Title of Invention

AN IMPROVED PROCESS FOR THE PREPARATION OF 3-AMINO-2-AROYL ACRYLIC ACID DERIVATIVES

Abstract

This invention pertains to an improved process for the preparation of 2-aroyl-3- amino acrylic acid derivatives. The process comprises reacting substituted acetophenones with sodium hydride in the presence of organic carbonates esters, a solvent and a .complex prepared from dimethyl formamide and dimethyl sulfate. 2-aroyl-3-amino acrylic acids are valuable intermediates for the preparation of quinoline drugs like Ciprofloxacin, Enrofloxacin, Norfloxacin, Sparfloxacin, Pefloxacin and number of other related compounds( Quinoline drugs).

Full Text

The present invention relates to an improved process for the preparation of 3-Amino- 2-Aroyl acrylic acid derivatives. The 3-amino-2-aroyl acrylic acid derivatives prepared by the process of the present invention have the general formula -I, and are valuable intermediates for the synthesis of highly active antibacterial agents. 3-Amino-2-aroyl acrylic acid derivatives of the formula-I. in which Ri represents an ester group -COOR4, nitrile group and carboxamide group. R4 denoting Ci-Ce alkyl aryl and aralkyl radical, R5 and Re representing C1-C3 alkyl or cyclo alkyl group, Ra represents hydrogen, cycloalkyl group (C3 - Ce), aromatic group, optionally substituted aromatic group, R3 represents a Ci - Ce alkyl radical or R2 and R3 each represent a C1 - C& alkyl radial or together with the nitrogen atom to which they are bonded, a 3 - 6 membered heterocyclic ring. X represents hydrogen, methyl, nitro or halogen preferably fluorine. Xi represents halogen preferably chlorine or fluorine X2 represents halogen preferably chlorine or fluorine X3 represents hydrogen or halogen , preferably fluorine and, X4 represents hydrogen or halogen, preferably fluorine are useful intermediates for the preparation of highly active antibacterial agents such as Sparfloxacin , Ciprofloxacin, Norfloxacin, Pefloxacin, Enrofloxacin and number of other related compounds of quinolone group. 2 Prior Art: a) 3-Amino-2-Aroyl acrylic acid derivatives of the formula-Ill were prepared by condensation of substituted benzoyl chloride of the formula-II with p-dimethyl amino acrylic acid derivatives of the formula (A) in the presence of an acid acceptors such as triethylamine (Canadian Patent by Bayer 1255678). The above said prior art process has the following disadvantages The starting material dimethyl amino acrylate of the formula (A) is very expensive. Hence to produce antibacterials at a cheaper price, it is necessary to produce the intermediates of the formula-Ill at a cheaper price. The supply of starting material of the formula (A) is controlled by few companies in the world . Hence to plan for the preparation of high volume of antibacterials is risky if we depend totally on imports. b) The second process which is presently practised in India is as follows. The halogenated ketone of the formula-IV is reacted with sodium hydride (NaH) and dimethyl carbonate (DMC) to produce betaketo ester of the formula-V. This betaketoester of the formula (V) is reacted with acetic anhydride (AC2O) arid triethyl orthoformate (TEOF) to produce enol ether of the formula-VI. The compound of the formula-VI is reacted with the amine to give 3-amino-2-Aroyl acrylic acid derivatives of the formula-VII. In all the above said formulae X, X\, X2, X3, X4 represent hydrogen, halogen (preferably CI or F} and/or alkyl (C1-C3) R2 = methyl, ethyl, cyclopropyl, 2,4-Difluorophenyl and optional substituted aromatic radicals. The above said process has the following draw backs. The reaction of betaketoester (V) with acetic anhydride and triethyl orthoformate is a high temperature reaction (140-150°C) and the yields are very sensitive to moisture and can vary from 30-85%. Since the antibacterial compounds Spariloxacin, Ciprofloxacin, Norfloxacin, Pefloxacin, and Enrofloxacin have become very useful drugs and there is a need for an economic and simple methodology for then commercial production overcoming the above problems. The main objective of the present invention is therefore to provide an improved process for the preparation of 3-Amino-2-aroyl acrylic acid derivatives of the formula-1 as defined above by overcoming the draw backs of