Title of Invention	GREEN PROCESS FOR PREPARATION OF HALOPHENYLACETIC ACIDS AND CORRESPONDING ESTERS.
Abstract	This invention describes a green process for preparation of a - halo - halophenyl acetic acids and corresponding esters thereof. There are several drawbacks of existing methods like generation of large quantities of waste material including highly acidic streams, handling of liquid bromine, use of costly and hazardous catalysts, use of low temperature conditions during the reaction, use of photo-bromination which make these processes unfriendly to the environment and also makes them uneconomical. Present invention describes solution to these drawbacks by use of brominating agent D13PMTD and by recovering DMID which is a spent of brominating agent. This methodology is used to prepare an intermediate for an oral antiplatelet agent used to inhibit blood clots in coronary artery disease, peripheral vascular disease, and cerebrovascular disease and can also be applied to other a-halo acids and esters having chloro, bromo group at a -position and various groups in other positions.

Title of Invention

GREEN PROCESS FOR PREPARATION OF HALOPHENYLACETIC ACIDS AND CORRESPONDING ESTERS.

Abstract

This invention describes a green process for preparation of a - halo - halophenyl acetic acids and corresponding esters thereof. There are several drawbacks of existing methods like generation of large quantities of waste material including highly acidic streams, handling of liquid bromine, use of costly and hazardous catalysts, use of low temperature conditions during the reaction, use of photo-bromination which make these processes unfriendly to the environment and also makes them uneconomical. Present invention describes solution to these drawbacks by use of brominating agent D13PMTD and by recovering DMID which is a spent of brominating agent. This methodology is used to prepare an intermediate for an oral antiplatelet agent used to inhibit blood clots in coronary artery disease, peripheral vascular disease, and cerebrovascular disease and can also be applied to other a-halo acids and esters having chloro, bromo group at a -position and various groups in other positions.

