WO2011070585A1 - Procédés de préparation de rivastigmine, de ses sels et produits intermédiaires - Google Patents

Procédés de préparation de rivastigmine, de ses sels et produits intermédiaires Download PDF

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Publication number
WO2011070585A1
WO2011070585A1 PCT/IN2010/000703 IN2010000703W WO2011070585A1 WO 2011070585 A1 WO2011070585 A1 WO 2011070585A1 IN 2010000703 W IN2010000703 W IN 2010000703W WO 2011070585 A1 WO2011070585 A1 WO 2011070585A1
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WIPO (PCT)
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formula
ethyl
phenol
solvent
reaction
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PCT/IN2010/000703
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English (en)
Inventor
Thota Giridhar
Gudipati Srinivasulu
Kotaru Srinivasa Rao
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Shodhana Laboratories Limited
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Publication of WO2011070585A1 publication Critical patent/WO2011070585A1/fr

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    • 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
    • C07C213/08—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 not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate 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 patent application relates to a process for the preparation of nvastigmine, its salts and intermediates thereof. More specifically, it relates to preparation of enantiomerically pure S-(-)-3-(l-dimethylamino) phenol, which is used as an intermediate in the preparation of rivastigmine and its salts.
  • Rivastigmine hydrogentartrate is chemically known as (S)-N-Ethyl-N- methyl-3-[l-(dimethylamino)ethyl]-phenyl carbamate hydrogen- (2R, 3R)- tartrate (hereinafter referred to as "Rivastigmine hydrogentartrate”) and has structural Formula I .
  • Rivastigmine hydrogentartrate is administered for the inhibition of reversible cholinesterase and is marketed under the brand name EXELON as capsules containing 0.5, 3, 4.5 and 6 mg rivastigmine base equivalent.
  • U.S. Patent No. 4,948,807 describes the compound N-ethyl, N-methyl- 3-[l-(dimethylamino) ethyl] phenyl carbamate and its pharmacologically acceptable salts along with a pharmaceutical composition useful for treating anti-cholinesterase activity in humans.
  • U.S. Patent No. 5,602,176 describes (S)-N-ethyl- N-methyl-3-[(l - dimethylamino) ethyl] - phenyl carbamate in free base or acid addition salt form as useful for its anti-cholinesterase activity. It also describes process for preparation involving resolution of N-ethyl, N-methyl-3-[l- (dimethylamino) ethyl] phenyl carbamate in presence of (+)-di-para-toluoyl tartaric acid ((+)-DPTTA). The yield of the resolution process is very low and resolution with resoluting agents such as (+)-DPTTA is of high cost.
  • rivastigmine represents as useless waste. Since the waste was too big result into high cost, making the process not suitable for commercial
  • JP 1106368 A discloses resolution of l-(3-methoxy phenyl) ethylamine with optically active mandelic acid in presence of water in methyl tert- butylether solvent.
  • the solvent used is volatile and not
  • JP 1003627 A discloses resolution of 1 -(3-methoxy phenyl) ethylamine with optically active N-(p-toluenesulfonyl)-proline in presence of alcohol solvents, ketone solvents or ester solvents. Resolution with optically active N-(p-toluenesulfonyl) -proline is of high cost and not favorable for
  • the present patent application relates to a process for the preparation of rivastigmine, its salts and intermediates thereof.
  • the present application provides a process for the preparation of S-(-)-3-[(l-dimethylamino) ethyl]-phenol of Formula II comprising the steps of:
  • Formula III Formula IV b) reacting the diastereomeric salt of Formula IV, with methylating agent to form S-(-) - (l-(3-methoxy phenyl)ethyl) dimethyl amine of Formula
  • the present application also provides a process for purification of S-(-)-3-[(l-dimethylamino) ethylj-phenol of Formula II in a chlorohydrocarbon solvent.
  • the present application also provides a process for purification of l-(3-methoxy phenyl) ethylamine L-(+)-mandelic acid salt of Formula IV in an ester solvent.
  • the present application relates to the process for the preparation of 3-((S)-l-aminoethyl)phenol compound of formula VII comprising,
  • the present application relates to the process for preparing rivastigmine or its pharmaceutically acceptable salt comprising the reaction of S-(-)-3-[(l-dimethylamino) ethylj-phenol of Formula II with N- methyl, N-ethyl carbamoyl chloride in the presence of an alkali metal hydroxide.
  • the present patent application relates to a process for the preparation of rivastigmine, its salts and intermediates thereof.