the hitherto known processes. The synthesis of most of the quinolone antibacterials go through the key derivative of acrylate of the formula-I. We have, due to our sustained research work, observed that the reaction between the anion of p-Keto ester (derived from Ketone of the formula-IV and dimethyl carbonate of the formula-VIII) with complex of the formula-IX provides an important basis for the development of the present invention. X represents hydrogen, methyl, nitro or halogen preferably fluorine. Xi represents halogen preferably chlorine or fluorine X2 represents halogen preferably chlorine or fluorine X3 represents hydrogen or halogen , preferably fluorine and, X4 represents hydrogen or halogen, preferably fluorine Ri has the meaning given earlier R2 represents hydrogen, alky], cycloalkyl group (C3 - Ce), aromatic group, optionally substituted aromatic group. R3 represents hydrogen, alkyl, cycloalkyl group (C3- Ce), aromatic group, optionally substituted aromatic group. R7 represents alkyl, aryl, optionally substituted aryl and benzyl radicals. Rs represents alkyl, aryl, optionally substituted aryl and benzyl radicals. M represents alkali and alkaline earth metal . X represents hydrogen, OR, NH2 Accordingly the present invention provides an improved process for the preparation of 3-Amino-2-aroyl acrylic acid derivatives of the formula-I, (where R1 represents an ester group -COOR4, nitrile group and carboxamide R4 represents Ci - Ce alkyl, aryl and aralkyl radical, R2 represents hydrogen, alkyl, cycloalkyl group (C3 - Ce), aromatic group, optionally substituted aromatic group, R3 represents hydrogen, alkyl, cycloalkyl group (C3 - Ce), aromatic group, optionally substituted aromatic group. X represents hydrogen, methyl, nitro or halogen preferably fluorine, Xi represents halogen preferably chlorine or fluorine, X2 represents halogen preferably chlorine or fluorine, X3 represents hydrogen or halogen, preferably fluorine and X4 represents hydrogen or halogen, preferably fluorine which comprises reacting acetophenone of the formula-IV with a base, carbonate of the formula-VHI, in the presence of an aromatic solvent and then reacting the resulting product with a complex of the formula-IX at a temperature in the range of 0-140°C and recovering the compound of the formula-I, where all the substitutents have the meaning given above except that R2 is not hydrogen and if desired reacting the resulting compound of the formual-I with appropriate amine of the formula-X to obtain the compounds of the formula-XL The compounds of the formula-XI, where X, Xi, X2, X3, X4 ,R2, R3 & R7 have the meanings given earlier and R9 represents C2-Ce alkyl preferably ethyl, are novel intermediates. These intermediates are useful for the preparation of Norfloxacin. 6 I X XI The above said reaction can be carried out with different bases (M+ X ") such as sodium hydride (NaH), Sodiumamide (NaNH2) and sodium methoxide (NaOMe) The carbonate reagent of the formula-VIII can be dialkyl carbonates preferably dimethyl carbonate (DMC), diethyl carbonate (DEC), dibenzyl carbonate (DBC)and the phenyl carbonates can be diphenyl carbonate and other optionally substituted phenyl cabonates. The aromatic solvents that may be used for the reaction can be benzene, toluene or Xylenes (ortho, para or mixed). The reaction can be carried out at a temperature preferably between 20-140°C (or reflux of the solvent). It is preferably carried out under inert atmosphere. The reactants of the formula IV and base (M+ X ")are used preferably in 1:2 molar ratio and in some cases reduced to 1:1 molar ratio. The complex of the formula-IX can be prepared according to the equation shown below. 