Title of Invention	PROCESS FOR THE PREPARATION OF N,N,6-TRIMETHYL-2(4-METHYPHENYL) IMIDAZO[1,2-a] PYRIDINE-3-ACETAMIDE
Abstract	A process for the preparation of N,N,6-trimethyl-2-(4-methylphenyl)-imidazo [1,2-a]pyridine-3-acetamide,compound of formula I, H3cr (CH3)2NOC Formula I comprising reacting mixed anhydride, compound of formula III, with dimethyiamine; formula III wherein R is selected from C| to Ce linear or branched alkyl groups and substituted phenyl groups.

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FORM 2 THE PATENTS ACT, 1970 (39 OF 1970) COMPLETE SPECIFICATION (See section 10) PROCESS FOR THE PREPARATION OF N,N,6-TRIIYIETIIYI -2(4 IVIE III VLPHENYL)-IMIDAZO| !,2-a|PYRlDINE-3-ACETAMlDE SUN PHARMACEUTICAL INDUSTRIES LTD. A company incorporated under the laws of India having their office at ACME PLAZA, ANDHBRl-KURLA ROAD, ANDHERl (E), MUMBAl-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. PROCESS FOR THE PREPARATION OF N,N,6-TRIMETHYL-2-(4-METHYLPHENYL) -IMIDAZO[l,2-a]PYRIDINE-3-ACETAMIDE The present invention relates to a process for the preparation of N,N,6-trimethyl-2-(4-methylphenyl)-imidazo[l,2-a]pyridine-3-acetamide, commonly known as Zolpidem (INN name), compound of formula I. N,N,6-trimethyl-2-(4-methylphenyl)-imidazo[l,2-a]pyridine-3-acetamide is indicated for the short term treatment of insomnia. (CH3)2NOC Formula I BACKGROUND OF THE INVENTION United States patent number 438293,8 (referred to herein as '938, Indian reference not available) exemplifies a process for the preparation of compound of formula I, by reacting compound of formula II with dimethyl amine in the presence of caibonyldi imidazole. HOOC Formula II Large scale production with carbonyldiimidazole is not viable as carbonyldiimidazole is a very expensive, toxic, allergenic and hygroscopic compound. Further, the decomposition products of carbonyldiimidazole would contaminate the compound of formula I thereby reducing the purity. Thus, purification steps are .required to obtain Zolpidem of acceptable purity. 2 The amidation reaction can also be carried out by reacting compound of formula II with lliionyl chloride followed by reaction with dimethyl amine. Il has been reported thai the reaction product of compound of formula 11 with thionyl chloride gives a black tar which requires additional purification steps, thus making the process unsuitable for industrial scale production. The process of the present invention prepares compound of formula I through a novel mixed anhydride, compound of formula III, without the use of carbonyldiimidazole. ^Fp'rnyt\\a III United states patent number 6407240 (Indian reference not available) describes a process for the preparation of compound of formula I by reducing a-hydroxy ester, compound of formula IV, followed by reaction with dimethylamine in a polyhydroxylated solvent medium. The process of the present invention prepares compound of formula I using a diffeient route via novel mixed anhydride, compound of formula 111. H-.C United states patent number 4794185 (Indian reference not available) describes a process for the preparation of compound of formula I by reacting a-hydroxy-N,N- 3 dimethyl-acetamide derivative with thionyl chloride followed by reduction with sodium borohydride. The drawback of this process is that the intermediate used to prepare a-hydroxy-N,N-dimethyl-acetamide viz., N,N-dimethyl-2.2-dimethoxy-acetamide is less stable as it is sensitive towards traces of water and acid. PCT publication 0138327 (Indian reference not available) describes a process for the preparation of compound of formula I by reacting an ester, compound of formula V, in a polar protic or aprotic solvent with dimethylamine. OR ->v ,•■ Formula V The process of the present invention prepares compound of formula I using novel mixed anhydride, compound of formula III. The stability of mixed anhydride, compound of formula III, of the present invention has been found to be superior to the intermediates reported in prior art. OBJECT OF THE INVENTION An object of the present invention is to provide a novel process for the preparation of compound of formula I, from stable mixed anhydride, compound of formula III. Another object of the present invention is to provide stable mixed anhydride, compound of formula 111, and its process of preparation. 