European Patent Office of Opposition to That Patent, in Accordance with the Implementing Regulations

(19) TZZ ¥Z_T

(11) EP 2 655 308 B1

(12) EUROPEAN PATENT SPECIFICATION

(45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07C 45/45 (2006.01) C07C 49/84 (2006.01) 07.03.2018 Bulletin 2018/10 (86) International application number: (21) Application number: 11804542.6 PCT/EP2011/073172

(22) Date of filing: 19.12.2011 (87) International publication number: WO 2012/084770 (28.06.2012 Gazette 2012/26)

(54) PROCESS FOR THE MANUFACTURE OF DIBENZOYLMETHANE DERIVATIVES VERFAHREN ZUR HERSTELLUNG VON DIBENZOYLMETHANDERIVATEN PROCÉDÉ DE PRODUCTION DE DÉRIVÉS DE DIBENZOYLMÉTHANE

(84) Designated Contracting States: • NANDURKAR NITIN S ET AL: "Synthesis of AL AT BE BG CH CY CZ DE DK EE ES FI FR GB sterically hindered 1,3-diketones", SYNTHETIC GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO COMMUNICATIONS, TAYLOR & FRANCIS PL PT RO RS SE SI SK SM TR GROUP, PHILADELPHIA, PA, vol. 37, no. 23, 1 January 2007 (2007-01-01), pages 4111-4115, (30) Priority: 20.12.2010 EP 10195971 XP009144707, ISSN: 0039-7911, DOI: DOI:10.1080/00397910701572803 (43) Date of publication of application: • GUOQING ZHANG ET AL: "Polymorphism and 30.10.2013 Bulletin 2013/44 Reversible Mechanochromic Luminescence for Solid-State Difluoroboron Avobenzone", (73) Proprietor: DSM IP Assets B.V. JOURNAL OF THE AMERICAN CHEMICAL 6411 TE Heerlen (NL) SOCIETY, AMERICAN CHEMICAL SOCIETY, US, vol. 132, 1 January 2010 (2010-01-01), pages (72) Inventor: WEHRLI, Christof 2160-2162, XP007917212, ISSN: 0002-7863, DOI: CH-4002 Basel (CH) DOI:10.1021/JA9097719 [retrieved on 2010-01-28] • FRANEK W: "New Dithio-bis-(diaroylmethanes) (74) Representative: Berg, Katja et al and Acetyl Diaroylchloromethyl Disulfides: DSM Nutritional Products AG Attractive Synthons and Precursors for the Wurmisweg 576 Liberation of Highly Reactive Dithiiranes or CH-4303 Kaiseraugst (CH) Thiosulfines", MONATSHEFTE FUR CHEMIE, SPRINGER VERLAG WIEN, AT, vol. 127, 1 (56) References cited: January 1996 (1996-01-01), pages 895-907, DE-A1- 4 427 512 US-A- 5 344 992 XP007917213, ISSN: 0026-9247 US-A1- 2009 246 156 US-B1- 6 410 795 • ISHIDA J ET AL: "Antitumor Agents. Part 214: Synthesis and Evaluation of Curcumin Analogues as Cytotoxic Agents", BIOORGANIC &MEDICINAL CHEMISTRY, PERGAMON, GB, vol. 10,1 January 2002 (2002-01-01), pages 3481-3487, XP002536790, ISSN: 0968-0896, DOI: DOI:10.1016/S0968-0896(02)00249-3

Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 655 308 B1

Printed by Jouve, 75001 PARIS (FR) EP 2 655 308 B1

Description

[0001] 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. 5 [0002] 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-tert-butyl-4’-methoxydibenzoylmethane, CAS No.: 70356-09-1]. [0003] Substituted dibenzoylmethane derivatives may be prepared by Aldol condensation of a ketone with an ester 10 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. [0004] US6410795 discloses the formation of 1,3-diketone by condensation of a carboxylic acid ester and a ketone in the presence of an alkali metal alcoholate and an aromatic hydrocarbon. DE4427512 discloses a process for the 15 preparation of linear 1,3-diketones by Claisen condensation and their use as polymer stabilizers. [0005] US5344992 discloses a process for the preparation of linear 1,3-diketones comprising the Claisen condensation of Me ketone derivatives with esters or lactones in the presence of an alkali or alkali earth metal hydride or alkoxide in a DMSO-containing solvent mixture. [0006] Nandurkar et al (Synthetic Communications (2007), 37(13), 4111-15) discloses a method for the synthesis of 20 sterically hindered aliphatic/ aromatic 1,3-diketones via coupling of ketones with esters using potassium tert-butoxide. [0007] Guoqing et al (Journal of the American Chemical Society (2010), 132(7), 2160-2) discloses difluoroboron avobenzone, a simple boron complex of a commercial sunscreen. [0008] Franek et al (Monatshefte fuer Chemie (1996), 127(8/9), 895-907) discloses a procedure to prepare diaroylmethanes from the respective carboxylic acid esters and methyl ketones. 25 [0009] Ishida et al (Bioorg. & Med. Chem, (2002), vol. 10, 3481-87) discloses the preparation of some curcumin analogues as well as their use as antitumor agents [0010] US2009246156 discloses avobenzone in sunscreen compositions, but no process for its preparation. [0011] 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 30 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. [0012] 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 35 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. [0013] Thus, the invention relates to a process for the preparation of substituted dibenzoylmethane derivatives of formula (I)

wherein

50 1 2 R and R are independently selected from the group consisting of hydrogen, C 1 to C12 alkyl, C1 to C12 alkoxy, C3 to C12 alkenyloxy and C2 to C12 alkenyl; 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)

2 EP 2 655 308 B1

wherein 10 R1 and R2 are as defined above R3 is hydrogen; 4 R is C1 to C12 alkyl and 5 1 2 R is C1 to C8 alkyl. with the proviso that at least one of R and R is not hydrogen and 15 with the proviso that the potassium alkoxide is potassium methylate, potassium-isopropylate and/ or potassium tert.-butylate, the reaction temperature is selected in the range of 80-150°C, the reaction is carried out in an inert solvent selected from the group of aromatic or hydrocarbon solvents as well as mixtures thereof and 20 wherein the alcohols R4 OH and R5 OH are removed continuously as formed. In another embodiment, the invention relates to a process for the preparation of substituted dibenzoylmethane derivatives of formula (I) 1 2 wherein R and R are independently selected from the group consisting of hydrogen, C1 to C12 alkyl, C1 to 1 2 C12 alkoxy, C3 to C12 alkenyloxy and C2 to C12 alkenyl with the proviso that at least one of R and R is not hydrogen and with the proviso that the potassium alcoholate is derived from an alcohol R 5-OH having a boiling 25 point below 100°C.

[0014] Ina particularembodiment, theinvention relates to a processfor the preparation of dibenzoylmethanederivatives 1 2 of formula (I) wherein R and R are independently selected from the group consisting of hydrogen, C 1 to C12 alkyl and 1 2 C1 to C12 alkoxy. More in particular R is a C1 to C8 alkoxy radical and R is a C1 to C8 alkyl radical, most in particular 30 1 R is a C 1 to C 4 alkoxy radical such as methoxy, ethoxy, isopropoxy, n-propoxy, 1-methylpropoxy, t-butoxy and n-butoxy 2 and R is a C1 to C4 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. R1 is methoxy and R2 is 1,1-dimethylethyl). [0015] Examples of alkyl, respectively alkenyl radicals are branched or unbranched alkyl, respectively alkenyl chains 35 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-unde- 40 cyl, n-dodecyl, ethenyl, 2-propenyl and 3-butenyl. [0016] 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. 4 [0017] In the process according to the invention R is advantageously a C1 to C4 alkyl radical such as methyl, ethyl, 45 n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl and 1,1-dimethylethyl. More advantageously, R 4 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 1 is methoxy, R 2 is 1,1-dimethylethyl, and R 4 is methyl, ethyl or 1,1-dimethylethyl. [0018] Suitable potassium alcoholates (IV) according to the invention encompass potassium methylate, potassium 50 tert.-butylate, potassium-iso propylate, in particular potassium methylate or potassium tert.-butylate which are e.g. com- mercially 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. 55 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.

