(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2012/084770 Al 28 June 2012 (28.06.2012) P O P C T (51) International Patent Classification: AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, C07C 45/45 (2006.01) C07C 49/84 (2006.01) CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, (21) International Application Number: HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, PCT/EP20 11/073 172 KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, (22) International Filing Date: MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, 19 December 201 1 (19. 12.201 1) OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, (25) Filing Language: English TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (26) Publication Language: English (84) Designated States (unless otherwise indicated, for every (30) Priority Data: kind of regional protection available): ARIPO (BW, GH, 10195971 .6 20 December 2010 (20. 12.2010) EP GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, (71) Applicant (for all designated States except US): DSM IP TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, ASSETS B.V. [NL/NL]; Het Overloon 1, NL-64 11 Te DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, Heerlen (NL). LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, (72) Inventor; and GW, ML, MR, NE, SN, TD, TG). (75) Inventor/Applicant (for US only): WEHRLI, Christof [CH/CH]; c/o DSM Nutritional Products Ltd, Patent De Published: partment / P.O. Box 2676, CH-4002 Basel (CH). — with international search report (Art. 21(3)) (74) Agent: BERG, Katja; Wurmisweg 573, CH-4303 Kais- — before the expiration of the time limit for amending the eraugst (CH). claims and to be republished in the event of receipt of (81) Designated States (unless otherwise indicated, for every amendments (Rule 48.2(h)) kind of national protection available): AE, AG, AL, AM, © 00 © o (54) Title: PROCESS FOR THE MANUFACTURE OF DIBENZOYLMETHANE DERIVATIVES (57) Abstract: The invention relates to a process for the manufacture of substituted dibenzoylmethane derivatives. This economical process provides products in high purity and yields and results in shorter reaction times. Process for the manufacture of dibenzoylmethane derivatives The invention relates to an improved process for the manufacture of substituted dibenzoylmethane derivatives. This novel economical process provides products in high purity and yields and results in shorter reaction times. Substituted dibenzoylmethane derivatives are highly effective UVA-absorbers which are, for example, used as light stabilizers in plastics or as light screening agents in cosmetic products. Customary dibenzoylmethane derivatives are, for example, Eusolex® 8020 [INCI Name: Isopropyldibenzoylmethane; CAS No.: 63250-25-9] or PARSOL® 1789 [ INCI Name: butyl methoxydibenzoylmethane; 4-te/f-butyl-4'-methoxydibenzoylmethane, CAS No.: 70356-09-1]. Substituted dibenzoylmethane derivatives may be prepared by Aldol condensation of a ketone with an ester in the presence of a strong base such as e.g. disclosed in DE 2945125 or US 6,278,025. Suitable bases cited by the references are sodium hydride, sodium amide or alkali or earth alkali metal alkoxides such as in particular sodium methylate. Because of the continuously increasing demand for dibenzoylmethane based light screening agents the object of the present invention was to provide a process for the preparation of substituted dibenzoylmethane derivatives which is easy to carry out and affords economic advantages as a result of high yields. Furthermore, the process yields purer products as the hardly removable symmetric by-products are formed to a lesser extend. This is particularly important because minor impurities tend to impart a color to the product which is unwanted for use in cosmetic formulations. Surprisingly, it has been found that the use of potassium alcoholate as base delivers higher yields and less side products compared to the use of other bases. Furthermore, the intermediate potassium salt formed during the reaction does not crystallize in the reaction mixture, thus facilitating industrial handling. Additionally, the reaction times can be reduced by the use of a potassium alcoholate as base. Thus, the invention relates to a process for the preparation of substituted dibenzoylmethane derivatives of formula (I) wherein R and R2 are independently selected from the group consisting of hydrogen, C to C alkyl, C to alkoxy, to alkenyloxy and to alkenyl; 2 C 2 C3 C 2 C2 C 2 characterized in that said process comprises