4 SUMMARY OF THE INVENTION Accordingly, the present invention provides a process for the preparation of N,N,6-lniiielhyl-2-(4-melhylphciiyl)-imida/,o 11,2-a'|pyi'idine-3-acetamide,compound of" formula Formula I comprising reacting mixed anhydride, compound of formula III, with dimethylamine, H3C 0 Formula III wherein R is selected from C|to C6 linear or branched alkyl groups and substituted phenyl groups. Optionally compound of formula I may be converted to an acid addition salt such as hemitartrate or tartrate. 5 The present invention also provides mixed anhydride, compound of formula 111,and its process of preparation, comprising reacting compound of formula II, with RCOX; HOOC Formula II DETAILED DESCRIPTION OF THE INVENTION According to the process of the present invention, N,N,6-trimethyl-2-(4-methylphenyl)-irnidazo[l,2-a]pyridine-3-acetamide, compound of formula I, is obtained by reacting mixed anhydride, compound of formula III, with dimethylamine. The novel mixed anhydride, compound of /opmula III, of the present invention may be prepared by reaction of compound of formula II with RCOX wherein R is selected from C|to Q, linear or branched alkyl and substituted phenyl groups, preferably pivaloyl and isobutyl groups and X is a halo group, such as chloro, bromo, fluoro & iodo, preferably chloro. The mixed anhydride, compound of formula III, may be isolated followed by nueleophilic addition reaction with dimethylamine to yield compound of formula I. Optionally compound of formula I may be prepared by reacting compound of formula II with RCOX followed by insitu addition of dimethylamine. According to one embodiment of the process of the present invention the reaction of mixed anhydride, compound of formula III, with dimethylamine may be carried out at about -10 to 100 °C, preferably the reaction is carried out at about -10 to 50°C. The reaction of mixed anhydride, compound of formula III, with dimethylamine may be carried out in an organic solvent in the presence of base. 6 The organic solvent may be selected from non-polar, polar, polar aprotic or polar protic solvents, preferably polar aprotic to non-polar solvent(s). The polar aprotic to non-polar solvent(s) may be selected from ethers such as diethylether, di-isopropylether, diphenylether, dioxane, tetrahydrofuran and the like; linear or cyclic aliphatic or aromatic hydrocarbons such as n-hcxane, n-hcplane, cyelohexane, methyleyclohexanc, toluene, ethylbenzene, xylene and the like; aliphatic or aromatic halogenated hydrocarbons such as methylene dichloride, ethylene dichloride, tetrachloroethane, trichloroethane, chlorobenzene, dichlorobenzene and the like; amides such as acetamide, dimethylformamide, dimethylacetamide and the like; nitriles such as acetonitrile, benzonitrile and the like; sulphoxides such as dimethylsulfoxide, sulfolane and the like. The base is preferably non-nucleophilic base selected from organic and inorganic bases such as linear and cyclic amines selected from CM lower alkyl tertiary amines e.g. trimethylamine triethylamine", l,8-diazabicyclo[5.4.0] undec-7-ene, tetramethylguanidine, pyridine, substituted pyridine, dimethylamino pyridine, lutidine and the like; and carbonates or bicarbonales of alkali or alkaline earth metals such as sodium, potassium, lithium, calcium, barium and the like. According to another embodiment of the process of the present invention mixed anhydride, compound of formula III, may be prepared from compound of formula II with RCOX followed by reaction of mixed anhydride, compound of formula III, with dimethylamine insitu at about -10 to 100 °C, preferably at about -10 to 50°C. Accordingly, the process for the preparation of mixed anhydride, compound of formula III, may be carried out by treating compound of formula II with RCOX wherein R is selected from C|to C6 linear or branched alkyl groups and substituted phenyl groups and X is a halo group; in an