Title of Invention

A PROCESS FOR THE PREPARATION OF 1-(3-HYDROXYPHENYL)- ALKYL-(N-MONO/DIALKYL) AMINE

Abstract

The present invention discloses a process for the preparation of a compound of formula I wherein R1 is a lower alkyl that may be linear or branched or cyclic; allyl. propargyl or benzul; R2 is hydrogen or lower alkyl; R3 is hydrogen or lower alkyl or R2 and R3 together with the nitrogen to which they are attahced may form a cyclic moiety of three to eight members, with or without a hetero atom like nitrogen or oxygen or sulfur; comprising dealkylating a compound of formula II- wherein R is methyl, ethyl or benzyl, R1, R2 and R3 are as defined above, said dealkylation comprising reaction of compound of formula II with a mixture of thioether and mineral acid.

Full Text

FORM 2 THE PATENTS ACT, 1970 (39 OF 1970) COMPLETE SPECIFICATION (See section 10) A PROCESS FOR THE PREPARATION OF 1(-3-HYDROXYPHENYL) ALKYL- (N-MONO/DIALKYL) AMINE SUN PHARMACEUTICAL INDUSTRIES LTD. A company incorporated under the laws of India having their office at ACME PLAZA, ANDHERI-KURLA ROAD, ANDHERI (E), MUMBAI-400059, MAHARASHTRA, INDIA. The following specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed. A PROCESS FOR THE PREPARATION OF l-(3-HYDROXYPHENYL) ALKYL- (N-MONO / DIALKYL) AMINE The present invention relates to a process for the preparation of l-(3-hydroxyphenyl) alky]- (N-mono/dialky]) amine of formula I, wherein R1 is a lower alkyl that may be linear or branched or cyclic; allyl, propargyl or benzyl: R2 is hydrogen or lower alkyl, R3 is hydrogen or lower alkyl or R2 and R3 together with the nitrogen to which they are attached may-form a cyclic moiety of three to eight members, with or without a hetero atom like nitrogen or oxygen or sulfur. The l-(3-hydroxyphenyl) alkyl- (N-mono/dialkyl)amine of formula I may be used as an intermediate in the preparation of phenyl carbamates of formula HI, that are useful as pharmaceutical agents producing anticholinesterase activity in the central nervous system, Formula III —wherein R1 ,R2, R3 are as mentioned above ; R4 is hydrogen, lower alkyl, cyclohexyl, allyl or benzyl; and R5 is hydrogen, methyl, ethyl or propyl; optionally R4 and R5 may, together with the nitrogen to which they are attached, form a morpholino or piperidino radical BACKGROUND OF THE INVENTION The process for the preparation of l-(3-hydroxyphenyl) alkyl- (N-mono/dialkyl) amine of formula I from l-(3-methoxyphenyl) alkyl- (N-mono/dialkyl) amine by demethylation is known in the prior art. For example, J. Labelled Comp. And Radiopharm., 1997, 39(8), 651-668 involving a final step of-demethylation of the methoxy function of l-(3-methoxyphenyl) ethyl-(N,N-aimethyl)amine, using hydrobromic acid in the presence of hexadecyltributyl phosphonium bromide as the phase transfer catalyst, to yield l-(3-hydroxyphenyl)ethyl- (N, N-dimethyl) amine. The use of hydrobromic acid, with or without the use of phase transfer catalysts, for demethylation of the methoxy function has a disadvantage in that the quality of the final product is not satisfactory due to-a number of impurities formed in the reacion and tne use of expensive reagents such as phase transfer catalysts. The present invention is advantageous over this prior art since cheaper reagents like sulfuric acid are used and phase transfer catalysts related drawbacks like low thermal stability, hygroscopicity, separation problems and reusability are not encountered. European Patent No. 359647(Indian reference not available) discloses a process for the preparation of morphinane derivatives involving demethylation of 3-methoxylated compounds using a sulphonic acid chosen from among methanesulphonic acid and trifluoromethanesulphonic acid, in tne presence of a sulphide. However, the disadvantage of using sulfonic acid such as methanesulfonic acid is that it is a very expensive reagent and large volumes of the acid are required to isolate the final product. Further, this prior art does not specifically provide the intermediate made by the process of the present invention. There exists a need for a process for the preparation of l-(3-hydroxyphenyi) alky!