon dioxide under suitable conditions to provide a compound of Formula VII.
  • the present process further includes contacting the compound of Formula VII with thionyl chloride under suitable conditions to provide a compound of Formula VIII.
  • Suitable conditions to obtain the compound of Formula VIII include carrying out the reaction in an alcoholic solvent.
  • the alcoholic solvent may be selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, butanol, iso-butanol and pentanol, or a mixture thereof.
  • the reaction may be carried out at a temperature of about 0°C to about 100°C; preferably at about 5°C to about 80°C, for about 1 hour to about 24 hours; preferably for about 3 hours to about 7 hours.
  • the compound of Formula VIII may be isolated from the reaction mixture by treatment with an antisolvent, extraction, precipitation, filtration, solvent evaporation, or a combination thereof.
  • the compound of Formula VIII may be reduced under suitable conditions to a provide compound of Formula IX.
  • Suitable conditions to obtain the compound of Formula IX include carrying out the reduction with metal hydride.
  • the metal hydride may be selected from the group consisting of sodium borohydride, lithium borohydride and diisobutylaluminum hydride.
  • the reduction may be carried out in an ether solvent.
  • An ether solvent may include preferably diethyl ether, dimethyl ether, tetrahydrofuran, dioxane, or mixture thereof.
  • the reaction may be carried out at a temperature of about 20°C to about 100°C; preferably at about 20°C to about 50°C, for about 1 hour to about 24 hours.
  • the compound of Formula IX may be isolated from the reaction mixture by treatment with an antisolvent, extraction, precipitation, filtration, solvent evaporation, or a combination thereof.
  • the present process for synthesizing fesoterodine and its salts includes exposing the compound of Formula IX to hydrogenation under suitable conditions to provide a compound of Formula X.
  • Suitable conditions for hydrogenation of the compound of Formula IX may include carrying out hydrogenation in an autoclave.
  • the hydrogenation may be carried out in an alcoholic solvent.
  • the alcoholic solvent may be selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, butanol, iso-butanol, pentanol, and a mixture thereof.
  • the reaction may be carried out at a temperature of about 20°C to about 80°C; preferably at about 25°C to about 40°C, for about 1 hour to about 24 hours; preferably for about 2 hours to about 7 hours.
  • the compound of Formula X may be isolated from the reaction mixture by treatment with an antisolvent, extraction, precipitation, filtration, solvent evaporation, or a combination thereof.
  • the present process for synthesizing fesoterodine and its salts may include exposing the compound of Formula X to isobutyryl chloride under suitable conditions to provide fesoterodine of Formula I and its salts. Suitable conditions include carrying out the reaction in a chlorinated solvent.
  • the chlorinated solvent may be selected from the group consisting of dichloromethane, chloroform and carbon tetrachloride.
  • the reaction may be carried out at a temperature of about 0°C to about 50°C; preferably at about 0°C to about 25°C, for about 1 hour to about 24 hours; preferably, for about 0.5 hour to about 3 hours.
  • the fesoterodine of Formula I may be isolated from the reaction mixture by treatment with an antisolvent, extraction, precipitation, filtration, solvent evaporation, or a combination thereof.
  • the fesoterodine of Formula I may be converted to its salts, such as, for example, the fumarate or hydrochloride salts.

Abstract

The present invention relates to a process for the resolution of (±)-3- (2-benzyloxy-5-bromophenyl)-3-phenylpropionic acid of Formula II, comprising the steps of: a) resolving (±)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionic acid of Formula II (II) X = Bromo (II) with (1R,2S)-(+)-cis-l-amino-2-hydroxyindane; and b) isolating R-(-)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionic acid of Formula III from the reaction mixture thereof.