7 In the above said formulae R2 & R3 may be similar or different alkyl, substituted alkyl (C2-C6), cyclo alkyl,(3-7 membered rings),aryls and optionally substituted aryls. And R2,R3 together can form a cycle of 3-7 membered rings, R8 represents alkyl aryl and benzyl radicals. The complex formation is done according to the procedure given in Org.Syn.Coll.Vol.V page 431 (Originally prepared by H.Bredereck, F.Effenberger and G.Simchem, Chem, Ber., 96 1350 (1963). The details of the present invention are described below with reference to the preparation of some specific compounds falling with in the general formula-I. 2,4-Dichloro-5-fluoro acetophenone of the formula-I is reacted with dimethyl carbonate and sodium hydride in the presence of toluene at the reflux temperature of toluene to form the anion of the formula-2^ After the anion is completely formed complex of formula-3 is added to get aroyl acrylic acid ester of the formula-4. a) The compound of the forumla-4 can be converted into a novel compound of the formula-5 (an intermediate for the preparation of norfloxacin and pefloxacin) on reaction with ethylamine. c) The compound of the forumla-4 can be converted into a compound of the formula-6 (an intermediate for ciprofloxacin and enrofloxacin) on reaction with cyclopropylamine (CPA). c) The compound of the forumla-4 can be converted into a compound of the formula-7 which is an intermediate for the preparation of Tosulfoxacin and sarafloxacin on reaction with a substituted aniline 8. 8 7 In the above scheme Dichlorofluoroacetophenone is taken as an example and is converted to ciprofloxacin and norfloxacin intermediates. Similarly number of other ketones can be converted easily into their Acrylate intermediates. (This matter Blue fonts- inserted now for making description part consistent with claims) Another objective of our invention is An improved process for the preparation of 3-amino-2-aroylacrylic acid derivatives of the formula-I in which Ri represents an ester group -COOR4, nitrile group and carboxamide group. R4 represents Ci-Ce alkyl, aryl and aralkyl radical, R5 and R6 represent C1-C3 alkyl or cyclo alkyl group, R2 represents hydrogen, cycloalkyl (C3 - C&) aromatic group or substituted aromatic group, R3 represents a Ci - Ce alkyl radical or R2 and R3 each represents a Ci - Ce alkyl radical or together with the nitrogen atom to which they are bonded forms a 3-7 membered heterocyclic ring. X, represents hydrogen, methyl, nitro or halogen preferably fluorine. Xi represents halogen preferably chlorine or fluorine X2 represents halogen preferably chlorine or fluorine X3 represents hydrogen or halogen , preferably fluorine and, X4 represents hydrogen or halogen, preferably fluorine which comprises reacting an acetophenone of the formula-II in which X,Xi,X2,X3,X4 have the same meaning given above with a base, a carbonate of the formula-VIII in which R7 represents C1-C6 alkyl, aryl, aralkyl radical in the presence of an aromatic solvent and then reacting the resultant product with the complex of the formula -IX Where R2 & R3 have above mentioned meaning and R8 represents alkyl, aryl optionally substituted aryl and benzyl radicals at a temperature in the range of 0-140°C, and recovering the farmula-I where all the symbols have the meaning 11 given above except that R2 is not hydrogen and if desired reacting the resultant compound of the formula-I with an appropriate amine of the formula-X NH2- R9 X Where R9 represents C 2 - Ce alkyl group, preferably ethyl to obtain the compounds of the formula-XI. Where all the symbols have the meaning given earlier. Yet another objective of our invention is a process according to claim 1 wherein the base used is selected from sodium hydride, sodium or potassium methoxide, sodium or potassium amide, sodium or potassium tert-butoxide, sodium or potassium amyloxide, sodium or potassium sec-butoxide. A process according to the above wherein the carbonate of the formula-VIII, used is selected from dimethyl carbonate, diethyl carbonate diphenyl carbonate or dibenzyl carbonate, the aromatic solvent used is selected from benzene, toluene or xylenes (o-, p- and mixed-xylenes} Another objective our our invention is a process for the preparation of methyl 3-dimethylamino 2- (2,4-dichloro-5-fluoro benzoyl) acrylate (compound of formula-I wherein Rl = -C02Me, R2 = R3 = CH3, X = X4 = H, XI = X2 = CI, X3 = F) which comprises reacting 2,4-dichloro-5-fluoro acetophenone with sodium hydride, dimethyl carbonate, toluene and DMS-DMF complex at a temperature in the range of 0 - 140°C. Yet another objective of the invention is a process for the preparation of methyl 3-ethylamino-2-(2,4-dichloro-5-fluoro) benzoyl acrylate (compound of formula-I wherein Rl = -C02Me, R2 = H, R3 = C2H5, X = X4 = H, XI = X2 = CI, X3 = F) which comprises reacting 2,4-dichloro-5-fluoro acetophenone with sodium hydride, diethyl carbonate, toluene and DMS-DMF complex at a temperature in the range of 0 - 140°C followed by in situ reaction of the resulting product with ethyl amine. 