WO2013046135A1 - Process for the preparation of fesoterodine or its salts - Google Patents

Process for the preparation of fesoterodine or its salts Download PDF

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Publication number
WO2013046135A1
WO2013046135A1 PCT/IB2012/055130 IB2012055130W WO2013046135A1 WO 2013046135 A1 WO2013046135 A1 WO 2013046135A1 IB 2012055130 W IB2012055130 W IB 2012055130W WO 2013046135 A1 WO2013046135 A1 WO 2013046135A1
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Prior art keywords
benzyloxy
formula
mixture
hours
bromophenyl
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PCT/IB2012/055130
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French (fr)
Inventor
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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Publication of WO2013046135A1 publication Critical patent/WO2013046135A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C07C217/62—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
    • 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 or its salts.
  • Fesoterodine of Formula I is used to treat overactive bladder and is available as its 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. Chemically, fesoterodine fumarate is 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 or its salts by reducing the R-(-)-N,N-diisopropyl-3-(2-benzyloxy-5-bromophenyl)-3- phenylpropionamide of Formula II with lithium aluminum hydride in tetrahydrofuran. The reduction takes place by refluxing the reaction mixture for 4 hours and quenching with water.
  • the aqueous phase is washed several times with diethyl ether, adjusted to pH 10- 12 and extracted with diethyl ether to get R-(-)-[3-(2-benzyloxy-5-bromophenyl)-3- phenylpropyl]diisopropylamine of Formula III.
  • the present inventors have developed an advantageous process for the preparation of fesoterodine or its salts by reducing the R-(-)-N,N-diisopropyl-3-(2-benzyloxy-5- bromophenyl)-3-phenylpropionamide of Formula II with lithium aluminum hydride in tetrahydrofuran in the presence of iodine.
  • the present process of reduction in the presence of iodine minimizes the prolonged refluxing time of reaction and avoids the repeated washing of the aqueous phase with diethyl ether.
  • the present invention provides a simple, cost effective and efficient process for the preparation of fesoterodine or its salts.
  • An aspect of the present invention provides a process for the preparation of R-(-)- [3-(2-benzyloxy-5-bromophenyl)-3-phenylpropyl]diisopropylamine of Formula III, wherein the process comprises reducing R-(-)-N,N-diisopropyl-3-(2-benzyloxy-5- bromophenyl)-3-phenylpropionamide of Formula II in the presence of iodine.
  • the R-(-)-N,N-diisopropyl-3-(2-benzyloxy-5-bromophenyl)-3- phenylpropionamide of Formula II may be prepared according to the method provided in U.S. Patent No. 7,384,980.
  • the R-(-)-N,N-diisopropyl-3-(2-benzyloxy-5-bromophenyl)- 3-phenylpropionamide of Formula II may be reduced with a hydride reducing agent in the presence of iodine.
  • the hydride reducing agent may be selected from a group consisting of sodium borohydride, lithium aluminum hydride and diisobutylaluminum hydride.
  • the reaction may be carried out in the presence of an ether solvent, for example, diethyl ether, dimethyl ether, tetrahydrofuran, dioxane, or mixture thereof.
  • the reaction may be carried out at a temperature of about 0°C to about 100°C, for example, at about 0°C to about 80°C.
  • the reaction may be carried out for about 0.5 hours to about 100 hours, for example, for about 0.5 hours to about 4 hours.
  • the reaction may be facilitated by stirring the reaction mixture.
  • the R-(-)-[3-(2-benzyloxy-5-bromophenyl)-3- phenylpropyl]diisopropylamine so obtained may be isolated from the reaction mixture by treatment with antisolvent, precipitation, filtration, solvent evaporation, or a combination thereof.
  • the R-(-)-[3-(2-benzyloxy-5-bromophenyl)-3-phenylpropyl]diisopropylamine so obtained has less than 10% of (3R)-3-[2-(benzyloxy)phenyl]-3-phenyl-N,N-di(propan-2- yl)propan- 1 -amine of Formula IIIA, preferably less than 5% of (3R)-3-[2-
  • the compound of Formula III may be further used for the preparation of fesoterodine or its salts.
  • the compound of Formula III may be isolated or carried forward in situ on to the next step to prepare the compound of Formula IV.
  • the compound Formula III may be exposed to ethyl halide and magnesium in the presence of solid carbon dioxide under suitable conditions to provide a compound of Formula IV.
  • the reaction may be carried out in an ether solvent.
  • the ether solvent may include, for example, diethyl ether, dimethyl ether, tetrahydrofuran, dioxane, or mixtures thereof.
  • the reaction may be carried out at a temperature of about -70°C to about 100°C, for example, -70°C to about 80°C, for about 1 hour to about 24 hours.
  • the compound of Formula IV may be taken as such to the next step or may be isolated from the reaction mixture by treatment with an antisolvent, extraction, precipitation, filtration, solvent evaporation, or combinations thereof.