Description

PROCESS FOR THE OPTICAL RESOLUTION OF
()-3- (2 -BENZYLOXY- 5 - BROMOPHENYL) - 3 - PHENYLPROPIONIC ACID
Field of the Invention
The present invention relates to a process for the preparation of fesoterodine and its salts.
Background of the Invention
Fesoterodine of Formula I is used to treat overactive bladder and is available as the fumarate salt. Fesoterodine rapidly de-esterifies to its active metabolite in the body, (R)-2- (3-diisopropylamino-l-phenylpropyl)-4-hydroxymethyl-phenol, which is a muscarinic receptor antagonist. Fesoterodine fumarate is chemically known as isobutyric acid 2-((R)- 3-diisopropylammonium- 1 -phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrogen fumarate.
Figure imgf000003_0001
Formula I
U.S. Patent No. 7,384,980 provides a process for the preparation of fesoterodine and its salts which involves the resolution of (±)-3-(2-benzyloxy-5-bromophenyl)-3- phenylpropionic acid of Formula II with ephedrine hemihydrate in absolute ethanol at 0°C to obtain ephedrinium salt of R-(-)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionic acid. This salt is recrystallized twice with boiling ethanol to obtain 97.6% e.e. of ephedrinium salt of R-(-)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionic acid. The salt so obtained is treated with concentrated (37%) aqueous hydrochloric acid in a mixture of ethanol and acetone. The solution is evaporated in a vacuum and the residue is re- dissolved in 1M aqueous hydrochloric acid and dichloromethane. The organic phase is separated, washed twice with water and evaporated to dryness to obtain R-(-)-3-(2- benzyloxy-5-bromophenyl)-3-phenylpropionic acid (99.9% e.e.) of Formula III. The mother liquor obtained from the resolution is further treated with excess of concentrated hydrochloric acid to obtain S-(+)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionic acid.
Figure imgf000004_0001
Formula II
X = Bromo
Figure imgf000004_0002
Formula III
Ephedrine, being a controlled substance, is difficult to obtain making the acquisition of ephedrine for use as a resolving agent a very complicated and time consuming process. Summary of the Invention
The present inventors have developed an advantageous process for the preparation of fesoterodine and its salts without the use of any narcotic resolving agent, such as, for example, ephedrine. Thus, the present invention provides a simple, cost-effective and efficient process for the preparation of fesoterodine and its salts.
Detailed Description of the Invention
An aspect of the present invention provides a process for the resolution of (±)-3-(2- benzyloxy-5-bromophenyl)-3-phenylpropionic acid of Formula II, comprising:
a) resolving (±)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionic acid of
Formula II
X = Bromo
Figure imgf000005_0001
Formula III with (lR,2S)-(+)-cis-l-amino-2-hydroxyindane; and
b) isolating R-(-)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionic acid of Formula III from the reaction mixture thereof.
Accordingly, (±)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionic acid of Formula II may be prepared according to the method provided in U.S. Patent No.
7,384,980. The compound, (±)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionic acid of Formula II, is treated with (lR,2S)-(+)-cis-l-amino-2-hydroxyindane. The reaction is carried out in the presence of an alcoholic solvent such as, for example, methanol, ethanol n-propanol, iso-propanol, butanol, pentanol, or a mixture thereof. The reaction may be carried out at a temperature of about 5°C to about 100°C; preferably at about 15°C to about 70°C. The reaction may be carried out for about 0.5 hour to about 100 hours;
preferably for about 0.5 hour to about 20 hours. The reaction may be facilitated by stirring the reaction mixture. The salt of R-(-)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionic acid (lR,2S)-(+)-cis-l-amino-2-hydroxyindane so obtained may be isolated from the reaction mixture by treatment with an antisolvent, extraction, precipitation, filtration, solvent evaporation, or a combination of these techniques.
The purification of the salt of R-(-)-3-(2-benzyloxy-5-bromophenyl)-3- phenylpropionic acid (lR,2S)-(+)-cis- l-amino-2-hydroxyindane may be carried using an alcoholic solvent; preferably, methanol, ethanol, n-propanol, iso-propanol, butanol, pentanol, or a mixture thereof. The purification may be carried out at a temperature of about 5°C to about 100°C; preferably at about 15°C to 70°C. The purification may be carried out for about 0.5 hour to about 100 hours; preferably for about 0.5 hour to about 20 hours. The purification may be facilitated by stirring the reaction mixture.
The purified salt of R-(-)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionic acid (1R, 2S)-(+)-cis-l-amino-2-hydroxyindane may be reacted with an organic acid or inorganic acid. The organic acid may be acetic acid, tetra fluoro acetic acid or perchloric acid. The inorganic acid may be hydrochloric acid or sulfuric acid. The reaction may be carried out in presence of a chlorinated solvent, such as, for example, dichloromethane, chloroform, carbon tetrachloride, or a mixture thereof. The R-(-)-3-(2-benzyloxy-5- bromophenyl)-3-phenylpropionic acid of Formula III is isolated from the reaction mixture by treatment with an antisolvent, extraction, precipitation, filtration, solvent evaporation, or a combination thereof.
