Title of Invention	PROCESS FOR THE PREPARATION OF TRIMEBUTINE MALEATE
Abstract	The present invention relates to a process for the preparation of trimebutine maleate having the structural Formula I.

Full Text

FORM 2 THE PATENTS ACT, 1970 (39 of 1970) COMPLETE SPECIFICATION. (See section 10] 1. Title of the invention: "Process for the preparation of Trimebutine Maleate" 2. Macleods Pharmaceuticals Ltd., an Indian Company, having its Registered Office at 304 - Atlanta Arcade, Opp. Leela Hotel, Marol Church Road, Andheri (East), Mumbai - 400 059, Maharashta, India. 3. The following specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed. Field of the Invention The present invention relates to a process for the preparation of trimebutine maleate. Background of the Invention Chemically, trimebutine maleate is 2-dimethylamino-2-phenylbutyl 3, 4, 5-trimethylbenzoate hydrogen maleate having the structural Formula I. H,C H3C H,C XOOH Trimebutine maleate has been used for the treatment of functional bowel disorders, including irritable bowel syndrome (IBS) and postoperative ileus. French Patent No. 1,344,455 describes a process for the preparation of trimebutine (Scheme I), which involves the reaction of 3, 4, 5-trimethoxy benzoyl chloride of Formula II with 2-(dimethylamino)-2-phenylbutanol of Formula III in benzene solvent. The disadvantages of this process are the use of benzene solvent, which is a known carcinogen and thionyl chloride, which is being used for the preparation of 3, 4, 5-trimethoxybenzoyl chloride of Formula II, which is a known hazardous reagent. H,C H,C Formula H3C o Formula II O Formula IV Scheme I British Patent No. 1,342,547 describes a process for the preparation of trimebutine (Scheme II), which involves the transesterification between methyl ester of 3, 4, 5-trimethoxy-benzoic acid of Formula V and 2-(dimethylarnino)-2-phenylbutanol of Formula III in toluene solvent in the presence of sodium methoxide at 110°C. The disadvantages of this process are low yield and high temperature of the reaction, which render the process not amenable to large-scale manufacture. H,C VCH3 NaOMe H3C OCI-U H3C H3C o Formula V H,C CH3 I 3 N Tolune Formula III Scheme II H,c O Formula IV Kim et al (Bull. Korean Chem. Soc. 2005, Vol. 26, No 2, Pages 340 to 342) describes a process for the preparation of trimebutine (Scheme III), which involves the reaction of 3, 4, 5-trimethoxybenzoyl chloride of Formula II with 2-(dimethylamino)-2-phenylbutanol of Formula III in tetrahydrofuran solvent in the presence of triethylamine and dimethylamino pyridine to obtain crude product, which is purified by means of flash column chromatography technique. The disadvantages of this process are the use of thionyl chloride, which is being used for the preparation of 3, 4, 5-trimethoxybenzoyl chloride of Formula II, which is a known hazardous reagent and purification of crude product by tedious and cumbersome procedures of flash chromatography technique. H,C H,C CH, TEA.DMAP H3C THF H3C H,C o Formula II Formula H,C O Formula IV Scheme III 2 Summary of the Invention It is, therefore desirable to solve the problems associated with the prior art and to provide an efficient process for the preparation of trimebutine maleate which process improves the economics by employing less hazardous raw materials and is more productive. The process avoids the tedious and cumbersome procedures of flash chromatography technique, is economical and convenient to operate on a commercial scale. The first aspect of the present invention is to provide a process for the preparation of trimebutine maleate of Formula I H3C .COOH vCOOH comprising a. reacting 3, 4, 5-trimethoxy benzoic acid of Formula VI with alkyl chloroformate of Formula VII, wherein R is alkyl or substituted alkyl to afford a mixed anhydride of Formula VIII, H3C' ^ H,C H3C Formula VI ROCOCI Formula VII 3 b. further reacting the mixed anhydride of Formula VIII with 2-(dimethylamino)-2-phenylbutanol of Formula III to afford a trimebutine of Formula IV, H,C -#0f •" HO Formula VIII Formula III c. and optionally converting the trimebutine of Formula IV into trimebutine maleate of Formula I. H,C H,C H,C. The second aspect of the present invention is to provide a compound of Formula VIII. HaC H,C wherein R is alkyl or substituted alkyl of C1 to C4 carbon atoms in straight or branched chain form. 4 Detailed Description of the Invention The alkyl chloroformate may be selected from the group comprising having alkyl or substituted alkyl of C1 to C4 carbon atoms in straight or branched chain form. The alkyl chloroformate may be selected from the group comprising of methyl chloroformate, ethyl chloroformate or butyl chloroformate. The reaction of 3, 4, 5-trimethoxy benzoic acid of Formula VI