12 Yet another objective or our invention is a process for the preparation of methyl 3-cydopropylamino-2-(2,4-dichloro-5-fiuoro) benzoyl acrylate (compound of formula-I wherein Rl = -C02Me, R2 = H, R3 = cyclopropyl, X = X4 = H, XI = X2 = CI, X3 = F) which comprises reacting 2,4-dichloro-5-fluoro acetophenone with sodium hydride, diethyl carbonate, toluene and DMS-DMF complex at a temperature in the range of 0 - 140°C followed by in situ reaction of the resulting product with cyclopropylamine. Yet another objective of our invention is a process for preparing compounds of the formula-A Where R = H and Rl = ethyl (Norfloxacin); R - Methyl, and Rl = ethyl (Pefloxacin); R = H, Rl = Cyclopropyl [ciprofloxacin] which comprises a) Reacting a compound of formula-I in which Ri =COOR4 in which R* represents methyl, R2 and R3 each represent methyl, 13 Xi,X2 represents chlorine, X^X =represents hydrogen, X3 = represents fluorine with 70% aqueous alkyl amine (alkyl = ethyl or cycloprpyl) to obtain compound of the formula-5. 5 a) Further cyclising and hydrolying the compound of the formula-5 prepared above with a base to obtain a compound of the formula-B B reacting the cyclized compound of the formula-B obtained in step (b) above with piperazine or N-methyl piperazine to obtain pharmaceutical drugs such as norfloxacin (R = H and Rl = ethyl); pefloxacin (R = Methyl, and Rl = ethyl); and ciprofloxacin (R = H, Rl = Cyclopropyl). The details of the process of the present invention are described in the examples given below which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention. 14 Example-1 a) Preparation of N.N-Dimethvl formamide - dimethyl sulfate complex of the formula-lX i where R2, R3 and Rg are methyl). This complex of the formula-IX is prepared as per the procedure (Ref. Org.Syn.CollVol.-V431 (1973). In a 500ml four necked flask equipped with mechanical stirrer, reflux condenser with calcium chloride drying tube, dropping funnel, and thermometer is placed 73 g (1.0 mole) of dimethyl formamide, and 126 g (1.0 mole) of dimethyl sulfate is added dropwise with stirring at 50-60°C. After the addition is complete, the mixture is heated for another 2 hrs at 70-80°C. The complex forms as a viscous pale yellow ether -insoluble oil. It is stable at RT if kept under anhydrous conditions for 2-3 months without any decomposition. b) Preparation of methyl-3-dimethylamino-2-(2,4-dichloro-5-fluorobenzoyl) acrylate of the formula {41. To a stirred solution of toluene (800 ml) and lOOgr of dimethyl carbonate 33g (0.825 mole) of sodium hydride (60% in mineral oil) was added under nitrogen blanket and was heated to reflux . Then 100 g (0.483 mole) of 2,4-dichloro-5- fluoro acetophenone in 100 ml of toluene was added to the above reaction mixture over a period of 90-120 min. After maintaining the reaction mixture for 30 min. At this temperature the reaction mixture was cooled to 15-20°c and freshly prepared dimethyl formamide -dimethyl sulphate complex (220 g) prepared as explained at step(a) above was slowly added into the reaction mass over a period of 30-40 min. The reaction mixture was allowed to rise to 25°c and maintained at this temperature for 2-3 hrs. The reaction mixture was poured into 400 ml of demineralized water (DM water) and the organic layer separated . The organic layer is distilled under vacuum and the obtained crude product triturated with 200 ml of hexane and cooled to 10°c. The methyl-3- 15 dimethyIamino-2-(2,4-dichIoro-5-fluorobenzoyl)-aerylate obtained was dried . Yield = 135 g ( 87.28% on ketone) MR; 106- 108 °c . Example -2 a. Preparation of methvl-3-cvclopropylamino -2-12,4—dichloro-5-fluoro benzoyl) acrvlate of the formula 16). To a stirred solution of methyl-3- dimethylamino-2-(2,4-dichloro-5-fluorobenzoyl) acrylate (compound of the formula (4}- 135 g) ( 0.4 mole) prepared as per step(b) of example 1 in 250 ml of methanol was slowly added 23 g( 0.4 mole) of cyclopropyl amine at 15 - 20°c over a period of 30-40 min. The reaction mixture was allowed to reach 25°c and the solid product filtered, washed with 100 ml of methanol and the product is dried to give 