The present method of synthesizing fesoterodine and its salts may further include exposing the compound of Formula III to thionyl chloride under suitable conditions to provide a compound of Formula IV.
Figure imgf000007_0001
Formula IV
X = Bromo
Suitable conditions for obtaining the compound of Formula IV may include carrying out the reaction in N,N-dimethylformamide. The reaction may be carried out at a temperature of about 30°C to about 120°C; preferably at about 45°C to about 60°C, for about 0.5 hour to about 24 hours; preferably for about 4 hours to about 7 hours. The compound of Formula IV may be isolated from the reaction mixture by treatment with an antisolvent, extraction, precipitation, filtration, solvent evaporation, or a combination thereof.
The compound of Formula IV may further be treated with diisopropylamine under suitable conditions to provide a compound of Formula V.
Figure imgf000008_0001
Formula V
X = Bromo
Suitable conditions for obtaining the compound of Formula V include carrying out the reaction in a hydrocarbon solvent. The hydrocarbon solvent may be selected from the group consisting of cycloheptane, cyclohexane, toluene and xylene. The reaction may be carried out at a temperature of about 0°C to about 60°C; preferably at about 0°C to about 40°C, for about 1 hour to about 24 hours. The compound of Formula V may be isolated from the reaction mixture by treatment with an antisolvent, extraction, precipitation, filtration, solvent evaporation, or a combination thereof.
The compound of Formula V may be reduced under suitable conditions to provide a compound of Formula VI.
Figure imgf000008_0002
Formula VI Suitable conditions for obtaining the compound of Formula VI may include carrying out the reduction with metal hydride. The metal hydride may be selected from the group consisting of sodium borohydride, lithium borohydride and diisobutylaluminum hydride. The reduction may be carried out in ether solvent. The ether solvent may include preferably diethyl ether, dimethyl ether, tetrahydrofuran, dioxane, or a mixture thereof. The reaction may be carried out at a temperature of about 20°C to about 120°C; preferably at about 30°C to about 80°C, for about 1 hour to about 24 hours. The compound of Formula VI may be isolated from the reaction mixture by treatment with an antisolvent, extraction, precipitation, filtration, solvent evaporation, or a combination thereof.
The compound of Formula VI may be exposed to ethyl halide and magnesium in the presence of solid carbon dioxide under suitable conditions to provide a compound of Formula VII.
Figure imgf000009_0001
Formula VII
The present process further includes contacting the compound of Formula VII with thionyl chloride under suitable conditions to provide a compound of Formula VIII.
Figure imgf000010_0001
Formula VIII
Suitable conditions to obtain the compound of Formula VIII include carrying out the reaction in an alcoholic solvent. The alcoholic solvent may be selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, butanol, iso-butanol and pentanol, or a mixture thereof. The reaction may be carried out at a temperature of about 0°C to about 100°C; preferably at about 5°C to about 80°C, for about 1 hour to about 24 hours; preferably for about 3 hours to about 7 hours. The compound of Formula VIII may be isolated from the reaction mixture by treatment with an antisolvent, extraction, precipitation, filtration, solvent evaporation, or a combination thereof.
The compound of Formula VIII may be reduced under suitable conditions to a provide compound of Formula IX.
Figure imgf000010_0002
Formula IX Suitable conditions to obtain the compound of Formula IX include carrying out the reduction with metal hydride. The metal hydride may be selected from the group consisting of sodium borohydride, lithium borohydride and diisobutylaluminum hydride. The reduction may be carried out in an ether solvent. An ether solvent may include preferably diethyl ether, dimethyl ether, tetrahydrofuran, dioxane, or mixture thereof. The reaction may be carried out at a temperature of about 20°C to about 100°C; preferably at about 20°C to about 50°C, for about 1 hour to about 24 hours. The compound of Formula IX may be isolated from the reaction mixture by treatment with an antisolvent, extraction, precipitation, filtration, solvent evaporation, or a combination thereof.
The present process for synthesizing fesoterodine and its salts includes exposing the compound of Formula IX to hydrogenation under suitable conditions to provide a compound of Formula X.
Figure imgf000011_0001
Formula X