Full Text	FORM 2 THE PATENTS ACT 1970 (39 of 1970) & The Patent Rules, 2003 Provisional Specification (See section 10 and rule 13) Green Proccss For Preparation Of Halophenylacetic Acids And Corresponding Esters Mr. Chaudhari, Sharad N An Indian Citizen Leeds Kem Group, D - 50, MI DC Area, Near Ajanta Road, Jalgaon - 425003, Maharashtra State, India. The following specification describes the invention: GREEN PROCESS FOR PREPARATION OF HALOPHENYLACETIC ACIDS AND CORRESPONDING ESTERS Field of Invention: This invention generally relates to a process for halogenation of 2-halophenyl acetic acid ester as well as 2-halophenyl acetic acid and esterification thereof to yield corresponding alpha halo ester and particularly relates to preparation of methyl alpha- bromo-2-chlorophenylacetate. Discussion of prior art: Many a halo acids and a halo acids esters are widely used in chemical industry as intermediates for many important class of compounds including pharmaceuticals, dyes, pigments, agro chemicals, fine chemicals and specialty chemicals. One of the important a halo acids is a bromo phenyl acetic acid. Similarly one of the important a halo acid esters is a bromo phenyl acetic acid methyl ester. Out of the many esters of a bromo acids, methyl a-bromo-2-chlorophenylacetate is an important intermediate for Clopidogrel [113665-84-2]; an oral antiplatelet agent (thienopyridine class) used to inhibit blood clots in coronary artery disease, peripheral vascular disease, and cerebrovascular disease. / Clopidogrel Fig. 1 Many processes for the preparation of cc-bromo-2-chlorophenyl acetic acid and methyl a-bromo-2-chlorophenylacetate are cited in the literature. Some of patents cited are GB 1,277,578 equivalent to DE 1,933,629, US 6,358,971 equivalent to WO 99,59857, JP 2000/034256, US 5,374,656, US 5,189,170, US 5,036,156, US 6,124,343, WO 2007/126258, WO 9111999A1. Widely used method of preparation for a-bromo-2-chlorophenyl acetic acid and methyl a-bromo-2-chlorophenylacetate, is bromination of 2-chlorophenyl acetic acid and niethylation thereof as represented in Fig. 2. (1) SOCI2 (2) (a) Bromine, catalyst Red P - or - (b) NBS, UV light or Redical generator (3) Esterification Fig, 2 There are several drawbacks of existing methods like generation of large quantities of waste material, handling of liquid bromine which is highly hazardous to human beings as well as to the environment. Use of costly and hazardous catalysts like red phosphorous in some of the processes makes these processes unfriendly to the environment and also makes them uneconomical. Use of low temperature conditions during the reaction requires use of "ozone depleting" refrigerants. Use of photo- bromination in some of the existing methods requires specialized equipment. On^ of the major drawbacks of the existing methods is generation of large quantity of highly acidic effluent which requires a large facility for effluent treatment and disposal of wastes. These factors impose location related constraints making it mandatory for these processes to be carried out only in designated areas. In general exiting processes are non-green that harms the environment to a large extent, which has become the major global concern in today's chemical industry. Hence there is a need for providing a process which is green that avoids above mentioned disadvantages and drawbacks and provides an environmentally sustainable and economical process. Objects and Advantages of Invention: Accordingly different objects and advantages of the present invention are described below. An object of the present invention is to provide an environmentally friendly (green) process that overcomes the problem of generation of large quantities of acidic wastes resulting from the conventional processes. Another object of the present invention is to provide a process wherein side products formation is minimized, thereby reducing the generation of organic wastes and making the process greener. Yet another object of the present invention is to provide a process which will prevent generation of large quantity of highly acidic effluent which requires a large facility for effluent treatment and disposal of wastes, thereby imposing location related constraints making it mandatory for these processes to be carried out only in designated areas. Further object of the present invention is to provide environment - friendly (green) process that overcomes the problem of generation of large quantities of liquid wastes resulting from the conventional processes, since the process described in the present invention uses bromine releasing agent l,3-Dibromo-5,5-dimethylimidazolidine-2.4- dione (DBDMID) as brominating agent in place of liquid bromine, and recovers 5,5- dimethylimidazolidine-2,4-dione (DMID)which is a spent of brominating agent from the reaction mixture. The different advantages of this invention are described below: An advantage of the present invention is that excess methyl a-bromo-2- chlorophenylacetate is used as a medium for the reaction described in the present invention. Other solvents including methylene dichloride, ethylene dichloride and other chlorinated solvents alone and / or in combination thereof can also be used in the process of the present invention. Another advantage of the present invention is that the end product, which is methyl a-bromo-2-chlorophenylacetate, is purer because the side products formation is minimized, thereby making the impurity profile acceptable for further conversion into Clopidogrel. Yet other advantage of the present invention is that the end product, which is methyl a-bromo-2-chlorophenylacetate, is separated from the reaction mixture by distillation under reduced pressure; which is one of the green unit operations leading to minimum waste generation as well as requires lesser energy. Further advantage of the present invention is that 5,5-dimethylimidazolidine-2,4- dione (DMID) is recovered from the reaction mixture by crystallization by cooling which does not generate any waste streams. Further objects and advantages of the present invention will become apparent to the reader after going through the detailed description of invention. Brief description of figures: The brief description of the drawings accompanying the specification is given below. Fig. 1 shows structure of Clopidogrel Fig. 2 shows reaction sequence of prior art method Fig. 3 shows esterification of 2-chlorophenyl acetic acid into methyl 2-chlorophenyl acetate followed by bromination of 2-chlorophenyl acetate into methyl a-bromo-2- chlorophenylacetate Fig. 4 shows bromination of 2-chlorophenyl acetic acid into a-bromo-2-chlorophenyl acetic acid followed by esterification of a-bromo-2-chlorophenyl acetic acid into methyl alpha-bromo-2-chlorophenylacetate Fig. 5 shows the compounds that can be prepared by using the methodology described in the present invention Detailed description of the invention: The present application discloses a sustainable chemical process for green bromination of methyl 2-chlorophenyl acetate into methyl a-bromo-2- chlorophenylacetate as shown in Fig. 3 and also a process of bromination of 2-chlorophenyl acetic acid into a-bromo-2- chlorophenyl acetic acid followed by esterification into methyl a-bromo-2- chlorophenylacetate as shown in Fig. 4. Methyl-Alpha-bromo-2- chlorophenylacetate Fig. 4 The present application also discloses a sustainable chemical process wherein 5,5- dimethylimidazolidine-2,4-dione (DMID) is recovered as shown in Fig. 3 and Fig. 4. (A) According to the most preferred embodiment of the present invention, is provided a green process for preparation of a-halo acids and corresponding esters comprising the following steps that is est^rification steps followed by bromination steps, wherein separate solvents are not used. Esterification steps: 1. Weighing and charging of 2-chlorophenyl acetic acid into the reaction vessel; 2. weighing and charging MeOH into the reaction vessel under stirring; 3. weighing and charging tosicacid into the reaction mass; 4. refluxing reaction mixture till completion (disappearance of starting material) under stirring; 9 5. removing excess MeOH by distillation under stirring; 6. washing residue with water; 7. washing organic phase with sodium bicarbonate for removal of acidity; 8. washing of organic phase with water to remove any residual alkalinity; and 9. drying organic phase to yield methyl-2-chlorophenyl acetate. Bromination steps: 1. Weighing and charging methyl-2-chlorophenyl acetate into the reaction vessel; 2. heating methyl-2-chlorophenyl acetate under stirring; 3. weighing and mixing brominating agent such as l,3-Dibromo-5,5- dimethylimidazolidine-2,4-dione (DBDMID) and free radical initiator; 4. charging mixture of DBDMID and free radical initiator into the reaction vessel under stirring in predetermined lots; 5. maintaining reaction mass at a particular temperature under stirring during the addition; 6. maintaining reaction mass under stirring at predetermined temperature till predetermined conversion is achieved; 7. cooling reaction mixture under stirring; 8. maintaining reaction mixture at predetermined temperature under stirring till compete crystallization of 5,5-dimethylimidazolidine-2J4-dione (DMID) is achieved; 9. filtering S^-dimethylimidazolidine^^-dione (DMID) from the cooled reaction mixture; 10. washing of the filtrate with water; 11. washing of the organic mass with alkali to remove acidity; 12. washing of the organic mass with water to remove any residual alkalinity; and 13. fractionating the organic mass under reduced pressure to yield methyl a- bromo-2-chlorophenylacetate and recovering starting product. In the above mentioned esterification steps, the following parameters are used. 2-Chlorophenyl acetic acid is esterified with MeOH to methyl-2-chlorophenyl acetate. Esterification is achieved by using various catalysts. Acidic catalysts including mineral acids, ptosicacid, resins, zeolites and / or combination thereof, are used in esterification. In this preferred embodiment of the invention, tosicacid and mineral acid are used as catalysts. The process of the present invention proceeds in a very broad range of temperatures. The reaction temperature is kept between about 40°C to 100°C., preferably between 60°C to 90°C, more preferably between 65°C to 85°C. 2-Chlorophenyl acetic acid / MeOH weight ratio varies within a broad range. 