Title of Invention	AN IMPROVED PROCESS FOR THE PREPARATION OF BENZOYLACRYLIC ACID DERIVATIVES
Abstract	An industrially adva~tageous, one-pot synthesis of 3-amino-2-benzoylacrylic acid derivatives of Fonnula I, which are valuable intennediates for the preparation of highly active antibacterials such as ciprofloxacin and enrofloxacin. wherein R' is methyl or ethyl

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FIELD OF THE INVENTION The present invention relates to an one-pot synthesis of 3-amino-2-benzoylacryUc acid derivatives of Formula I which are valuable intermediates for the preparation of Ciprofloxacin and Enrofloxacin BACKGROUND OF THE INVENTION 3-Amino-2-benzoylacrylic acid derivatives of Formula I are valuable intermediates for the synthesis of highly reactive antibacterial agents such as Ciprofloxacin and Enrofloxacin. Several synthetic methods are known in literature for the preparation of 3-amino-2-benzoylacrylic acid derivatives of Formula I. For example, US Patent 4,670j444 -reported the preparation of the title compounds by the method which comprises the acylation of diethyl malonate with halogenated benzoyl chlorides in the presence of magnesium alcoholates to give acylmalonate, which on subsequent partial hydrolysis and decarboxylation results in the formation of ethylaroylacetate. This ethylaroylacetate is converted with triethyl orthoformate / acetic anhydride into the halogenated aroyl 3-ethoxyacrylate which on reaction with cyclopropylamine leads to the preparation of desired product as shown below in Scheme 1. The above process comprises four reaction steps to prepare the title compounds. Moreover, during partial hydrolysis and decarboxylation of the acyl esters there is the risk of by-products being formed which results in low yields. us patent 4,699,992 describes alternate approach to prepare the 3-amino-2-benzoylacrylic acid derivatives of Formula I overcoming the problems in US patent 4,670,444, Thus, 3-amino-2-benzoylacrylic acid derivatives of Formula I were prepared by the reaction of halogenated benzoyl halides with 3-aminoacrylic acid derivatives of Formula II in the presence of a base, wherein R' is nitrile group, ester group or carboxamide group R" and R'" may be identical or different and represent Ci-Ca alkyl radical. The resulting intermediate of Formula III, is then reacted with cyclopropylamine to prepare title compound of Formula I wherein (R' = CH3 or C2H5). However, this process is also a multi step process and involves use of expensive and lachrymatory raw materials. us patent 5,075,319 described the preparation of 3-amino-2-benzoylacrylic acid derivatives of Formula I in multi steps, the process comprises the condensation of 2,4-dihalo-5-fluoroacetophenone with dialkyl carbonate in the presence of sodium hydride to give 2,4-dihalo-5-fluorobenzoylacetate derivative of Formula IV is isolated by using column chromatography. Alternatively, 2,4-dihalo-5-fluorobenzoylacetate derivative of Formula IV is prepared by converting 2,4-dihalo-5-fluorobenzoic acid to its acid chloride with thionyl chloride and treating the acid chloride a half ester of malonic acid in the presence of n-butyllithium at very low temperature range of-30°C to -5°C. The benzoylacetate derivative of Formula IV prepared by any of the above methods is then treated with dimethylformamide and dimethyl acetal to form 3-dimethylamino-2-benzoylacrylic acid derivative. This resulting intermediate is then treated with cyclopropylamine to produce the corresponding 3-cyclopropylamino-2-benzoylacrylic acid derivatives as shown in scheme-2. However, this synthetic method suffers from several disadvantages such as multi step reactions, isolation of intermediates involving chromatography and conducting the reactions at very low temperature using «-butyllithium. This method is tedious and time consuming. The major disadvantages realized in the known processes are that the title compounds are prepared in multi step using expensive raw materials, yields are low. Further, complicated separations and drying operation for all intermediates, large amount of solvent is used to separate all intermediates and moreover elaborate analytical method development for characterizing them. So, there is an urgent need to develop an efficient and cost-effective