Title of Invention	"PROCESS FOR PREPARING 2-ETHYLHEXYL 4-METHOXYCINNAMATE"
Abstract	A process for the preparation of 2-ethylhexyl 4-methoxycinnamate which is used as a UV-B sunscreen agent in cosmetics by reacting p-haloanisole with 2-ethylhexyl acrylate in an ionic liquid, in presence of a base and a coupling catalyst.

Full Text

Field of invention: The present invention relates to a process of preparing 2-ethylhexyl 4-rnethoxycinnamate. More particularly, the invention relates to an economic and efficient process in which 2-ethylhexyl 4-methoxycinnamate is prepared using eco-friendly ionic liquids which along with the coupling catalyst can be recycled several times. Background of the invention: 2-ethylhexyl 4-methoxycinnamate or Octyl p-methoxycinnamate is a well-known ultraviolet (UV-B) sunscreen agent. It is used along with other sunscreen products to protect the skin from diseases caused by (Figure Removed) Figure 1: (2-ethylhexyl 4-methoxycinnamate) exposure to the sunlight, especially skin cancer. Various processes are known for the preparation of this compound in the prior art. Among them, those that use Heck reaction are the most elegant ones. It is known that olefins can be arylated by haloaromatic compounds in the presence of palladium catalyst, phosphine ligand and a base (Org. React. 1982, 27, 345-391). The reaction is generally carried out with various amines like trialkylamines, which may serve simultaneously as solvent. The bases could also be alkali-metal carbonates or hydrogen carbonates taken in a polar aprotic solvent like dimethylformamide, hexamethylphosphoric triamide, acetonitrile etc. (Tet Lett. 1985, 26, 2667-2670 and J. Org. Chem. 1991,56,1289-1293). Patent application WO 9010617 by Caskey Douglas in 1990 discloses that, in a two-step process, p-mefhoxyaniline can first of all be diazotized and then the product can be converted using potassium iodide to 4-iodoanisole. This product is then reacted with 2-ethylhexyl acrylate, in the presence of triethylamine and Pd/C, to give 2-ethylhexyl 4-methoxycinnamate. This process involves number of steps and requires the recovery of alkali-metal iodide. Moreover, the coupling step is low yielding. A. Eisenstadt and Y. Keren in 1992 (EP 509426) used Heck reaction to obtain octyl p-methoxycinnamate (OMC ) by coupling p-bromoanisole with 2-ethylhexyl acrylate using inert, high boiling solvent like N-methyl pyrrolidone (NMP) and a palladium catalyst taken from Pd/C or palladium acetate and triphenylphosphine. The process suffers from having tedious work-up. In particular, NMP has to be removed and since, it is high boiling, the distillation has to be done under reduced pressure to avoid product polymerization. EP 0564919 by Kaufmann Dieter et al, published in 1993, describes the reaction of bromoaromatic compounds with acrylic acid derivatives in the presence of palladium catalysts and a large excess of phosphines based on palladium. The phosphine produced in relatively large quantities in this reaction creates additional difficulties in product isolation. Initially tried Heck reactions on chloroarene generally gave very poor results. EP 103544 by Spencer Alwyn in 1984 describes a process for the arylation of acrylonitrile with /?-chlorobenzaldehyde in the presence of chloro-(4-formylphenyl) bis(triphenylphosphine) palladium (II), the product being obtained in a yield of only 18%. EP 746539 granted in 1998, discloses a process whereby 4-chloroanisole is reacted with 2-ethylhexylacrylate in N-methyl pyrrolidone (NMP ) in the presence of sodium carbonate and palladium acetate (2.0 mole% wrt 4-chloroanisole) along with aliphatic phosphine as co-catalyst, like tricyclohexylphosphine, at 140-150°C for 60 h to get only 68% conversion. Ewenson Ariel in 1998 (US 5728865) proposed two-step process for the preparation of 2-ethylhexyl 4-methoxycinnamate. The first step involves the condensation of 4-bromoanisole with acrylic acid or its salt in water in presence of triethylamine and Pd/C at elevated temperature and pressure. The second