WO2011151669A1 - Procédé de production d'un isomère énantiomériquement enrichi d'un dérivé du 3-(1-aminoéthyle) phényle et son utilisation pour produire de la rivastigmine ou son sel pharmaceutiquement acceptable - Google Patents

Procédé de production d'un isomère énantiomériquement enrichi d'un dérivé du 3-(1-aminoéthyle) phényle et son utilisation pour produire de la rivastigmine ou son sel pharmaceutiquement acceptable Download PDF

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WO2011151669A1
WO2011151669A1 PCT/IB2010/002072 IB2010002072W WO2011151669A1 WO 2011151669 A1 WO2011151669 A1 WO 2011151669A1 IB 2010002072 W IB2010002072 W IB 2010002072W WO 2011151669 A1 WO2011151669 A1 WO 2011151669A1
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acid
formula
process according
group
compound
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Vikas Bansal
Ved Prakash Verma
Shailendra Kumar Dubey
Sujay Biswas
Dharam Vir
Ashutosh Agarwal
Jag Mohan Khanna
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Jubilant Life Sciences Limited
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    • 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
    • C07B57/00—Separation of optically-active compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
    • C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
    • C07C303/30—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reactions not involving the formation of esterified sulfo groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/42—Separation; Purification; Stabilisation; Use of additives
    • C07C303/44—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/42—Separation; Purification; Stabilisation; Use of additives
    • C07C51/487—Separation; Purification; Stabilisation; Use of additives by treatment giving rise to chemical modification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the present invention relates to economic and industrial friendly process for producing enantiomerically enriched isomer of 3-(l-aminoethyl)phenyl derivative, a key intermediate used in the preparation of Rivastigmine or its pharmaceutically acceptable salts.
  • Rivastigmine structurally represented as compound (I), (5)-3-[(l- dimethylamino)ethyl] phenyl-N-ethyl-N-methyl-carbamate,
  • US 4,948,807 describes the compound ' N-ethyl-7V-methyl-3-[l- (dimethylamino)efhyl]phenyl carbamate (phenyl carbamate), its pharmacological salts and process of its preparation.
  • the process disclosed for the preparation of phenyl carbamate moiety is comprised of the reaction of -m-hydroxyphenylisopropyldimethylamine or a- fft-hydroxyphenylethyldimethylamine with appropriate isocyanates.
  • the other alternative method reports the use of carbamoyl halides along with reactive base like sodium hydride to prepare phenyl carbamates.
  • US 4,948,807 only refers to the racemic phenyl carbamate.
  • US 5,602,176 describes (5)-N-ethyl-N-methyl-3-[l-(dimethylamino)ethyl]phenyl carbamate as a free base and acid addition salt.
  • US 5,602,176 reported the preparation of ( ⁇ -isomer of N-ethyl-iV-methyl-3-[l-(dimethylamino)ethyl]phenyl carbamate by resolution of racemic N-ethyl-N-methyl-3-[l-(dimethylamino)ethyl]phenyl carbamate (obtained according to method of US 4,948,807) by formation of diastereomeric salt with dir( , ( '-p-toluoyl-D-tartaric acid and the subsequent separation of desired diastereomer by repeated crystallizations in methanol/water.
  • the desired (S)-isomer is then obtained by treating the diastereomeric salt with sodium hydroxide.
  • the process has 20-25% yield and also 50% of the (i?)-isomer of N-ethyl-N-methyl-3-[l-(dimethylamino)ethyl]phenyl carbamate is discarded.
  • the main drawback of the said process is that it unnecessarily utilizes an expensive reagent, i.e., carbamoyl halide for the preparation of the undesired (7?)-isomer.
  • US 7,544,840 describes a process for the preparation of (5)-3-[l- (dimethylamino)ethyl]phenyl-N-ethyl-N-methyl carbamate by the reaction of optically active m-hydroxyphenylethyl dimethylamine with carbamoyl chloride.
  • the optically active m-hydroxyphenylethyl dimethylamine is obtained by resolution of corresponding racemic amine using (S)-(+)-camphor-10-sulfonic acid with 25-31% yield of resolution step with repeated crystallizations to improve optical purity of desired isomer.
  • US 7,544,840 does not disclose the fate of the undesired (i?)-isomer.
