WO2011151669A1 - Process for producing enantiomerically enriched isomer of 3-(1-aminoethyl) phenyl derivative and employing the same to produce rivastigmine or its pharmaceutically acceptable salt - Google Patents
Process for producing enantiomerically enriched isomer of 3-(1-aminoethyl) phenyl derivative and employing the same to produce rivastigmine or its pharmaceutically acceptable salt Download PDFInfo
- Publication number
- 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
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- acid
- formula
- process according
- group
- compound
- Prior art date
Links
- 0 C[C@@](*)c1cc(O*)ccc1 Chemical compound C[C@@](*)c1cc(O*)ccc1 0.000 description 4
- WFRNDUQAIZJRPZ-UHFFFAOYSA-N CC(c1cccc(O)c1)N Chemical compound CC(c1cccc(O)c1)N WFRNDUQAIZJRPZ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
Abstract
The present invention relates to an economic and efficient process for producing enatiomerically enriched 3-(1-aminoethyl)phenyl derivative and employing the same to produce Rivastigmine or its pharmaceutically acceptable salt.
Description
PROCESS FOR PRODUCING ENANTIO ERICALLY ENRICHED ISOMER OF 3-(l - AMINOETHYL)PHEN YL DERIVATIVE AND EMPLOYING THE SAME TO PRODUCE RIVASTIGMINE OR ITS PHARMACEUTICALLY ACCEPTABLE
SALT
Field of the Invention
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.
Background of the Invention
Rivastigmine, structurally represented as compound (I), (5)-3-[(l- dimethylamino)ethyl] phenyl-N-ethyl-N-methyl-carbamate,
0)
is known to possess cholinesterase inhibitor activity and is useful in the treatment of Alzheimer's disease. ' 1
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. Further, 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. Further, 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. However, 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. Also, 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 . ?-(-)- [1 -(3-
methoxyphenyl)ethyl]dimethylan ine with a base having a high ionic counter ion in a polar aprotic solvent. But the said application lacks the disclosure of any resolution method to be used for the racemic [l-(3-methoxyphenyl)ethyl]dimethylamine obtained, which reduces the applicability of racemization process in improving the overall yields of the process. Also, US'383 does not disclose any method for the racemization of i?-(+)-l-(3- methoxyphenyl)ethylamine mandelate salt obtained as a by-product of resolution process.
The processes disclosed in above mentioned prior arts are not industrially feasible and cost effective process to obtain Rivastigmine or its pharmaceutically acceptable salt, as during chiral resolution, the desired (S)-isomer is separated from the undesired(R)- isomer, and the undesired (R)-isomer is waste as a result overall yield of the process can not reach more than 50%. Also, from the foregoing, it can be understood that the prior art processes do not disclose the racemization process for the undesired (R)-isomer preferably amine intermediates thereby resulting in a relatively high amount of undesired (R)-isomer being obtained as a result of resolution, which when racemized can be recycled and utilized to increase the overall yields of Rivastigmine or its pharmaceutically acceptable salts.
Therefore, in order to get the maximum yield during the preparation of Rivastigmine and its pharmaceutically acceptable salts, there is a continuous need for the development of a cost-effective and efficient synthetic route by racemization of undesired amine intermediate and recycling it for the preparation of Rivastigmine intermediates and subsequently to Rivastigmine or its pharmaceutically acceptable salts.
Ob jects and Summary of the Invention
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 above and other objects are further attained and supported by the following embodiments described herein. However, the scope of the invention is not restricted to described embodiments hereinafter.
In accordance with an embodiment, the present invention provides an improved process for producing (i?)-3-(l-aminoethyl)phenyl derivative. The said process comprises of:
(a) reacting a compound of Formula (II) with a protecting agent of Formula RX in presence of a base and solvent to obtain a racemic compound of Formula (III);
(b) optically resolving the racemic compound of Formula (III) by employing a resolving agent of compound HA to obtain diastereomeric salts of Formula (IV) and Formula (V);
(c) treating the diastereomeric salt of undesired isomer of Formula (V) with a base in a solvent to obtain a compound of Formula (VII);
(d) reacting compound of Formula (VII) with an aldehyde (R'CHO) to obtain a compound of Formula (VIII);
(e) treating compound of Formula (VIII) with a base to obtain a racemic compound of Formula (IX); and
(f) converting the compound of Formula (IX) with an acid or by hydrogenolysis in a solvent, to obtain racemic compound of Formula (III).