2- Chlorophenyl acetic acid / MeOH weight ratio is preferably between about 1 and 5, more preferably between about 1 and 3, still more preferably between about 1 and 2. 2-Chlorophenyl acetic acid / tosicacid weight ratio varies within a broad range. 2- Chiorophenyl acetic acid / tosicacid weight ratio is preferably between about 0.01 and 0.1, more preferably between about 0.015 and 0.08, still more preferably between about 0.02 and 0.06. The isolation of methyl-2-chlorophenyl acetate from the reaction mixture is done by applying various procedures. Isolation method in present invention uses standard procedures such as removal of excess MeOH, quenching of the reaction mass in water and the like, and standard equipment such as distillation assembly, stirred kettle and the like. In this preferred embodiment of the invention, methyl-2-chlorophenyl acetate is isolated by recovering excess MeOH. Recovery of excess MeOH of this invention proceeds in a very broad range of temperatures in accordance with the reduced pressure applied. During the recovery the reaction temperature is ke'pt between about 20°C to 65°C., preferably between 20°C to 50°C., more preferably between 30°C to 40°C. Recovery of excess MeOH of this invention proceeds in a very broad range of reduced pressure conditions. Reduced pressure during recovery is kept between about 718 mm of Hg to 1mm of Hg, preferably between 318 mm of Hg and 630 mm of Hg, more preferably between 680 mm of Hg and 668 mm of Hg. In the above mentioned bromination steps, the following parameters are used Excess methyl-2-chlorophenyl acetate is used as a medium for bromination reaction described in this most preferred embodiment of the present invention. Free radical initiator is used as a catalyst. The process of this invention proceeds with a broad range of free radical initiators including peroxides, UV light . In this most preferred embodiment of the invention, Acetoxyl is used as a free radical initiator. The process of this invention proceeds in a very broad range of temperatures. The reaction temperature is kept between about 40°C to 120°C., preferably between 60°C to 100°C., more preferably between 80°C to 90°C. Methyl-2-chlorophenyl acetate / DBDMID weight ratio varies within a broad range. The methyl-2-chlorophenyl acetate / DBDMID weight ratio is preferably between about 0.1 and 1.0, more preferably between about 0.2 and 0.9, still more preferably between about 0.4 and 0.8. Methyl-2-chlorophenyl acetate / free radical initiator weight ratio varies within a broad range. The methyl-2-chlorophenyl acetate / free radical initiator weight ratio is preferably between about 0.005 and 5.0, wore preferably between about 0.02 and 3. 0. still more preferably between about 0.04 and 0.08. The isolation of methyl a-bromo-2-chlorophenylacetate from the reaction mixture is done by applying various procedures. Isolation method in present invention uses standard procedures such as distillation, quenching in water and the like, and standard equipment such as distillation kettle, stirred kettle and the like. In this most preferred embodiment of this invention, methyl a-bromo-2- chlorophenylacetate is isolated by distillation. This distillation process proceeds in a very broad range of temperatures in accordance with the reduced pressure applied. The reaction temperature is kept between about 70°C to 170°C., preferably between 80°C to 140°C., more preferably between 100°C to 130°C. This distillation proceeds in a very broad range of reduced pressure conditions. The reduced pressure during recovery is kept between about 724mm of Hg to 628mm of Hg, preferably between 718mm of Hg and 653mm of Hg, more preferably between 680mm of Hg and 668rnm of Hg. 5,5-Dimethylimidazolidine-2,4-dione (DMID) is recovered from the reaction mixture by crystallization by cooling. The crystallsation process of this invention proceeds by following a very broad range of cooling curves. This crystallization process also proceeds in a very broad range of temperatures. The reaction temperature is kept between about -10°C to 60°C., preferably between l0°C to 50°C., more preferably between 20°C to 40°C. fn another embodiment of the present invention, instead of using excess methyf-2- chlotophenyl acetate as reaction medium, various solvents alone or in combination thereof can be used from a wide range of solvents including halogenated hydrocarbons with number of carbon atoms in the range of 1 to 20, aromatic solvents, saturated aliphatic or unsaturated aliphatic or aromatic halogenated solvents with number of halogens in the range of 1 to 6, ethers ROR' wherein R and R' are same or different and wherein saturated alkyl group or unsaturated alkyl group or saturated straight chain alkyl group or unsaturated straight chain alkyl group or saturated branched chain alkyl group or unsaturated branched chain alkyl group or aromatic rings wherein number of aromatic rings are in the form of fused rings or otherwise ranges from 1 to 5, esters like RCOOR' wherein saturated alkyl group or unsaturated alkyl group or saturated straight chain alkyl group or unsaturated straight chain alkyl group or saturated branched chain alkyl group or unsaturated branched chain alkyl group or aromatic rings wherein number of aromatic rings are in the form of fused rings or otherwise ranges from 1 to 5. Other solvents from the class of solvents including formaamides, formanilides, amines, nitroaromatics, haloaromatics can also be used. In this embodiment of the present invention, wherein separate solvent is used, the following additional steps are used, at appropriate stages in the bromination steps of the process. Additional steps (in bromination steps): 1. Weighing and charging solvent; 2. distillation of the organic mass to recover solvent. In the above mentioned additional steps, (in bromination steps) the following parameters are used. Methyl-2-chlorophenyl acetate / solvent weight ratio varies within a broad range. The methyl-2-chlorophenyl acetate / solvent weight ratio is preferably between about 0.1 and 10, more preferably between about 0.5 and 5, still more preferably between about 1 and 3. Recovery of solvent of this invention proceeds in a very broad range of temperatures in accordance with the reduced pressure applied. During the recovery the reaction temperature is kept between about 20°C to 135°C., preferably between 20°C to 120°C., more preferably between 90°C to 120°C, Recovery of solvent of this invention proceeds in a very broad range of reduced pressure conditions. Reduced pressure during recovery is kept between about 718mm of Hg to 628mm of Hg, preferably between 718mm of Hg and 653mm of Hg, more preferably between 688mm of Hg and 668mm of Hg. (C) In yet another embodiment of the present invention, the green process for preparation of a-halo acids and corresponding esters comprises the following steps, that is, initial bromination steps followed by esterification steps, wherein separate solvents are not used. Bromination steps: 1. Weighing and charging 2-chlorophenyl acetic acid into the reaction vessel; 2. heating 2-chlorophenyl acetic acid to melt under stirring; 3. weighing and mixing brominating agent such as l,3-Dibromo-5,5- dimethylimidazolidine-2,4-dione (DBDMID) and free radical initiator; 4. charging mixture of DBDMID and free radical initiator into the reaction vessel under stirring in predetermined lots; 5. maintaining reaction mass at a predetermined temperature under stirring during the addition; 6. maintaining reaction mass under stirring at a predetermined temperature till predetermined conversion is achieved; 7. cooling reaction mixture under stirring; 8. cooling the reaction mass to room temperature; 9. weighing and charging water to the reaction mass; 10. filtering a-bromo-2-chlorophenyl acetic acid from the reaction mixture; 11. washing of a-bromo-2-chlorophenyl acetic acid with water till free from acidity; 12. drying of a-bromo-2-chlorophenyl acetic acid; 14. cooling filtrate; 15. filtering 5,5-dimethylimidazolidine-2,4-dione (DMID) from the filtrate; 16. washing with water till free from acidity; and 17. drying of the 5,5-dimethylimidazolidine-2,4-dione (DMID). Esterification steps: 1. Weighing and charging of alpha-bromo-2-chloropheny] acetic acid into the reaction vessel; 2. weighing and charging MeOH into the reaction vessel under stirring; 3. weighing and charging tosicacid into the reaction vessel under stirring; 4. refluxing reaction mixture till completion (disappearance of starting material) under stirring; 5. removing excess MeOH by distillation under stirring; 6. washing residue with water to remove acidity: and 7. fractionating organic mass to yield methyl a-bromo-2-chlorophenylacetate. In the above mentioned bromination steps, the following parameters are used in this embodiment of the present invention. Molten 2-chIorophenyI acetic acid is used as a medium for bromination reaction described in this embodiment of the present invention. Free radical initiator is used as a catalyst. The process of this invention proceeds with a broad range of free radical initiators including peroxides, UV light. In this embodiment of the invention, Acetoxyl is used as a free radical initiator. The process of this invention proceeds in a very broad range of temperatures. The reaction temperature is kept between about 95°C to 150°C., preferably between 95°C to 125°C., more preferably between 95°C to 105°C. 2-Chlorophenyl acetic acid / DBDMID weight ratio varies within a broad range. The 2-chlorophenyl acetic acid / DBDMID weight ratio is preferably between about 0.1 and 5, more preferably between about 0.5 and 4, still more preferably between about 0.6 and 2. 