with alkyl chloroformate of Formula VII may be carried out in a suitable organic solvent in the presence of an organic base. The alkyl chloroformate may be used in an amount of 1.0-2.0 molar equivalents of compound of Formula V. The term " suitable organic solvent " may include chlorinated solvents, esters, ketones, ethers, aromatic solvents or mixture(s) thereof. The chlorinated solvents may be selected from the group comprising of dichloromethane, dichloroethane, chloroform or mixture(s) thereof. The esters solvents may be selected from the group comprising of methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, butyl acetate, amyl acetate or mixture(s) thereof. The ketones solvents may be selected from the group comprising of dimethyl ketone, ethyl methyl ketone, methyl isobutyl ketone, diisobutyl ketone or mixture(s) thereof. The ethers may be selected from the group comprising of tetrahydrofuran, 1,4-dioxane or mixture(s) thereof. 5 The aromatic solvents may be selected from the group comprising of toluene, xylene or mixture(s) thereof. The suitable organic solvent may be used in an amount of about 5 to about 25 times of weight of the compound of Formula VI. The organic base may be selected from the group comprising of trimethylamine, triethylamine, picolines, pyridine, pyridine derivatives, morpholine, N-methylmorpholine , morpholine derivatives or N-methylpyrrolidinone. The organic base may be used in an amount of about 1.0 to about 2.5 molar equivalents of the compound of Formula VI. The reaction of 3, 4, 5-trimethoxy benzoic acid of Formula VI with alkyl chloroformate of Formula VII may be carried out at a temperature in the range of about -20°C to about 70°C. The reaction of 3, 4, 5-trimethoxy benzoic acid of Formula VI with alkyl chloroformate of Formula VII may be carried out for about 5 minutes to about 45 minutes. The mixed anhydride of Formula VIII obtained from step a, may be further reacted with 2-(dimethylamino)-2-phenylbutanol of Formula III in the presence of an organic base at a temperature in the range of about 0°C to about 30°C for about 30 minutes to about 3 hours. The organic base may be selected from the group comprising of trimethylamine, triethylamine, picolines, pyridine, pyridine derivatives, morpholine, N-methylmorpholine , morpholine derivatives or N-methylpyrrolidinone. 6 The trimebutine of Formula IV may be isolated from the reaction mixture through the salt formation of trimebutine of Formula IV with inorganic acids. The salt of trimebutine of Formula IV may include trimebutine hydrochloride, trimebutine hydrobromide or trimebutine hydroiodide. The inorganic acids may include hydrochloric acid, hydrobromic acid or hydroiodic acid. The salt formation of trimebutine of Formula IV with inorganic acids may be carried out at a temperature in the range of about 0°C to about 30°C. The trimebutine of Formula IV may be isolated from the organic layer after washing with water / aqueous sodium bicarbonate solution and stirring the residue with hydrocarbon solvents or ether solvents at a temperature in the range of about 0°C to about 30°C. The hydrocarbon solvents may include n-hexane, hexanes, toluene, xylene, or mixture(s) thereof. The ether solvents may include diethyl ether, isopropyl ether or mixture(s) thereof. The trimebutine of Formula IV may be optionally converted into trimebutine maleate by reacting trimebutine of Formula IV with maleic acid in aromatic hydrocarbon solvents at ambient temperature. The aromatic hydrocarbon solvents may include toluene, xylene or mixture(s) thereof. The ambient temperature may be in the range of about 0°C to about 30°C. 7 The trimebutine maleate of Formula I obtained from step c may be dried at a temperature in the range of about 30°C to about 50°C under reduced pressure. The schematic diagram for the process of preparing trimebutine maleate of Formula I is provided below: H,C H,C H,C H,C H,C H,C H,C H°°-o + L.OH ROCOCI AJ 0 Form lulaV Formula VI _COOH Formula I ^COOH H,C o Formula VII HaC Scheme IV 8 The following non-limiting examples illustrate specific embodiments of the present invention. They are, however, not intended to be limiting the scope of present invention in anyway. EXAMPLES: Example 1: Preparation of trimebutine. Triethylamine (47.7 gm) was added to solution of 3, 4, 5-trimethoxybenzoic acid (100 gm) in toluene (1000 ml) at 20-25°C. The solution thus obtained was stirred for 15 minutes and cooled to 0-5°C and ethyl chloroformate (63.9 gm) was added at 0-5°C. The reaction mixture thus obtained was stirred at 0-5 °C for about 30 minutes and to it was added 2-(dimethylamino)-2- phenylbutanol (120 gm), triethylamine (71.5 gm) and toluene (100 ml) at 0-5°C. The reaction mixture thus obtained was stirred at 20-25°C for