step involves the esterification with 2-ethyl hexanol. Finally, a Korean patent KR 2001002594 by Baek Seong et al has come up with the preparation of 2-ethylhexyl 4-methoxycinnamate by reacting 4-bromoanisole with 2-ethylhexyl acrylate in an inert organic solvent in presence of a base, a phase transfer catalyst like PEG and a catalyst. Thus, although some of the procedures reported in prior art involve single step of preparation of octyl methyl cinnamate by vinylation reaction of anisole derivatives, these processes require solvents which are both expensive and hazardous. The products need to be removed by distillation under high temperature and at reduced pressure conditions often leading to partial polymerization. Therefore, there is a need to develop eco-friendly processejrwhich would do away with hazardous and polluting solvents. It would be further advantageous if the reaction media can be easily reused. The use of ionic liquids as reaction media for the palladium catalyzed Heck reaction since 1996 when it was first reported (Kaufmann, D. E.; Nouroozion, N.; Henz, H. Synlett. 1996, 1091-1092), is steadily increasing. The results indicate that the application of ionic solvents show clear advantages over commonly used solvents like dimethylformamide (DMF) and N-methyl pyrrolidone (NMP) for conversion of industrially important haloarenes. With almost all tested palladium catalysts, an additional activation and stabilization was observed. Molten tetrabutylammonium bromide (m.p 103°C) proved to be a particular suitable reaction medium among the ionic solvent systems investigated. Hermann and Bohm ( J. Organomet. Chem. 1999, 572,141-145.) report that the reaction of bromobenzene with styrene using diiodobis-(l,3-dimethylimidazolin-2-ylidene) with palladium (II) as catalyst, the yield of stilbene was increased from 20% in DMF to around 99% in [NBu4]Br under otherwise identical conditions. They had recycled the ionic liquid upto several times. In JP 2002265394 by Yokoyama Chiaki and Hagiwara Hisahiro, the catalyst Pd/C used in Heck reaction in ionic liquid, is recycled. Objects of the invention: It is therefore an object of the present invention to provide an ecologically clean and safe single step synthesis process for the preparation of 2-ethylhexyl 4-methoxycinnamate by reacting 4-haloanisole and 2-ethylhexyl acrylate in good yield and with high degree of purity. It is another objective of present invention to provide a process which is economically advantageous and industrially convenient, characterized in that it requires only small amounts of catalysts and/or co-catalysts, and is completed in short period of time. It is another objective to provide an economically advantageous process wherein the reaction can be effectively performed even in the presence of relatively low excesses of some of the reactants. It is another objective to provide for simple work-up procedure for this reaction devoid of dealing with hazardous and expensive solvents. It is another major objective of present invention to provide for the reuse of the palladium catalyst along with the ionic liquid for several reaction runs. Summary of the invention: This invention provides an eco-friendly and economic process for the preparation of 2-ethylhexyl 4-methoxyciimamate, a known UV absorbing sunscreen agent, using ionic liquid as reaction media and in which both the media and the palladium catalyst are recycled several times. Statement of Invention: Accordingly the invention provides a process for preparing 2-ethylhexyl 4- methoxycinnamate comprising the steps of a) reacting 4-haloanisole with 2-ethylhexyl acrylate in a tatui of 1:1.5 in an ionic liquid selected from tetraalkylammonium salt, pyridinium salt or 1,3-dialkylimidazolium salt in the presence of a base, a palladium based catalytic system such as hereindescribed at 105 to 200°C, and b) obtaining 2-ethylhexyl 4-methoxycinnamate in a manner as hereindescribed and oplionally recy cling the catalyst and ictuc liquid inedia The molar ratio of the palladium