2-Chlorophenyl acetic acid / free radical initiator weight ratio varies within a broad range. The 2-chlorophenyl acetic acid / free radical initiator weight ratio is preferably between about 0.005 and 5.0, more preferably between about 0.02 and 3, still more preferably between about 0.04 and 1. The isolation of a-bromo-2-chloropheny] acetic acid from the reaction mixture is done by applying various procedures. Isolation method in this embodiment of the present invention uses standard procedures such as, quenching in water, filtration and the like and standard equipment such as stirred kettle, filtration assembly and the like. In this embodiment of the invention, a-bromo-2-chlorophenyl acetic acid is isolated by diluting the reaction mass with water. This dilution process proceeds in a very broad range of temperatures. The dilution temperature is kept between about -10°C to 95°C., preferably between 20°C to 60°C., more preferably between 35°C to 45°C. Solid a-bromo-2-chlorophenyl acetic acid is isolated from the reaction mixture by filtration. This wet cake of a-bromo-2-chlorophenyl acetic acid is washed with water to remove acidity. The drying of the wet cake of a-bromo-2-chlorophenyl acetic acid is done at a very broad range of temperatures. The drying temperature is kept between about 40°C to 100°C., preferably between 50°C to 90°C more preferably between 60°C to 80°C. This drying is done till predetermined moisture content is achieved. 5,5-Dimethylimidazolidine-2,4-dione (DMID) is recovered from the filtrate by crystallization by cooling. The crystallization process of this invention proceeds by following a very broad range of cooling curves. This crystallization process proceeds in a very broad range of temperatures. The temperature of the filtrate is kept between about -10°C to 100°C., preferably between 0°to 80°C., more preferably between 5°C to 30°C, Solid DBH is isolated from the filtrate by filtration. This wet cake of 5,5- dimethylimidazolidine-2,4-dione (DMID) is washed with water to remove acidity. The drying of the wet cake of 5,5-dimethylimidazolidine-2?4-dione (DMID) is done at a very broad range of temperatures. The drying temperature is kept between about 30°C to 100°C., preferably between 40C to 90°C., more preferably between 50°C to 80 C. This drying is done till predetermined moisture content is achieved. In the above mentioned esterification steps, the following parameters are used in this embodiment of the present invention: a-bromo-2-chlorophenyl acetic acid is esterified with MeOH to methyl a-bromo-2- chloropheny I acetate . Esterification is achieved by using various catalysts. Aacidic catalysts including mineral acids, ptosicacid, resins, zeolites and / or combination thereof, are used in esterification. In this embodiment of the invention, tosicacid and mineral acid are used as catalysts. The process of the present invention proceeds in a very broad range of temperatures. The reaction temperature is kept between about 30°C to 100°C., preferably between 50°C to 90°C., more preferably between 70°C to 80°C. a-bromo-2-chlorophenyl acetic acid / MeOH weight ratio varies within a broad range. a-bromo-2-chIorophenyI acetic acid / MeOH weight ratio is preferably between about 1 and 10, more preferably between about 1.5 and 8, still more preferably between about 2 and 4. a-bromo-2-chlorophenyl acetic acid / tosicacid weight ratio varies within a broad range, a-bromo-2-chlorophenyl acetic acid / tosicacid weight ratio is preferably between about 0.005 and 5.0, more preferably between about 0.02 and 3, still more preferably between about 0.04 and 0.08. The isolation of methyl-2-chloropheny! acetate from the reaction mixture is done by applying various procedures. Isolation method in present invention uses standard procedures such as removal of excess MeOH, quenching of the reaction mass in water and the like, and standard equipment such as distillation assembly, stirred kettle and the like. In this embodiment of the invention, methyl-2-chlorophenyl acetate is isolated by recovering excess MeOH. Recovery of excess MeOH of this invention proceeds in a very broad range of temperatures in accordance with the reduced pressure applied. During the recovery the reaction temperature is kept between about 30°C to 100°C., preferably between 50°C to 80°C„ more preferably between 60°C to 75°C. Recovery of excess MeOH of this invention proceeds in a very broad range of reduced pressure conditions. Reduced pressure during recovery is kept between about 718mm of Hg to 628mm of Hg, preferably between 718mm of Hg and 653mm of Hg, more preferably between 688mm of Hg and 668mm of Hg. (D) In still other embodiment of the present invention, wherein the process comprises initial bromination steps followed by esterification steps, instead of using excess methyl-2-chlorophenyl acetate as reaction medium various solvents alone or in combination thereof can be used from a wide range of solvents including halogenated hydrocarbons with number of carbon atoms in the range of 1 to 20, aromatic solvents, saturated aliphatic or unsaturated aliphatic or aromatic halogenated solvents with number of halogens in the range of 1 to 6, ethers ROR' wherein R and R' are same or different and wherein saturated alkyl group or unsaturated alkyl group or saturated straight chain alkyl group or unsaturated straight chain alkyl group or saturated branched chain alkyl group or unsaturated branched chain alkyl group or aromatic rings wherein number of aromatic rings are in the form of fused rings or otherwise ranges from 1 to 5, esters like RCOOR' wherein saturated alkyl group or unsaturated alkyl group or saturated straight chain alkyl group or unsaturated straight chain alkyl group or saturated branched chain alkyl group or unsaturated branched chain alkyl group or aromatic rings wherein number of aromatic rings are in the form of fused rings or otherwise ranges from I to 5. Other solvents from the class of solvents including formaamides, formanilides, amines, nitroaromatics, haloaromatics can also be used. According to this embodiment of the present invention, in which separate solvent is used the following additional steps are used, at appropriate stages in the bromination steps of the process. Additional steps (in bormination steps): 1. Weighing and charging solvent; 2. distillation of the organic mass to recover solvent. In the above mentioned additional steps (in bromination steps), the following parameters are used. a-bromo-2-chlorophenylacetate / solvent weight ratio varies within a broad range. The a-bromo-2-chlorophenylacetate / solvent weight ratio is preferably between about 0.2 and 10, more preferably between about 0.5 and 8, still more preferably between about 1 and 4. Recovery of solvent of this invention proceeds in a very broad range of temperatures in accordance with the reduced pressure applied. During the recovery the reaction temperature is kept between about 30°C to 140°C., preferably between 30°C to 130°C., more preferably between 120°C to 125°C. Recovery of solvent of this invention proceeds in a very broad range of reduced pressure conditions. Reduced pressure during recovery is kept between about 718mm of Hg to 628mm of Hg, preferably between 718mm of Hg and 653mm of Hg, more preferably between 688mm of Hg and 668mm of Hg. Following surprising advantages are observed by the inventor as a result of the process of the present invention: 1. It is an environmentally friendly (green) process that overcomes the problem of generation of large quantities of liquid wastes resulting from the conventional processes; since the process described in the present invention uses bromine releasing agent l,3-Dibromo-5,5-dimethylimidazolidine-2,4- dione (DBDMID) as brominating agent in place of liquid bromine; and recovers 5,5-dimethylimidazolidine-2,4-dione (DMID)which is a spent of brominating agent from the reaction mixture. 2. Acidic catalysts including tosicacid, mineral acids, resins, zeolites and /or combination of these can be used the in esterification. 3. Excess methyl a-bromo-2-chlorophenylacetate is used as a medium for the reaction described in the present invention. Other solvents including methylene dichloride, ethylene dichloride, and other chlorinated solvents alone and / or in combination thereof can also be used in the process of the present invention. 4. Molten 2-chloro-phenylacetic acid is used as a medium for the reaction described in the present invention. Other solvents including methylene dichloride, ethylene dichloride, and other chlorinated solvents alone and / or in combination thereof can also be used in the process of the present invention. 5. The end product, which is methyl a-bromo-2-chlorophenylacetate, is purer because the side products formation is minimized, thereby making the impurity profile acceptable for further conversion into Clopidogrel. 6. The end product, which is a-bromo-2-chlorophenylacetic acid, is purer because the side products formation is minimized, thereby making the impurity profile acceptable for further conversion into methyl a-bromo-2- chlorophenylacetate and Clopidogrel. 7. The end product, which is methyl a-bromo-2-chlorophenylacetate, is separated from the reaction mixture by distillation under reduced pressure; which is one of the green unit operations leading to minimum waste generation. 8. 5,5-Dimethylimidazolidine-2,4-dione (DMID) is recovered from the reaction mixture by crystallization by cooling which does not generate any waste streams. 9. Other a-halo acid esters such as shown in Fig. 5 Fig, 5 wherein; Z is attached to a carbon atom adjacent to carbonyl group; X, Y, Ri, R2, R3, R4, R5 can be various groups including but not limited to following, X can be chloro, bromo; Y can be CnH2n wherein n is 1 to 20; Rl, R2, R3, R4, R-s can be H, halogen, straight chain or branched chain alkyl groups with number of carbon atoms ranging from 1 to 20, aryl groups, nitro groups, amino groups, cyano groups, hydroxyl groups, thio- groups, ester groups, ether groups, aldehyde groups; A can 1 to 5 as linear or angular fused rings; can also be prepared using the methodology described in this invention.