  • the present application provides a process for the preparation of S-(-)-3-[(l-dimethylamino) ethylj-phenol of Formula II comprising the steps of:
  • Formula III Formula IV b) reacting the diastereomeric salt of Formula IV, with methylating agent to form S-(-) - (l-(3-methoxy phenyl)ethyl) dimethyl amine of Formula
  • Formula II Step a) involves reacting l-(3-methoxy phenyl) ethylamine of Formula ⁇ with L-(+)-mandelic acid in an ester solvent to form a salt.
  • Suitable ester solvent for conducting the reaction includes
  • ethylacetate n-propylacetate, isopropylacetate, butyl acetate and ethyl butyrate or their mixtures with water.
  • the preferable solvent is aqueous ethylacetate.
  • the volume of solvent used in reaction may be from about 5 times to about 30 times, preferably for about 15 times to the weight of l-(3- methoxy phenyl) ethylamine of Formula ⁇ .
  • Suitable temperature for conducting the reaction can range from about 20°C to about reflux temperature of the solvent used, preferably 25- 35°C.
  • the reaction may be carried out for about 30 minutes to about 5 hours, preferably for about 30-60 minutes.
  • the diastereomeric salt of Formula IV may be isolated by suitable techniques such as filtration by gravity, or by suction, centrifugation and the like.
  • the diastereomeric salt of Formula IV may be further purified by any process including the process described in this application.
  • the diasteromeric salt obtained in step a) may be further dried. Drying may be suitable carried out in a tray drier, vacuum oven, fluidized bed drier and spin flash drier.
  • the present application also provides a process for purification of l-(3-methoxy phenyl) ethylamine L-(+)-mandelic acid salt of Formula IV in an ester solvent.
  • Suitable ester solvent for conducting purification includes
  • ethylacetate n-propylacetate, isopropyl acetate, butyl acetate and ethyl butyrate or their mixtures with water.
  • the preferable solvent is aqueous ethylacetate (1:1).
  • the volume of solvent used in purification may be from about 3 times to about 6 times, preferably for about 4 to 5 times to the weight of wet l-(3-methoxy phenyl) ethylamine L-(+)-mandelic acid salt.
  • the reaction mixture may be heated to reflux temperature of the solvent used and stirred for about 30 minutes to 1 hour. Then the reaction mixture may be cooled to room temperature for complete solid separation.
  • the purified diastereomeric salt of Formula IV may be isolated by suitable techniques such as filtration by gravity, or by suction,
  • Step b) involves reaction of the diastereomeric salt of Formula IV with a methylating agent to obtain S-(-)-(l-(3-methoxy phenyl)ethyl) dimethyl amine of Formula V.
  • the diastereomeric salt of Formula IV obtained in step a) may be directly used in the step b) or it may be converted to free base by
  • the diastereomeric salt of Formula IV obtained in step a) is directly used in the step b) without converting to freebase.
  • Suitable methylating regent that may be used in the process of step b) includes dimethylsulfate, methyl bromide, methyl iodide, mixture of formaldehyde and formic acid.
  • the preferable methylating reagent is mixture of formaldehyde and formic acid.
  • Suitable temperature for conducting the reaction can range from about 80-120 °C, most preferably at about 95-100 °C.
  • the reaction may be carried out for about 2 to about 10 hours, preferably for about 6-8 hours.
  • reaction mixture may be quenched with water; reaction mixture is washed with toluene.
  • the aqueous layer may be basified and extracted with a suitable solvent such as ethyl acetate.
  • the organic layer containing the product may be directly used in the next step or distilled off completely to obtain residue.
  • Step c) involves reaction S-(-)-(l-(3-methoxy phenyl) ethyl) dimethyl amine of Formula V with hydrobromic acid to obtain S-(-)-3-[(l- dimethylamino) ethylj-phenol of Formula II.
  • Hydrobromic acid that may be used in step c) includes gaseous, aqueous or acetic acid hydrobromic acid. Preferably about 40% w/ v to about 48% w/v aqueous hydrogen bromide is used in the reaction. Suitable temperature for conducting the reaction may range from about 90-120°C.
  • reaction mixture may be quenched with water; reaction mixture is washed with toluene.
  • the aqueous layer may be basified and extracted with a suitable solvent such as ethyl acetate.
  • the organic layer containing the product may be directly used in the next step or distilled off completely to obtain solid.
  • the obtained solid may be isolated by slurry in a non-polar solvent such as n-hexane, cyclohexane, petroleum ether and the like.
  • the present application also provides a process for purification of S-(-)-3-[(l-dimethylamino) ethyl]-phenol of Formula II in a chlorohydrocarbon solvent.