  • WO 2005/058804 describes a process for the preparation of chiral tertiary amines having chiral carbon center, which includes rivastigmine, by stereoselective reduction of ketones.
  • the chiral hydroxy compounds obtained by stereoselective reduction of ketone are activated and afterwards reacted with amines to get the desired product.
  • the reported advantage is avoiding the formation of undesired (i?)-isomer in terms that only desired isomer is formed in stereoselective reduction.
  • the process involving stereoselective reduction employs the use of chiral coordinated transition metal complex as reagents for catalyzing the hydrogenation. These chiral coordinated transition metal complexes are very expensive and thereby make the process uneconomical on industrial scale.
  • the stereoselectivity reported for the said process is only 95%, which does not fulfill the pharmacopeial standards of pharmaceutical ingredients, thus, further rendering the process industrially uneconomical.
  • US 2008/255383 describes a process for the preparation of Rivastigmine by reaction of S-(-)-[ 1 -(3 -hydroxyphenyl)ethyl] dimethylamine with N-ethyl-iV-mefhyl carbamoyl chloride.
  • the US '383 reports resolution of l-(3-methoxyphenyl) ethylamine with L-(+)-mandelic acid, the resulting desired diastereomer is separated.
  • the desired isomer is then N-dimethylated with subsequent O-demethylation to get _?-(-)- [1 -(3- hydroxyphenyl)ethyl]dimethylamine. Further, it reports the racemization of .
  • the principal object of present invention is to alleviate the drawbacks of the prior art processes by providing an industrially applicable, cost effective and environment friendly process for the racemization of (i?)-3-(l-aminoethyl)phenyl derivative and the use of racemized 3-(l-aminoethyl)phenyl derivative to obtain Rivastigmine or its pharmaceutically acceptable salts.
  • the present invention provides an improved process for producing (i?)-3-(l-aminoethyl)phenyl derivative.
  • the said process comprises of:
  • the present invention provides a process for the use of racemized 3-(l-aminoethyl)phenyl derivative for the preparation of Rivastigmine or its pharmaceutically acceptable salts thereof.
  • Rivastigmine (I) or its pharmaceutically acceptable salt thereof comprising the steps of:
  • the process according to the present invention for producing the enantiomerically pure or enriched (i?)-3-(l-aminoethyl)phenyl derivative, a key intermediate used in the preparation of Rivastigmine or its pharmaceutically acceptable salts comprises of:
  • R is a substituted sulphonyl group or any phenol protecting group and X is a leaving group.
  • the substituted sulphonyl group R is selected from phenyl sulphonyl, Ci -4 alkyl substituted phenyl sulphonyl, C alkoxy substituted phenyl sulphonyl, halogen substituted phenyl sulphonyl, nitro substituted phenyl sulphonyl, benzoyl sulphonyl or substituted benzoyl sulphonyl or alkyl sulphonyl.
  • the X is selected from the group comprising of fluoride, chloride, bromide, iodide and the like.
  • the compound of Formula (III) is resolved with a suitable resolving agent of optically active acid HA in a suitable solvent to obtain diastereomeric salt of desired (5)-3-(l-aminoethyl)phenyl derivative (IV) and diastereomeric salt of undesired ( ?)-3-(l-aminoethyl)phenyl derivative (V);
  • the suitable resolving agent of optically active acid HA used for optical resolution is selected from a group comprising of mandelic acid, tartaric acid, camphor sulphonic acid, dibenzoyl tartaric acid, di-/? ⁇ toluoyl tartaric acid and the like.
  • the suitable solvent employed during the resolution is selected from a group comprising of water, alcohols such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, pentanol and the like; ketones such as acetone, methyl ethyl ketone, methyl iso-butyl ketone and the like; ethers such as diethyl ether, tetrahydrofuran, dioxane and the like; esters such as ethyl acetate, iso-propyl acetate, butyl acetate and the like; and mixtures thereof.
  • the resolution reaction takes place at a temperature between 20 to 80°C, preferably 25 to 50°C, most preferably between 25 to 30°C for 1-4 h, preferably 1-2 h.
  • the undesired (7?)-3-(l-ammo-ethyl)-phenyl derivative diastereomeric salt (V) is reacted with a base in a solvent to obtain (i?)-3-(l -amino-ethyl)- phenyl derivative of Formula (VII);
  • the base is selected from organic or inorganic base.
  • the organic base is selected form the group comprising of ⁇ , ⁇ -dimethylamine, triethylamine, N-ethyl-N-methyl amine, diethylbenzyl amine, diisopropylethylamine and the like.
  • the inorganic base is selected form the group comprising of ammonia, alkali metal or alkaline earth metal hydroxide, carbonate, bicarbonate and the like, wherein alkali metal and alkaline earth metal is selected from a group comprising of lithium, sodium, potassium, magnesium, calcium, barium and the like.
  • Preferred base used is inorganic base, more preferably ammonia.
  • the solvent used in the reaction is selected from a group comprising of water, halogenated solvents such as dichloromethane, ethylene dichloride, chloroform and the like, esters such as ethyl acetate, n-propyl acetate, isopropyl acetate, butyl acetate and the like, hydrocarbon solvents such as toluene, xylene, n-hexane, n-heptane, cyclohexane and mixtures thereof.
  • the solvent is selected from a group comprising of mixture of water and a hydrocarbon solvent, more preferably used hydrocarbon solvent is toluene.
  • the reaction takes place at a temperature between 20 to 80°C, preferably 25 to 50°C, most preferably between 25 to 30°C for 0.5-2 h, preferably 0.5-1 h.
  • the aldehyde (R'CHO) used is selected from aromatic or aliphatic aldehyde.
  • the aromatic aldehyde is selected from the group comprising of a substituted or unsubstituted benzaldehyde, fused aromatic aldehydes, heterocyclic aldehydes and the like.
  • Suitable substituents for the benzaldehyde are selected from alkyl, alkoxy, halogens, nitro group, amino group and the like.
  • the alkyl substituent is selected from a group comprising of Ci -6 carbon atoms.
  • the alkyl from the alkoxy substituent is selected from a group comprising of Ci-6 carbon atoms.
  • the halogen substituent is selected from a group comprising of fluorine, chlorine, bromine and iodine.
  • the fused aromatic aldehyde is selected from a group comprising of naphthaldehyde, 9-anthracene aldehyde and the like.
  • the hetreocyclic aldehyde is selected form a group comprising of furan carboxaldehyde, thiophene carboxaldehyde, pyridine carboxaldehyde and the like.
  • the aliphatic aldehyde used for the reaction is selected from a group comprising of substituted or unsubstituted straight chain or branched aldehydes having Ci -6 atoms.
  • Preferably used aldehyde is aromatic aldehyde, more preferably benzaldehyde.
  • the acid used is selected from a group comprising of organic or inorganic acid.
  • the organic acid is selected from the group comprising of oxalic acid, acetic acid, formic acid, propionic acid, methane sulphonic acid, p-toluene sulphonic acid, benzene sulphonic acid, trifiuoromethane sulphonic acid, trifiuoroacetic acid, camphor sulphonic acid and the like.
  • the inorganic acid is selected from the group comprising of hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid, perchloric acid, phosphoric acid, sulphamic acid, boron trifluride, potassium hydrogen sulphate and the like.
  • the acid used is preferably an organic acid, more preferably p-toluene sulphonic acid.
  • the suitable organic solvent used is selected from a group comprising of halogenated solvents such as dichloromethane, ethylene dichloride ; chloroform and the like; esters such as ethyl acetate, n-propyl acetate, isopropyl acetate, butyl acetate and the like; hydrocarbon solvents such as toluene, xylene, n-hexane, n-heptane, cyclohexane and the like.
  • the preferably used organic solvent is hydrocarbon solvent, more preferably toluene.
  • Suitable temperature for conducting the reaction may range from about 40°C to about 200°C, preferably from in the range of 80°C to 150°C for ' bout 10-30 h, preferably about 15-25 h, more preferably 18-20 h.
  • the base used is selected from a group comprising of triethylamine, dimethylamine, pyridine, piperidine, diisopropylethylamine, 1 ,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] undec-7-ene, 4-dimethylaminopyridine, 1,5-diazabicyclo [4.3.0] non-5-ene, tri-n-octyl amine and the like.
  • Preferably used base is 1,8- diazabicyclo[5.4.0]undec-7-ene.
  • the organic solvent used is selected from a group comprising of halogenated solvents such as ethylene dichloride, chloroform and the like; esters such as ethyl acetate, n-propyl acetate, isopropyl acetate, butyl acetate and the like; hydrocarbon solvents such as toluene, xylene, n-hexane, n-heptane, cyclohexane and the like.
  • the preferably used organic solvent is hydrocarbon solvent, more preferably toluene.
  • the reaction with base is carried out at a temperature range of about 60°C to about 110°C, preferably 70-80°C for a period of about 35 h till the desired amount of product is obtained according to HPLC/TLC, preferably for 44-46 h.
  • compound of Formula (IX) is reacted with an acid in a solvent to obtain racemic compound of Formula (III).
  • the acid is selected from a group comprising of inorganic or organic acid.
  • the inorganic acid is selected from the group comprising of hydrochloric acid, sulphuric acid, hydrobromic acid, perchloric acid, nitric acid, boron trifluoride, phosphoric acid and the like in presence or absence of water.
  • the inorganic acid acid can also be used with organic solvent selected from methanol, ethanol, propanol and the like.
  • the organic acid is selected from oxalic acid, acetic acid, formic acid, propionic acid, methane sulphonic acid, p-toluene sulphonic acid, benzene sulphonic acid, trifluoromethane sulphonic acid, camphor sulphonic acid, trifluoroacetic acid and the like.
  • Preferably used acid is inorganic acid and more preferably aqueous hydrochloric acid.
  • the solvent used is selected from a group comprising of water, ketones such as acetone, methyl ethyl ketone, methyl iso-butyl ketone; alcohols such as methanol, ethanol, n- propanol, iso-propanol, n-butanol, iso-butanol, pentanol; halogenated solvents such as ethylene dichloride, chloroform and the like; esters such as ethyl acetate, n-propyl acetate, isopropyl acetate, butyl acetate and the like; hydrocarbon solvents such as toluene, xylene, n-hexane, n-heptane, cyclohexane and the like and mixtures thereof.
  • the preferably used solvent is hydrocarbon solvent, more preferably toluene.
  • phase transfer catalyst includes but are not limited to tetrabutyl ammonium bromide, benzyl trimethyl ammonium chloride, methyltrioctylammonium chloride, crown ethers, and the like.
  • phase transfer catalyst is tetrabutyl ammonium bromide.
  • potassium bromide potassium iodide, magnesium bromide, lithium bromide can also be used as catalyst.
  • the conversion of compound' of Formula (IX) to the racemic compound of Formula (III) can be alternatively carried out by hydrogenolysis in presence of a metal catalyst such as Raney nickel, palladium on carbon, platinum on carbon and the like in alcoholic solvent such as methanol, ethanol, propanol, butanol and the like, ester such as ethyl acetate, propyl acetate, butyl acetate and the like or mixture thereof.
  • a metal catalyst such as Raney nickel, palladium on carbon, platinum on carbon and the like
  • alcoholic solvent such as methanol, ethanol, propanol, butanol and the like
  • ester such as ethyl acetate, propyl acetate, butyl acetate and the like or mixture thereof.
  • the hydogenolysis is carried out at a pressure of 1 to 10 Kg/cm 2 at a temperature between 25 to 60°C.
  • the starting compound of Formula (II) is prepared from 3-hydroxyacetophenone by the methods known in prior art.
  • compound of Formula (II) is prepared according to the methods known in the prior arts.
  • the compounds of Formula (VII), (VIII) or (IX) can be optionally carried forward with or without isolation i.e., in situ for further reaction.
  • the present invention provides processes for converting the racemized 3 -( 1 -aminoethy l)phenyl derivative III obtained by racemization process to Rivastigmine or its pharmaceutically acceptable' salts thereof (Scheme 1).
  • the conversion of racemized 3-(l-amino-ethyl)-phenyl derivative (III) to Rivastigmine or its pharmaceutically acceptable salts thereof may be performed by any method known in prior art, such as the one described in WO 2010/023535.
  • the conversion is performed by optically resolving the compound of Formula (III) by employing a resolving agent of compound HA to obtain diastereomeric salts of Formula (IV) and Formula (V); treating the diastereomeric salt of desired isomer of Formula (IV) with a base in a solvent to obtain a compound of Formula (VI), methylating compound of Formula (VI) to obtain compound of Formula (X).
  • the compound of Formula (X) is then deprotected to obtain a compound of Formula (XI).
  • reaction mixture was further cooled to 0-5°C and jo-toluenesulphonyl chloride solution (104.2 g dissolved in 300 ml of toluene) was added to the reaction mixture over 3-4 hours under stirring at 0- 5°C.
  • the temperature of the reaction mixture was allowed to rise to room tempertaure and stirred at same temperature for 2 hour.
  • the progress of the reaction was monitored using HPLC/TLC.
  • solvent was distilled off under reduced pressure at 50-55°C and the reaction mass was cooled to room temperature. Water and toluene were added to the reaction mixture and stirred for 30-45 minutes. Subsequently the reaction mixture was filtered through hyflo bed.
  • Toluene-4-sulfonic acid-3-[l-(benzylidene-amino)-ethyl]-phenyl ester, (VIII), obtained in Example 4 was dissolved in toluene (100 ml) at room temperature. To the solution, added l,8-diazabicyclo[5.4.0]undec-7-ene (PBU) (3.07 ml) and heated the reaction mass to 70-80°C. Stirred the reaction mass at 7Q-80°C for 18-20 hour. Cooled the reaction mass to room temperature and partitioned between toluene and water.
  • PBU l,8-diazabicyclo[5.4.0]undec-7-ene

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

Abstract

La présente invention a pour objet un procédé économique et efficace de production d'un dérivé énantiomériquement enrichi du 3-(1-aminoéthyle) phényle et son utilisation pour produire de la rivastigmine ou son sel pharmaceutiquement acceptable.
PCT/IB2010/002072 2010-06-02 2010-08-25 Procédé de production d'un isomère énantiomériquement enrichi d'un dérivé du 3-(1-aminoéthyle) phényle et son utilisation pour produire de la rivastigmine ou son sel pharmaceutiquement acceptable WO2011151669A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4948807A (en) 1985-03-05 1990-08-14 Proterra Ag Phenyl carbamates
US5602176A (en) 1987-03-04 1997-02-11 Sandoz Ltd. Phenyl carbamate
WO2005058804A1 (fr) 2003-12-18 2005-06-30 Avecia Pharmaceuticals Limited Procede pour la preparation d'amines tertiaires fixes a un centre de carbone secondaire
US20080255383A1 (en) 2007-04-10 2008-10-16 Venkata Naga Brahmeswara Rao Mandava Preparation of rivastigmine and its salts
US7544840B2 (en) 2002-10-24 2009-06-09 Zentiva, A.S. Method of production of (−)-(S)-3-[1-(dimethylamino)ethyl]phenyl-N-ethyl-N-methylcarbamate
WO2010023535A1 (fr) 2008-08-25 2010-03-04 Jubilant Organosys Limited Procédé de production de (s)-3-[(1-diméthylamino)éthyl]phényl-n-éthyl-n-méthyl-carbamate par le biais de nouveaux intermédiaires

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4948807A (en) 1985-03-05 1990-08-14 Proterra Ag Phenyl carbamates
US5602176A (en) 1987-03-04 1997-02-11 Sandoz Ltd. Phenyl carbamate
US7544840B2 (en) 2002-10-24 2009-06-09 Zentiva, A.S. Method of production of (−)-(S)-3-[1-(dimethylamino)ethyl]phenyl-N-ethyl-N-methylcarbamate
WO2005058804A1 (fr) 2003-12-18 2005-06-30 Avecia Pharmaceuticals Limited Procede pour la preparation d'amines tertiaires fixes a un centre de carbone secondaire
US20080255383A1 (en) 2007-04-10 2008-10-16 Venkata Naga Brahmeswara Rao Mandava Preparation of rivastigmine and its salts
WO2010023535A1 (fr) 2008-08-25 2010-03-04 Jubilant Organosys Limited Procédé de production de (s)-3-[(1-diméthylamino)éthyl]phényl-n-éthyl-n-méthyl-carbamate par le biais de nouveaux intermédiaires

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BRINGMANN G ET AL: "THE ENANTIOSELECTIVE SYNTHESIS OF OPTICALLY, ACTIVE, BENZENE NUCLEUS-SUBSTITUTED 1-PHENYLETHYLAMINES FROM THE CORRESPONDING ACETOPHENONES", LIEBIGS ANNALEN DER CHEMIE, VERLAG CHEMIE GMBH. WEINHEIM, DE, vol. 8, 1 January 1990 (1990-01-01), pages 795 - 805, XP001109797, ISSN: 0170-2041 *

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