about 2 hours, washed with water (100 ml), saturated sodium bicarbonate solution (100 ml), and finally with concentrated hydrochloric acid (230 ml). The aqueous layer was separated and pH of the aqueous layer was adjusted to 6.5-7.5 by sodium bicarbonate solution. The solid separated was filtered and dried under reduced pressure to get trimebutine. Yield: 102 gm Purity (By HPLC): 99.7% Example 2: Preparation of trimebutine. Triethylamine (4.7 gm) was added to solution of 3, 4, 5-trimethoxybenzoic acid (10 gm) in tetrahydrofuran (40 ml) at 20-25°C. The solution thus obtained was stirred for 15 minutes and cooled to 0-5°C and ethyl chloroformate (6.3 gm) was added at 0-5°C. The reaction mixture thus obtained was stirred at 0-5 °C for about 30 minutes and to it was added 2-(dimethylamino)-2-phenylbutanol (12 gm), triethylamine (7.15 gm) and tetrahydrofuran (10 ml) at 0-5°C. The reaction mixture thus obtained was stirred at 20- 9 25°C for about 3 hours, washed with water (250 ml) and extracted by toluene (150 ml). The organic layer was separated and washed with saturated sodium bicarbonate solution (50 ml), and concentrated hydrochloric acid (23 ml). The aqueous layer was separated and pH of the aqueous layer was adjusted to 6.5-7.5 by saturated sodium bicarbonate solution and trimebutine was extracted by toluene (100 ml). The organic layer was concentrated under reduced pressure, and the residue was stirred with hexanes (20 ml). The solid separated was filtered and dried under reduced pressure at 20-25°C to get trimebutine. Yield: 6 gm Purity (By HPLC): 99.6% Example 3: Preparation of trimebutine maleate. Trimebutine (79 gm) obtained from example 1 was dissolved in toluene (320 ml) and maleic acid (28.5) in solution of water (320 ml) was added at 20-25°C. The resulting solution was stirred for 24 hours at 20-25°C. The solid separated was filtered and dried under reduced pressure at 20-25° to get trimebutine maleate. Yield: 80 gm Purity (By HPLC): 99.8% 10 We claim: 1. A process for the preparation of trimebutine maleate of Formula I H3C .COOH XOOH comprising a. reacting 3, 4, 5-trimethoxy benzoic acid of Formula VI with alkyl chloroformate of Formula VII, wherein R is alkyl or substituted alkyl to afford a mixed anhydride of Formula VIII, H3C' V* Formula VI + ROCOCI Formula VII b. further reacting the mixed anhydride of Formula VIII with 2-(dimethylamino)-2-phenylbutanol of Formula III to afford a trimebutine of Formula IV, O^.OR Formula H,C Formula VIII H3CS 11 c. and optionally converting the trimebutine of Formula IV into trimebutine maleate of Formula I. H3C H,C XOOH XOOH 2. The process according to claim 1, wherein alkyl chloroformate is selected from the group comprising of methyl chloroformate, ethyl chloroformate or butyl chloroformate. 3. The process according to claim 1, wherein reaction of 3, 4, 5-trimethoxy benzoic acid of Formula VI with alkyl chloroformate of Formula VII is carried out in a suitable organic solvent in the presence of an organic base. 4. The process according to claim 3, wherein suitable organic solvent is selected from the group comprising of chlorinated solvents, esters, ketones, ethers, aromatic solvents or mixture(s) thereof. 5. The process according to claim 3, wherein organic base is selected from the group comprising of trimethylamine, triethylamine, picolines, pyridine, pyridine derivatives, morpholine, N-methylmorpholine, morpholine derivatives or N-methylpyrrolidinone. 12 6. The process according to claim 1 or 3, wherein reaction of 3, 4, 5-trimethoxy benzoic acid of Formula VI with alkyl chloroformate of Formula VII is carried out at a temperature in the range of about -20°C to about 70°C. 7. The process according to claim 1, wherein mixed anhydride of Formula VIII obtained from step a, is further reacted with 2-(dimethylamino)-2-phenylbutanol of Formula III in the presence of an organic base at a temperature in the range of about 0°C to about 30°C for about 30 minutes to about 3 hours. 8. The process according to claim 7, wherein organic base is selected from the group comprising of trimethylamine, triethylamine, picolines, pyridine, pyridine derivatives, morpholine, N-methylmorpholine, morpholine derivatives or N-methylpyrrolidinone. 9. A compound of Formula VIII. H3C^o A, HO ^ wherein R is alkyl or substituted alkyl of C1 to C4 carbon atoms in straight or branched chain form. 13 10. Use of the compound of Formula VIII H,C H,C for the preparation of trimebutine maleate of Formula I H,C .COOH COOH 14 ABSTRACT The present invention relates to a process for the preparation of trimebutine maleate having the structural Formula I. H,C H3C H,C. COOH To The Controller of Patents The patent Office, At Mumbai 15

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