135 g (0.406 mole) of the product MR= 147-149°C (it matches by IR & NMR with the authentic sample) Example -3 Preparation of methvl-3-cyclopropvlamino -2-(2,4—dichloro-5-fluoro benzoyl) acrylate. (6). To a stirred solution of toluene (800 ml) and lOOgr of dimethyl carbonate 33g (0.825 mole) of sodium hydride (60% in mineral oil) was added under nitrogen blanket and was heated to reflux . Then 100 g (0.483 mole) of 2,4-dichloro-5-fluoro acetophenone in 100 ml of toluene was added to the above reaction mixture over a period of 90-120 min. After maintaining for 30 min at this temperature the reaction mixture was cooled to 15-20°c and freshly prepared dimethyl fornamide -dimethyl sulphate complex (220 g) as explained in step (a) of example 1) was slowly added into the reaction mass over a period of 30-40 min. The reaction mixture was allowed to rise to 25Qc and maintained at this temperature for 2-3 hrs. the reaction mixture was poured into 400 ml of DM water and the organic layer separated . the organic layer is distilled under vacuum to get the crude product - 145 g of methyl-3-dimethylamino-2-[2, 4-dichloro-5-fluoro benzoyl acrylate of the formula-4. The crude compound of the formula 4 was dissolved in 250 ml of methanol and cooled to 15-20 °C. Cyclopropylamine (23 gr) was slowly added at this temperature and the reaction mass was allowed to reach 25°c. After maintaining for 2-3 hrs it was cooled to 5°c and the solid is filtered; the solid was washed with 100 ml of methanol and the product is dried to give 135 g of light coloured product. Of methylcyclopropyl amino-2-[2,4-dichloro-5-fluorobenzoyl] acrylate. MR : 147-149ac. Example-4 Preparation of 7-chloro-l-ethyl-6-fluoro-1.4-dihydro-4-oxo quinoline-3- carboxlic acid. a) Preparation of methyl-3-ethylamino-2(2,4-dichloro-5-fluoro benzoyl)acrylate of the formula-5. To a stirred solution of methyl-3-dimethyl amino-2-(2,4-dichIoro-5-fluorobenzoyljacrylate prepared by the process described in example 1 the compound of the formula 4 (128g 0.4 mole) in 250 ml of methanol was slowly added 33g of n-ethylamine (70% aq.solution, 0.51 mole) at 15-20 °c over a period of 30-40 min. the reaction mixture was allowed to reach 25 °c and maintained for 2 hrs.; the solid is filtered and washed with 200 ml of methanol and 200 ml of hexane.; the cake is dried to give 120 g (0.375 moie) of the methyl-3-ethylamino-2[2,4-dichloro-5-fluorobenzoyl] acrylate of the formula-5 with MR : 126-127 °c . b. Cyclization and hydrolysis: 17 To a stirred solution of the acrylate prepared by the process described in step(a) (120 g) in 60 ml of dimethyl formamide (DMF) and 70 ml of toluene was added 36 g of anhydrous potassium carbonate and azeotropically refluxed for 4-5 hrs. After the cyclization is completed toluene is distilled and cooled to 60 °c and 500 ml of water is added and the pH is adjusted to 7 with acetic acid, stirred at 30°c for 15 mts and the product is filtered and washed with water, wet weight is 130 g. The wet compound is taken in 11 sodium hydroxide (1.85%w/v) solution and heated to 80°c and maintained at that temperature for 90 mts. it was cooled to 30°c and pH adjusted to 4 with acetic acid, ( 50ml) stirred for 15 min and the product is filtered and washed with water. The crude product is washed with methanol (100ml) and dried. Dry weight - 95 g (0.353 mole, 88.14%) Chemical assay : 99.65, MR : 284 - 285°c HPLC purity 99.8% The product matches in all respects with the known 7-chloro-l-ethyl-6-fluoro- l,4-dihydro-4-oxo quinoline-3-carboxlic acid (reported in J.Med.Chem 1980, 23^ 1358-1363). This material is further converted to norfloxacin and pefloxacin by the known methods(as reported in J.Med.Chem., 1980, 23,1358-1363) . Example-5 Preparation of methvl-3-dimethvlamino-2-f2.4-dichloro-5-fluorobenzovll acrylate with sodium methoxide powder as a base. To a stirred solution of toluene (800ml) and lOOgr dimethyl carbonate 54 g (0.1 mole) of Sodium methoxide powder was added under nitrogen blanket and was heated to reflux. Then 100 g (0.483 mole) of 2,4-dichloro-5-fluoroacetophenone 18 in 100ml of toluene was added to the above reaction mixture over a period of 90-120 min. After maintaining for 30 min at this temperature the reaction mixture was cooled to 15-20°C and freshly prepared dimethyl formamide -dimethyl sulphate complex (220 g} prepared as explained in step (a) of example-I) was slowly added into the reaction mass over a period of 30-40 min. the reaction mixture was allowed to rise to 25 °C and maintained at this temperature for 2-3 hrs. the reaction mixture was poured into 400 ml of DM water and the organic layer separated . Triturated with 200ml of hexane and cooled to 10 °C. the obtained methyl-3-dimethyl amino-2-(2,4-dichloro-5-fluorobenzoyljacylate was dried . Yield = 115 g (74.35% on ketone). MR: 106- 108 °C. Example-6 Preparation of Methyl-3-dimethylamino-2-{2.4-dichloro-5-fluoro benzoyl) acrylate with sodium amide as base : To a stirred mixture of toluene (800ml) and 100 gr of dimethyl carbonate 40 g (1.025 mole) of sodium amide was added under nitrogen blanket and was heated to reflux. Then lOOg (0.483 mole) of 2,4-dichloro-5-fluoroacetophenone in 100 ml of toluene was added to the above reaction mixture over a period of 90-120min. After maintaining for 30 min at this temperature the reaction mixture was cooled to 15-20°C and freshly prepared dimethyl formamide -dimethyl sulphate complex (220 g) prepared as explained in step (a) of example-I) was slowly added into the reaction mass over a period of 30-40 min. the reaction mixture allowed to rise to 25°C. and maintained at this temperature for 2-3 hrs. ;the reaction mixture was poured into 400ml of DM water and the organic layer separated, the organic layer is distilled under vacuum and the obtained crude product triturated with 200ml of hexane and cooled to 10°C. The product obtained, methyl-3- dimethylamino-2-(2,4-dichloro-5-fluorobenzoyl)acrylate was dried. Yield = 110 g (71.11%) MR : 106 - 108 °C. Example-7 Preparation of Methvl-3-dimethvlamino-2-!2.4-dichloro-5-fluoro benzoyl) acrylate with potassium-t-butoxide as base To a stirred solution of toluene (800ml) and lOOgr of dimethyl carbonate 112,2 g (1.00 mole) Potasium -t-butoxide was added under nitrogen blanket and was heated to reflux. Then lOOg (0.483 mole) of 2,4-dichIoro-5-fIuoro acetophenone in 100ml of toluene was added to the above reaction mixture over a period of 90-120 min. after maintaining for 30 min at this temperature the reaction mixture was cooled to 15-20°C and freshly prepared dimethyl formamide -dimethyl sulphate complex (220 g) prepared as explained in step (a) of example-I) was slowly added into the reaction mass over a period of 30-40 min.; the reaction mixture was allowed to rise to 25°C and maintained at this temperature for 2-3 hrs; the reaction mixture was poured into 400ml of DM water and the organic layer separated. The organic layer is distilled under vacuum and the obtained product triturated with 200ml of hexane and cooled to 10°C; the obtained solid methyl-3-dimethylamino-2-(2,4-dichloro-5-fluorobenzoyl)acrylate was dried. Yield = 90 g (58.19% on ketone) MR : 106 - 108 °C. The reaction was carried out in different bases and found that sodium hydride gives better yields as shown in the table given below. a) The complex of the formula-IX can be prepared from easily available raw materials at a fraction of the cost compared with other methods. b) It is easy to perform and the whole process can be performed in one pot (reactor) thereby increasing the productivity. c) The reaction is at room temperature hence energy requirement is minimum for its production. d) The process of preparing norfloxacin and pefloxacin from the novel intermediate of the formula-V in free from regio-isomers thereby reducing the purification problems. WE CLAIM: 1. An improved process for the preparation of 3-amino-2-aroylacrylic acid derivatives of the formula-I in which R1 represents an ester group -COOR4, nitrile group and carboxamide group. R4 represents C1-C6 alkyl, aryl and aralkyl radical, R5 and Re represent C1-C3 alkyl or cyclo alkyl group, R2 represents hydrogen, cycloalkyl (C3 - C6) aromatic group or substituted aromatic group, R3 represents a C1 - C6 alkyl radical or R2 and R3 each represents a C1 - C6 alkyl radical or together with the nitrogen atom to which they are bonded forms a 3-7 membered heterocyclic ring. X, represents hydrogen, methyl, nitro or halogen preferably fluorine. Xi represents halogen preferably chlorine or fluorine X2 represents halogen preferably chlorine