WO2010092500A2 - Procédé de préparation du tartrate de toltérodine - Google Patents

Procédé de préparation du tartrate de toltérodine Download PDF

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Publication number
WO2010092500A2
WO2010092500A2 PCT/IB2010/050384 IB2010050384W WO2010092500A2 WO 2010092500 A2 WO2010092500 A2 WO 2010092500A2 IB 2010050384 W IB2010050384 W IB 2010050384W WO 2010092500 A2 WO2010092500 A2 WO 2010092500A2
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Prior art keywords
methylphenyl
formula
methoxy
acid
group
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PCT/IB2010/050384
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WO2010092500A3 (fr
Inventor
Ravi Ponnaiah
Sanjay Desai
Chankrakant Chunilal Shah
Kalpesh Shantibhai Patel
Viral Maheshbhai Parekh
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Alembic Ltd
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Alembic Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C07C59/255—Tartaric acid
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C07C41/26—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/16—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation
    • C07C51/31—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation of cyclic compounds with ring-splitting
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids
    • C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
    • 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
    • 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
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to a process for the preparation of (+)-(R)-Tolterodine-L-tartrate of formula (I)
  • Tolterodine is a muscarinic receptor antagonist.
  • the chemical name of Tolterodine tartrate is (+)- (R)-N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) - 3-phenylpropanamine-L-hydrogen tartrate and molecular formula is C 26 H 37 N0 7 and molecular weight is 475.28 .
  • (+)-(R)-Tolterodine tartrate is represented by formula (I):
  • Tolterodine tartrate is marketed by Pharmacia & Upjohn under brand name Detrol ® and is indicated for the treatment of Urinary incontinence.
  • the ester thus obtained is reduced with lithium aluminum hydride in ether to the corresponding propanol, which is reacted with tosyl chloride and pyridine to yield the tosylate, which on condensation with diisopropylamine in hot acetonitrile is converted into the tertiary amine.
  • the tertiary amine is treated with boron tribromide in dichloromethane to give the amine as a racemic mixture, which is resolved with L-(+) tartaric acid.
  • U.S. Patent No. 5,922,914 provides an alternate method for the preparation of tolterodine as shown in scheme-2.
  • the process involves the cyclization of trans- cinnamic acid with p-cresol in hot sulfuric acid to give 3,4-dihydro-6-methyl-4- phenyl-2H- benzopyran-2-one, which is reduced with diisobutyl aluminum hydride (DIBAL) in toluene to yield 6-methyl-4-phenyl-3,4- dihydro- 2H-l-benzopyran-2-ol.
  • DIBAL diisobutyl aluminum hydride
  • U.S. Patent No. 6,822,119 provides another alternate method for the preparation of tolterodine as shown in Scheme-3.
  • the process involves reacting 3,4-dihydro- 6-methyl-4- phenyl- 2H- benzopyran-2-one with dimethyl sulphate in the presence of sodium hydroxide, and a phase transfer catalyst to obtain methyl-3- (2-methoxy-5-methylphenyl) -3-phenyl propionate. Reducing the ester thus obtained with a reducing agent in the presence of a Lewis acid to obtain 3-(2-methoxy-5-methylphenyl) -3-phenyl propanol.
  • the present invention relates to provide a process for the preparation of
  • (+)-(R)-Tolterodine-L-tartrate comprises a step of aminating hydroxyl protected 3-(2-methoxy-5-methylphenyl)-3-phenyl propanol of formula (V) with diiso- propylamine in the presence of water to obtain N, N-di- isopropyl-3-(2-methoxy-5-methylphenyl)-3-phenylpropyl amine of formula (VI).
  • the present invention relates to provide an improved process for the preparation of
  • (+)-(R)-Tolterodine-L-tartrate comprises steps of
  • Another object of the invention is to provide process for the preparation of process for the preparation of (+)-(R)-Tolterodine-L -tartrate of formula (I) having high purity.
  • Yet another object of the present invention is to provide a process for the preparation of (+)-(R)-Tolterodine-L-tartrate , comprises a step of aminating hydroxyl protected 3-(2-methoxy-5-methylphenyl) -3-phenyl propanol of formula (V) with diiso- propylamine in the presence of water to obtain N, N-diisopropyl-3- (2-methoxy-5-methylphenyl) -3-phenylpropyl amine of formula (VI).
  • Further object of the present invention is to provide a process for the preparation of
  • (+)-(R)-Tolterodine-L-tartrate comprises steps of
  • Yet further object of the present invention is to provide a process for the preparation of (+)-(R)-Tolterodine-L-tartrate, comprises a step of converting 3-(2-methoxy-5-methylphenyl)-3-phenyl propanol of formula (IV) into hydroxyl protected 3-(2-methoxy-5-methylphenyl)-3-phenyl propanol of formula (V), optionally isolating hydroxyl protected 3-(2-methoxy-5-methylphenyl)-3-phenyl propanol of formula (V) followed by crystallization in alcohol.