3 EP 2 655 308 B1

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 5 removed without the removal of the solvent. Accordingly it is preferred that at atmospheric pressure the solvent has a boiling point of about 70° to 250°C, more preferably of about 80° to 150°C. suitable solvents for the process according to the present invention are aromatic solvents such as alkyl or dialkyl benzenes or hydrocarbon solvents such a cy- clohexane, methylcyclohexane, heptane or octane. Particularly advantageous solvents to be used in the process according to the present invention are toluene or xylene as well as mixtures thereof, in particular if R1 is methoxy and R2 10 is 1,1-dimethylethyl (thus the compound of formula (I) being butyl methoxydibenzoylmethane) as the potassium salt of butyl methoxydibenzoylmethane is particularly soluble in toluene or xylene which further facilitates the industrial handling. [0019] Without being bound to theory, the structure of the intermediate potassium salt of butyl methoxydibenzoylmethane is believed to be as depicted below:

The reaction temperature is advantageously selected such that the in situ formed alcohols R4OH and R5OH are suc- cessively removed, preferably by distillation while refluxing the solvent. In all embodiment of the invention, the reaction 25 temperature is selected in the range of 80°C to 150°C and most preferably in the range of 80° - 120°C. Pressure is not critical to the present process, except to the extent that the selection of a particular pressure may lower the boiling point and may also facilitate removal of the alcohol(s) released in the reaction medium. The ester of formula (III) is advantageously used in a slight excess in the process according to the present invention. In particular, the molar ratio of the ketone of formula (II) to the ester of formula (III) is selected in the range of about 0.5 t o 30 1.25, such as more in particular in the range of 0.8 to 1, such as e.g. in the range of about 0.9 to 1. Generally, an excess of 1 to 10 mol-% of ester of formula (III) is used in relation to the ketone of formula (II). The molar ratio of the ketone of formula (II) to the potassium alcoholate is advantageously less than 1. Particularly, the molar ratio is selected in the range of about 0.5 and 1.1, such as in the range of 0.8 to 1. Generally, an excess of about 0-30 mole-%, such as in particular of about 1-20 mole-% and more in particular of about 1-10 mol-% of potassium 35 alcoholate is used based on the molar amount of the ketone of formula (II). [0020] According to a preferred embodiment according to the invention a reaction mixture is provided that contains the potassium alcoholate, the ester of formula (III) and an inert solvent. To this mixture the ketone of formula (II) is added. The ketone of formula (II) can be added in pure form or in solution, alone or with a portion of the ester of formula (III) which is not in the starting mixture. In a preferred embodiment the alcohols are removed from the reaction mixture as 40 they are formed. [0021] Advantageously, the rate of addition of the ketone of formula (II) is selected such that the alcohol content in the reaction medium is kept low, preferably such that during the addition the alcohol is constantly being distilled off. [0022] In a specific embodiment of the invention R 1 is methoxy, R2 is 1,1-dimethylethyl, and R4 is methyl, the solvent is toluene, the potassium base is potassium methylate or tert.-butylate and the reaction temperature is selected in the 45 range of 80 to 120°C at normal pressure. Even more in particular, the molar ratio of ketone of formula (II) to the ester of formula (III) is additionally selected in the range of 0.8 to 1 such as in particular in the range of about 0.9 to 1 and the molar ratio of the ketone of formula (II) to the potassium alcoholate is selected in the range of about 0.5 and 1.1 such as in the range of about 0.8 to 1. [0023] Each reaction of the process according to the invention can in principle be carried out in any reactor suitable 50 for the respective reaction type. Without restricting generality, the following are mentioned by way of example: suspension reactor, stirred tank, stirred tank cascade, tubular reactor, shell-type reactor, shell and tube reactor, fixed-bed reactor, fluidized-bed reactor, reactive distillation column. [0024] In a further embodiment, when R1 ≠ R2 (i.e. R1 different from R2), the disclosure also relates to substituted dibenzoylmethane derivatives of formula (I) obtained by the process according to the present invention as this process 55 leads to a significant reduction of the respective symmetrical byproducts. Particularly, the disclosure relates to substituted dibenzoylmethane derivatives (I) obtained by the process according to the present invention, wherein the substituted dibenzoylmethane are chosen from the group consisting of

4 EP 2 655 308 B1

[0025] More in particular, the substituted dibenzoylmethane derivatives of formula (I) have a mol ratio of (V) (i.e. butyl 20 methoxydibenzoylmethane) to the sum of (VI) (i.e. 4,4’-Dimethoxydibenzoylmethane) and (VII) (i.e. 4,4’-Di-tert-butyldibenzoylmethane) is in the range of 75: 1 to 55 to 1. [0026] In a further embodiment, the mol ratio of (V) to the sum of (VI) and (VII) is in the range of 75: 1 to 55 to 1. [0027] In one preferred embodiment, the mol ratio of (V) to the sum of (VI) and (VII) is in the range of 75: 1 to 55 to 1 [0028] The term ’consisting of’ as used according to the present invention means that the total amount of the compounds 25 (V), (VI) and (VII) ideally sum up to 100 wt.-%. It is however not excluded that small amount of impurities or additives may be present such as e.g. in amounts of less than 5 wt.-%, preferably less than 3 wt.-%. [0029] The following examples are provided to further illustrate the processes of the present invention. These examples are illustrative only and are not intended to limit the scope of the invention in any way.