Suitable conditions for hydrogenation of the compound of Formula IX may include carrying out hydrogenation in an autoclave. The hydrogenation may be carried out in an alcoholic solvent. The alcoholic solvent may be selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, butanol, iso-butanol, pentanol, and a mixture thereof. The reaction may be carried out at a temperature of about 20°C to about 80°C; preferably at about 25°C to about 40°C, for about 1 hour to about 24 hours; preferably for about 2 hours to about 7 hours. The compound of Formula X may be isolated from the reaction mixture by treatment with an antisolvent, extraction, precipitation, filtration, solvent evaporation, or a combination thereof.
The present process for synthesizing fesoterodine and its salts may include exposing the compound of Formula X to isobutyryl chloride under suitable conditions to provide fesoterodine of Formula I and its salts. Suitable conditions include carrying out the reaction in a chlorinated solvent. The chlorinated solvent may be selected from the group consisting of dichloromethane, chloroform and carbon tetrachloride. The reaction may be carried out at a temperature of about 0°C to about 50°C; preferably at about 0°C to about 25°C, for about 1 hour to about 24 hours; preferably, for about 0.5 hour to about 3 hours. The fesoterodine of Formula I may be isolated from the reaction mixture by treatment with an antisolvent, extraction, precipitation, filtration, solvent evaporation, or a combination thereof. The fesoterodine of Formula I may be converted to its salts, such as, for example, the fumarate or hydrochloride salts.
While the present invention has been described in terms of its specific
embodiments, 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 R-(-)3-(2-Benzyloxy-5-Bromophenyl)-3-Phenylpropionic Acid
A mixture of (±)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionic acid (20 g), (lR,2S)-(+)-cis-l-amino-2-hydroxyindane (7.3 g) and methanol (250 mL) were taken together at 25°C to 30°C. The reaction mixture was stirred for 20 minutes. The reaction mixture was refluxed at 60°C to 65°C to obtain a clear solution. The clear solution was stirred for 30 minutes, cooled to 20°C to 25°C and stirred for 14 hours. The solid obtained was filtered, washed with methanol (40 mL) and dried to obtain salt of R-(-)-3-(2- benzyloxy-5-bromophenyl)-3-phenylpropionic acid (lR,2S)-(+)-cis-l-amino-2- hydroxyindane.
Yield = 14.0 g
The salt of R-(-)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionic acid (1R,2S)- (+)-cis- l-amino-2-hydroxyindane (6.75 g) and methanol (80 mL) were taken together at 25°C to 30°C. The reaction mixture was refluxed at 60°C to 65°C to obtain a clear solution and stirred for an additional 0.5 hour at 60°C to 65°C. The mixture was cooled to 20°C to 25°C and stirred for 14 hours. The solid obtained was filtered, washed with methanol (20 mL) and dried to obtain salt of R-(-)-3-(2-benzyloxy-5-bromophenyl)-3- phenylpropionic acid (lR,2S)-(+)-cis-l-amino-2-hydroxyindane.
Yield = 2.6 g The salt of R-(-)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionic acid (1R,2S)- (+)-cis- l-amino-2-hydroxyindane (2.3 g), dichloromethane (50 mL) and IN hydrochloric acid (50 mL) were taken together at 20°C to 25°C. The reaction mixture was stirred for 0.5 hour and the organic layer was separated, washed with IN hydrochloric acid (50 mL) at 20°C to 25°C. The organic layer was concentrated under reduced pressure to obtain the title compound.
Yield = 1.5 g
Example 2: Preparation of R-(-)3-(2-Benzyloxy-5-Bromophenyl)-3-Phenylpropionic Acid
A mixture of (±)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionic acid (20 g), (lR,2S)-(+)-cis-l-amino-2-hydroxyindane (5.4 g) and methanol (200 mL) were taken together at 25°C to 30°C. The reaction mixture was stirred for 20 minutes. The reaction mixture was refluxed at 60°C to 65°C to obtain a clear solution. The clear solution was stirred for 30 minutes, cooled to 20°C to 25°C and stirred for 14 hours. The solid obtained was filtered, washed with methanol (40 mL) and dried to obtain salt of R-(-)-3-(2- benzyloxy-5-bromophenyl)-3-phenylpropionic acid (lR,2S)-(+)-cis-l-amino-2- hydroxyindane.
Yield = 1 1.4 g
The salt of R-(-)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionic acid (1R,2S)- (+)-cis- 1 -amino-2-hydroxyindane (5.5 g) and methanol (80 mL) were taken together at 25°C to 30°C. The reaction mixture was refluxed at 60°C to 65°C to obtain a clear solution and stirred for an additional 0.5 hour at 60°C to 65°C. The mixture was cooled to 20°C to 25°C and stirred for 14 hours. The solid obtained was filtered, washed with methanol (20 mL) and dried to obtain salt of R-(-)-3-(2-benzyloxy-5-bromophenyl)-3- phenylpropionic acid (lR,2S)-(+)-cis-l-amino-2-hydroxyindane.
Yield = 2.6 g
The salt of R-(-)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionic acid (1R,2S)- (+)-cis- l-amino-2-hydroxyindane (3.3 g), dichloromethane (50 mL) and IN hydrochloric acid (50 mL) were taken together at 20°C to 25°C. The reaction mixture was stirred for 0.5 hour and the organic layer was separated and washed with IN hydrochloric acid (50 mL) at 20°C to 25°C. The organic layer was concentrated under reduced pressure to obtain the title compound.
Yield = 2.1 g

