Title of Invention

A PROCESS FOR THE PREPARATION OF PHENYL CARBAMATES

Abstract

A process for the preparation of a compound of formula I wherein R1 is hydrogen, linear, branched or cyclic lower alkyl, cyclohexyl, allyl, propargyl or benzyl; R is hydrogen, methyl, ethyl or propyl; or R and R together with the nitrogen to which they are attached form a cyclic moiety of three to eight-membered ring, with or without a hetero atom like nitrogen or oxygen; R3 is hydrogen or lower alkyl; R4 and R5 are the same or different and each is a lower , alkyl; comprising reacting a compound of formula II. wherein R3, R4 and R5 are as defined above, with a compound of formula III wherein R1 and R2 are as defined above, in the presence of a base.

Full Text

FORM 2 THE PATENTS ACT, 1970 (39 OF 1970) COMPLETE SPECIFICATION (See section 10) A PROCESS FOR THE PREPARATION OF PHENYLCARBAMATES 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. 3 1 MAY 2002 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 PHENYLCARBAMATES The present invention relates to a process for the preparation of phenyl carbamates of formula I, Formula I wherein R1 is hydrogen, linear, branched or cyclic lower alkyl, cyclohexyl, allyl, propargyl or benzyl; R is hydrogen, methyl, ethyl or propyl; or R and R together with the nitrogen to which they are attached form a cyclic moiety of three to eight-membered ring, with or without a hetero atom like nitrogen or oxygen; R3 is hydrogen or lower alkyl; R4 and R5 are the same or different and each is a lower alkyl. Particularly, the process of the present invention relates to the preparation of ethylmethylcarbamic acid 3-[l-(dimethylamino)ethyl]phenyl ester. More particularly, the present invention relates to a process for the preparation of the racemate and the enantiomerically active form of ethylmethylcarbamic acid 3-[l-(dimethylamino)ethyl]phenyl ester. BACKGROUND OF THE INVENTION European Patent 193926 claims phenyl carbamate compounds and their pharmacologically acceptable salts for use as pharmaceutical agents producing anticholinesterase activity in the central nervous system. The patent discloses the process for the preparation of the title phenyl carbamate compounds involving reaction of hydroxyphenyl-substituted alkylamines with appropriate isocyanates or carbamoyl halides. The process using isocyanates involves the use of benzene as a solvent. Isocyanates such as lower alkyl isocyanates are hazardous to handle due to their toxic and non-volatile nature. The other alternative reported is the use of carbamoyl halides along with reactive bases like sodium hydride, to prepare the carbamates. The carbamoyl halides are not easy to handle at industrial scales and involve safety hazards. The use of a reactive base like sodium hydride on an industrial scale is hazardous and operationally non-user friendly due to its pyrophoric and reactive nature. More importantly, as per the process, 200% excess of the reagent is required for the reaction, and absolutely anhydrous conditions need to be employed. The excess reagent is quenched with water. This process would cause uncontrollable exothermicity at an industrial scale, and it is also possible that the highly alkaline conditions resulting from the formation of sodium hydroxide during the quenching of excess sodium hydride would cause degradation of the product formed, the degradation being more extensive at reaction temperatures above ambient temperature. The present invention provides a process for the preparation of a compound of formula I wherein R is hydrogen, linear, branched or cyclic lower alkyl, cyclohexyl, allyl, propargyl or benzyl; R2 is hydrogen, methyl, ethyl or propyl; or R1 and R2 together with the nitrogen to which they are attached form a cyclic moiety of three to eight-membered ring, with or without a hetero atom like nitrogen or oxygen; R3 is hydrogen or lower alkyl; R4 and R5 are the same or different and each is a lower alkyl; comprising reacting a compound of formula II wherein R3, R4 and R5 are as defined above, with a compound of formula III wherein R1 and R2 are as defined above, in the presence of a base. OBJECT OF THE INVENTION The prior art employs reagents like isocyanates and carbamoyl halides to make carbamates