or fluorine X3 represents hydrogen or halogen , preferably fluorine and, X4 represents hydrogen or halogen, preferably fluorine which comprises reacting an acetophenone of the formula-II in which X,X1,X2,X3,X4 have the same meaning given above with a base, a carbonate of the formula-VIII in which R7 represents C1-C6 alkyl, aryl, aralkyl radical in the presence of an aromatic solvent and then reacting the resultant product with the complex of the formula -IX Where R2 & R3 have above mentioned meaning and R8 represents alkyl, aryl optionally substituted aryl and benzyl radicals at a temperature in the range of 0-l40°C, and recovering the formula-I where all the symbols have the meaning given above except that R2 is not hydrogen and if desired reacting the resultant compound of the formula-I with an appropriate amine of the formula-X NH2- R9 X Where R9 represents C 2 - Ce alkyl group, preferably ethyl to obtain the compounds of the formula-XI. Where all the symbols have the meaning given earlier. XI 2 A process according to claim 1 wherein the base used is selected from sodium hydride, sodium or potassium methoxide, sodium or potassium amide, sodium or potassium tert-butoxide, sodium or potassium amyloxide, sodium or potassium sec-butoxide. 3. A process according to claims 1 & 2 wherein the carbonate of the formula-VIII, used is selected from dimethyl carbonate, diethyl carbonate diphenyl carbonate or dibenzyl carbonate. 4. A process according to claims 1 to 3 wherein the aromatic solvent used is selected from benzene, toluene or xylenes (ortho-xylene, para-xylene, or mixed-xylene). 5. A process for the preparation of methyl 3-dimethylamino 2- (2,4-dichloro-5-fluoro benzoyl) acrylate (compound of formula-I wherein Rl = -C02Me, R2 = R3 = CH3, X = X4 = H, XI = X2 = CI, X3 = F) which comprises reacting 2,4-dichloro-5-fluoro acetophenone with sodium hydride, dimethyl carbonate, toluene and DMS-DMF complex at a temperature in the range of 0 - 140°C. 6. A process for the preparation of methyl 3-ethylamino-2-(2,4-dichloro-5-fluoro) benzoyl acrylate (compound of formula-I wherein Rl = -C02Me, R2 = H, R3 = C2H5, X = X4 = H, XI = X2 = CI, X3 = F) which comprises reacting 2,4-dichloro-5-fIuoro acetophenone with sodium hydride, diethyl carbonate, toluene and DMS-DMF complex at a temperature in the range of 0 - 140°C followed by in situ reaction of the resulting product with ethyl amine. 7. A process for the preparation of methyl 3-cyclopropylamino-2-(2,4-dichloro-5-fluoro) benzoyl acrylate (compound of formula-I wherein Rl - -C02Me, R2 = H, R3 = cyclopropyl, X = X4 = H, XI = X2 = CI, X3 = F) which comprises reacting 2,4-dichloro-5-fluoro acetophenone with sodium hydride, diethyl carbonate, toluene and DMS-DMF complex at a temperature in the range of 0 - 140°C followed by in situ reaction of the resulting product with cyclopropylamine. 8. A process for preparing compounds of the formula-A Where R = H and Rl = ethyl (Norfloxacin); R = Methyl, and Rl = ethyl (Pefloxacin); R - H, Rl = Cyclopropyl [ciprofloxacin] which comprises b) Reacting a compound of formula-I in which Ri =COOR4 in which R4 represents methyl, R2 and R3 each represent methyl, Xi,X2 represents chlorine, X4,X represents hydrogen, X3 = represents fluorine with 70% aqueous alkyl amine (alkyl = ethyl or cycloprpyl) to obtain compound of the formula-5. b) Further cyclising and hydrolying the compound of the formula-5 prepared above with a base to obtain a compound of the formula-B reacting the cyclized compound of the formula-B obtained in step (b) above with piperazine or N-methyl piperazine to obtain pharmaceutical drugs such as norfloxacin (R = H and Rl = ethyl); pefloxacin (R = Methyl, and Rl = ethyl}; and ciprofloxacin (R = H, Rl = Cyclopropyl). 9. Novel 3-amino-2aroyl acrylic acid derivatives of the formula I as defined above substantially as herein described with reference to the examples 1 tO 7. 10. A process for the preparation of 3-amino-2aroyl acrylic acid derivatives of the formula I defined above substantially as herein described with reference to the examples 1 to 7. 11. A process for the preparation of compounds of the formula A defined above substantially as herein described with reference to the examples.

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