-(N-mono/dialkyl)amines such that the process utilizes easily available starting materials, simple reagents and standard reaction conditions. The process should result in l-(3-hydroxyphenyI)alkyi-(N-mono/dialkyl)amines of satisfactory quality, in a satisfactory yield. OBJECT OF THE INVENTION The object of the present invention is to provide a process for the preparation of l-(3-hydroxypheny!) a]kyJ-(N-mono/dialkyl)amine, wherein readily available starting material such as l-(3-alkoxyphenyl) aIkyl-(N-mono/dialkyl)amine, compound of formula H wherein R maybe selected from methyl, ethyl and benzyl, is subjected to dealkylation using simple reagents. The process of the present invention yields the l-(3-hydroxyphenyl) alkyl-(N-mono/dialkyl)amine in a satisfactory quality and quantity. A more specific object is to provide a process for the preparation of l-(3-hydroxy phenyl)ethyr-(N,N"-dimethyl)arnine by demethylation of compound of formula II (wherein R is methyl). SUMMARY OF THE INVENTION The present invention provides a process for the preparation of compound of formula I wherein R1 is a lower alkyl that may be linear or branched or cyclic; allyl, propargyl or benzyl; R2 is hydrogen or lower alkyl; R3 is hydrogen or lower alkyl or R2 and R3 together with the nitrogen to which they are attached may form a cyclic moiety of three to eight members, with or without a hetero atom like nitrogen or oxygen or sulfur; comprising dealkylating compound of formula II wherein R is methyl, ethyl or benzyl; R , R and R are as defined above, said dealk-ylation comprising reaction of compound of formula II with a mixture of thioether and mineral acid. In particular, the present invention provides a process for the preparation of compound of formula I wherein R1 , R2 and R3 are methyl, comprising demethylating compound of formula II wherein R, R1, R2 and R3 are methyl, said demethylation comprising reaction of compound of formula II with a mixture of methionine and sulphuric acid. DETAILED DESCRIPTION OF THE INVENTION According to the process of the present invention, a mixture of thioether and mineral acid is used to carry out dealkylation of l-(3-alkoxyphenyl)alkyl-(N-mono/dialkyl)amine. compound of formula II, wherein R may be selected from methyl, ethyl and benzyl, most preferred being methyl. Preferably, the process of the present invention comprises demethylation of l-(3-methoxypheny])alkyl-(N-monp/dia]ky])amine. The thioether may be selected from a group comprising of alky] sulphides, 3-(rnethylthio)propionic acid, cycloalkyl methyl sulphides, dicycloalkyl sulphides, diphenyl or substituted diphenyl sulphides, phenyl or substituted phenyl methyl sulphide, dibenzyiidene sorbitol -4- thioether, S-carboxymethylcysteine, S-carboxymethyl homocysteine,thioIane-3,4-dioI, thiolane-3,4-diol S-oxide, tetrahydrothiophene, dithiane, " trithiane ,methionine and the like, preferred being methionine. The dealkylation step is carried out by adding methionine to l-(3-alkoxyphenyl)alkyl-(N-mono/dia!kyl)amine , compound of formula H, in molar ratio ranging from about 0.5:1 to 3.0: 1, preferred being 1:1 to 2.5:1 and most preferred being 1.5:1 to 2.0:1. The mineral acid may be selected from the group comprising of hydrochloric acid, nitric acid, sulfuric acid and the like, preferably sulfuric acid. The concentration of sulfuric acid that can be used may range from 20% to 100%, preferred being 35% to 70% and most preferred being 50 %, which is easier to handle than concentrated sulfuric acid on large scale. The process of dealkylation leads to formation of l-(3-hydroxyphenyl)alkyl-(N-mono/dialkyl)amine, compound of formula I, of a satisfactory quality and yield. Also the amount of the sulfuric acid required is not a concern in terms of cost and the volume of effluent generated, as compared to the large volumes of methanesulfonic acid that are required according to the prior art process. This improves the economic viability of the process of the present invention when carried out on an industrial scale. The -process is carried out at a temperature ranging from ambient to about 150°C, preferably about 70°C to 130°C , the most preferred being about 110 to 120°C. The reaction takes place at mild to moderate pressure, preferred being atmospheric pressure. The final product may be further purified by methods known to those skilled in the art. The. most common techniques being distillation, solvent extraction, chromatography, crystallization, recrystallization etc., preferably by recrystallization. Recrystallization may be carried out in solvent(s) or mixture of solvents, selected from the group comprising of ketones e.g. acetone-, methylethvl ketone , cyclohexanone, 2-propanone,4-methly-2 pentanone and the like; esters e.g. methyl acetate and ethyl acetate; nitriles e.g. acetonitrile and propionitrile; ethers e.g. diethylether, diisopropylether, dioxane, 1,2-dimethoxyethane ,tetrahydrofuran and the like; preferred being ethers and the most preferred being diisopropylether. The recrystallized l-(3-hydroxy phenyl)ethyl-(N,N"-dimethyl)amine, compound of formula I wherein R1, R2 and R3 are methyl, of the present invention has a characteristic melting range of about 85 to 86° C. The l-(3-hydroxyphenyl)alkyl-(N-mono/dialkyl)amine obtained by the process of the present invention can be used as an intermediate in the preparation of compounds of the formula III wherein R1, R2 ,R3,R4 and R5 are as defined above. In.one preferred embodiment of the process of the present invention, the l-(3-hydroxy "phenyl)alkyl-(N-mono/dialkyl)amine is l-(3-.hydroxyphenyl) ethyl- (N, N"-dirnethyl) amine of the formula -1, an intermediate of rivastigmine. Formula I wherein R1, R2 and R3 are methyl The intermediate of ri vastigmine, compound of formula I wherein R , R and R are methyl, maybe converted, to rivastigmine, compound of formula III, wherein-R1, R2, R3, R4 are methyl and R5 is ethyl; by a process known in prior.art such as European Patent No. 193926, preferably by the process as claimed in Indian Patent application No. 484 / MUM/2002. The compounds of the above general formula HI are useful,as pharmaceutical agents that produce anticholinesterase activity in the central nervous system and can be used in the treatment of senile dementia, Alzheimer"s disease, Huntingdon"s chorea, tardive dyskinesia, hyperkinesia, mania, acute confusion conditions, Friedrich"s ataxia and •Down"s syndrome The invention is illustrated but not restricted by the description in the following example. Example-1 a) Preparation of 3-(l-dimethyIamino ethyl)phenoI. Experimental procedure: To the solution of 50 % sulfuric acid in water (400.0 ml), was added at 10° to 15° C temperature, DL-methionine (124.9 gm, 0.837 moles) and stirred for 15 minutes. To this solution, was added [l-(3-methoxyphenyl) ethyl]dimethylamine (100.0 gm, 0.553 moles) at 10° to 15° C temperature within 2 hours and stirred for 30 minutes. Reaction mixture was then heated to 110° to 120°C temperature for 28 hours. The reaction mixture was diluted with water, basified to pH 8.5 to 9.0 using ammonia solution and extracted with dichloromethane. Organic extract was then washed with water, charcoalized and concentrated. Hexane was then added to the residue and crude product filtered. Purification : Crude product was recrystallized from diisopropylether to give pure [l-(3-. hydroxyphenyl) ethyljdimethylamine (55.0 gm, 60 % yield,Purity - >99%) melting range : 85 to 86°C temperature) We claim - 1. A process for the preparation of l-(3-hydroxyphenyl)alkyl-(N-mono/dialkyl)amine, a compound of formula I wherein R1 is a lower alkyl that may be linear or branched or cyclic; ally], propargyl or benzyl; R2 is hydrogen or lower alkyl; R3 is hydrogen or lower alkyl or R2 and R3 together with the nitrogen to which they are attached may form a cyclic moiety of three to eight members, with or without a hetero atom like nitrogen or oxygen or sulfur; comprising dealkylating compound of formula II wherein R is methyl, ethyl or benzyl, R1, R2 and R3 are as defined above, said dealkylation comprising reaction of compound of formula II with a mixture of thioether and mineral acid. 2. A process as claimed in claim 1 wherein the compound of formula I is 1-(3-hydroxy phenyl)ethyl-(N,N"-dimethyl)amine. 3. A process as claimed in claim 1 wherein R is methyl. 4. A process as claimed in claim 1 wherein the thioether is methionine. 5. A process as claimed in claim 1 wherein the mineral acid is sulfuric acid. 6. A process as claimed in claim 5 wherein the concentration of sulfuric acid used is about 20% to 100%. 7. A process as claimed in claim 1 wherein the dealkylation is carried out at a temperature ranging from ambient to about 150°C. 8. A process as claimed in claim 1 wherein the molar ratio of methionine to compound of formula II ranges from about 0.5:1 to 3.0:1. 9. A process as claimed in claim 1 wherein the compound of formula I is optionally re-crystallized from ether. 10. A process as claimed in claim 9 wherein the ether is diisopropylether. 11. A process a claimed in claim 9 wherein the recrystallised compound of formula I wherein R1, R2 and R3 are methyl is characterized by a melting range of about 85 to 86°C. 12. A process as claimed in claims 1-11 substantially as herein described and illustrated by example -1. Dated this 5th day of February, 2003 DILIP SHANGHVI CHAIRMAN AND MANAGING DIRECTOR SUN PHARMACEUTICAL INDUSTRIES LIMITED.

Documents:

166-mum-2003-abstract(04-12-2007).doc

166-mum-2003-abstract(04-12-2007).pdf

166-mum-2003-cancelled pages(04-12-2007).pdf

166-mum-2003-claim(granted)-(04-12-2007).doc

166-mum-2003-claim(granted)-(04-12-2007).pdf

166-mum-2003-correspondence(04-12-2007).pdf

166-MUM-2003-CORRESPONDENCE(11-5-2010).pdf

166-mum-2003-correspondence(ipo)-(20-12-2006).pdf

166-mum-2003-form 1(06-02-2003).pdf

166-MUM-2003-FORM 15(11-5-2010).pdf

166-mum-2003-form 18(13-03-2006).pdf

166-mum-2003-form 2(granted)-(04-12-2007).doc

166-mum-2003-form 2(granted)-(04-12-2007).pdf

166-mum-2003-form 3(06-02-2003).pdf