Full Text

FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
The Patent Rules, 2003
Provisional Specification
(See section 10 and rule 13)
Green Proccss For Preparation Of Halophenylacetic Acids And Corresponding Esters
Mr. Chaudhari, Sharad N
An Indian Citizen
Leeds Kem Group, D - 50, MI DC Area, Near Ajanta Road, Jalgaon - 425003, Maharashtra State, India.

The following specification describes the invention:

GREEN PROCESS FOR PREPARATION OF HALOPHENYLACETIC ACIDS AND CORRESPONDING ESTERS
Field of Invention:
This invention generally relates to a process for halogenation of 2-halophenyl acetic acid ester as well as 2-halophenyl acetic acid and esterification thereof to yield corresponding alpha halo ester and particularly relates to preparation of methyl alpha- bromo-2-chlorophenylacetate.
Discussion of prior art:
Many a halo acids and a halo acids esters are widely used in chemical industry as intermediates for many important class of compounds including pharmaceuticals, dyes, pigments, agro chemicals, fine chemicals and specialty chemicals. One of the important a halo acids is a bromo phenyl acetic acid. Similarly one of the important a halo acid esters is a bromo phenyl acetic acid methyl ester.
Out of the many esters of a bromo acids, methyl a-bromo-2-chlorophenylacetate is an important intermediate for Clopidogrel [113665-84-2]; an oral antiplatelet agent (thienopyridine class) used to inhibit blood clots in coronary artery disease, peripheral
vascular disease, and cerebrovascular disease.
/

Clopidogrel
Fig. 1
Many processes for the preparation of cc-bromo-2-chlorophenyl acetic acid and methyl a-bromo-2-chlorophenylacetate are cited in the literature. Some of patents cited are GB 1,277,578 equivalent to DE 1,933,629, US 6,358,971 equivalent to WO 99,59857, JP 2000/034256, US 5,374,656, US 5,189,170, US 5,036,156, US 6,124,343, WO 2007/126258, WO 9111999A1.
Widely used method of preparation for a-bromo-2-chlorophenyl acetic acid and methyl a-bromo-2-chlorophenylacetate, is bromination of 2-chlorophenyl acetic acid and niethylation thereof as represented in Fig. 2.

(1) SOCI2
(2) (a) Bromine, catalyst Red P - or - (b) NBS, UV light or Redical generator
(3) Esterification

Fig, 2
There are several drawbacks of existing methods like generation of large quantities of waste material, handling of liquid bromine which is highly hazardous to human beings as well as to the environment. Use of costly and hazardous catalysts like red phosphorous in some of the processes makes these processes unfriendly to the environment and also makes them uneconomical. Use of low temperature conditions during the reaction requires use of "ozone depleting" refrigerants. Use of photo- bromination in some of the existing methods requires specialized equipment.
On^ of the major drawbacks of the existing methods is generation of large quantity of highly acidic effluent which requires a large facility for effluent treatment and disposal of wastes. These factors impose location related constraints making it mandatory for these processes to be carried out only in designated areas. In general exiting processes are non-green that harms the environment to a large extent, which has become the major global concern in today's chemical industry.
Hence there is a need for providing a process which is green that avoids above mentioned disadvantages and drawbacks and provides an environmentally sustainable and economical process.
Objects and Advantages of Invention:
Accordingly different objects and advantages of the present invention are described below.
An object of the present invention is to provide an environmentally friendly (green) process that overcomes the problem of generation of large quantities of acidic wastes resulting from the conventional processes.
Another object of the present invention is to provide a process wherein side products formation is minimized, thereby reducing the generation of organic wastes and making the process greener.
Yet another object of the present invention is to provide a process which will prevent generation of large quantity of highly acidic effluent which requires a large facility for effluent treatment and disposal of wastes, thereby imposing location related constraints making it mandatory for these processes to be carried out only in designated areas.
Further object of the present invention is to provide environment - friendly (green) process that overcomes the problem of generation of large quantities of liquid wastes resulting from the conventional processes, since the process described in the present invention uses bromine releasing agent l,3-Dibromo-5,5-dimethylimidazolidine-2.4- dione (DBDMID) as brominating agent in place of liquid bromine, and recovers 5,5- dimethylimidazolidine-2,4-dione (DMID)which is a spent of brominating agent from the reaction mixture.
The different advantages of this invention are described below:
An advantage of the present invention is that excess methyl a-bromo-2- chlorophenylacetate is used as a medium for the reaction described in the present invention. Other solvents including methylene dichloride, ethylene dichloride and other chlorinated solvents alone and / or in combination thereof can also be used in the process of the present invention.
Another advantage of the present invention is that the end product, which is methyl a-bromo-2-chlorophenylacetate, is purer because the side products formation is minimized, thereby making the impurity profile acceptable for further conversion into Clopidogrel.
Yet other advantage of the present invention is that the end product, which is methyl a-bromo-2-chlorophenylacetate, is separated from the reaction mixture by distillation under reduced pressure; which is one of the green unit operations leading to minimum waste generation as well as requires lesser energy.
Further advantage of the present invention is that 5,5-dimethylimidazolidine-2,4- dione (DMID) is recovered from the reaction mixture by crystallization by cooling which does not generate any waste streams.
Further objects and advantages of the present invention will become apparent to the reader after going through the detailed description of invention.
Brief description of figures:
The brief description of the drawings accompanying the specification is given below.
Fig. 1 shows structure of Clopidogrel
Fig. 2 shows reaction sequence of prior art method
Fig. 3 shows esterification of 2-chlorophenyl acetic acid into methyl 2-chlorophenyl acetate followed by bromination of 2-chlorophenyl acetate into methyl a-bromo-2- chlorophenylacetate
Fig. 4 shows bromination of 2-chlorophenyl acetic acid into a-bromo-2-chlorophenyl acetic acid followed by esterification of a-bromo-2-chlorophenyl acetic acid into methyl alpha-bromo-2-chlorophenylacetate
Fig. 5 shows the compounds that can be prepared by using the methodology described in the present invention
Detailed description of the invention:
The present application discloses a sustainable chemical process for green bromination of methyl 2-chlorophenyl acetate into methyl a-bromo-2- chlorophenylacetate as shown in Fig. 3

and also a process of bromination of 2-chlorophenyl acetic acid into a-bromo-2- chlorophenyl acetic acid followed by esterification into methyl a-bromo-2- chlorophenylacetate as shown in Fig. 4.