catalyst of the said catalytic system and that of the p- bromoanisole being is in the range of 1:10 to 1:1000, under high temperature. After the product is removed from the ionic liquid, it, along with the catalyst, is reused in further runs. The major aspect of the invention is the utilization of ionic liquid as the reaction medium which is a non-pollutant and at the same time, a very efficient medium for such reactions. The ionic liquid used in the reaction is tetraalkylammonium salt, pyridinium salt or 1,3-dialkylimidazolium salt. The most preferred among them cost wise is tetraalkylammonium salt; more specifically tetrabutylammonium bromide. According to another aspect of invention, the base which is taken in the reaction medium may be : a) An inorganic base selected from alkali or alkaline earth oxides, hydroxides, acetates or carbonates such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium acetate, sodium acetate and sodium formate and most preferably sodium acetate, or b) An organic base, generally a tertiary amine and most preferably a trialkylamine such as triethylamine. The reaction in tetrabutylammonium bromide with an organic base is carried out at a temperature in the range of 105 to 120°C. Within this range, the said quaternary salt is a liquid; the preferred temperature range for carrying out the reaction is between 105-110°C. The mixture is stirred during the reaction for a period ranging between 1-8 h, preferably for 6h. The reaction is efficiently catalyzed by palladium based catalytic system as herein defined. Preferably, the catalyst is selected from PdCl2, Pd(OAc)2, with or without phosphine ligands and heterogeneous Pd supported on carbon or any other inactive supports. The ratio of the said catalytic system is determined by the type of palladium compound used in the said catalytic system. Preferably, the molar ratio of the palladium catalyst to 4-bromoanisole is in the range between 1:10 to 1:10000. The palladium salts such as PdCl2, or Pd(OAc)2 have been found extremely suitable. Typically, the molar ratio of the palladium catalyst to 4-bromoanisole is in the range of 1:100 to 1:500, the most preferred is in the ratio of 1:250. The palladium based catalytic system may comprise other forms of palladium such as palladium supported preparations, together with co-catalysts. Most typically, Pd/C is used. Suitable co-catalyst can be combined in the catalytic systems, in these cases are palladium complexing agents, such as phosphines, ketones and amides. The preferred co-catalyst being tris-o-tolyl phosphine. The reaction is preferably carried out in an inert atmosphere, to avoid possible reaction of 2-ethylhexyl acrylate with oxygen, thereby forming considerable byproducts; the inert atmosphere being that of nitrogen. In order to isolate the product after the reaction, A. The reaction mixture is cooled to 70-90°C. B. Hexane (approximately 30 parts with respect to p-bromoanisole) is added and mixture well stirred. C. The reaction mixture is then cooled to room temperature; the ionic liquid solidifies along with the catalyst. D. The hexane fraction, the only liquid fraction in the reaction mixture, is removed by positive nitrogen pressure. E. Hexane is distilled out to obtain the product. F. The product may be purified to > 99% purity by distillation under reduced pressure, preferably at 80°C at l0rnm of Hg; the yield is between 82-90%. This yield is comparable to or better than that given in prior art. In case the reaction is carried out in bigger scale, using more than lOg of 4-bromoanisole, the work-up is further simplified. In this case, after the reaction is over, the product is straight away distilled out from the reaction mixture at 80°C at 10mm of Hg. The temperature during work-up is not taken beyond 105°C in order to avoid decomposition of the said ionic liquid. Another important aspect of this invention is the reuse of the said ionic liquid along with the palladium catalyst which is left in it and which is recycled several times over, preferably six times