process, which should be commercially attractive. In order to avoid multi step synthesis processes, consideration can be given to the development of so called one pot processes. In these processes, the synthesis is carried out in one and the same reaction vessel, without isolating the intermediates, by consecutive addition of the reactants. Therefore, it is an object of the present invention to develop an efficient and cost effective one pot process to prepare 3-amino-2-benzoylacrylic acid derivative of Formula I, which is amenable at industrial scale. SUMMARY OF THE INVENTION The present invention relates to the one-pot process for the preparation of 3-amino-2-benzoylacrylic acid derivative of Formula 1. with (dimethylamino)methoxymethylium methyl sulphate of Formula V subjecting the compound of Formula IX to an amine exchange reaction at a temperature of 5-25°C and isolating the compound of Formula I by removal of solvents. Preferably the process is carried out without isolation of intermediate compounds. DETAILED DESCRIPTION OF INVENTION The instant invention relates to a simple and cost effective one pot process to prepare 3-amino-2-benzoylacrylic acid derivatives Formula I. Further, this invention does not require the isolation and purification of intermediates which means fewer number of process operations resuUing in safety and cost effectiveness. Specifically, the present invention describes a highly efficient process to prepare 3-amino-2-benzoylacrylic acid derivatives of Formula I, which comprises the novel use of (dimethylamino)methoxymethylium methyl sulfate of Formula V. This novel reagent is very cheap and can be easily prepared by mixing A'^A^-dimethyl-formamide and dimethyl sulfate as compared to dimethylformamide dimethylacetal which are expensive, although both reagents are performing the same function. Preferably (dimethylamino)methoxymethylium methyl sulfate of Formula V is prepared by stirring the equimolar quantities of dimethyl sulfate and A^,/^-dimethylformamide at a temperature in the range of 55°C to 80°C. Typically no solvent was used to prepare this adduct and stirring can be carried out for about 4 to 5 hours. The process for the preparation of 3-amino-2-benzoylacrylic acid derivatives of Formula I comprises the reaction of 2,4-dichloro-5-fluoroacetophenone of Formula VI with dialkyl carbonate of Formula VII in the presence of a base, preferably sodium hydride in any suitable solvent. Any suitable solvent can be selected from toluene, benzene or like. The resulting reaction mixture is treated successively with (dimethylamine)methoxymethylium methyl sulfate and cyclopropylamine, in-situ and 3-amino-2-benzoylacrylic acid derivative of Formula I is isolated in high yield and high purity. More specifically, the method involves the reaction of 2,4-dichloro-5-fluoroacetopheneone with compound of Formula VI in the presence of sodium hydride at a temperature in the range of 15°C to 80°C in any suitable solvent such as benzene, toluene preferably toluene of Formula VII. The reaction is preferably conducted at 60°C to 75°C for about 4 to 5 hours. Then reaction mass is cooled and pH is adjusted to 9.0-9.5 by use of any acid preferably acetic acid. The reaction mixture is then subjected to treatment with (dimethylamino)methoxymethylium methyl sulfate at a temperature range of 10°C to 40°C, but preferably at 25°C to 35°C, Further, the organic layer is washed with water or aqueous sodium carbonate solution to remove any acidic impurity. Thereafter, some of the solvent was removed under reduced pressure and rest of the organic layer is cooled and treated with cyclopropylamine. The reaction is preferably conducted at a temperature in the range of 5°C to 25°C. Further the solvent is removed and the highly pure 3-amino-2-benzoylacrylic acid derivatives of Formula I can be isolated by filtration. In one of the embodiment of the present invention, the process is carried out by isolation of all intemiediate in each step. The major advantages reahzed in the present invention as compared with earlier processes are enhanced productivity, consistent yield, simple operational convenience and high purity. Further, novel use of reagent (dimethylamino)methoxymethylium methyl sulfate resulted in increased efficiency and contributes to the lower production