  • the compound of Formula IV may be isolated or carried forward in situ on to the next step to prepare the compound of Formula V.
  • the compound of Formula IV may be treated with an acid chloride, for example, thionyl chloride, under suitable conditions to provide the compound of Formula V.
  • the suitable conditions to obtain the compound of Formula V may include carrying out the reaction in an alcoholic solvent.
  • An alcoholic solvent may be selected from a group consisting of methanol, ethanol, n-propanol, isopropanol, butanol, iso- butanol and pentanol, or mixtures thereof.
  • the reaction may be carried out at a temperature of about 0°C to about 100°C, for example, 5°C to about 80°C for about 1 hour to about 24 hours, for example, for about 3 hours to about 7 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 isolated or carried forward in situ on to the next step to prepare the compound of Formula VI.
  • the compound of Formula V may be reduced under suitable conditions to provide the compound of Formula VI.
  • the suitable conditions for the formation of compound of Formula VI may include carrying out the reduction reaction with a metal hydride.
  • the metal hydride may be selected from a group consisting of sodium borohydride, lithium borohydride, lithium aluminum hydride and diisobutylaluminum hydride.
  • the reduction may be carried out in an ether solvent.
  • An ether solvent may include, for example, 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 100°C, for example, 0°C to about 50°C, preferably at 0°C to 10°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 isolated or carried forward in situ on to the next step to prepare the compound of Formula VII.
  • the compound of Formula VI may be hydrogenated under suitable conditions to provide a compound of Formula VII.
  • the suitable conditions for hydrogenation of the compound of Formula VI 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 a group consisting of methanol, ethanol, n-propanol, isopropanol, butanol, iso-butanol and pentanol, or mixtures thereof.
  • the reaction may be carried out at a temperature of about 20°C to about 80°C, for example, 25°C to about 40°C, for about 1 hour to about 24 hours, for example, for about 2 hours to about 7 hours.
  • the compound of Formula VII 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 VII may be isolated or carried forward in situ on to the next step to prepare fesoterodine or its salts.
  • the compound of Formula VII may be treated with isobutyryl chloride under suitable conditions to provide fesoterodine of Formula I or its salts.
  • the suitable conditions may include carrying out the reaction in a chlorinated solvent.
  • the chlorinated solvent may be selected from a group consisting of dichloromethane, chloroform and carbon tetrachloride, or a mixture thereof.
  • the reaction may be carried out at temperature of about -5°C to about 50°C, for example, -2°C to about 25°C for about 1 hour to about 24 hours, for example, for about 0.5 hours to about 3 hours.
  • the reaction may be facilitated by the addition of seed of fesoterodine or its salt.
  • the seed of fesoterodine or its salt may be prepared, for example, by the method disclosed in the present application without the aid of seed.
  • the fesoterodine of Formula I or its salts 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, for example, fumarate or hydrochloride salts.
  • 6-Bromo-4-phenyl-3,4-dihydro-2H-chromen-2-one 50 g
  • potassium carbonate 27.6 g
  • benzyl chloride 23.8 g
  • methanol 250 mL
  • the reaction mixture was cooled to 25°C to 30°C and filtered under a vacuum.
  • the solid was washed with methanol (50 mL).
  • the filtrate was concentrated under reduced pressure and methanol was recovered completely.
  • Toluene (200 mL) was added to the residue.
  • the mixture was washed with water (2 x 125 mL).
  • the toluene was recovered to obtain the title compound.
  • (+)-ephedrine hemihydrate (1 15 g), toluene (400 mL), and distilled water (575 mL) were taken together at 20°C to 25°C and concentrated hydrochloric acid (23 mL) was added to the mixture.
  • the reaction mixture was stirred for 1 hour and the organic layer was separated and washed with 1M hydrochloric acid (1 15 mL) at 20°C to 25°C.
  • the organic layer was concentrated under reduced pressure to obtain the title compound.
  • Diisopropyl amine (32.5 g) in toluene (300 mL) was taken to obtain a clear solution and the solution was cooled to 0°C.
  • Toluene (210 mL) was added to the residue obtained from Example 4 and the mixture was added to the clear solution at 0°C over a period of 1 hour.
  • the mixture was stirred for 6 to 8 hours at 25°C to 35°C.
  • the organic layer was washed with water (500 mL), 1M aqueous hydrochloric acid (45 mL), and 5% aqueous sodium bicarbonate solution sequentially.
  • the toluene was recovered completely under vacuum to obtain the title compound.
  • reaction mixture was cooled and quenched with a saturated aqueous solution of sodium sulphate (80 g). The precipitate so obtained was removed and the solvent was evaporated to obtain an oily residue.
  • Toluene 400 ml was added to the residue. The mixture was washed with water (400 mL). The toluene was evaporated under vacuum to obtain the title compound.
  • Powdered solid carbon dioxide (100 g) was added to the mixture in portions at a temperature below -50°C. The mixture was stirred for 1 hour and then quenched with 20% aqueous ammonium chloride (700 mL). The quenched mixture was stirred for 0.5 hours at 20°C to 25°C. The organic layer was separated. The pH of the aqueous layer was adjusted to 1.0 with dilute hydrochloric acid (6N HC1). The aqueous layer was extracted with dichloromethane (500 mL). The dichloromethane was concentrated to obtain the title compound.
  • Example 7 The residue obtained in Example 7 and methanol (1200 mL) were taken together and the mixture was cooled to 0°C. Thionyl chloride (55.5 g) was added to the mixture. The temperature was gradually raised to 60°C to 65°C. The mixture was refluxed for 5 to 6 hours. The methanol was recovered completely and dichloromethane (750 mL) was added to the residue. The mixture was washed sequentially with a saturated aqueous sodium bicarbonate solution (3 x 300 mL) and water (1 x 300 mL). The washed organic layer was concentrated to obtain a residue. The residue was crystallized with isopropanol (600 mL) to obtain the title compound.
  • Thionyl chloride 55.5 g
  • the mixture was refluxed for 5 to 6 hours.
  • dichloromethane 750 mL was added to the residue.
  • the mixture was washed sequentially with a saturated aqueous sodium bicarbonate solution (3 x 300 mL)
  • the mixture was allowed to cool gradually to 20°C to 25°C and was stirred at 20°C to 25°C for 5 hours.
  • the solid obtained was filtered, washed with an ethyl acetate (10 mL) and hexanes (50 mL) mixture under vacuum and dried in an air oven at 35°C to 40°C for 4 hours.
  • the seed of fesoterodine fumarate was added to the mixture and the mixture was stirred for 3 hours to 4 hours at 20°C to 25°C.
  • the mixture was then cooled to 0°C to 5°C and stirred for 2 hours.
  • the solid so obtained was filtered under a nitrogen atmosphere and washed with a mixture of cyclohexane and 2-butanone (1 :3.8).
  • the solid was dried in a vacuum oven at 30°C to 32°C for 6 hours. The solid was then recrystallized repeating the same procedure as above to obtain the title compound.
  • the residue was dissolved in dilute sulfuric acid (32.4 g in 570 mL distilled water, -5.3%).
  • the aqueous solution was washed several times with diethyl ether and the pH of the aqueous layer was adjusted to 1 1 with aqueous sodium hydroxide (28 gm in 54 mL distilled water, 50% solution).
  • the aqueous layer was extracted with diethyl ether (300 mL). The diethyl ether was concentrated under a vacuum to obtain the title compound.

Abstract

The present invention relates to a process for the preparation of fesoterodine or its salts.

Description

PROCESS FOR THE PREPARATION OF FESOTERODINE OR ITS SALTS
Field of the Invention
The present invention relates to a process for the preparation of fesoterodine or its salts.
Background of the Invention
Fesoterodine of Formula I is used to treat overactive bladder and is available as its 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. Chemically, fesoterodine fumarate is isobutyric acid 2-((R)-3- diisopropylammonium- 1 -phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrogen fumarate.
Figure imgf000002_0001
Formula I
U.S. Patent No. 7,384,980 provides a process for the preparation of fesoterodine or its salts by reducing the R-(-)-N,N-diisopropyl-3-(2-benzyloxy-5-bromophenyl)-3- phenylpropionamide of Formula II with lithium aluminum hydride in tetrahydrofuran. The reduction takes place by refluxing the reaction mixture for 4 hours and quenching with water. The aqueous phase is washed several times with diethyl ether, adjusted to pH 10- 12 and extracted with diethyl ether to get R-(-)-[3-(2-benzyloxy-5-bromophenyl)-3- phenylpropyl]diisopropylamine of Formula III.
Figure imgf000003_0001
Figure imgf000003_0002
Summary of the Invention
The present inventors have developed an advantageous process for the preparation of fesoterodine or its salts by reducing the R-(-)-N,N-diisopropyl-3-(2-benzyloxy-5- bromophenyl)-3-phenylpropionamide of Formula II with lithium aluminum hydride in tetrahydrofuran in the presence of iodine. It is observed by the present inventors that when R-(-)-N,N-diisopropyl-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionamide of Formula II is reduced with lithium aluminum hydride in tetrahydrofuran without using iodine, the undesired (3R)-3-[2-(benzyloxy)phenyl]-3-phenyl-N,N-di(propan-2-yl)propan- 1 -amine of Formula IIIA is obtained in substantially high amounts along with the desired product R-(-)-[3-(2-benzyloxy-5-bromophenyl)-3-phenylpropyl]diisopropylamine of Formula III. Further, the present process of reduction in the presence of iodine minimizes the prolonged refluxing time of reaction and avoids the repeated washing of the aqueous phase with diethyl ether. Thus, the present invention provides a simple, cost effective and efficient process for the preparation of fesoterodine or its salts.
Figure imgf000004_0001
Formula IIIA
Detailed Description of the Invention
An aspect of the present invention provides a process for the preparation of R-(-)- [3-(2-benzyloxy-5-bromophenyl)-3-phenylpropyl]diisopropylamine of Formula III, wherein the process comprises reducing R-(-)-N,N-diisopropyl-3-(2-benzyloxy-5- bromophenyl)-3-phenylpropionamide of Formula II in the presence of iodine.
The R-(-)-N,N-diisopropyl-3-(2-benzyloxy-5-bromophenyl)-3- phenylpropionamide of Formula II may be prepared according to the method provided in U.S. Patent No. 7,384,980. The R-(-)-N,N-diisopropyl-3-(2-benzyloxy-5-bromophenyl)- 3-phenylpropionamide of Formula II may be reduced with a hydride reducing agent in the presence of iodine. The hydride reducing agent may be selected from a group consisting of sodium borohydride, lithium aluminum hydride and diisobutylaluminum hydride. The reaction may be carried out in the presence of an ether solvent, for example, diethyl ether, dimethyl ether, tetrahydrofuran, dioxane, or mixture thereof. The reaction may be carried out at a temperature of about 0°C to about 100°C, for example, at about 0°C to about 80°C. The reaction may be carried out for about 0.5 hours to about 100 hours, for example, for about 0.5 hours to about 4 hours. The reaction may be facilitated by stirring the reaction mixture. The R-(-)-[3-(2-benzyloxy-5-bromophenyl)-3- phenylpropyl]diisopropylamine so obtained may be isolated from the reaction mixture by treatment with antisolvent, precipitation, filtration, solvent evaporation, or a combination thereof. The R-(-)-[3-(2-benzyloxy-5-bromophenyl)-3-phenylpropyl]diisopropylamine so obtained has less than 10% of (3R)-3-[2-(benzyloxy)phenyl]-3-phenyl-N,N-di(propan-2- yl)propan- 1 -amine of Formula IIIA, preferably less than 5% of (3R)-3-[2-
(benzyloxy)phenyl]-3-phenyl-N,N-di(propan-2-yl)propan-l-amine of Formula IIIA.
The compound of Formula III may be further used for the preparation of fesoterodine or its salts. The compound of Formula III may be isolated or carried forward in situ on to the next step to prepare the compound of Formula IV. The compound Formula III may be exposed to ethyl halide and magnesium in the presence of solid carbon dioxide under suitable conditions to provide a compound of Formula IV.
Figure imgf000005_0001
Formula IV
The reaction may be carried out in an ether solvent. The ether solvent may include, for example, diethyl ether, dimethyl ether, tetrahydrofuran, dioxane, or mixtures thereof. The reaction may be carried out at a temperature of about -70°C to about 100°C, for example, -70°C to about 80°C, for about 1 hour to about 24 hours. The compound of Formula IV may be taken as such to the next step or may be isolated from the reaction mixture by treatment with an antisolvent, extraction, precipitation, filtration, solvent evaporation, or combinations thereof.
The compound of Formula IV may be isolated or carried forward in situ on to the next step to prepare the compound of Formula V. The compound of Formula IV may be treated with an acid chloride, for example, thionyl chloride, under suitable conditions to provide the compound of Formula V.
Figure imgf000006_0001
Formula V
The suitable conditions to obtain the compound of Formula V may include carrying out the reaction in an alcoholic solvent. An alcoholic solvent may be selected from a group consisting of methanol, ethanol, n-propanol, isopropanol, butanol, iso- butanol and pentanol, or mixtures thereof. The reaction may be carried out at a temperature of about 0°C to about 100°C, for example, 5°C to about 80°C for about 1 hour to about 24 hours, for example, for about 3 hours to about 7 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 isolated or carried forward in situ on to the next step to prepare the compound of Formula VI. The compound of Formula V may be reduced under suitable conditions to provide the compound of Formula VI.
Figure imgf000007_0001
Formula VI
The suitable conditions for the formation of compound of Formula VI may include carrying out the reduction reaction with a metal hydride. The metal hydride may be selected from a group consisting of sodium borohydride, lithium borohydride, lithium aluminum hydride and diisobutylaluminum hydride. The reduction may be carried out in an ether solvent. An ether solvent may include, for example, 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 100°C, for example, 0°C to about 50°C, preferably at 0°C to 10°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 isolated or carried forward in situ on to the next step to prepare the compound of Formula VII. The compound of Formula VI may be hydrogenated under suitable conditions to provide a compound of Formula VII.
Figure imgf000007_0002
Formula VII The suitable conditions for hydrogenation of the compound of Formula VI 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 a group consisting of methanol, ethanol, n-propanol, isopropanol, butanol, iso-butanol and pentanol, or mixtures thereof. The reaction may be carried out at a temperature of about 20°C to about 80°C, for example, 25°C to about 40°C, for about 1 hour to about 24 hours, for example, for about 2 hours to about 7 hours. The compound of Formula VII 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 VII may be isolated or carried forward in situ on to the next step to prepare fesoterodine or its salts. The compound of Formula VII may be treated with isobutyryl chloride under suitable conditions to provide fesoterodine of Formula I or its salts. The suitable conditions may include carrying out the reaction in a chlorinated solvent. The chlorinated solvent may be selected from a group consisting of dichloromethane, chloroform and carbon tetrachloride, or a mixture thereof. The reaction may be carried out at temperature of about -5°C to about 50°C, for example, -2°C to about 25°C for about 1 hour to about 24 hours, for example, for about 0.5 hours to about 3 hours. The reaction may be facilitated by the addition of seed of fesoterodine or its salt. The seed of fesoterodine or its salt may be prepared, for example, by the method disclosed in the present application without the aid of seed. The fesoterodine of Formula I or its salts 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, for example, 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 Methyl 3-r2-(Benzyloxy)-5-Bromophenyl1-3-Phenylpropanoate
6-Bromo-4-phenyl-3,4-dihydro-2H-chromen-2-one (50 g), potassium carbonate (27.6 g), benzyl chloride (23.8 g), and methanol (250 mL) were taken together and the mixture was refluxed for 3 to 4 hours at 60°C to 65°C. The reaction mixture was cooled to 25°C to 30°C and filtered under a vacuum. The solid was washed with methanol (50 mL). The filtrate was concentrated under reduced pressure and methanol was recovered completely. Toluene (200 mL) was added to the residue. The mixture was washed with water (2 x 125 mL). The toluene was recovered to obtain the title compound.
Yield: 68 g
Example 2: Preparation of 3-r2-(Benzyloxy)-5-Bromophenyl1-3-Phenylpropanoic Acid
Methyl 3-[2-(benzyloxy)-5-bromophenyl]-3-phenylpropanoate (65 g) and denatured spirit (338 mL) were taken together. The mixture was stirred at 45°C to 50°C to obtain a clear solution. A 50% aqueous sodium hydroxide solution (10.4 g NaOH in 10.4 mL distilled water) was added to it and the mixture was stirred for 2 to 3 hours at 45°C to 50°C. The mixture was cooled to 20°C to 25°C and acidified with concentrated hydrochloric acid (21.5 mL) to obtain pH of 1-2. The mixture was stirred for 0.5 hours to 1 hour and the solid was filtered under vacuum, washed with water (3 x 216 mL), and dried in an air oven at 35°C to 40°C for 12 to 15 hours to obtain the title compound.
Yield: 58 g
HPLC: 98.8%
Example 3: Preparation of R-(-)-3-(2-Benzyloxy-5-Bromo Phenyl)-3-Phenylpropionic Acid
(±)-3-(2-Benzyloxy-5-bromophenyl)-3-phenylpropionic acid (250 g), (1S,2R)- ephedrine hemihydrate (71.1 g), and ethanol (837 mL) were taken together at 25°C to 30°C. The reaction mixture was stirred for 20 minutes. The reaction mixture was refluxed at 70°C to 75°C to obtain a clear solution. The clear solution was stirred for 1 hour, cooled to 20°C to 25°C and stirred for 1.5 hours. The solution was further cooled to 0°C to 5°C and stirred for 3 hours. The solid obtained was filtered, washed with ethanol (250 mL) and dried to obtain a salt of R-(-)3-(2-benzyloxy-5-bromophenyl)-3- phenylpropionic acid (l S,2R)-(+)-ephedrine hemihydrate.
Yield: 220 g
The salt of R-(-)3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionic acid (1 S,2R)- (+)-ephedrine hemihydrate (220 g) and ethanol (500 mL) were taken together at 25°C to 30°C. The reaction mixture was refluxed at 75°C to 78°C to obtain a clear solution and stirred for an additional hour at 60°C to 65°C. The mixture was cooled to 20°C to 25°C and stirred for 14 hours. The solution was further cooled to 0°C to 5°C and stirred for 3 hours. The solid obtained was filtered, washed with ethanol (250 mL), and dried to obtain a salt of R-(-)3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionic acid (l S,2R)-(+)- ephedrine hemihydrate.
Yield: 120 g
The salt of R-(-)3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionic acid (1 S,2R)-
(+)-ephedrine hemihydrate (1 15 g), toluene (400 mL), and distilled water (575 mL) were taken together at 20°C to 25°C and concentrated hydrochloric acid (23 mL) was added to the mixture. The reaction mixture was stirred for 1 hour and the organic layer was separated and washed with 1M hydrochloric acid (1 15 mL) at 20°C to 25°C. The organic layer was concentrated under reduced pressure to obtain the title compound.
Yield: 85 g
Example 4: Preparation of (3r)-3 2-(Benzyloxy)-5-Bromophenyl1-3-Phenyrpropanoyl Chloride
R-(-)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionic acid (45 g) and toluene
(270 mL) were taken together and a clear solution was obtained. Dimethyl formamide (1 mL) and thionyl chloride (19.7 g) were added to the solution and the mixture was heated to 50°C to 55°C for 5 to 6 hours. The toluene was recovered completely under vacuum to obtain the title compound. Example 5: Preparation of R-(- -N,N-Diisopropyl-3-(2-Benzyloxy-5-Bromophenyl -3- Phenylpropionamide
Diisopropyl amine (32.5 g) in toluene (300 mL) was taken to obtain a clear solution and the solution was cooled to 0°C. Toluene (210 mL) was added to the residue obtained from Example 4 and the mixture was added to the clear solution at 0°C over a period of 1 hour. The mixture was stirred for 6 to 8 hours at 25°C to 35°C. The organic layer was washed with water (500 mL), 1M aqueous hydrochloric acid (45 mL), and 5% aqueous sodium bicarbonate solution sequentially. The toluene was recovered completely under vacuum to obtain the title compound.
Yield: 54 g
Example 6: Preparation of R-(-)-r3-(2-Benzyloxy-5-Bromophenyl)-3-PhenylpropyH Diisopropylamine
R-(-)-N,N-diisopropyl-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionamide (80 g) and tetrahydrofuran (400 mL) were taken together and the mixture was cooled to 0°C to 5°C. Iodine (21 g in 80 mL tetrahydrofuran) was added to the mixture at 0°C to 5°C. Lithium aluminum hydride (10 g) was added to the mixture in small portions over a period of 15 minutes. The reaction mixture was refluxed for 2 hours at 60°C to 65°C. The reaction mixture was cooled and quenched with a saturated aqueous solution of sodium sulphate (80 g). The precipitate so obtained was removed and the solvent was evaporated to obtain an oily residue. Toluene (400 ml) was added to the residue. The mixture was washed with water (400 mL). The toluene was evaporated under vacuum to obtain the title compound.
Yield: 57 g
HPLC purity: 79.77%
(3R)-3-[2-(benzyloxy)phenyl]-3-phenyl-N,N-di(propan-2-yl)propan- 1 -amine (Formula Ilia): 4.3% Example 7: Preparation of 4-(Benzyloxy -3-r(lr -3-(Dipropan-2-Ylamino - l- PhenylpropyllBenzoic Acid
Magnesium turnings (26 g), tetrahydrofuran (200 mL), iodine crystals (catalytic amount) and ethyl bromide (0.5 mL) were taken together under a nitrogen atmosphere. R- (-)-[3-(2-Benzyloxy-5-bromophenyl)-3-phenylpropyl]diisopropylamine (100 g) and ethyl bromide (54 mL) in tetrahydrofuran (400 mL) were added to the mixture over a period of 1 hour at 60°C to 65°C. The mixture was refluxed for 1 hour at 60°C to 65°C. The mixture was then cooled to -70°C. Powdered solid carbon dioxide (100 g) was added to the mixture in portions at a temperature below -50°C. The mixture was stirred for 1 hour and then quenched with 20% aqueous ammonium chloride (700 mL). The quenched mixture was stirred for 0.5 hours at 20°C to 25°C. The organic layer was separated. The pH of the aqueous layer was adjusted to 1.0 with dilute hydrochloric acid (6N HC1). The aqueous layer was extracted with dichloromethane (500 mL). The dichloromethane was concentrated to obtain the title compound.
Example 8: Preparation of Methyl 4-(Benzyloxy)-3-r(lr)-3-(Dipropan-2-Ylamino)-l- PhenylpropyllBenzoate (Formula V)
The residue obtained in Example 7 and methanol (1200 mL) were taken together and the mixture was cooled to 0°C. Thionyl chloride (55.5 g) was added to the mixture. The temperature was gradually raised to 60°C to 65°C. The mixture was refluxed for 5 to 6 hours. The methanol was recovered completely and dichloromethane (750 mL) was added to the residue. The mixture was washed sequentially with a saturated aqueous sodium bicarbonate solution (3 x 300 mL) and water (1 x 300 mL). The washed organic layer was concentrated to obtain a residue. The residue was crystallized with isopropanol (600 mL) to obtain the title compound.
Yield: 64 g
HPLC purity: 98.62% Example 9: Preparation of {4-(Benzyloxy)-3 (l )-3-(Dipropan-2-Ylamino)-l- PhenylpropyllPhenyl} Methanol (Formula VI)
Methyl 4-(benzyloxy)-3-[(lR)-3-(dipropan-2-ylamino)-l-phenylpropyl]benzoate (100 g) in tetrahydrofuran (250 mL) was added to a suspension of lithium aluminum hydride (12.4 g) in tetrahydrofuran (250 mL) over the period of 0.25 hours at 30°C. The mixture was stirred at 30°C for 5 to 6 hours. The reaction mixture was quenched with water (100 ml) at 25°C to 30°C and filtered. The filtrate was concentrated and tetrahydrofuran was recovered (completely) to obtain a residue. Toluene (500 mL) was added to the residue and the toluene layer was washed with water (2 x 150 mL). The toluene was completely recovered to obtain the title compound.
Yield: 100 g
HPLC purity: 99.08%
Example 10: Preparation of 2-r(lr)-3-(Dipropan-2-Ylamino)-l-Phenylpropyl"|-4- (Hydroxymethyl)Phenol (Formula VII)
{4-(Benzyloxy)-3-[(lR)-3-(dipropan-2-ylamino)-l-phenylpropyl]phenyl}methanol (50 g) and isopropyl alcohol were taken together in an autoclave at 40 to 50 psi. The 10% palladium-carbon (10 g) was added to the mixture and the mixture was subjected to hydrogenation for 2 to 3 hours at 25°C to 30°C. The mixture was filtered under nitrogen and the filtrate was concentrated under reduced pressure to obtain a residue. Ethyl acetate (35 mL) and hexanes (175 mL) were added to the residue and stirred at 40°C to obtain the clear solution. The mixture was allowed to cool gradually to 20°C to 25°C and was stirred at 20°C to 25°C for 5 hours. The solid obtained was filtered, washed with an ethyl acetate (10 mL) and hexanes (50 mL) mixture under vacuum and dried in an air oven at 35°C to 40°C for 4 hours.
Yield: 26 g
HPLC: 100% Example 1 1 : Preparation of 2-r(lr)-3-(Dipropan-2-Ylamino)-l-Phenylpropyl"|-4- (HydroxymethyDPhenyl 2-Methylpropanoate (Formula I)
2-[(lR)-3-(Dipropan-2-ylamino)- l-phenylpropyl]-4-(hydroxymethyl)phenol (25 g), sodium bicarbonate (6 g in 125 mL water), and dichloromethane (250 mL) were taken together. The mixture was cooled to -2°C to 3°C and isobutyryl chloride (9.1 g) in dichloromethane (125 mL) was added to the mixture over a period of 1.5 hours at -2°C to 3°C. The mixture was stirred for 1.5 hours. The mixture was warmed to 20°C to 25°C and the organic layer was separated. The organic layer was washed sequentially with water (125 mL), 5% aqueous sodium bicarbonate solution (125 mL), and finally with water again (125 mL). The organic layer was concentrated under a vacuum to obtain the title compound.
Yield: 32 g
Example 12: Preparation of Fumarate Salt of 2-r(lr)-3-(Dipropan-2-Ylamino)-l- Phenylpropyll -4-(Hydroxymethyl)Phenyl 2-Methylpropanoate
2-[(lR)-3-(dipropan-2-ylamino)-l-phenylpropyl]-4-(hydroxymethyl)phenyl 2- methylpropanoate (25 g) and 2-butanone (100 mL) were taken together and the mixture was stirred to obtain a clear solution at 30°C to 35°C. Fumaric acid (7.6 g) and 2- butanone (50 mL) were added to the solution at 30°C to 35°C. The mixture was stirred at 40°C for 1.5 hours and the 2-butanone was recovered partially (about 50 mL).
Cyclohexane (37.5 mL) was added to the mixture slowly and the mixture was stirred for 3 hours to 4 hours at 20°C to 25°C. The mixture was then cooled to 0°C to 5°C for 12 hours to 15 hours. The solid so obtained was filtered under a nitrogen atmosphere and washed with a mixture of cyclohexane and 2-butanone (1.5:4). The solid was dried under a vacuum oven at 30°C to 32°C for 6 hours. The solid was then recrystallized repeating the same procedure as above to obtain the title compound.
Yield: 10.2 g
HPLC purity: 99.38% Example 13: Preparation of Fumarate Salt of 2 (l )-3-(Dipropan-2-Ylamino)-l- Phenylpropyll -4-(Hvdroxymethyl)Phenyl 2-Methylpropanoate
2-[(lR)-3-(dipropan-2-ylamino)-l-phenylpropyl]-4-(hydroxymethyl)phenyl 2- methylpropanoate (19 g) and 2-butanone (76 mL) were taken together and the mixture was stirred to obtain a clear solution at 20°C to 25°C. Fumaric acid (5.1 g) was added to the mixture and the mixture was warmed to 35°C to 36°C. The reaction mixture was stirred for 15 minutes. Cyclohexane (19 mL) was added to the mixture slowly until turbidity appeared. The mixture was stirred at 35°C to 36°C for 1.5 hours and gradually cooled to 20°C to 25°C. The seed of fesoterodine fumarate was added to the mixture and the mixture was stirred for 3 hours to 4 hours at 20°C to 25°C. The mixture was then cooled to 0°C to 5°C and stirred for 2 hours. The solid so obtained was filtered under a nitrogen atmosphere and washed with a mixture of cyclohexane and 2-butanone (1 :3.8). The solid was dried in a vacuum oven at 30°C to 32°C for 6 hours. The solid was then recrystallized repeating the same procedure as above to obtain the title compound.