organic solvent in the presence of base. The organic solvent may be selected from non-polar, polar, polar aprotic or polar protic solvents, preferably polar aprotic to non-polar solvent(s). The polar aprotic to non-polar solvent(s) may be selected from ethers such as diethylether, di-isopropylether, 7 (.liphcnyloihci", dioxanc, tetrahydrofuran and the like; linear or cyclic aliphatic or aromatic hydrocarbons such as n-hexane, n-heptane, cyclohexane, methylcyclohexane, toluene, ethyl benzene, xylene and the like; aliphatic or aromatic halogenated hydrocarbons such as methylene dichloride, ethylene dichloride, tetrachloroethane, trichloroethane, chlorobenzene, dichlorobenzene and the like; amides such as acetamide, (liinelhyllbiinaiiiidc, dimolhylacetamidc and the like; nilriles such as acctonitrile, benzonitrile and the like; sulphoxides such as dimethylsulfoxide, sulfolane and the like. The base is preferably non-nucleophilic base selected from organic and inorganic bases such as linear and cyclic amines selected from CM lower alkyl tertiary amines e.g. triinelhylamine triethylamine, l,8-diazabicyclo[5.4.0] undec-7-ene, tetramethylguanidine, pyridine, substituted pyridine, dimethylamino pyridine, lutidine and the like; and carbonates or bicarbonates of alkali or alkaline earth metals such as sodium, potassium, lithium, calcium, barium and the like. Compound of formula II used in the preparation of compound of formula III may be prepared as per any prior art method such as United States patent number 4382938. Further, the compound of formula I may be converted to acid addition salts such as acetic, citric, malic, succinic, maleic, fumaric, oxalic, tartaric, alkyl or aryl sulfonic, pamoic, xinafoic, ascorbic and the like or mineral acids such as hydrochloric, hydrobromic, sulfuric and the like. The invention is illustrated but not restricted by the description in the following examples. 8 Examples: Example-1 Preparation of 2-(4-methylphenyl)-6-methyl-imidazo(l,2-a)pyridine-3-acetic acid, compound of formula II Charge 150 It of cone, hydrochloric acid along with 15 kg of 2-(4-methylphenyl)-6-methyl-imidazo(l,2-a)pyridine-3-acetonitrile into a reaction vessel under stirring at 25 to 30 deg.C. Heal: the reaction mixture upto 97-100 deg.C. Maintain at reflux temperature for 12 hrs. Cool the reaction mixture to 30 to 35 deg.C and then further cool to 15 to 20 deg.C for an hour and filter. Wash with chilled demin. water, chilled acetone to obtain crude compound of formula II. Treat with 18%w/v of aqueous potassium hydroxide solution at 25 to 30 deg.C and heat to 100 to 105 deg.C for 2-3 hrs. Cool to 30 to 35 deg.C and add demin. water and cool. Then charge glacial acetic acid and adjust pH between 5 to 5.2 at 30 to 40 deg.C, further cool to 25 to 30 deg.C and maintain for an hour and filter. Wash the cake with chilled demin. water, acetone and dry to obtain compound of formula II. Example-2 Preparation of N,N16-Trimethvl-2-(4-methylphenyl)-imidazo[l,2-a|pvridine-3- acctamide (Formula I) Charge 13 kg of 2-(4-methylphenyl)-6-methyl -imidazo[l,2-a]pyridine-3-acetic acid, compound of formula II, followed by methylene dichloride 195 Its to the reaction vessel, stir and cool the contents to 10 to 15° C under nitrogen atmosphere. Charge triethylamine 9.23 It to the chilled contents and further cool to 0 to 2 deg.C. Add Pivaloyl chloride 7.28 kg to the above reaction mixture slowly at 0 to 10°C.The compound of formula III is obtained in the reaction mass. Add 40% aqueous dimethyl amine solution (15.6 kg) to the above mentioned reaction mass within 20 to 30 minutes at 0 to 2 ° C and stir for 30 mins at 0 to 5 deg.C. Charge 52 Its of 4% aqueous sodium hydroxide solution into the reaction mixture and maintain temperature at 25 to 30 deg C for 15 minutes and separate the organic layer. Then charge 52 Its of 4% aqueous sodium hydroxide solution into the separated organic layer in a 9 reactor. Stir at 25 to 30 deg C for 15 mins. Allow the phases to separate and repeat the washing with aqueous sodium hydroxide twice. Then wash with demin water twice. Dry the organic' layer over