In accordance with another embodiment, 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.
In accordance with yet another embodiment of the present invention, there is provided a process for producing Rivastigmine (I) or its pharmaceutically acceptable salt thereof, wherein the process comprising the steps of:
(a) reacting a compound of Formula (II) with a protecting agent of Formula RX in presence of a base and solvent to obtain a racemic compound of Formula (III);
(b) optically resolving the racemic compound of Formula (III) by employing a resolving agent of compound HA to obtain diastereomeric salts of Formula (IV) and Formula (V);
(c) treating the diastereomeric salt of undesired isomer of Formula (V) with a base in a solvent to obtain a compound of Formula (VII);
(d) reacting compound of Formula (VII) with an aldehyde (R'CHO) to obtain a compound of Formula (VIII);
(e) treating compound of Formula (VIII) with a base to obtain a racemic compound of Formula (IX); and
(f) converting the compound of Formula (IX) with an acid or by hydrogenolysis in a solvent, to obtain racemic compound of Formula (III).
(g) converting resulting racemic compound of Formula (III) to Rivastigmine or the pharmaceutical salts thereof.
Description of the Invention
While this specification concludes with claims particularly pointing out and distinctly claiming that, which is regarded as the invention, it is anticipated that the invention can be more readily understood through reading the following detailed description of the invention and study of the included examples.
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:
(a) reacting a compound of Formula (II) with a protecting agent of Formula RX in presence of a base and solvent to obtain a racemic compound of Formula (III);
(b) optically resolving the racemic compound of Formula (III) by employing a resolving agent of compound HA to obtain diastereomeric salts of Formula (IV) and Formula (V);
(c) treating the diastereomeric salt of undesired isomer of Formula (V) with a base in a solvent to obtain a compound of Formula (VII);
(d) reacting compound of Formula (VII) with an aldehyde to obtain a compound of Formula (VIII);
(e) treating compound of Formula (VIII) with a base to obtain a racemic compound of Formula (IX); and
(f) converting the compound of Formula (IX) with an acid or by hydrogenolysis in a solvent, to obtain racemic compound of Formula (III).
Tartrate
Scheme 1
According to the present invention, the racemization of (i?)-3-(l~aminoethyl)phenyl derivative (VII) (Scheme 1) is carried out by reacting a compound of Formula (II) with a protecting agent of formula RX to obtain a compound of Formula (III),
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.
According to the present invention, 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);
(IV) (V) wherein HA is an optically active acid.
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.
According to the invention, 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);
(VII)
The base is selected from organic or inorganic base. The organic base is selected form the group comprising of Ν,Ν-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. Preferably, 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 compound of Formula (VII) is reacted with an aldehyde (R'CHO) in the presence of an acid in a suitable organic solvent to obtain a compound of Formula (VIII);
(VIII)
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 compound of Formula (VIII) is treated with a base in an organic solvent to obtain a racemic compound of Formula (IX);
(IX) '
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.
According to the sixth aspect of the invention, compound of Formula (IX) is reacted with an acid in a solvent to obtain racemic compound of Formula (III).
According to the present invention, 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.
The reaction is optionally carried out in the presence of a phase transfer catalyst. Suitable phase transfer catalyst includes but are not limited to tetrabutyl ammonium bromide, benzyl trimethyl ammonium chloride, methyltrioctylammonium chloride, crown ethers, and the like. Preferably used phase transfer catalyst is tetrabutyl ammonium bromide.
Furthermore, 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.
The hydogenolysis is carried out at a pressure of 1 to 10 Kg/cm2 at a temperature between 25 to 60°C.
According to present invention, the starting compound of Formula (II) is prepared from 3-hydroxyacetophenone by the methods known in prior art.
According to present invention, compound of Formula (II) is prepared according to the methods known in the prior arts.
In essence, in the present invention, the compounds of Formula (VII), (VIII) or (IX) can be optionally carried forward with or without isolation i.e., in situ for further reaction.
In another embodiment, 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. Preferably, 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). Reacting the compound of Formula (XI) with N-ethyl-N-methyl carbamoyl chloride thereby to afford S-rivastigmine of Formula (I) and finally, reacting the rivastigimine of Formula (I) with a pharmaceutically acceptable acid; and recovering rivastigmine pharmaceutically acceptable salt.
The following examples are provided only to exemplify, but not to limit the scope of the invention.
Example 1
Preparation of 3-(l -Aminoethyl)phenyl)-p-toluenesulphonate, (HI): A mixture of 600 ml of tert-butanol, 100 g of l-(3-hydroxyphenyl)ethyl amine (II) and 48 g of potassium hydroxide was heated at 80-85°C for lh. The reaction mass was then cooled to room temperature and 100 ml of toluene was added. The 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. After the completion of reaction, 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. The layers were then separated and to the organic layer, 20% (w/v) sodium, hydroxide solution (40 g of sodium hydroxide in 200 ml of water) was added. The reaction mixture was allowed to stir for 30 minutes. After separating the aqueous layer, the organic layer was washed with water (4 x 200 ml) and concentrated under reduced pressure at 50-55°C to obtain the title compound, III, as oily mass. Yield: 70 %
Example 2
Preparation of (i?)-3-(l-Ammoethyl)phenyl)-jP-toluenesulphonate mandelate, (V):
77.64 g of (£)-(+)-mandelic acid and 3-(l-aminoethyl)phenyl)- -toluenesulphonate (III), (as obtained from Example 1) was stirred in a mixture of acetone (400 ml) and water (70 ml) at 55-60°C for 30 minutes to obtain a clear solution. The solution was then cooled to room temperature and stirred for another 1 hour and filtered. The solid thus obtained was washed with acetone and dried at 45-50°C to obtain (jS)-3-(l-aminoethyl)phenyl)-p- toluenesulphonate mandelate, IV. The mother liquor obtained was concentrated to dryness under vacuum at 55-60°C, to obtain a residue that contained (i?)-3-(l-amino-ethyl)phenyl)- jt toluenesulphonate mandelate, (V).
Example 3
Preparation of (i?)-3-(l -Aminoethvnphenyl-p-toluenesulphonate, VII: To a solution of (i?)-3-(l-aminoethyl)phenyl- ?-toluenesulphonate mandelate, (V) (32.0 g) in toluene (160 ml), added water (64 ml). Adjusted the pH of reaction mass between 10-11 by addition of liquor ammonia (14 ml) at room temperature. Stirred the reaction mass for 15 minutes at room temperature and separated the organic layer. Washed aqueous layer with toluene (32 ml). Combined the organic layers and washed with water, distilled out the solvent completely under vacuum at 50-55°C to afford (R)-3-(l- aminoethyl)phenyl-p-toluenesulphonate, (VII), as an oil. Yield: 98.4%
Example 4
Preparation of Toluene-4-sulfonic acid-3-|"l-(benzylidene-amino -ethyll -phenyl ester.