and in the process solvents like benzene, in case of isocyanates, or anhydrous reaction conditions with the use of sodium hydride, are necessary to carry out the reaction. Performing these reactions on a large scale entails several safety measures, in terms of storage, handling and quenching excess of reagents, as well as the poor quality of the end product. The object of the invention is to avoid these difficulties, for which we envisaged the reaction of arylcarbamates (compounds of formula III), especially 4-nitrophenylcarbamates, with hydroxyphenyl-substituted alkylamines (compounds of formula II) to prepare carbamates (compounds of formula I). The present invention is materially different in that it uses simple reagents that are easy to handle and store. Another object of the present invention is to provide S-isomer of the phenyl carbamates. Interestingly it was observed that the process of the present invention can be carried out using mild and cheap bases like alkali and alkaline earth metal oxides or hydroxides or carbonates, or secondary or tertiary amine bases. SUMMARY OF THE INVENTION The present invention provides a process for the preparation of a compound of formula I wherein R1 is hydrogen, linear, branched or cyclic lower alkyl, cyclohexyl, allyl, propargyl or benzyl; R2 is hydrogen, methyl, ethyl or propyl; or R and R together with the nitrogen to which they are attached form a cyclic moiety of three to eight-membered ring, with or without a hetero atom like nitrogen or oxygen; R3 is hydrogen or lower alkyl; R4 and R5 are the same or different and each is a lower alkyl; comprising reacting a compound of formula II wherein R3, R and R5 are as defined above, with a compound of formula III wherein R and R are as defined above, in the presence of a base. DETAILED DESCRIPTION OF THE INVENTION The process of the present invention involves the reaction of a hydroxyphenyl-substituted alkylamine of formula II with an arylcarbamate of formula III in the presence of a base. The base used in this reaction is selected from a group comprising alkali and alkaline earth metal oxides or hydroxides or carbonates, and secondary or tertiary amine bases such as dimethylaminopyridine, N-ethyldiisopropyl amine, collidine and the, like. In a preferred embodiment the base used is an alkali or alkaline earth metal carbonate, more preferably potassium carbonate. The base is used in a mole ratio ranging from about 0.5 moles to about 5 moles, preferably from about 1 mole to about 3 moles, more preferably from about 1.5 moles to about 2 moles. The process of the present invention can be carried out using polar protic, aprotic, aromatic or aliphatic hydrocarbon solvents having a boiling point higher than 60 C. In preferred embodiments polar protic or aprotic solvents selected from the group comprising amides, ethers, polyethylene glycols (molecular weight 200 to 10,000), sulfoxides, sulphones and the like, are used to carry out the reaction. Preferably, amides and sulfoxides like dimethyl sulfoxide are used as solvents in the process of the present invention. The process of the present invention may be carried out at a temperature ranging from ambient temperature to about 150°C, preferably from about 50°C to about 120 °C, more preferably from about 80°C to about 110°C. The reaction mixture is then filtered and quenched to obtain the desired product. In one embodiment, the process of the present invention provides a racemate of compound of formula I. In a preferred embodiment, the (S)-isomer of ethylmethylcarbamic acid 3-[l-(dimethylamino)ethyl]phenyl ester, a compound of formula I, is separated from the racemate of the compound of formula I, by methods such as conversion of the isomers to diastereomeric chiral acid addition salts, separation of these salts by fractional crystallization, and various other procedures known to a person skilled in the art. The 3-[l-(dialkylamino)alkyl]phenol, which is used as the starting material in the process of the present invention, may be obtained by various processes known to a person skilled in the art. A preferred process involves conversion of a 3-methoxyphenyl ketone to 2-(3-methoxyphenyl)alkyl chloride, reaction of the alkyl chloride thus obtained with a mono/di-substituted alkyl amine, followed by demeth; ; methionine to obtain the 3-[l-(mono/dialkylamino)alkyl] A preferred embodiment of the process of the present (dimethylamino)ethyl]phenol with N-ethyl-N-methyl-presence of potassium carbonate and dimethyl sulfoxi about 80°C to about 120°C for about 30 to 4 ethylmethylcarbamic acid 3-[l-(dimethylamino)ethyl]] This racemate is then resolved to obtain the (S)- ethylme. (dimethylamino)ethyl]phenyl ester. The preferred method of resolution of the (S)-isomer from the racemate involves dissolving a mixture of the free base of the racemate and (+)-di-0,0'-p-toluoyl tartaric acid monohydrate in a 2:1 mixture of methanol: water by heating, collecting the precipitate on cooling by filtration, crystallizing the precipitate from a 2:1 mixture of ethanol: water, and obtaining the substantially pure (S)-isomer by partitioning it between IN sodium hydroxide and a suitable organic solvent. The base may further be converted to its pharmaceutically acceptable acid addition salts, such as L(+)-tartrate salt. The examples that follow do not limit the scope of the present invention and are included as illustrations. Example 1 Preparation of (±)-ethylmethylcarbamic acid 3-[l-(dimethylamino)ethyl "[phenyl ester (± - Rivastigmine) - 3-(l-dimethylaminoethyl)phenol (200gm, 1.21 moles), anhydrous potassium carbonate (252gm, 1.82 moles), N-ethyl-N-methyl-4-nitrophenyl carbamate (340gm, 1.515 moles) and dimethylsulfoxide (1 liter) are mixed and heated at a temperature of about 90° to about 110°C, under nitrogen atmosphere, for 35-40 hours. The reaction mixture is cooled gradually to room temperature and filtered. The filtered solution is quenched in ice-water mixture and extracted with organic solvents to furnish racemic Rivastigmine. We claim - 1. A process for the preparation of a compound of formula I wherein R1 is hydrogen, linear, branched or cyclic lower alkyl, cyclohexyl, allyl, propargyl or benzyl; R is hydrogen, methyl, ethyl or propyl; or R and R together with the nitrogen to which they are attached form a cyclic moiety of three to eight-membered ring, with or without a hetero atom like nitrogen or oxygen; R3 is hydrogen or lower alkyl; R4 and R5 are the same or different and each is a lower , alkyl; comprising reacting a compound of formula II. wherein R3, R4 and R5 are as defined above, with a compound of formula III wherein R1 and R2 are as defined above, in the presence of a base. 2. A process as claimed in claim 1 further comprising resolution of the compound of formula I to obtain (S)-isomer of the compound of formula I, substantially free of the R-isomer. 3. A process as claimed in claim 1, wherein the base is selected from a group comprising alkali and alkaline earth metal oxides or hydroxides or carbonates, and secondary or tertiary amine bases. 4. A process as claimed in claim 3 wherein the base is an alkali carbonate. 5. A process as claimed in claim 4 where the base is potassium carbonate. 6. A process as claimed in claim 1 wherein the base is used in a ratio ranging from about 1.5 moles to about 2 moles with respect to the compound of formula II. 7. A process as claimed in claim 1, wherein the reaction is carried out using polar protic, aprotic, aromatic or aliphatic hydrocarbon solvents having a boiling point higher than 60°C. 8. A process as claimed in claim 7 wherein the solvent is selected from the group comprising amides, ethers, polyethylene glycols (molecular weight 200 to 10,000), sulfoxides, sulphones and mixtures thereof. 9. A process as claimed in claim 1, wherein the reaction is carried out at a temperature ranging from about 80°C to about 110°C. Dated this 31st day of May 2002.

Documents:

484-mum-2002-cancelled pages(25-07-2006).pdf

484-mum-2002-claims(granted)-(25-07-2006).doc

484-mum-2002-claims(granted)-(25-07-2006).pdf

484-mum-2002-correspondence(01-09-2006).pdf

484-mum-2002-correspondence(ipo)-(16-06-2006).pdf

484-mum-2002-form 1(31-05-2002).pdf

484-mum-2002-form 18(28-11-2005).pdf

484-mum-2002-form 2(granted)-(25-07-2006).doc

484-mum-2002-form 2(granted)-(25-07-2006).pdf

484-mum-2002-form 3(25-07-2006).pdf

484-mum-2002-form 3(31-05-2002).pdf

484-mum-2002-form-pct-ipea-409(31-05-2002).pdf

484-mum-2002-form-pct-isa-210(31-05-2002).pdf