  • the present invention relates to provide a process for the preparation of
  • (+)-(R)-Tolterodine-L-tartrate comprises a step of aminating hydroxyl protected 3-(2-methoxy-5-methylphenyl)-3-phenyl propanol of formula (V) with diisopropylamine in the presence of water to obtain N, N-di- isopropyl-3-(2-methoxy-5-methylphenyl)-3-phenylpropyl amine of formula (VI).
  • (+)-(R)-Tolterodine-L-tartrate comprises steps of
  • the process for the preparation of (+)-(R)-Tolterodine-L-tartrate comprises a step of converting 3-(2-methoxy-5-methylphenyl)-3-phenyl propanol of formula (IV) into hydroxyl protected 3-(2-methoxy-5-methylphenyl)-3-phenyl propanol of formula (V), optionally isolating hydroxyl protected 3-(2-methoxy-5-methylphenyl)-3-phenyl propanol of formula (V) followed by crystallization in alcohol.
  • Step-a The reaction of 3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-one with dimethylsulphate is carried out in the presence of an aqueous alkali metal hydroxide followed by treatment with an inorganic acid.
  • Alkali metal hydroxide is selected from group comprising of sodium hydroxide, potassium hydroxide or mixture thereof. Most preferable alkali metal hydroxide is sodium hydroxide.
  • Inorganic acid is selected from group comprising of hydrochloride, hydrobromic acid, hydroiodic acid and sulfuric acid or mixture thereof. Most preferable inorganic acid is hydrochloride.
  • Step-b The reduction of 3-(2-methoxy-5-methylphenyl)-3-phenyl propionic acid is carried out in the presence of a reducing agent, an acidic reagent and a solvent.
  • the reaction is carried out at 60-75 0 C for 8-10 hrs.
  • the reducing agent is selected from the group comprising of sodium borohydride.
  • An acidic reagent is selected from the group comprising of methanesulfonic acid, sulfuric acid, trifluoroacetic acid or mixture thereof. Most preferable acidic reagent is methanesulfonic acid.
  • the solvent is selected from the group comprising of dioxane, tetrahydrofuran (THF), ethylene glycol dimethyl ether, methyl t-butyl ether, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile, dimethylacetamide or mixture thereof.
  • reaction mixture is cooled at 0-5 0 C.
  • the reaction mixture is acidified with IM aq. HCl up to pH 2-3, followed by extraction with ethyl acetate. The organic layers are washed with water and brine. The solvent is distilled out completely to dryness under reduced pressure to obtain 3 - (2-methoxy- 5 -methylphenyl) -3 -phenyl propanol.
  • Step-c The conversion of hydroxy group of 3-(2-methoxy-5-methylphenyl) -
  • the reaction is carried out at RT for 4-6 hrs.
  • the good leaving group can be generated by using reagent selected from the group comprising of p-toluenesulfonyl chloride, methanesulfonyl chloride, p-nitrobenzenesulfonyl chloride. Most preferable leaving group is p-toluenesulfonyl chloride.
  • the base is selected from the group comprising of inorganic or organic base.
  • the inorganic base is selected from the group comprising of potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide or mixture thereof.
  • the organic base is selected from the group comprising of triethylamine, trimethylamine, pyridine or mixture thereof.
  • Most preferable base is triethylamine.
  • the solvent is selected from the group comprising of dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, acetone, dichloromethane, toluene, xylene, methanol, ethanol, isopropanol, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile, dimethylacetamide or mixture thereof.
  • Most preferable solvent is dichloromethane.
  • the crystallization is carried out in the presence of alcohol.
  • Alcohol is selected from the group comprising of methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, isobutanol and the like or mixture thereof.
  • alcohol is isopropyl alcohol.
  • reaction mixture is acidified with IM aq.HCl up to pH 2-3. Then it is extracted with dichloromethane. The organic layers are washed with DM water, brine & dried over sodium sulfate. The solvent is completely distilled out at reduced pressure.
  • Crude hydroxyl protected 3-(2-methoxy-5-methylphenyl)-3-phenyl propanol of formula (V) is dissolved in isopropyl alcohol and heat it up to 70-80 0 C for 1-3 hrs and then cool it at RT. The solid is filtered & washed with isopropyl alcohol. The solid is dried at 50-55 0 C to obtain pure hydroxyl protected 3-(2-methoxy-5-methylphenyl)-3-phenyl propanol of formula (V).
  • reaction is carried out at 80-100 0 C for 130-150 hrs. After the completion of the reaction, product is extracted with dichloromethane. The organic layer is washed with DM water, 0.5 L brine & dried over sodium sulfate. The solvent was completely distilled out at reduced pressure (30-40mm Hg) to get crude and then basified it with IM NaOH up to pH 11-12, then extracted it with dichloromethane. The organic layer is washed with DM water, brine & dried over sodium sulfate. The solvent was completely distilled out at reduced pressure to get crude N, N-di- isopropyl-3-(2-methoxy-5-methylphenyl)-3-phenylpropyl amine of formula (VI).