or more, without much loss in the efficiency of the process. In another aspect of the invention, it is stated that by adding 10% of fresh catalyst to the recycled catalyst in any run, improves the yield of the product. All the above characteristics and advantages of the invention will be better understood by the following examples. These are however non-limiting description of preferred embodiments thereof. Example 1: Preparation of 2-ethylhexyl 4-methoxycinnamate/octyl 4-methoxycinnamate (OMC) p-bromoanisole (PBA, 5g, 0.026 mole), octyl acrylate (OA, 5.88g, 0.032 mole), tetrabutylammoniurn bromide (TBAB, 15g, 0.046 mole) and palladium acetate (24mg, 0.0001 mole) were placed in a 3-necked 100ml round bottom flask fitted with a reflux condenser. Nitrogen gas is passed through the flask for 30 seconds. Then triethylamine was added (TEA, 5.58ml/4.05g, 0.04 mole) and the reaction mixture was heated at 110-115°C in an oil bath with vigorous stirring with a magnetic stirrer under nitrogen for nearly 6 hours. After the completion of the reaction as checked by thin layer chromatography and gas chromatography (which showed more than 96% conversion to OMC), the reaction mixture was allowed to cool to about 70-80°C. The product was extracted from the mixture by the addition of hexane and vigorous stirring for 15 mins. After extraction, the reaction mixture was allowed to cool to room temperature. The hexane layer was separated by applying the positive nitrogen pressure. Then it was filtered through celite and concentrated. From this concentrated mixture, product was distilled out at 80°C at 10mm of Hg (after removal of unreacted octyl acrylate at 70°C at 10mm of Hg). Final product so obtained was in more than 99% purity. Yield: 87% Example 2: Preparation of 2-ethylhexyl 4-methoxycinnamate/octyl 4-methoxycinnamate (OMC) />-bromoanisole (PBA, 5g, 0.026 mole), octyl acrylate (OA, 5.88g, 0.032 mole), tetrabutylammonium bromide (TBAB, 15g, 0.046 mole) and palladium chloride (19mg, 0.0001 mole) were placed in a 3-necked 100ml round bottom flask. Nitrogen gas is passed through the flask for 30 seconds. Then triethylamine was added (TEA, 5.58ml/4.05g, 0.04 mole) and the reaction mixture was heated at 110-115°C in an oil bath with vigorous stirring with a magnetic stirrer under nitrogen for nearly 6 hours. Completion of the reaction was judged by gas chromatography, which showed 96% conversion to OMC. Work-up of the reaction is same as mentioned in example 1. Yield: 82% Example 3: Preparation of 2-ethylhexyl 4-methoxycinnamate/octyl 4-methoxycinnamate (OMC) p-bromoanisole (PBA, 5g, 0.026 mole), octyl acrylate (OA, 5.88g, 0.032 mole), tetrabutylammonium bromide (TBAB, 15g, 0.046 mole) and palladium chloride (19mg, 0.0001 mole) along with tris-o-tolylphosphine (64.17mg, 0.00021 mole) were placed in a 3-necked 100ml round bottom flask. Nitrogen gas is passed through the flask for 30 seconds. Then triethylamine was added (TEA, 5.58ml/4.05g, 0.04 mole) and the reaction mixture was heated at 110-115°C in an oil bath with vigorous stirring with a magnetic stirrer under nitrogen for nearly 6 hours. Completion of the reaction was judged by gas chromatography, which showed 98%) conversion to OMC. Workup of the reaction is same as mentioned in example 1. Yield: 88%, Example 4: Preparation of 2-ethylhexyl 4-methoxycinnamate/octyl 4-methoxycinnamate (OMC) p-bromoanisole (PBA, 5g, 0.026 mole), octyl acrylate (OA, 5.88g, 0.032 mole), tetrabutylammonium bromide (TBAB, 15g, 0.046 mole), palladium chloride (19mg, 0.0001 mole) and sodium acetate (3.28g, 0.04 mole) were placed in a 3-necked 100ml round bottom flask. Nitrogen gas is passed through the flask for 30 seconds. Reaction mixture was heated at 110-115°C in an oil bath with vigorous stirring with a magnetic stirrer under nitrogen for nearly 6 hours. Completion of the reaction was judged by gas chromatography, which showed 95% conversion to OMC. Work-up of the reaction is same as mentioned in example 1. Yield: 82% Example 5: Preparation of 2-ethylhexyl 4-methoxy