Methyl-Alpha-bromo-2- chlorophenylacetate
Fig. 4

The present application also discloses a sustainable chemical process wherein 5,5- dimethylimidazolidine-2,4-dione (DMID) is recovered as shown in Fig. 3 and Fig. 4.
(A) According to the most preferred embodiment of the present invention, is provided a green process for preparation of a-halo acids and corresponding esters comprising the following steps that is est^rification steps followed by bromination steps, wherein separate solvents are not used.
Esterification steps:
1. Weighing and charging of 2-chlorophenyl acetic acid into the reaction vessel;
2. weighing and charging MeOH into the reaction vessel under stirring;
3. weighing and charging tosicacid into the reaction mass;
4. refluxing reaction mixture till completion (disappearance of starting material) under stirring;
9

5. removing excess MeOH by distillation under stirring;
6. washing residue with water;
7. washing organic phase with sodium bicarbonate for removal of acidity;
8. washing of organic phase with water to remove any residual alkalinity; and
9. drying organic phase to yield methyl-2-chlorophenyl acetate.
Bromination steps:
1. Weighing and charging methyl-2-chlorophenyl acetate into the reaction vessel;
2. heating methyl-2-chlorophenyl acetate under stirring;
3. weighing and mixing brominating agent such as l,3-Dibromo-5,5- dimethylimidazolidine-2,4-dione (DBDMID) and free radical initiator;
4. charging mixture of DBDMID and free radical initiator into the reaction vessel under stirring in predetermined lots;
5. maintaining reaction mass at a particular temperature under stirring during the addition;
6. maintaining reaction mass under stirring at predetermined temperature till predetermined conversion is achieved;
7. cooling reaction mixture under stirring;
8. maintaining reaction mixture at predetermined temperature under stirring till compete crystallization of 5,5-dimethylimidazolidine-2J4-dione (DMID) is achieved;
9. filtering S^-dimethylimidazolidine^^-dione (DMID) from the cooled reaction mixture;
10. washing of the filtrate with water;
11. washing of the organic mass with alkali to remove acidity;
12. washing of the organic mass with water to remove any residual alkalinity; and

13. fractionating the organic mass under reduced pressure to yield methyl a- bromo-2-chlorophenylacetate and recovering starting product.
In the above mentioned esterification steps, the following parameters are used.
2-Chlorophenyl acetic acid is esterified with MeOH to methyl-2-chlorophenyl acetate. Esterification is achieved by using various catalysts. Acidic catalysts including mineral acids, ptosicacid, resins, zeolites and / or combination thereof, are used in esterification. In this preferred embodiment of the invention, tosicacid and mineral acid are used as catalysts.
The process of the present invention proceeds in a very broad range of temperatures. The reaction temperature is kept between about 40°C to 100°C., preferably between 60°C to 90°C, more preferably between 65°C to 85°C.
2-Chlorophenyl acetic acid / MeOH weight ratio varies within a broad range. 2- Chlorophenyl acetic acid / MeOH weight ratio is preferably between about 1 and 5, more preferably between about 1 and 3, still more preferably between about 1 and 2.
2-Chlorophenyl acetic acid / tosicacid weight ratio varies within a broad range. 2- Chiorophenyl acetic acid / tosicacid weight ratio is preferably between about 0.01 and 0.1, more preferably between about 0.015 and 0.08, still more preferably between about 0.02 and 0.06.
The isolation of methyl-2-chlorophenyl acetate from the reaction mixture is done by applying various procedures. Isolation method in present invention uses standard procedures such as removal of excess MeOH, quenching of the reaction mass in water and the like, and standard equipment such as distillation assembly, stirred kettle and the like.
In this preferred embodiment of the invention, methyl-2-chlorophenyl acetate is isolated by recovering excess MeOH.
Recovery of excess MeOH of this invention proceeds in a very broad range of temperatures in accordance with the reduced pressure applied. During the recovery the reaction temperature is ke'pt between about 20°C to 65°C., preferably between 20°C to 50°C., more preferably between 30°C to 40°C.
Recovery of excess MeOH of this invention proceeds in a very broad range of reduced pressure conditions. Reduced pressure during recovery is kept between about 718 mm of Hg to 1mm of Hg, preferably between 318 mm of Hg and 630 mm of Hg, more preferably between 680 mm of Hg and 668 mm of Hg.
In the above mentioned bromination steps, the following parameters are used
Excess methyl-2-chlorophenyl acetate is used as a medium for bromination reaction described in this most preferred embodiment of the present invention. Free radical initiator is used as a catalyst.
The process of this invention proceeds with a broad range of free radical initiators including peroxides, UV light . In this most preferred embodiment of the invention, Acetoxyl is used as a free radical initiator.
The process of this invention proceeds in a very broad range of temperatures. The reaction temperature is kept between about 40°C to 120°C., preferably between 60°C to 100°C., more preferably between 80°C to 90°C.
Methyl-2-chlorophenyl acetate / DBDMID weight ratio varies within a broad range. The methyl-2-chlorophenyl acetate / DBDMID weight ratio is preferably between about 0.1 and 1.0, more preferably between about 0.2 and 0.9, still more preferably between about 0.4 and 0.8.
Methyl-2-chlorophenyl acetate / free radical initiator weight ratio varies within a broad range. The methyl-2-chlorophenyl acetate / free radical initiator weight ratio is
preferably between about 0.005 and 5.0, wore preferably between about 0.02 and 3. 0. still more preferably between about 0.04 and 0.08.
The isolation of methyl a-bromo-2-chlorophenylacetate from the reaction mixture is done by applying various procedures. Isolation method in present invention uses standard procedures such as distillation, quenching in water and the like, and standard equipment such as distillation kettle, stirred kettle and the like.
In this most preferred embodiment of this invention, methyl a-bromo-2- chlorophenylacetate is isolated by distillation. This distillation process proceeds in a very broad range of temperatures in accordance with the reduced pressure applied. The reaction temperature is kept between about 70°C to 170°C., preferably between 80°C to 140°C., more preferably between 100°C to 130°C. This distillation proceeds in a very broad range of reduced pressure conditions. The reduced pressure during recovery is kept between about 724mm of Hg to 628mm of Hg, preferably between 718mm of Hg and 653mm of Hg, more preferably between 680mm of Hg and 668rnm of Hg.
5,5-Dimethylimidazolidine-2,4-dione (DMID) is recovered from the reaction mixture by crystallization by cooling. The crystallsation process of this invention proceeds by following a very broad range of cooling curves. This crystallization process also proceeds in a very broad range of temperatures. The reaction temperature is kept between about -10°C to 60°C., preferably between l0°C to 50°C., more preferably between 20°C to 40°C.
fn another embodiment of the present invention, instead of using excess methyf-2- chlotophenyl acetate as reaction medium, various solvents alone or in combination thereof can be used from a wide range of solvents including halogenated hydrocarbons with number of carbon atoms in the range of 1 to 20, aromatic solvents, saturated aliphatic or unsaturated aliphatic or aromatic halogenated solvents with
number of halogens in the range of 1 to 6, ethers ROR' wherein R and R' are same or different and wherein saturated alkyl group or unsaturated alkyl group or saturated straight chain alkyl group or unsaturated straight chain alkyl group or saturated branched chain alkyl group or unsaturated branched chain alkyl group or aromatic rings wherein number of aromatic rings are in the form of fused rings or otherwise ranges from 1 to 5, esters like RCOOR' wherein saturated alkyl group or unsaturated alkyl group or saturated straight chain alkyl group or unsaturated straight chain alkyl group or saturated branched chain alkyl group or unsaturated branched chain alkyl group or aromatic rings wherein number of aromatic rings are in the form of fused rings or otherwise ranges from 1 to 5. Other solvents from the class of solvents including formaamides, formanilides, amines, nitroaromatics, haloaromatics can also be used.
In this embodiment of the present invention, wherein separate solvent is used, the following additional steps are used, at appropriate stages in the bromination steps of the process.
Additional steps (in bromination steps):
1. Weighing and charging solvent;
2. distillation of the organic mass to recover solvent.
In the above mentioned additional steps, (in bromination steps) the following parameters are used.
Methyl-2-chlorophenyl acetate / solvent weight ratio varies within a broad range. The methyl-2-chlorophenyl acetate / solvent weight ratio is preferably between about 0.1 and 10, more preferably between about 0.5 and 5, still more preferably between about 1 and 3.