iVIII :
To a solution of (i?)-toluene-4-sulfonic acid-3-(l-amino-ethyl)-phenyl ester, VII, (20.0 g), obtained in Example 3, in toluene (200 ml), added benzaldehyde (7.75 ml) and p- toluene sulphonic acid (1.3 g). The reaction mass was heated to 110-120°C using Dean- stark apparatus, and stirred at this temperature for 10 hour. The reaction mass after cooling was partitioned between toluene and water. The organic phase was separated, washed with water and evaporated to afford the title compound, (VIII). Yield: 92.3%
Example 5
Preparation of racemic Toluene-4-sulfonie acid-3-[l-(benzylidene-aminoVethyll -phenyl ester, (IX):
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. The organic layer was separated and concentrated under vacuum at 50-55°C to afford racemic toluene- 4-sulfonic acid-3-[l-(benzylidene-amino)-ethyl]-phenyl ester, (IX), as an oil. Yield: 98%
Example 6
Preparation of racemic 3-(l-Aminoethyl)phenyl)-p-toluenesulphonate, (III):
To a solution of toluene-4-sulfonic acid-3-[l-(benzylidene-amino)-ethyl]-phenyl ester, (IX) (obtained as an oil in above example), in toluene, added concentrated hydrochloric acid (75 ml), tetra butyl ammonium bromide (0.22 g) and water (20 ml). The reaction mass was heated to 70-80°C and stirred for 44-46 hour. Cooled the reaction mass to room temperature and separated the aqueous layer. Washed the aqueous layer with toluene (3 x 40 ml). Adjusted the pH of aqueous layer to 9-10 with 40% sodium hydroxide with prior cooling to 10-15°C. The resulting reaction mass was then partitioned between toluene and water (200 ml). Aqueous layer was then washed with toluene (40 ml). The organic layer was distilled under vacuum at 50-55°C to afford racemic 3-(l- aminoethyl)phenyl)-p-toluenesulphonate, (III), as an oil. Yield: 79%.
Example 7
Preparation of racemic 3-(l-Aminoethyl)phenyl)-p-toluenesulphonate, III:
To a solution of toluene-4-sulfonic acid-3-[l-(benzylidene-amino)-ethyl]-phenyl ester, IX (obtained as an oil from example 5), in methanol (50 ml), added Raney nickel (0.5g) and hydrogenated at pressure of SKg/cm2 * The reaction mass was stirred for 5 hour at 25-30°C. The reaction mass was then heated at 55-60°C at the above pressure for 4-5 hour. After completion of the reaction, the reaction mass was filtered through hyflo bed and washed the bed with methanol. Solvent was distilled off under vacuum at 50-55°C to obtain racemic 3-(l-aminoethyl)phenyl)-p-toluenesulphonate, III, as brown oil.
Example 8
Preparation of (!S^-S-fl-Aminoethv phenylVp^oluenesulpl onate mandelate. (IV :
77.64 g of (5 -(+)-mandelic acid and 3-( 1 -aminoethyl)phenyl)-p-toluenesulphonate (III), (as obtained from Example 6) was stirred in a mixture of acetone (400 ml) and water (70 ml) at 55-60°C for 30 minutes to obtain a clear solution. The solution was then cooled to room temperature and stirred for another 1 hour and filtered. The solid thus obtained was washed with acetone and dried at 45-50°C to obtain (<S)-3-(l-aminoethyl)phenyl)-7- toluenesulphonate mandelate, IV, as a solid.
Example 9
Preparation of 6SV3-n -Aminoethyl)ph^ (VI):
To a solution of (5 -3-(l-aminoethyl)phenyl)-p-toluenesulphonate mandelate, (IV), obtained in Example 8, (32.0 g) in toluene (160 ml), added water (64 ml). Adjusted the pH of reaction mass between 10-11 by addition of liquor ammonia (14 ml) at room temperature. Stirred the reaction mass for 15 minutes at room temperature and separated the organic layer. Washed the aqueous layer with toluene (32 ml). Combined the organic layers and washed with water, distilled out the solvent completely under vacuum at 50-55 °C to afford (5)-3-(l-aminoethyl)phenyl)-p-toluenesulphonate, (VI), as an oil.
Example 10
Preparation of (S)-\3 -( 1 -pimethylaminolethv^phenvn-^-toulenesuphonate, (X) :
(iS -3-(l-Aminoethyl)phenyl)-p-toluenesulphonate (VI) obtained in Example 9 was taken in 385 ml of water and cooled to 10-15°C Formic acid (33.3 ml in 33.3 ml water) was added slowly to the reaction mixture over a period of 30 minutes under stirring followed by addition of formaldehyde solution (55.4 ml) over 30 minutes. The reaction mixture was then heated to 60-65°C for 14-1 hours and monitored by HPLC/TLC. After the reaction completion, the reaction mass was cooled to room temperature and the pH of the resulting mixture was adjusted to 1-2 with concentrated hydrochloric acid. Subsequently, 330 ml of toluene was added and stirred for 30 minutes. After separating the organic layer, the aqueous layer was washed with toluene (2 x 220 ml). To the aqueous layer, toluene (330 ml) was added and the pH of the mixture was adjusted to 9-10 with liquid ammonia. The reaction mixture was then stirred for 30 minutes. The layers were separated and aqueous layer was washed with toluene. The combined organic layer was
concentrated under pressure at 50-55°C to yield the title compound as oily mass, which is further used in the next step without purification.
Example 11
Preparation of *- Γ1 -(3 -HvdroxyphenvDethyll dimethyl amine, (XI):
44.6 g of KOH pellets were taken in 300 ml of methanol at room temperature under nitrogen atmosphere. The suspended solution was then cooled to 10-15°C. To the resulting solution, methanolic solution of 5'-[3-(l-dimethylamino)ethyl]phenyl)- 7- toulenesuphonate (X) obtained in Example 10 was added over 30 minutes. The reaction mixture was stirred for 2-3 hours at room temperature. After completion of the reaction, the reaction mixture was filtered and washed with methanol. Methanol was removed completely under reduced pressure and water was added to the resulting reaction mixture. The reaction mixture was cooled to 10-15°C and pH was adjusted between 1-2 using concentrated hydrochloric acid. Water was then added and the layers were mixed and aqueous separated. The aqueous layer was washed' with toluene (3 x 200 ml). To the aqueous layer, ethyl acetate was added, followed by the adjustment of pH to 9.5-1 1 with liquid ammonia. After separating and washing the aqueous layer with ethyl acetate, the combined organic layer was concentrated under reduced pressure. Cyclohexane (100 ml) was then added and distilled off. Again 200 ml of cyclohexane was added to the residue and heated to 80-85°C for 30 minutes. The reaction mass was cooled to room temperature and stirred for 1 hour. The solid thus obtained Was washed with cyclohexane and dried to obtain the title compound, (XI) as a solid.
Example 12
Preparation of Rivastifimine Tartrate
To a solution of 100 g of S- [1 -(3 -Hydroxyphenyl)ethyl] dimethyl amine (XI) obtained in Example 1 1 in 500 ml of acetone, pulverized potassium carbonate (125.2 g) was added. The reaction mixture was heated to 55-60°C for 1 hour. A solution of N-ethyl- N-methyl carbamoyl chloride (77.5 g) was added to the reaction mixture followed by stirring at the same temperature for 8-10 hours. After the completion of the reaction, the reaction mixture was cooled and filtered. The solvent was then removed under reduced pressure, water (500 ml) and toluene (500 ml) were added followed by pH adjustment to 1-2 using concentrated hydrochloric acid. After separating the organic layer, toluene (500 ml) was added to the aqueous layer and pH was adjusted to 9-11 with 10% sodium hydroxide solution. The organic layer was separated and concentrated under reduced pressure to obtain oil. To this oily mass, acetone (750 ml) and activated charcoal (5 g) were added and stirred for 30 minutes. The reaction mixture was then first filtered through hyflo bed and then through micron filter. L-(+ -tartaric acid was added to the filtrate and the reaction mixture was stirred for 4-5 hours and filtered. The solid thus obtained was washed with acetone and dried to obtain the title compound as solid.
While this invention has been described in detail with reference to certain preferred embodiments, it should be appreciated that the present invention is not limited to those precise embodiments. Rather, in view of the present disclosure, which describes the current best mode for practicing the invention, many modifications and variations would present themselves to those skilled in the art without departing from the scope and spirit of this invention.
Claims
1. A process for producing enantiomerically enriched isomer of 3-(l- aminoethyl)phenyl derivative of Formula (III),
(in)
wherein R is a substituted sulphonyl group, the process comprising:
(a) reacting a compound of Formula (II) with a protecting agent of formula RX to obtain a racemic compound of Formula (III),
(II) wherein X is a leaving group;
(b) resolving the compound of Formula (III) by employing a resolving agent of an optically active acid HA in a solvent to obtain diastereomeric salt of desired (5)-3-(l-amino-ethyl)-phenyl derivative of Formula (IV) and diastereomeric salt of undesired (i?)-3-(l-amino-ethyl)-phenyl derivative of Formula (V);
(IV) (V) wherein HA is an optically active acid;
(c) reacting the undesired (i?)-3-(l -amino-ethyl)-phenyl derivative diastereomeric salt of Formula (V) with a base in a solvent to obtain (i?)-3-(l- amino-ethyl)-phenyl derivative of Formula (VII),
(VII)
(d) reacting the compound of Formula (VII) with an aldehyde (R'CHO) in the presence of an acid in an organic solvent to obtain a compound of Formula (VIII),
(VIII)
(e) treating the compound of Formula (VIII) with a base in an organic solvent to obtain a racemic compound of Formula (IX),
(IX)
(f) converting the compound of Formula (IX) with an acid or by hydrogenolysis in a solvent to obtain racemic compound of Formula (III).
2. The process according to claim 1, wherein the substituted sulphonyl group is selected from a, group comprising of phenyl sulponyl, C alkyl substituted phenyl sulphonyl, CM alkoxy substituted phenyl sulphonyl, halogen substituted phenyl sulphonyl, nitro substituted phenyl sulphonyl, benzoyl sulphonyl or substituted benzoyl sulphonyl or alkyl sulphonyl,
3. The process according to claim 1, wherein the X in step 1(a) is selected from the group comprising of chloride, bromide, iodide.
4. The process according to claim 1, wherein the resolving agent used for optical resolution in step 1(b) is selected from a group comprising of mandelic acid, tartaric acid, camphor sulphonic acid, dibenzoyl tartaric acid, di-p-toluoyl tartaric acid.
5. . The process according to claim 1, wherein the solvent employed during the resolution in step 1(b) is selected from a group comprising of water, alcohols, ketones, ethers, esters and mixtures thereof.
6. The process according to claim 1, wherein the base used in step 1(c) is selected from inorganic or organic base.
7. The process according to claim 6, wherein the inorganic base is selected from the group comprising of ammonia, alkali metal or alkaline earth metal hydroxide, carbonate, bicarbonate.
8. The process according to claim 7, wherein alkali metal and alkaline earth metal is selected from a group comprising of lithium, sodium, potassium, magnesium, calcium, barium.
9. The process according to claim 6, wherein the organic base is selected from the group comprising of Ν,Ν-dimethylamine, triethylamine, N-ethyl-N-methyl amine, diethylbenzylamine, diisopropylethylamine.
10. The process according to claim 1, wherein the solvent used in step 1(c) is selected from a group comprising of water, halogenated solvents, esters, hydrocarbon solvents and mixtures thereof.
11. The process according to claim 1 , wherein the aldehyde used in step 1 (d) is selected from a group comprising of aromatic or alipahtic aldehyde.
12. The process according to claim 11, wherein the aromatic aldehyde is selected from a group comprising of a substituted or unsubstituted benzaldehyde, fused aromatic aldehyde and heterocyclic aldehyde.
13. The process according to claim 12, wherein the aromatic aldehyde is benzaldehyde.
14. The process according to claim 11, wherein the aliphatic aldehyde is selected from a group comprising of straight chain or branched chain aldehydes.
15. The process according to claim 1, wherein the acid used in step 1(d) is selected from organic or inorganic acid.
16. The process according to claim 15, wherein 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, trifluoromethane sulphonic acid, trifluoroacetic acid and camphor sulphonic acid.
17. The process according to claim 15, wherein the inorganic acid is selected from a group comprising of hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid, perchloric acid, phosphoric acid, sulphamic acid, boron trifluride and potassium hydrogen sulphate.
18. The process according to claim 1, wherein the solvent used in step 1(d) is selected from a group comprising of halogenated solvents, esters, hydrocarbon solvents.
19. The process according to claim 1, wherein the base used in step 1(e) 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-diazabicycIo [4.3.0] non-5-ene and tri-n-octyl amine.
20. The process according to claim 19, wherein the base used is 1,8- diazabicyclo [5.4.0]undec-7-ene.
21. The process according to claim 1, wherein the solvent used in step 1(e) is selected from a group comprising of halogenated solvents, esters and hydrocarbon solvents.
22. The process according to claim 1, wherein the acid used in step 1(f) is selected from a group comprising of inorganic or organic acid.
23. The process according to claim 22, wherein the inorganic acid is selected from the group comprising of hydrochloric acid, sulphuric acid, hydrobromic acid, perchloric acid, nitric acid, boron trifluoride and phosphoric acid.
24. The process according to claim 23, wherein the inorganic acid is hydrochloric acid.
25. The process according to claim 22, wherein 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 and trifluoroacetic acid.
26. The process according to claim 1, wherein the solvent used in step 1(f) is selected from a group comprising of water, ketones, alcohols, halogenated solvents, esters, hydrocarbon solvents and mixtures thereof.
27. The process according to claim 1(f), wherein reaction of compound of Formula (IX) with an acid is carried out in presence of the phase transfer catalyst.
28. The process according to claim 27, wherein the phase transfer catalyst used in step 1 (f) is selected from a group comprising of tetrabutyl ammonium bromide, benzyl trimethyl ammonium chloride, methyltrioctylammonium chloride, crown ethers, potassium bromide, potassium iodide, magnesium bromide, lithium bromide.
29. The process according to claim 1(f), wherein the conversion of compound of Formula (IX) is carried out by hydrogenolysis.
30. The process according to claim 29, wherein the hydrogenolysis is carried out using metal catalyst in presence of solvent.
31. The process according to claim 30, wherein the metal catalyst is selected from Raney Nikel, Pt / C or Pd / C.
32. The process according to claim 30, wherein the solvent is selected from alcohol, ester or mixtures thereof.
33. The process according to claim 1, wherein the resultant racemic compound of Formula (III) is further converted to Rivastigmine or the pharmaceutical salts thereof.
34. A process for the preparation of Rivastigmine (I) or its pharmaceutically acceptable salt thereof,
(I)
the process comprising the steps of:
(a) reacting a compound of Formula (II) with a protecting agent of formula RX to obtain a racemic compound of Formula (III),
(Π) (ΠΓ) where R is a substituted sulphonyl group and X is a leaving group;
(b) resolving the compound of Formula (III) with an optically active acid HA in a solvent to obtain diastereomeric salt of desired (5)-3-(l-amino-ethyl)- phenyl derivative (IV) and diastereomeric salt of undesired (i?)-3-(l-amino-ethyl)- phenyl derivative (V);
(IV) (V) wherein HA is an optically active acid;
(c) reacting the undesired (i?)-3-(l-amino-ethyl)-phenyl derivative diastereomeric salt (V), with a base in a solvent to obtain (i?)-3-(l-amino-ethyl)- phenyl derivative of Formula (VII),
(VII)
(d) reacting the compound of Formula (VII) with an aldehyde (R'CHO) in the presence of an acid in an organic solvent to obtain a compound of Formula (VIII),
(VIII)
(e) treating the compound of Formula (VIII) with a base in an organic solvent to obtain a racemic compound of Formula (IX),
(IX)
(f) converting the compound of Formula (IX) with an acid or by hydro genolysis in a solvent to obtain racemic compound of Formula (III) and g) converting resulting racemic compound of Formula (III) to Rivastigmine or the pharmaceutical salts thereof.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN1288/DEL/2010 | 2010-06-02 | ||
IN1288DE2010 | 2010-06-02 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2011151669A1 true WO2011151669A1 (en) | 2011-12-08 |
Family
ID=43085737
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IB2010/002072 WO2011151669A1 (en) | 2010-06-02 | 2010-08-25 | Process for producing enantiomerically enriched isomer of 3-(1-aminoethyl) phenyl derivative and employing the same to produce rivastigmine or its pharmaceutically acceptable salt |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2011151669A1 (en) |