cinnamate/octyl 4-methoxy cinnamate (OMC) Residues obtained in above examples after extraction of the product were recycled by addition of 10% of respective catalysts. To the three-necked flask, p-bromoanisole (PBA, 5g, 0.026 mole) & octyl acrylate (OA, 5.88g, 0.032 mole) were added. Nitrogen gas was passed for 30 seconds. Then triethylamine (TEA, 4.05g/5.58ml, 0.04 mole) was added (or sodium acetate was added, wherever earlier used). Reaction mixture was heated at 110-115°C in an oil bath with vigorous stirring with a magnetic stirrer under nitrogen for nearly 6 hours. Completion of the reaction was judged by gas chromatography, which showed 95% conversion to OMC. Work-up of the reaction is same as mentioned in above examples. We claim: 1. A process for preparing 2-ethylhexyl 4-methoxycinnamate comprising the steps of a) reacting 4-haloanisole with 2-ethylhexyl acrylate in a molar ratio of 1:1.5 in an ionic liquid selected from tetraalkylammonium salt, pyridinium salt or 1,3-dialkylimidazolium salt in the presence of a base, a palladium based catalytic-system such as hereindescribed at 105 to 200°C, and b) obtaining 2-ethylhexyl 4-methoxycinnamate in a maimer as hreindescribed and optionally recycling the catalyst and ionic liquid media by known methods. 2. A process as claimed in claim 1 wherein 4-haloanisole is selected from 4-bromoanisole, 4-chloroanisole and 4-iodoanisole. 3. A process as claimed in claim 1 wherein the catalytic system comprises of a palladium based catalyst and a co-coupling catalyst. 4. A process as claimed in claim 2 wherein the palladium based catalyst is selected from PdCl2, Pd(OAc)2, PdCl2 with phosphine ligands and heterogeneous Pd supported on carbon. 5. A process as claimed in claim 2 wherein the co-catalyst is phosphine preferably tris-o-tolyl phosphine. 6. A process as claimed in claim 1 wherein the base is selected from an organic and inorganic base. 7. A process as claimed in claim 6 wherein the inorganic base is selected from an alkali and alkaline earth oxide, hydroxide, acetate, a carbonate such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium acetate or sodium acetate and sodium formate. 8. A process as claimed in claim 6 wherein the organic base is trialkylamine. 9. A process as claimed in claim 6 wherein the base is triethylamine. 10. A process as claimed in claim 1 wherein the temperature is 105-120°C. 11. A process as claimed in claim 1 wherein the concentration of the reactants p-bromoanisole and octyl acrylate is more than one molar. 12. A process as claimed in claim 1 wherein the molar ratio of 2-ethylhexyl acrylate and 4-bromoanisole is between 1.2 : 1 13. A process as claimed in claim 1 wherein the amount of base is between 0.5 to 4 moles per mole of 4-bromoanisole, preferably 1.5 moles. 14. A process as claimed in claim 1 wherein the molar ratio of palladium catalyst : 4-bromoanisole is 1 : 100 to 1 : 10000 preferably 1 : 250. 15. A process as claimed in claim 1 wherein the ionic liquid media along with the palladium catalyst is recycled 15 times preferably for 6 times. 16. A process as claimed in claim 1 wherein after completion of the reaction, the reaction mixture of step (a) is cooled to 70-80°C, hexane added and cooled to room temperature and the 2-ethylhexyl 4-methoxy cinnamate is obtained by separating the hexane layer. 17. A process as claimed in claim 17 wherein after completion of reaction the product is isolated from the reaction mixture by distillation under reduced pressure. 18. A process for the preparation of 2-ethylhexyl 4-methoxycinnamate, susbtantially as described and with reference to the examples.

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179-del-2004-abstract.pdf

179-del-2004-claims.pdf

179-del-2004-complete specification (granded).pdf

179-del-2004-correspondence-others.pdf

179-del-2004-correspondence-po.pdf

179-del-2004-description (complete).pdf

179-del-2004-form-1.pdf

179-del-2004-form-19.pdf

179-del-2004-form-2.pdf

179-del-2004-form-26.pdf

179-del-2004-form-3.pdf

179-del-2004-form-5.pdf