anhydrous sodium sulfate and distill off methylene dichloride below 60 deg.C. Charge 26 Its of ethyl acetate to the residue and heat to distillation temperature to distill off 19 Its of ethyl acetate and repeat the addition and distillation of ethyl acetate Then charge 39 l;ts of ethyl acetate in to the reactor. Cool the reaction mixture to 30 to 35 deg. C, further cool to 20 to 25 deg. C, stir for 60 minutes and filter. Wash the solids with ethyl acetate and dry to yield compound of formula I. ICxampIc-3 Preparation of N,N,6-Trimethvl-2-(4-methylpheiivl)-imidazo[l,2-alpvridine-3- acetamide liemitartrate Charge 100 Its of methanol and 10 kg of compound of formula I obtained from example 2 into a reactor and stir for 10 mins. Add a solution of 2.43 kg L(+) tartaric acid to 50 Its of methanol to the reactor. Gradually raise the temp of reaction mixture to 30 to 35 deg.C and maintain the temp for 2 hrs. Cool to 0 to 2 deg.C and stir for 1 hr and filter. Wash the solids with methanol and dry to yield hemitartrate of compound of formula I. 10 1. A process for the preparation of N,N,6-trimethyl-2-(4-methylphenyl)-imidazo F1,2-n'|pyridinc-3-iicctamidc,compound of formula I, / N. CH, ,N H-.C (CH3)2NOC rormula 1 comprising reacting mixed anhydride, compound of formula III, with dimethylamine; HiC Formulii I'll wherein R is selected from C|to C6 linear or branched alkyl groups and substituted phenyl groups. 2. A process as claimed in 1 wherein the mixed anhydride, compound of formula III is prepared by reacting compound of formula II with RCOX; / CH-, H-.CT N' l-IOOC Formula II wherein R is selected from C|to Q, linear or branched alkyl groups and substituted phenyl groups and X is a halo group 3. A process for the preparation of compound of formula I as claimed in claim 1 further comprising converting compound of formula 1 to its hemitartrnte or tartrate salt. 4. A process for the preparation of compound of formula I as claimed in claim 1 wherein R is selected from pivaloyl and isobutyl groups. 5. A process for the preparation of compound of formula I as claimed in claim 2 wherein X is chloro. 6. A process for the preparation of compound of formula I as claimed in claim 1 wherein the reaction is carried out in polar aprotic to non-polar solvent(s). 7. A process for the preparatioiVof compound of formula I as claimed in claim 1 wherein the reaction is carried out in the presence of non-nucleophilic base. 8. A process for the preparation of compound of formula I as claimed in claim 1 wherein the reaction is carried out at about -10 to 100°C. 9. Mixed anhydride, compound of formula III, H,c Formula III 12 wherein R is selected from C|to Q, linear or branched alkyl groups and substituted phenyl groups. 10. Mixed anhydride, compound of formula III, as claimed in claim 9 wherein R is selected from pivaloyl and isobutyl groups. I I. A process for the preparation of mixed anhydride, compound of formula Hi, comprising reacting compound of formula II, with RCOX; Formula II wherein R is selected from C|to C6 linear or branched alkyl and substituted phenyl groups and X is a halo group. 12. A process for the preparation of mixed anhydride, compound of formula III, as claimed in claim 11 wherein R is selected from pivaloyl and isobutyl groups. 13. A process for the preparation of mixed anhydride, compound of formula III, as claimed in claim 11 wherein X is Chloro. 14. A process for the preparation of mixed anhydride, compound of formula III, as claimed in claim 11 wherein the reaction is carried out in polar aprotic to non-polar solvent. 15. A process for the preparation of mixed anhydride, compound of formula III, as claimed in claim 11 wherein the reaction is carried cut in the presence of non-nucleophilic base. 13 16. A process for the preparation of mixed anhydride, compound of formula III, as claimed in claim 11 wherein reaction is carried out at about -10 to 100°C. 17. A process for the preparation of compound of formula I as claimed in claims 1 to 16 substantially as herein described and illustrated by examples 1,2 and 3. 14

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