  • the reaction is carried out at 45-6O 0 C for 1-2 hrs in the presence of a solvent.
  • the solvent is selected from the group comprising of dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, acetone, dichloromethane, toluene, xylene, methanol, ethanol, isopropanol, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile, dimethylacetamide or mixture thereof.
  • Most preferable solvent is acetone.
  • the organic acid is selected from the group comprising of oxalic acid, acetic acid, formic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, phthalic acid, terephthalic acid, citric acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, trifluoroacetic acid, ascorbic acid and the like. Most preferable organic acid is fumaric acid.
  • reaction mass is cool to ambient temperature then O 0 C for 1-2 hrs.
  • the solid is filtered & washed with acetone.
  • the solid is dried at 50-55 0 C to obtain organic acid salt of N, N-di- isopropyl-3-(2-methoxy-5-methylphenyl)-3-phenylpropyl amine of formula (VII).
  • Step-f The treatment of organic acid salt of
  • Step-g The treatment of hydrobromide salt of
  • the reaction is carried out at ambient temperature.
  • the base is selected from the group comprising of inorganic base.
  • the inorganic base is selected from the group comprising of potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide or mixture thereof. Most preferable base is sodium hydroxide.
  • the solvent is selected from the group comprising of dioxane, tetrahydrofuran, methyl t-butyl ether, ethylacetate, dichloromethane, diethyl ether, acetonitrile or mixture thereof. Most preferable solvent is dichloromethane.
  • the reaction mixture is cooled to RT.
  • the solid is filtered and washed with DM water to obtain wet cake.
  • the wet cake is dissolved in 2N NaOH & stirred and extracted it with dichloromethane.
  • the organic layer is separated and washed with DM water, brine & dried over sodium sulfate.
  • the solvent is completely distilled out at reduced pressure to obtain N,N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropyl amine, followed by the resolution reaction is carried out at 75-85°C for 1-2 hrs.
  • Alcohol is selected from the group comprising of methanol, ethanol, isopropyl alcohol, t-butanol or mixture thereof. Most preferable alcohol is ethanol.
  • the reaction mixture is cooled to RT and then at 0 0 C to obtain a solid.
  • the present invention provides process of preparation of
  • reaction mixture 0.75 kg 3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-one, 0.262 kg sodium hydroxide and 0.93 L DM water was stirred at 55-65°C for 2-3 hrs. The reaction was cooled to RT. 0.825 kg dimethylsulphate was added drop wise to reaction mixture within 1-2 hr. After the completion of addition, reaction mixture was stirred at same temperature for 1-2 hrs. Again solution of 0.186 kg sodium hydroxide in 0.93 L DM water was added at RT within 1 hr. The reaction mixture was stirred at 70-80 0 C for 3-5 hrs. After completion of reaction, reaction was cooled to RT.
  • reaction mixture was acidified with 0.25 L IM aq.HCl up to pH 2-3. Then reaction mixture was extracted with dichloromethane (0.5L x 2). The combined organic layers was washed with 1.0 L DM water, 1.0 L brine & dried over 0.25 kg sodium sulfate. The solvent was completely distilled out at reduced pressure (30-40 mm Hg). Crude 0.78 kg
  • Example-4a (without autoclave) [176] Preparation of N, N-di- isopropyl-3-(2-methoxy-5-methylphenyl)-3-phenylpropylamine [177]
  • the solvent was completely distilled out at reduced pressure (30-40mm Hg) to get crude and then basified it with 0.250 L IM NaOH up to pH 11-12, then extracted it with dichloromethane(0.200 L x 2).
  • the organic layers were washed with 1.0 lit DM water,0.5 Lit brine & dried over 0.1 kg sodium sulfate.
  • the solvent was completely distilled out at reduced pressure (30-40mm Hg) to get crude N, N-diisopropyl-3-(2-methoxy-5-methylphenyl)-3-phenylpropylamine.
  • N,N-diisopropyl-3-(2-methoxy-5-methylphenyl) -3-phenylpropyl amine in 0.111 L aqueous hydrobromic acid & 0.66 L acetic acid was stirred at 100-125 0 C for 12-16 hrs till completion of reaction.
  • the reaction mixture was cooled to RT to obtain a solid.
  • the solid was filtered & washed with DM water till washing of cake was neutral.
  • the solid was dried at 50-55 0 C to obtain hydrobromic salt of N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropyl amine.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un procédé de préparation du L-tartrate de (+)-(R)-toltérodine, comprenant une étape d'amination de l'hydroxyle protégé du 3-(2-méthoxy-5-méthylphényl)-3-phényl-propanol de formule (V) avec la diisopropylamine en présence d'eau afin d'obtenir la N,N-diisopropyl-3-(2-méthoxy-5-méthylphényl)-3-phénylpropyl-amine de formule (VI).
PCT/IB2010/050384 2009-02-12 2010-01-28 Procédé de préparation du tartrate de toltérodine Ceased WO2010092500A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN312/MUM/2009 2009-02-12
IN312MU2009 2009-02-12

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WO2010092500A2 true WO2010092500A2 (fr) 2010-08-19
WO2010092500A3 WO2010092500A3 (fr) 2010-12-02

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017137955A1 (fr) * 2016-02-14 2017-08-17 Celestis Pharmaceuticals Pvt. Ltd. Nouveau (r) et 3-(2-(allyloxy)-5-méthylphényl)-n,n-diisopropyl-3- phénylpropan-1-amine racémique et son utilisation pour la synthèse de (r) et de 2-(3- (diisopropylamino)-1-phénylpropyl)-4-(hydroxyméthyl)phénol racémique

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5382600A (en) 1988-01-22 1995-01-17 Pharmacia Aktiebolag 3,3-diphenylpropylamines and pharmaceutical compositions thereof
US5922914A (en) 1996-12-31 1999-07-13 Pharmacia & Upjohn Company Process to prepare tolterodine
WO2004078700A1 (fr) 2003-03-06 2004-09-16 Ranbaxy Laboratories Limited Derives de 3,3-diarylpropylamine et procedes permettant de les isoler
US6822119B1 (en) 2001-08-03 2004-11-23 Ranbaxy Laboratories Limited Process for the preparation of tolterodine

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1701932B1 (fr) * 2003-12-24 2012-07-18 Cipla Ltd. Tolterodine, compositions et leurs utilisations, et preparations desdites compositions

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5382600A (en) 1988-01-22 1995-01-17 Pharmacia Aktiebolag 3,3-diphenylpropylamines and pharmaceutical compositions thereof
US5922914A (en) 1996-12-31 1999-07-13 Pharmacia & Upjohn Company Process to prepare tolterodine
US6822119B1 (en) 2001-08-03 2004-11-23 Ranbaxy Laboratories Limited Process for the preparation of tolterodine
WO2004078700A1 (fr) 2003-03-06 2004-09-16 Ranbaxy Laboratories Limited Derives de 3,3-diarylpropylamine et procedes permettant de les isoler

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
JOURNAL OF ORGANIC CHEMISTRY, vol. 63, 1998, pages 8067 - 8070
ORGANIC PROCESS RESEARCH & DEVELOPMENT, vol. 6, no. 4, 2002, pages 379 - 383

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017137955A1 (fr) * 2016-02-14 2017-08-17 Celestis Pharmaceuticals Pvt. Ltd. Nouveau (r) et 3-(2-(allyloxy)-5-méthylphényl)-n,n-diisopropyl-3- phénylpropan-1-amine racémique et son utilisation pour la synthèse de (r) et de 2-(3- (diisopropylamino)-1-phénylpropyl)-4-(hydroxyméthyl)phénol racémique

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