Recovery of solvent of this invention proceeds in a very broad range of temperatures in accordance with the reduced pressure applied. During the recovery the reaction temperature is kept between about 20°C to 135°C., preferably between 20°C to 120°C., more preferably between 90°C to 120°C,
Recovery of solvent of this invention proceeds in a very broad range of reduced pressure conditions. Reduced pressure during recovery is kept between about 718mm of Hg to 628mm of Hg, preferably between 718mm of Hg and 653mm of Hg, more preferably between 688mm of Hg and 668mm of Hg.
(C) In yet another embodiment of the present invention, the green process for preparation of a-halo acids and corresponding esters comprises the following steps, that is, initial bromination steps followed by esterification steps, wherein separate solvents are not used.
Bromination steps:
1. Weighing and charging 2-chlorophenyl acetic acid into the reaction vessel;
2. heating 2-chlorophenyl acetic acid to melt under stirring;
3. weighing and mixing brominating agent such as l,3-Dibromo-5,5- dimethylimidazolidine-2,4-dione (DBDMID) and free radical initiator;
4. charging mixture of DBDMID and free radical initiator into the reaction vessel under stirring in predetermined lots;
5. maintaining reaction mass at a predetermined temperature under stirring during the addition;
6. maintaining reaction mass under stirring at a predetermined temperature till predetermined conversion is achieved;
7. cooling reaction mixture under stirring;
8. cooling the reaction mass to room temperature;
9. weighing and charging water to the reaction mass;
10. filtering a-bromo-2-chlorophenyl acetic acid from the reaction mixture;
11. washing of a-bromo-2-chlorophenyl acetic acid with water till free from acidity;
12. drying of a-bromo-2-chlorophenyl acetic acid;
14. cooling filtrate;
15. filtering 5,5-dimethylimidazolidine-2,4-dione (DMID) from the filtrate;
16. washing with water till free from acidity; and
17. drying of the 5,5-dimethylimidazolidine-2,4-dione (DMID).
Esterification steps:
1. Weighing and charging of alpha-bromo-2-chloropheny] acetic acid into the reaction vessel;
2. weighing and charging MeOH into the reaction vessel under stirring;
3. weighing and charging tosicacid into the reaction vessel under stirring;
4. refluxing reaction mixture till completion (disappearance of starting material) under stirring;
5. removing excess MeOH by distillation under stirring;
6. washing residue with water to remove acidity: and
7. fractionating organic mass to yield methyl a-bromo-2-chlorophenylacetate.
In the above mentioned bromination steps, the following parameters are used in this embodiment of the present invention.
Molten 2-chIorophenyI acetic acid is used as a medium for bromination reaction described in this embodiment of the present invention. Free radical initiator is used as a catalyst.
The process of this invention proceeds with a broad range of free radical initiators including peroxides, UV light. In this embodiment of the invention, Acetoxyl is used as a free radical initiator.
The process of this invention proceeds in a very broad range of temperatures. The reaction temperature is kept between about 95°C to 150°C., preferably between 95°C to 125°C., more preferably between 95°C to 105°C.
2-Chlorophenyl acetic acid / DBDMID weight ratio varies within a broad range. The 2-chlorophenyl acetic acid / DBDMID weight ratio is preferably between about 0.1 and 5, more preferably between about 0.5 and 4, still more preferably between about 0.6 and 2.
2-Chlorophenyl acetic acid / free radical initiator weight ratio varies within a broad range. The 2-chlorophenyl acetic acid / free radical initiator weight ratio is preferably between about 0.005 and 5.0, more preferably between about 0.02 and 3, still more preferably between about 0.04 and 1.
The isolation of a-bromo-2-chloropheny] acetic acid from the reaction mixture is done by applying various procedures. Isolation method in this embodiment of the present invention uses standard procedures such as, quenching in water, filtration and the like and standard equipment such as stirred kettle, filtration assembly and the like.
In this embodiment of the invention, a-bromo-2-chlorophenyl acetic acid is isolated by diluting the reaction mass with water. This dilution process proceeds in a very broad range of temperatures. The dilution temperature is kept between about -10°C to 95°C., preferably between 20°C to 60°C., more preferably between 35°C to 45°C. Solid a-bromo-2-chlorophenyl acetic acid is isolated from the reaction mixture by filtration. This wet cake of a-bromo-2-chlorophenyl acetic acid
is washed with water to remove acidity. The drying of the wet cake of a-bromo-2-chlorophenyl acetic acid is done at a very broad range of temperatures. The drying temperature is kept between about 40°C to 100°C., preferably between 50°C to 90°C more preferably between 60°C to 80°C. This drying is done till predetermined moisture content is achieved.
5,5-Dimethylimidazolidine-2,4-dione (DMID) is recovered from the filtrate by crystallization by cooling. The crystallization process of this invention proceeds by following a very broad range of cooling curves. This crystallization process proceeds in a very broad range of temperatures. The temperature of the filtrate is kept between about -10°C to 100°C., preferably between 0°to 80°C., more preferably between 5°C to 30°C, Solid DBH is isolated from the filtrate by filtration. This wet cake of 5,5- dimethylimidazolidine-2,4-dione (DMID) is washed with water to remove acidity. The drying of the wet cake of 5,5-dimethylimidazolidine-2?4-dione (DMID) is done at a very broad range of temperatures. The drying temperature is kept between about 30°C to 100°C., preferably between 40C to 90°C., more preferably between 50°C to 80 C. This drying is done till predetermined moisture content is achieved.
In the above mentioned esterification steps, the following parameters are used in this embodiment of the present invention:
a-bromo-2-chlorophenyl acetic acid is esterified with MeOH to methyl a-bromo-2- chloropheny I acetate . Esterification is achieved by using various catalysts. Aacidic catalysts including mineral acids, ptosicacid, resins, zeolites and / or combination thereof, are used in esterification. In this embodiment of the invention, tosicacid and mineral acid are used as catalysts. The process of the present invention proceeds in a very broad range of temperatures. The reaction temperature is kept between about 30°C to 100°C., preferably between 50°C to 90°C., more preferably between 70°C to 80°C.
a-bromo-2-chlorophenyl acetic acid / MeOH weight ratio varies within a broad range. a-bromo-2-chIorophenyI acetic acid / MeOH weight ratio is preferably between about 1 and 10, more preferably between about 1.5 and 8, still more preferably between about 2 and 4.
a-bromo-2-chlorophenyl acetic acid / tosicacid weight ratio varies within a broad range, a-bromo-2-chlorophenyl acetic acid / tosicacid weight ratio is preferably between about 0.005 and 5.0, more preferably between about 0.02 and 3, still more preferably between about 0.04 and 0.08.
The isolation of methyl-2-chloropheny! acetate from the reaction mixture is done by applying various procedures. Isolation method in present invention uses standard procedures such as removal of excess MeOH, quenching of the reaction mass in water and the like, and standard equipment such as distillation assembly, stirred kettle and the like. In this embodiment of the invention, methyl-2-chlorophenyl acetate is isolated by recovering excess MeOH.
Recovery of excess MeOH of this invention proceeds in a very broad range of temperatures in accordance with the reduced pressure applied. During the recovery the reaction temperature is kept between about 30°C to 100°C., preferably between 50°C to 80°C„ more preferably between 60°C to 75°C.
Recovery of excess MeOH of this invention proceeds in a very broad range of reduced pressure conditions. Reduced pressure during recovery is kept between about 718mm of Hg to 628mm of Hg, preferably between 718mm of Hg and 653mm of Hg, more preferably between 688mm of Hg and 668mm of Hg.
(D) In still other embodiment of the present invention, wherein the process comprises initial bromination steps followed by esterification steps, instead of using excess methyl-2-chlorophenyl acetate as reaction medium various solvents alone or in
combination thereof can be used from a wide range of solvents including halogenated hydrocarbons with number of carbon atoms in the range of 1 to 20, aromatic solvents, saturated aliphatic or unsaturated aliphatic or aromatic halogenated solvents with number of halogens in the range of 1 to 6, ethers ROR' wherein R and R' are same or different and wherein saturated alkyl group or unsaturated alkyl group or saturated straight chain alkyl group or unsaturated straight chain alkyl group or saturated branched chain alkyl group or unsaturated branched chain alkyl group or aromatic rings wherein number of aromatic rings are in the form of fused rings or otherwise ranges from 1 to 5, esters like RCOOR' wherein saturated alkyl group or unsaturated alkyl group or saturated straight chain alkyl group or unsaturated straight chain alkyl group or saturated branched chain alkyl group or unsaturated branched chain alkyl group or aromatic rings wherein number of aromatic rings are in the form of fused rings or otherwise ranges from I to 5. Other solvents from the class of solvents including formaamides, formanilides, amines, nitroaromatics, haloaromatics can also be used.
According to this embodiment of the present invention, in which separate solvent is used the following additional steps are used, at appropriate stages in the bromination steps of the process.
Additional steps (in bormination steps):
1. Weighing and charging solvent;
2. distillation of the organic mass to recover solvent.
In the above mentioned additional steps (in bromination steps), the following parameters are used.
a-bromo-2-chlorophenylacetate / solvent weight ratio varies within a broad range. The a-bromo-2-chlorophenylacetate / solvent weight ratio is preferably between about 0.2 and 10, more preferably between about 0.5 and 8, still more preferably between about 1 and 4.
Recovery of solvent of this invention proceeds in a very broad range of temperatures in accordance with the reduced pressure applied. During the recovery the reaction temperature is kept between about 30°C to 140°C., preferably between 30°C to 130°C., more preferably between 120°C to 125°C.
Recovery of solvent of this invention proceeds in a very broad range of reduced pressure conditions. Reduced pressure during recovery is kept between about 718mm of Hg to 628mm of Hg, preferably between 718mm of Hg and 653mm of Hg, more preferably between 688mm of Hg and 668mm of Hg.
Following surprising advantages are observed by the inventor as a result of the process of the present invention:
1. It is an environmentally friendly (green) process that overcomes the problem of generation of large quantities of liquid wastes resulting from the conventional processes; since the process described in the present invention uses bromine releasing agent l,3-Dibromo-5,5-dimethylimidazolidine-2,4- dione (DBDMID) as brominating agent in place of liquid bromine; and recovers 5,5-dimethylimidazolidine-2,4-dione (DMID)which is a spent of brominating agent from the reaction mixture.
2. Acidic catalysts including tosicacid, mineral acids, resins, zeolites and /or combination of these can be used the in esterification.
3. Excess methyl a-bromo-2-chlorophenylacetate is used as a medium for the reaction described in the present invention. Other solvents including
methylene dichloride, ethylene dichloride, and other chlorinated solvents alone and / or in combination thereof can also be used in the process of the present invention.
4. Molten 2-chloro-phenylacetic acid is used as a medium for the reaction described in the present invention. Other solvents including methylene dichloride, ethylene dichloride, and other chlorinated solvents alone and / or in combination thereof can also be used in the process of the present invention.
5. The end product, which is methyl a-bromo-2-chlorophenylacetate, is purer because the side products formation is minimized, thereby making the impurity profile acceptable for further conversion into Clopidogrel.
6. The end product, which is a-bromo-2-chlorophenylacetic acid, is purer because the side products formation is minimized, thereby making the impurity profile acceptable for further conversion into methyl a-bromo-2- chlorophenylacetate and Clopidogrel.
7. The end product, which is methyl a-bromo-2-chlorophenylacetate, is separated from the reaction mixture by distillation under reduced pressure; which is one of the green unit operations leading to minimum waste generation.
8. 5,5-Dimethylimidazolidine-2,4-dione (DMID) is recovered from the reaction mixture by crystallization by cooling which does not generate any waste streams.
9. Other a-halo acid esters such as shown in Fig. 5

