WO2013046135A1 - Procédé pour la préparation de fésotérodine ou de ses sels - Google Patents

Procédé pour la préparation de fésotérodine ou de ses sels 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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WO
WIPO (PCT)
Prior art keywords
benzyloxy
formula
mixture
hours
bromophenyl
Prior art date
Application number
PCT/IB2012/055130
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English (en)
Inventor
Shyam Sunder Verma
Sourav HANDIQUE
Seema Ahuja
Kaptan Singh
Mohan Prasad
Sudershan Kumar Arora
Original Assignee
Ranbaxy Laboratories Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
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Application filed by Ranbaxy Laboratories Limited filed Critical Ranbaxy Laboratories Limited
Publication of WO2013046135A1 publication Critical patent/WO2013046135A1/fr

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Classifications

    • 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un procédé pour la préparation de fésotérodine ou de ses sels.
PCT/IB2012/055130 2011-09-26 2012-09-26 Procédé pour la préparation de fésotérodine ou de ses sels WO2013046135A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2800DE2011 2011-09-26
IN2800/DEL/2011 2011-09-26

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Publication Number Publication Date
WO2013046135A1 true WO2013046135A1 (fr) 2013-04-04

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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 (fr) * 2007-09-21 2009-03-26 Actavis Group Ptc Ehf Procédé amélioré de préparation de fésotérodine
WO2009126844A2 (fr) * 2008-04-09 2009-10-15 Concert Pharmaceuticals Inc. Dérivés de 3-(2-hydroxy-5-méthylvinyl)-n,n-diisopropyl-3-phénylpropylamine, et leur procédé d'utilisation
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 (fr) * 2007-09-21 2009-03-26 Actavis Group Ptc Ehf Procédé amélioré de préparation de fésotérodine
WO2009126844A2 (fr) * 2008-04-09 2009-10-15 Concert Pharmaceuticals Inc. Dérivés de 3-(2-hydroxy-5-méthylvinyl)-n,n-diisopropyl-3-phénylpropylamine, et leur procédé d'utilisation
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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