Yield: 1 1.5 g
HPLC purity: 99.88 %
Comparative Example: Preparation of R-(-)-r3-(2-Benzyloxy-5-Bromophenyl)-3- PhenylpropyUDiisopropylamine
R-(-)-N,N-diisopropyl-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionamide (95 g) and tetrahydrofuran (400 mL) were taken together. A suspension of lithium aluminum hydride (1 1.5 g in 100 mL of tetrahydrofuran) was added to the mixture. The reaction mixture was refluxed for 4.5 hours at 60°C to 65°C. The reaction mixture was cooled and quenched with a saturated aqueous solution of sodium sulphate (55 gm in 175 mL distilled water, 24%). The precipitate so obtained was removed and the solvent was evaporated to obtain an oily residue. The residue was dissolved in dilute sulfuric acid (32.4 g in 570 mL distilled water, -5.3%). The aqueous solution was washed several times with diethyl ether and the pH of the aqueous layer was adjusted to 1 1 with aqueous sodium hydroxide (28 gm in 54 mL distilled water, 50% solution). The aqueous layer was extracted with diethyl ether (300 mL). The diethyl ether was concentrated under a vacuum to obtain the title compound.
Yield: 69 g
HPLC purity: 54.46%
(3R)-3-[2-(benzyloxy)phenyl]-3-phenyl-N,N-di(propan-2-yl)propan-l -amine: 41.58%

Claims

We claim:
1. A process for the preparation of R-(-)-[3-(2-benzyloxy-5-bromophenyl)-3- phenylpropyl]diisopropylamine of Formula III, wherein the process comprises reducing R- (-)-N,N-diisopropyl-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionamide of Formula II in the presence of iodine.
Figure imgf000017_0001
2. The process of claim 1 , wherein the reducing agent is selected from a group consisting of sodium borohydride, lithium aluminum hydride and diisobutylaluminum hydride.
3. The process of claim 1, wherein the reduction is carried out in the presence of an ether solvent.
4. The process of claim 3, wherein the ether solvent is selected from diethyl ether, dimethyl ether, tetrahydrofuran, dioxane, or mixtures thereof.
5. The process of claim 1, wherein reduction is carried out at a temperature of about 0°C to about 100°C.
6. R-(-)-[3-(2-Benzyloxy-5-bromophenyl)-3-phenylpropyl]diisopropylamine of Formula III having less than 10% of (3R)-3-[2-(benzyloxy)phenyl]-3-phenyl-N,N- di(propan-2-yl)propan- 1 -amine of Formula IIIA.
Figure imgf000018_0001
Formula IIIA
7. R-(-)-[3-(2-Benzyloxy-5-bromophenyl)-3-phenylpropyl]diisopropylamine of Formula III having less than 5% of (3R)-3-[2-(benzyloxy)phenyl]-3-phenyl-N,N- di(propan-2-yl)propan- 1 -amine of Formula IIIA.
8. 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 or its salts.
PCT/IB2012/055130 2011-09-26 2012-09-26 Process for the preparation of fesoterodine or its salts WO2013046135A1 (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7384980B2 (en) 1998-05-12 2008-06-10 Schwarz Pharma Ag Derivatives of 3,3-diphenylpropylamines
WO2009037569A2 (en) * 2007-09-21 2009-03-26 Actavis Group Ptc Ehf An improved process for the preparation of fesoterodine
WO2009126844A2 (en) * 2008-04-09 2009-10-15 Concert Pharmaceuticals Inc. Derivatives of 3-(2-hydroxy-5-methyphenyl)-n,n-diisopropyl-3-phenylpropylamine and methods of use thereof
US20110124903A1 (en) * 2009-11-20 2011-05-26 Actavis Group Ptc Ehf Solid state forms of fesoterodine intermediates

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7384980B2 (en) 1998-05-12 2008-06-10 Schwarz Pharma Ag Derivatives of 3,3-diphenylpropylamines
WO2009037569A2 (en) * 2007-09-21 2009-03-26 Actavis Group Ptc Ehf An improved process for the preparation of fesoterodine
WO2009126844A2 (en) * 2008-04-09 2009-10-15 Concert Pharmaceuticals Inc. Derivatives of 3-(2-hydroxy-5-methyphenyl)-n,n-diisopropyl-3-phenylpropylamine and methods of use thereof
US20110124903A1 (en) * 2009-11-20 2011-05-26 Actavis Group Ptc Ehf Solid state forms of fesoterodine intermediates

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BHANU PRASAD A S ET AL: "Convenient Methods for the Reduction of Amides, Nitriles, Carboxylic Esters, Acids and Hydroboration of Alkenes Using NaBH4/I2 System", TETRAHEDRON, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 48, no. 22, 1 January 1992 (1992-01-01), pages 4623 - 4628, XP008122042, ISSN: 0040-4020 *

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