30 Example 1: 4-tert-butyl-4’-methoxydibenzoylmethane: condensation with various bases

[0030] In a reaction flask with a 30 ml toluene and the base were provided under a blanket of inert gas. 20 mmole 4- tert-Butyl benzoic acid methyl ester (TBBM) and 20 mmole p-methoxy acetophenone (pMAc) was added. The mixture was stirred at about 110°C/ 1 bar while alcohol and toluene was slowly distilled off (toluene was occasionally replenished 35 to maintain 20 ml volume). After complete conversion of TBBM and pMAc the reaction mixture was cooled and acidified with 2M acetic acid. An aliquot was analyzed by HPLC for the chemical yield of 4- tert-Butyl-4’-methoxydibenzoylmethane. The results are given in table 1.

Table 1: Results 40 Base Base [mmole] Reaction [h] Yield [mole%] Appearance of reaction mixture LiOMe 30 22 18 inhomogeneous NaOMe 22 6 74 inhomogeneous

45 NaOtBu 30 3 77 inhomogeneous

Mg(OMe)2 30 4 0 inhomogeneous NaH* 22 2 81 inhomogeneous

NaNH2 22 2 64 inhomogeneous 50 KOtBu 22 2 87 homogeneous KOMe 22 2 95 homogeneous

KOC(CH3)2C2H5 22 2 95 homogeneous

55 *60% in mineral oil

[0031] As can be seen from the results in table 1 the use of a potassium alcoholate results in higher yields and shorter

5 EP 2 655 308 B1

reaction times compared to the use of other alkali or earth alkali alcoholates. [0032] Furthermore, the potassium salt did not crystallize and remained homogeneously dissolved in toluene whereas the sodium, magnesium and the lithium salt formed a crystalline inhomogeneous mixture.

5 Example 2: 4-tert-butyl-4’-methoxydibenzoylmethane: Influence of solvent/ temperature

[0033] In a reaction flask with a stirrer-was provided at ambient temperature under a blanket of inert gas: 20 ml solvent, 22 mmole potassium tert.-butylate and 20.4 mmole tert.-butyl benzoic acid methyl ester. The mixture was heated to the reaction temperature given in table 2. Then, a 3 molar solution of p-methoxy acetophenone (pMAc) in the corresponding 10 solvent was added over a period of about 1h under slow distillation of a mixture of methanol,tert .-butanol and the respective solvent at the pressure given in table 2. Afterwards the homogeneous reaction mixture was stirred for additional 3 h during which the solvent was occasionally replenished to 20 ml volume. Then the reaction mixture was cooled and acidified with 2m acetic acid. An aliquot was analyzed by HPLC giving the yields of 4-tert-butyl-4’-methoxydibenzoylmethane as indicated in table 2. 15 Table 2 Solvent Addition time pMAc [h] T [°C] Time [h] Pressure [bar] Yield [mol%] Xylene 0.5 140° 3 1 86 20 Toluene 0.5 110° 3 1 91 Toluene 1.0 80° 3 0.4 93

[0034] As can be retrieved from table 2, the reaction temperature is preferably kept in the range of 80 - 120 °C. 25 Example 3: 4-tert-butyl-4’-methoxydibenzoylmethane

[0035] In a reaction flask with a stirrer was provided at ambient temperature under a blanket of inert gas: 16 ml toluene, 24 mmole base and 20.4 mmole 4-tert. butyl benzoic acid methylester (TBBM), respectively 20.4 mmole 4-tert. butyl 30 benzoic acid tert.-butyl ester (TBBT) as indicated in table 3. The resulting reaction mixture was heated to boiling. After- wards a 3 molar solution of p-methoxy acetophenone (pMAc) in toluene was added within 1 h under slow distillation of a mixture of methanol and/ or tert.-butanol and toluene at 1 bar. The mixture was stirred for x additional hours as indicated in table 3. The reaction mixture was occasionally replenished to 20 ml volume by addition of toluene. The reaction mixture was cooled and acidified with 2M acetic acid. An aliquot was analyzed by HPLC for the chemical yield of 4- tert-butyl-4’- 35 methoxydibenzoylmethane. The results are presented in table 3.