Fig, 5
wherein; Z is attached to a carbon atom adjacent to carbonyl group; X, Y, Ri, R2, R3, R4, R5 can be various groups including but not limited to following, X can be chloro, bromo; Y can be CnH2n wherein n is 1 to 20; Rl, R2, R3, R4, R-s can be H, halogen, straight chain or branched chain alkyl groups with number of carbon atoms ranging from 1 to 20, aryl groups, nitro groups, amino groups, cyano groups, hydroxyl groups, thio- groups, ester groups, ether groups, aldehyde groups; A can 1 to 5 as linear or angular fused rings; can also be prepared using the methodology described in this invention.

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Patent Number

278114

Indian Patent Application Number

525/MUM/2010

PG Journal Number

52/2016

Publication Date

16-Dec-2016

Grant Date

14-Dec-2016

Date of Filing

26-Feb-2010

Name of Patentee

CHAUDHARI SHARAD N

Applicant Address

LEEDS KEM GROUP, D-50,MIDC AREA, NEAR AJANTA ROAD, JALGAON-425 003, MAHARASHTRA STATE, INDIA.

Inventors:

#	Inventor's Name	Inventor's Address
1	CHAUDHARI SHARAD N	LEEDS KEM GROUP, D-50,MIDC AREA, NEAR AJANTA ROAD, JALGAON-425 003, MAHARASHTRA STATE, INDIA.

PCT International Classification Number

C07C69/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA