| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | February 16, 1993 |
| PATENT TITLE |
Process for the preparation of octyl methoxy cinnamate |
| PATENT ABSTRACT | Octyl methoxy cinnamate of the formula ##STR1## is prepared by reacting p-bromoanisole with octyl-acrylate in an inert solvent, in the presence of a base and of a coupling catalyst. |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | April 14, 1992 |
| PATENT FOREIGN APPLICATION PRIORITY DATA | This data is not available for free |
| PATENT REFERENCES CITED |
Tour, J. M. et al., J. Org. Chem. 55(11) 3452-3, 1990. Abedi, J. et al., Synth. Comm. 19(9-10) 1539-49, 1989 |
| PATENT CLAIMS |
We claim: 1. A process for the preparation of octyl methoxy cinnamate of the formula ##STR4## comprising reacting p-bromoanisole with octyl-acrylate in an inert solvent, in the presence of a base and of a coupling catalyst. 2. A process according to claim 1, wherein the solvent is an aprotic polar solvent. 3. A process according to claim 2, wherein the solvent is selected from N-methyl-pyrrolidone, dimethylformamide, N,N-dimethylacetamide and dimethylsulfoxide. 4. A process according to any one of claims 3, wherein the catalyst is a palladium catalyst. 5. A process according to claim 4, wherein the catalyst is 5% palladium, supported on carbon. 6. A process according to any one of claims 5, wherein the base is selected from NaHCO.sub.3, Na.sub.2 CO.sub.3, KHCO.sub.3 and K.sub.2 CO.sub.3. 7. A process according to any one of claims 6, wherein the reaction is carried out at a temperature comprised between 160.degree.-210.degree. C., preferably between 180.degree.-200.degree. C. 8. A process for the preparation of octyl methoxy cinnamate which tests Ames-negative, comprising reacting p-bromoanisole with octyl-acrylate in an inert solvent, in the presence of a base and of a coupling catalyst and substantially without adding any antioxidants during the reaction. 9. A process according to claim 1, further comprising the steps of: a) filtering the reaction mixture after the reaction has been substantially completed, to separate NaBr and the catalyst therefrom; b) distilling the filtrate to remove the solvent and excess raw materials; c) vaporizing the raw distillation product to separate light and heavy residues; and d) fractionally distilling the product so obtained to yield highly pure OMC product; all the above steps being carried out without adding any substantial amount of antioxidant. 10. A process according to claim 7, in which an antioxidant is further added to hinder or avoid polymerization of octyl-acrylate. 11. A process according to claim 10, wherein the antioxidant is methyl hydroquinone or butylated hydroxyanisole. 12. A process according to claim 10, wherein the reaction is carried out in an inert atmosphere. 13. A process according to claim 12, wherein the inert atmosphere is an N.sub.2 atmosphere. 14. A process according to any one of claims 13, comprising utilizing catalyst and solvent recycled from a previous batch. -------------------------------------------------------------------------------- |
| PATENT DESCRIPTION |
FIELD OF THE INVENTION The present invention relates to a process for the preparation of octyl methoxy cinnamate. More particularly the invention relates to an economic and efficient process in which octyl methoxy cinnamate is prepared by a catalytic coupling reaction. BACKGROUND OF THE INVENTION Octyl p-methoxy cinnamate, is referred to hereinafter as OMC for the sake of brevity, and has the formula: ##STR2## OMC is a well known sunscreening agent and along with other sunscreening products, is used to protect the skin from skin diseases due to the sun, particularly skin cancer. OMC is one of the most widely used ultra violet (UV) sunscreeners, and its importance in this field is increasing steadily. The Prior Art Various processes are known in the art, which involve cinnamic acid derivatives. For instance, European Patent No. 856.411, is directed to the preparation of methoxy alkyl esters of p-methoxycinnamic acid, by the reaction of alkyl p-methoxy cinnamate with an alcohol in the presence of alkoxide (transesterification process). In other processes, rather than starting from the methoxy cinnamate, cinnamic acid esters are prepared by reacting styrene with aliphatic alcohols, CO and oxygen in the presence of catalysts (Japan Kokai JP 60,126,245). The major route for preparing OMC passes through the preparation of p-methoxy cinnamic acid (p-MCA) [Zh. Org. Khim. 25 (9), 1876 (1989)], and starts from anisaldehyde which is both expensive and rather difficult to synthesize. Furthermore, the use of p-MCA, or the corresponding low-alcohol esters, as a raw material, requires an extra step to form OMC, viz., esterification or transesterification. The preparation of OMC is described in EP 229,394 and in U.S. Pat. No. 4,713,473 which teaches to heat OMC in the presence of a phenol to insure that the ester is considered Ames negative. It is an object of the present invention to provide a simple and economic process, which can be used to produce OMC in good yields and purity. It is another object of the invention to provide a process which employs easily available and inexpensive starting materials. It has further been found, and this is an object of the present invention, that it is possible to prepare OMC of good quality and which tests Ames negative, while carrying out a preparation process substantially in the absence of any added antioxidant. Furthermore it has been found, and this is another object of the invention, that it is not necessary to add antioxidants, such as BHT, to the reaction mixture resulting from the process of the invention when distilling OMC therefrom, and that OMC distilled from the reaction mixture so obtained, without adding any substantial amount of antioxidant, tests Ames-negative. The term "added antioxidant" is meant to indicate substantial amounts of antioxidant added in the course or for the purpose of the reaction, or during work-up of the final product, but should not be taken to include small amounts of antioxidants which can normally be present in the commercial reactants. As will be apparent to the skilled person, some antioxidants are often present in various raw materials, for the purpose of improving their shelf life, to inhibit polymerization, etc. Such small amounts are not considered "added antioxidant", as meant herein. The process for the preparation of octyl methoxy cinnamate according to the invention comprises reacting p-bromoanisole with octyl-acrylate in an inert solvent, in the presence of a base and of a coupling catalyst. Preferably, the solvent is an aprotic polar solvent, more preferably N-methyl-pyrrolidone. This process can be schematically written as follows: ##STR3## While, as stated, no added antioxidant is required for carrying out the invention, the addition of an antioxidant to the reaction mixture, if effected for any reason, e.g., to avoid or at least substantially to hinder, the polymerization of octyl-acrylate, during the coupling reaction, does not substantially affect the invention. Many known inhibitors can be used, but preferred antioxidants are, e.g., methyl hydroquinone and BHT. The reaction is preferably carried out in an inert atmosphere, to avoid reaction of octyl-acrylate with oxygen, preferably the inert atmosphere being substantially N.sub.2 atmosphere, as oxygen may initiate free-radical polymerisation of the .alpha.,.beta.-unsaturated entities, and lead to the formation of undesirable by-products. A further advantage of the process of the invention is that it is possible to utilize the catalysts and the solvents in subsequent batches, after a simple regeneration of the recovered catalyst and make-up of catalyst and solvent, as required. Thus, as will be apparent to the skilled person, inter alia, the following advantages result from the invention, as compared, e.g., with prior art processes, such as that described in U.S. Pat. No. 4,713,473: The necessity to purchase and handle an extra raw material, such as BHT, is eliminated. The necessity to monitor BHT levels during the reaction is eliminated. This is true even if some amounts of BHT are added, as optionally possible and as explained above. The work-up of the reaction mixture is simplified by eliminating the need to remove BHT at the end of the reaction. It simplifies the handling of waste material. It eliminates the need to add BHT continuously during the distillation of the final product. The catalyst employed in the process of the invention is a palladium catalyst, preferably palladium supported on carbon, as well as a variety of palladium salts and complexes, such as, e.g., PdCl.sub.2, Pd(OAc).sub.2 and PdCl.sub.2 (Ph.sub.3 P).sub.2. A convenient catalyst is a 5% Pd/C of the type manufactured by Fluka or Aldrich. While the desirable amount of catalyst employed varies substantially from one manufacturer to the other, and, as will be appreciated by the skilled chemist, even between two different batches of the same manufacturer, the desirable Br:Pd ratio will be in the order of 300-4000. In any case, the skilled chemist will easily determine the necessary amount of catalyst employed, for a specific type of catalyst. Examples of suitable solvents are N-methylpyrrolidone, dimethylformamide, N,N-dimethylacetamide and dimethylsulfoxide. The reaction is carried out in the presence of a base which reacts with HBr formed in the reaction to form an inert material. The base is preferably selected from alkali bicarbonates and carbonates, such as NaHCO.sub.3, Na.sub.2 CO.sub.3 (and potassium salts), and organic amines such as tributylamine, and is present in a substrate:base ratio of between 1:1 and 1:2. The reaction can be carried out in a temperature range comprised between 160.degree.-210.degree. C., and is preferably carried out at temperature comprised between 180.degree.-200.degree. C. It is desirable, though not imperative, to carry out the reaction in an inert atmosphere, to avoid possible reaction of octyl-acrylate with oxygen, which may lead to the formation of undesirable by-products. As will be apparent to a person skilled in the art, the actual nature of the product, from the point of view of purity and by-products content, is very much dependent on the preparation method employed. Therefore, OMC prepared according to different processes may differ in critical contents of trace impurities. The preparation route may be responsible for the fact that OMC so prepared tests Ames-negative. Accordingly, OMC prepared according to the process of the invention, also forms a part of the present invention. DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS The above and other characteristics and advantages of the process of the invention will be better understood from the following illustrative and non-limitative description of preferred embodiments thereof. Ames Test Procedure A Salmonella/mammalian microsome mutagenicity test was conducted to determine whether a DMSO test article solution of OCTYL METHOXY CINNAMATE (OMC) would cause mutagenic changes in histidine-dependent mutant strains of Salmonella typhimurium. The method of Ames et al. [Mutation Research 31 (1975), pp. 347-364] was followed. After the solution was found to be noninhibitory to growth of the tester strains, aliquots of the test solution, negative control and positive control solutions were added to duplicate plates containing histidine-deficient medium. Separate plates were inoculated with the Ames Salmonella typhimurium tester strains TA98, TA100, TA1535, TA1537 and TA1538. The rate of mutation to nonhistidine-dependent wild types was determined for each plate; the spontaneous reversion rate for each strain in the presence of the DMSO blank was compared to the corresponding rate of reversion in the presence of the test article solution and in the presence of known mutagens. The study was conducted in accordance with the United States requirements of Good Laboratory Practice (GLP) Regulations, as described in the U.S. Federal Register at 21 CFR 58. Under the conditions described above, all tested DMSO solutions of OCTYL METHOXY CINNAMATE (OMC) did not cause mutagenic changes in the Salmonella typhimurium tester strains employed. |
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| PATENT PHOTOCOPY | available on request |
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