  • Suitable chlorohydrocarbon solvent includes dichloromethane.
  • S-(-)-3- [(1-dmiethylarnino) ethyl]-phenol of Formula II solid is recrystallized from dichloromethane by conventional process such as described in Example 5.
  • the present application relates to the process for the preparation of 3-((S)-l-aminoethyl)phenol compound of formula VII comprising,
  • Step a) involves conversion of the diastereomeric compound of formula IV to (S)-l-(3-met ⁇ ioxyphenyl)ethanamine the compound of formula VI in a conventional method.
  • Step b) reacting the compound of formula VI with Hydrobromic acid to obtain 3-((S)-l-aminoethyl)phenol the compound of formula VII similar to the process described in step c) of the first aspect of the invention.
  • the present application relates to the process for preparing rivastigrnine or its pharmaceutically acceptable salt comprising the reaction of S-(-)-3-[(l-dimethylamino) ethylj-phenol of Formula II with N- methyl, N-ethyl carbamoyl chloride in the presence of an alkali metal hydroxide.
  • Suitable solvent that may be used in the reaction include polar aprotic solvents such as dimethylformamide(DMF), dimethylacetamide(DMAC), dimethylsulfoxide(DMSO) and the like; aromatic hydrocarbons such as toluene, xylene and the like; tetrahydrofuran (THF), acetonitrile and the like.
  • polar aprotic solvents such as dimethylformamide(DMF), dimethylacetamide(DMAC), dimethylsulfoxide(DMSO) and the like
  • aromatic hydrocarbons such as toluene, xylene and the like
  • THF tetrahydrofuran
  • Suitable alkali metal hydroxide that may be used in the reaction includes sodium hydroxide, potassium hydroxide and the like.
  • the reaction is preferably conducted in the presence of nitrogen atmosphere.
  • N-methyl, N-ethyl carbamoyl chloride is slowly added to the reaction mixture to avoid exothermic reaction.
  • Rivastigrnine base obtained by the process of present application is substantially pure and having a purity of more than 99 %, preferably 99.5% as determined by HPLC.
  • Rivastigrnine base may be reacted with a pharmaceutically acceptable acid to form a corresponding salt.
  • Suitable pharmaceutically acceptable acids include hydrobromic acid, hydrochloric acid, and organic acids such as acetic acid, succinic acid, oxalic acid, tartaric acid, formic acid, and maleic acid.
  • Preferable acid is L(+) tartaric acid.
  • the solvent employed is a lower alkanol, such as methanol, ethanol or isopropanol; ketone solvents such as acetone, methyl ethyl ketone or methyl isobutyl ketone.
  • ketone solvent such as acetone, methyl ethyl ketone or methyl isobutyl ketone.
  • Preferable solvent is acetone.
  • the product obtained may be further dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like. The drying can be carried out at temperatures of about 35° C to about 70° C with or without vacuum. The drying can be carried out for any desired time periods to achieve the desired product purity, time from about 1 to 20 hours frequently being appropriate.
  • the process of the present invention is simple and convenient for commercial manufacturing.
  • the wet solid was added to a mixture of ethylacetate (86 ml) and water (86 ml) in another flask.
  • the reaction mixture was heated to reflux and stirred for about 20 minutes at reflux.
  • the reaction mixture was cooled to 25-35°C and stirred for 1 hour.
  • the solid was filtered and washed with ethylacetate (10 ml) to obtain 20 gm of title compound.
  • the wet solid was added to a mixture of ethylacetate (350 ml) and water (350 ml) in another flask.
  • the reaction mixture was heated to reflux and stirred for about 20 minutes at reflux.
  • the reaction mixture was cooled to 25-35°C and stirred for 1 hour.
  • the solid was filtered and washed with ethylacetate (10 ml) to obtain 56 gm of wet solid.
  • the wet solid was dried to get 30 gm of title compound.
  • Example 3 15 gm of the residue obtained in Example 3 was charged in a flask containing 84 ml of 48% aqueous hydrogen bromide solution and heated to about 100-110°C. The reaction mixture was stirred for about 10 hours at reflux. After completion of the reaction, the reaction mixture was cooled to 25-35°C and quenched into 150 ml of water. The reaction mass was basified with 60 ml of 40 % aqueous sodium hydroxide solution. The reaction mixture was extracted with ethylacetate (75 ml X 1, 50 ml X 2). The total ethyl acetate organic layer was washed with 10% aqueous NaCl solution (75 ml).
  • Total organic layer was extracted with 20 % aqueous HCl solution.
  • the aqueous layer pH was adjusted to about 10 using aqueous sodium hydroxide solution.
  • the aqueous layer was extracted with dichloromethane (200 ml). The total dichloromethane layer was washed with water and distilled off completely to get 34 gm of rivastigmine base.

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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

L'invention concerne des procédés de préparation de rivastigmine, de ses sels et des produits intermédiaires correspondants. De manière plus spécifique, l'invention porte sur un procédé de préparation de S-(-)-3-[(1-diméthylamino)éthyl]- phénol.
PCT/IN2010/000703 2009-10-28 2010-10-28 Procédés de préparation de rivastigmine, de ses sels et produits intermédiaires WO2011070585A1 (fr)

Applications Claiming Priority (2)

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IN2619CH2009 2009-10-28
IN2619/CHE/2009 2009-10-28

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WO2011070585A1 true WO2011070585A1 (fr) 2011-06-16

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102285904A (zh) * 2011-07-11 2011-12-21 中国科学院成都生物研究所 一种卡巴拉汀的制备方法
CN103193720A (zh) * 2013-04-11 2013-07-10 湖南海利化工股份有限公司 一种抗蚜威的制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004037771A1 (fr) * 2002-10-24 2004-05-06 Zentiva, A.S. Procede de production de (-)-(s)-3-[1-(dimethylamino)ethyl]phenyl-n-ethyl-n-methylcarbamate
US20080255383A1 (en) * 2007-04-10 2008-10-16 Venkata Naga Brahmeswara Rao Mandava Preparation of rivastigmine and its salts

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004037771A1 (fr) * 2002-10-24 2004-05-06 Zentiva, A.S. Procede de production de (-)-(s)-3-[1-(dimethylamino)ethyl]phenyl-n-ethyl-n-methylcarbamate
US20080255383A1 (en) * 2007-04-10 2008-10-16 Venkata Naga Brahmeswara Rao Mandava Preparation of rivastigmine and its salts

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102285904A (zh) * 2011-07-11 2011-12-21 中国科学院成都生物研究所 一种卡巴拉汀的制备方法
CN103193720A (zh) * 2013-04-11 2013-07-10 湖南海利化工股份有限公司 一种抗蚜威的制备方法

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