Claims

We Claim:
1. A process for the resolution of (±)-3-(2-benzyloxy-5-bromophenyl)-3- phenylpropionic acid of Formula II, comprising the steps of:
a) resolving (±)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionic acid of Formula II
Figure imgf000015_0001
Formula II
Figure imgf000015_0002
Formula III
with (lR,2S)-(+)-cis-l-amino-2-hydroxyindane; and
b) isolating R-(-)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionic acid of Formula III from the reaction mixture thereof.
2. The process of claim 1, wherein step a) is carried out in the presence of an alcoholic solvent.
3. The process of claim 2, wherein the alcoholic solvent is methanol.
4. The process of claim 1, wherein step a) is carried out at a temperature of about 15°C to about 70°C.
5. The process of claim 1, wherein a salt of R-(-)-3-(2-benzyloxy-5-bromophenyl)-3- phenylpropionic acid (lR,2S)-(+)-cis-l-amino-2-hydroxyindane is isolated.
6. The process of claim 5, further involving the step of purifying the salt of R-(-)-3- (2-benzyloxy-5-bromophenyl)-3-phenylpropionic acid (lR,2S)-(+)-cis-l-amino-2- hydroxyindane in the presence of an alcoholic solvent.
7. The process of claim 5, wherein the salt of R-(-)-3-(2-benzyloxy-5-bromophenyl)- 3 -phenylpropionic acid (lR,2S)-(+)-cis-l-amino-2-hydroxyindane is treated with an inorganic acid or an organic acid.
8. The process of claim 1, wherein R-(-)-3-(2-benzyloxy-5-bromophenyl)-3- phenylpropionic acid of Formula III is isolated from the reaction mixture by treatment with an antisolvent, extraction, precipitation, filtration, solvent evaporation, or a combination thereof.
9. Use of R-(-)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionic acid of Formula III as prepared by claim 1 for the preparation of fesoterodine of Formula I and its salts.
PCT/IB2012/054015 2011-08-05 2012-08-06 Process for the optical resolution of () -3- (2 -benzyloxy- 5 - bromophenyl) - 3 - phenylpropionic WO2013021343A1 (en)

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EP0937710A1 (en) * 1998-02-16 1999-08-25 Ajinomoto Co., Inc. Method for producing an optically active phenylpropionic acid derivative
US7384980B2 (en) 1998-05-12 2008-06-10 Schwarz Pharma Ag Derivatives of 3,3-diphenylpropylamines

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WO1996036584A1 (en) * 1995-05-18 1996-11-21 Sepracor, Inc. Process for resolving chiral acids with 1-aminoindan-2-ols
EP0937710A1 (en) * 1998-02-16 1999-08-25 Ajinomoto Co., Inc. Method for producing an optically active phenylpropionic acid derivative
US7384980B2 (en) 1998-05-12 2008-06-10 Schwarz Pharma Ag Derivatives of 3,3-diphenylpropylamines

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