cost. These intermediates can be successfully used in the preparation of highly active antibacterial such as ciprofloxacin, enrofloxacin etc. Further details of present invention are to be found in the following examples without limiting it: Example 1 PREPARA TION OF (DIMETHYLAMINO)METHOXYMETHYLIUM METHYL SULPHATE Dimethylsulphate (80 g; 0.63 mol) was added slowly to //^T^-dimethylformamide (46 g, 0.63 mol) at 55-60°C and heated to 70-75°C. The reaction mass was stirred at 70-75°C for 4-5 hours. Example 2 PREPARA TION OF METHYL 3-CYCLOPROPYLAMINO-2-(2,4-DICHLORO'5-FL UOROBENZO YL)A CR YLA TE To a solution of dimethylcarbonate (90 g, 1.0 mol) in dry toluene (800 ml), sodium hydride (36.4 g, 60%, 0.91 mol) was added under dry nitrogen atmosphere at 30°C to SS^'C. The reaction mixture was heated to 70°C to 75°C. A solution of 2,4-dichloro-5-fluoroacetophenone (100 g, 0.48 mol) in toluene (200 ml) was added to the reaction mass at 70°C to 75°C. After maintaining for 4 hours at 70°C to 75°C, the reaction mass was cooled to 18°C to 20°C and pH of the reaction mass was adjusted to 9.0-9.2 with acetic acid. (Dimethylamino)methoxymethylium methyl sulphate (126 g, 0.63 mol) was added at 18°C to 20°C to the reaction mass and it was stirred at 30°C to 35°C for 7 to 9 hours. The resulting mass was cooled to 20°C to 25 °C and washed successively with water (500 ml) and aqueous sodium carbonate (0.5%, 300 ml). The organic layer was concentrated to about half of its volume (-400 ml) and cooled to 10°C to 15°C. Cyclopropylamine (24.4 g, 0.43 mol) was slowly added to the organic layer at 10 to 15°C and stirred for 4 to 5 hours. Toluene (--200 ml) was distilled out at 40-50°C under reduced pressure and reaction mixture was cooled to 0 to 5°C. The product was filtered, washed with chilled toluene (100 ml) and dried to give 135g of the title compound. MELTING POINT: I47-I49'C CHROMA TOGRAPHIC PURITY (HPLC) : 99 .18% Example 3 PREPARA TION OF ETHYL 3CYCLOPROPYLAMINO-2-(2,4-DICHLORO-5-FLUROBENZOYLJACRYLATE To a solution of diethylcarbonate (118 g, 1.0 mol) in dry toluene (800 ml), sodium hydride (36.4 g, 60%, 0.91 mol) was added under dry nitrogen atmosphere at 30°C to 35°C. The reaction suspension was heated to 70°C to 75°C. A solution of 2,4-dichloro-5-fluoroacetophenone (100 g, 0.48 mol) in toluene (200 ml) was added to the reaction mass at 70°C to 75°C. After maintaining for 4 hours at 70°C to 75°C, the reaction mass is cooled to 18°C to 20°C and pH of the reaction mass was adjusted to 9.0-9.2 with acetic acid. To the reaction mass (dimethylamino)methoxymethylium methyl sulphate (126 g, 0.63 mol) was added at 18°C to 20°C to the reaction mass and it was stirred at 30°C to 35°C for 7 to 9 hours. The resulting mass was cooled to 20°C to 25°C and washed successively with water (500 ml) and aqueous sodium carbonate (0.5%, 300 ml). The organic layer was concentrated to about half of its volume (-400 ml) and cooled to 10°C to 15°C. Cyclopropylamine (24.4 g, 0.43 mol) was slowly added to the organic layer at 10-15*^0 and stirred for 4-5 hours. Toluene was distilled out completely at 40-50'^C under reduced pressure. Cyclohexane (150 ml) was added and the reaction mixture was cooled to 0 to 5°C and stirred for 2 h. The product was filtered, washed with chilled cyclohexene (50 ml) and dried to obtain 122g of the title compound. WE CLAIM: 1. A process for the preparation of 3-amino-2-benzoylacrylic acid derivative of Formula I (ii) reacting the compound of Formula VIII with (dimethylamino)methoxymethylium methyl sulphate of Formula V iii) subjecting the compound of Formula IX to an amine exchange reaction at a temperature of 5°C to 25°C and isolating the compound of Formula I by removal of solvent, wherein the process is carried out without isolation of intermediate compounds. 2. A process according to claim 1, wherein the reaction to obtain compound of Formula I is carried out without isolation of intermediates in a one-pot reaction. 3. A process according to claim 1, wherein the said condensation reaction is carried out by making novel use of reagent (dimethylamino)methoxymethylium methyl sulphate. 4. A process according to claim 2, wherein the amine exchanges reaction is carried out at a temperature of 10°C to 20°C.

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