the step of forming the potassium salt of (I) by condensing a ketone of formula (II) with an ester of formula (III) in the presence of a potassium alcoholate (IV) (condensation step) wherein R and R2 are as defined above R3 is hydrogen; 4 R is C to C 2 alkyl and 5 R is Ci to C8 alkyl. In another embodiment, the invention relates to a process for the preparation of substituted dibenzoylmethane derivatives of formula (I) wherein R and R2 are independently selected from the group consisting of hydrogen, C to C 2 alkyl, C to C 2 alkoxy, C3 to C 2 alkenyloxy and C2 to C 2 alkenyl with the proviso that at least one of R and R2 is not hydrogen and with the proviso that the potassium alcoholate is derived from an alcohol R -OH having a boiling point below 100°C. In a particular embodiment, the invention relates to a process for the preparation of dibenzoylmethane derivatives of formula (I) wherein R and R2 are independently selected from the group consisting of hydrogen, C to C12 alkyl and C to C12 alkoxy. More in 2 particular R is a C to C 8 alkoxy radical and R is a C to C 8 alkyl radical, most in particular R is a C to C 4 alkoxy radical such as methoxy, ethoxy, isopropoxy, n-propoxy, 1-methylpropoxy, t-butoxy and n-butoxy and R2 is a C to C alkyl radical such as methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl and 1,1- dimethylethyl. Most in particular, the invention relates to a process for the preparation of butyl methoxydibenzoylmethane (i.e. R is methoxy and R2 is 1,1-dimethylethyl). Examples of alkyl, respectively alkenyl radicals are branched or unbranched alkyl, respectively alkenyl chains such as methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1- methylpropyl-, 2-methylpropyl, 1,1-dimethylethyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3- methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1,1-dimethylpropyl, 1,2- dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1- dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, n-heptyl, 2-ethylhexyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, ethenyl, 2-propenyl and 3-butenyl. Examples of alkoxy, respectively alkenyloxy radicals are e.g. methoxy, ethoxy, isopropoxy, n-propoxy, 1-methylpropoxy, n-butoxy, n-pentoxy, 2-methylpropoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 2,2-dimethylpropoxy, hexoxy, 1-methyl-1- ethylpropoxy, heptoxy, octoxy, 2-ethylhexoxy, 1,1-dimethylethoxy and allyloxy. In the process according to the invention R4 is advantageously a C to C alkyl radical such as methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl and 1,1-dimethylethyl. More advantageously, R4 is methyl, ethyl or 1,1-dimethylethyl. Thus, in a specific embodiment, the invention relates to a process for the preparation of substituted dibenzoylmethane derivatives of formula (I) wherein R is methoxy, R2 is 1,1-dimethylethyl, and R4 is methyl, ethyl or 1,1-dimethylethyl. Suitable potassium alcoholates (IV) according to the invention encompass in particular potassium methylate, potassium tert.-butylate, potassium n-butylate, potassium-iso propylate, potassium tert.-amylate such as in particular potassium methylate or potassium te/f.-butylate which are e.g. commercially available at Fluka or Suparna Chemicals. The potassium alcoholate may be used as such or it may be formed in situ e.g. by slow addition of a solution of the alcoholate in the respective alcohol into boiling toluene at continuous removal of the alcohol by distillation, thus forming a fine suspension/ mixture of the potassium alcoholate in toluene which is subsequently used in the process according to the invention. After the condensation step, the potassium salt of (I) is subsequently hydrolyzed to the respective substituted dibenzoylmethane derivative of formula (I) by known methods in the art, preferably by using a mineral or hydrocarbon acid such as sulphuric acid or acetic acid, in particular 5-85% sulphuric acid. The amount of acid can easily be adjusted by a person skilled in the art in order to achieve complete hydrolysis. The process according to the present invention is advantageously carried out in an inert solvent. As known to a person skilled in the art, the term inert solvent refers to solvents which do not react chemically with the dissolved compounds. The solvent, which may be a pure substance or a mixture, is advantageously selected to have a high boiling point at atmospheric pressure so that the alcohol(s) released by the various reactions (from the alcoholate and the ester) may be removed without the removal of the solvent.