Citations (6)
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 (en) | 2003-12-18 | 2005-06-30 | Avecia Pharmaceuticals Limited | Process for the preparation of tertiary amines attached to a secondary carbon centre |
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 (en) | 2008-08-25 | 2010-03-04 | Jubilant Organosys Limited | A process for producing (s)-3-[(1-dimethylamino)ethyl] phenyl-n-ethyl-n-methyl-carbamate via novel intermediates |
-
2010
- 2010-08-25 WO PCT/IB2010/002072 patent/WO2011151669A1/en active Application Filing
Patent Citations (6)
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 (en) | 2003-12-18 | 2005-06-30 | Avecia Pharmaceuticals Limited | Process for the preparation of tertiary amines attached to a secondary carbon centre |
US20080255383A1 (en) | 2007-04-10 | 2008-10-16 | Venkata Naga Brahmeswara Rao Mandava | Preparation of rivastigmine and its salts |
WO2010023535A1 (en) | 2008-08-25 | 2010-03-04 | Jubilant Organosys Limited | A process for producing (s)-3-[(1-dimethylamino)ethyl] phenyl-n-ethyl-n-methyl-carbamate via novel intermediates |
Non-Patent Citations (1)
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 * |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
KR100926723B1 (en) | Method for preparing duloxetine and intermediates for use therein | |
EP2403823B1 (en) | Process for the preparation of cinacalcet and salts thereof, and intermediates for use in the process | |
JP2007525532A (en) | Process for producing N-alkyl-N-methyl-3-hydroxy-3- (2-thienyl) -propylamine | |
US6822119B1 (en) | Process for the preparation of tolterodine | |
US8420846B2 (en) | Process for producing (S)-3-[(1-dimethylamino)ethyl] phenyl-N-ethyl-N-methyl-carbamate via novel intermediates | |
AU2011222644A1 (en) | Improved resolution methods for isolating desired enantiomers of tapentadol intermediates and use thereof for the preparation of tapentadol | |
US8552219B2 (en) | Process for preparing L-phenyl-3-dimethylaminopropane derivative | |
WO2012146978A2 (en) | A novel process for the preparation of tapentadol or a pharmaceutically acceptable salt thereof | |
WO2007026373A2 (en) | Process for preparing rivastigmine | |
US9085509B2 (en) | Process for preparing fesoterodine | |
EP2132192B1 (en) | Novel process for preparation of duloxetine hydrochloride | |
WO2011151669A1 (en) | Process for producing enantiomerically enriched isomer of 3-(1-aminoethyl) phenyl derivative and employing the same to produce rivastigmine or its pharmaceutically acceptable salt | |
US20130296608A1 (en) | Novel stereospecific synthesis of (-) (2s, 3s)-1-dimethylamino-3-(3-methoxyphenyl)-2-methyl pentan-3-ol | |
US7199260B2 (en) | Process for reductive dehalogenation | |
US6903233B2 (en) | Process for producing optically active 3-halogenocarboxylic acid ester and 3-azidocarboxylic acid ester | |
WO2008026227A2 (en) | A process for the preparation of atomoxetine hydrochloride | |
CZ296345B6 (en) | Process for preparing (R)-N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine hydrochloride (atomoxetine) | |
US9663456B2 (en) | Intermediate of tapentadol | |
JP2002003453A (en) | METHOD FOR PURIFYING OPTICALLY ACTIVE alpha-METHYL- BIS-3,5-(TRIFLUOROMETHYL) BENZYLAMINES | |
EP3160937B1 (en) | A novel method for synthesis of optically pure beta-amino alcohols | |
EP3242879B1 (en) | Novel process for the preparation of dipeptidyl peptidase-4 (dpp-4) enzyme inhibitor | |
CZ20031571A3 (en) | Process for preparing N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropylamine in racemic or optically active form thereof | |
JP5510040B2 (en) | Optical resolution to obtain optically active (R) -1- (4-fluorophenyl) ethylamine | |
ES2537378T3 (en) | A process to prepare Fesoterodina | |
JP2002308836A (en) | Method for purifying optically active 1-(fluorophenyl) ethylamine |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 10762748 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 10762748 Country of ref document: EP Kind code of ref document: A1 |