Table 3 Base Ester Appearance of reaction mixture time [h] Yield [mole%]

40 KOMe TBBT homogeneous 1.75 91 KOtBu TBBT homogeneous 2 85 KOtBu TBBM homogeneous 3 92 NaOtBu TBBT inhomogeneous 1.75 63 45 NaOMe TBBT inhomogeneous 4 80 NaOtBu TBBM inhomogeneous 3 85 TBBT = 4-(1,1-dimethylethyl)-benzoic acid tert-butyl ester

50 TBBM = 4-(1,1-dimethylethyl)-benzoic acid methyl ester

[0036] As can be retrieved from table 3 highest yields of butyl methoxydibenzoylmethane were achieved with either the tert-butylester TBBT and potassium methylate or the methylester TBBM with potassium tert-butylate, whereas the combination of the tert-butylester TBBT with potassium tert-butylate resulted in lower yields. 55 Furthermore, as can be retrieved from table 3, the use of the respective sodium alcoholate resulted in significant lower yields compared to the use of the respective potassium alcoholate. Furthermore, the use of sodium alcoholate resulted in inhomogeneous badly stirrable reaction mixtures.

6 EP 2 655 308 B1

Example 4 4-tert-butyl-4’-methoxydibenzoylmethane

[0037] In a reaction flask with a stirrer-was provided under a blanket of nitrogen a solution of 20.21 g 4-t-butylbenzoic acid methylester 98% (103 mmole) in 100 ml toluene. To the solution was added 8.57 g potassium methoxide solid 5 >90% Fluka (110 mmole) and the mixture was heated to boiling. To the boiling mixture was added in 1h at continuous distillation of the formed methanol a solution of 15.32 g p-methoxyacetophenone Fluka 98% (100 mmole) in 20g toluene. The clear brownish reaction solution was stirred for additional 2h and slow distillation. The mixture was cooled and acidified by addition of 115 ml 0.5 mol/l sulfuric acid. The water-phase was separated followed by extraction in a funnel with 100 ml toluene. The organic phases where washed with water, combined and the toluene evaporated at a rotavapor 10 resulting in 30.81g of a residue. The respective yields of 4-tert-butyl-4’-methoxydibenzoylmethane (BMDBM) 4,4’-dimethoxydibenzoylmethane (DMDBM) and 4,4’-di-tert-butyldibenzoylmethane (DTBDBM) are given in table 5. [0038] The experiment was repeated with different bases resulting in the yields as indicated in table 5 as well.

Table 5 15 Toluene Base Yield [mol-%] Mol ratio [ml] [g] BMDBM DMDBM DTBDBM BMDBM/ ∑ DMDBM&DTBDBM 160 NaOMe: 6.48 80 1.9 0.9 29:1

20 100 KOtBu: 12.34 93 1.1 0.5 58:1 100 KOMe: 8.57 90 0.8 0.5 69:1 As can be retrieved from table 5, the yields of 4-tert-butyl-4’-methoxydibenzoylmethane are significantly higher when a potassium alcoholate is used. Furthermore the amount of the symmetrical by-products 4,4’-dimethoxydibenzoylmethane and 4,4’-di-tert.-butyldibenzoylmethane is significantly reduced which results in a decreased yellow discol- 25 oration after incorporation into a topical composition.

Example 5: 4-Allyloxy-4’-tert.butyl-dibenzoylmethane

30 [0039] To a mixture of 2.9g 4-tert-butylbenzoic acid methylester (15 mmole), 1.25g potassium methoxide (18 mmole) in 10ml toluene was added a solution of 2.47g 4-allyloxy acetophenone (14 mmole) in 5ml toluene. The mixture was boiled for 1h at 105°C-110°C resulting in a homogeneous mixture. The solution was acidified at ambient temperature with diluted sulfuric acid, extracted with toluene and washed with water. The extract was evaporated and the residue crystallized from methanol yielding 3.39g (72%) of 4-tert.butyl-4’allyloxy-dibenzoylmethane. 35 Example 6: 4,4’-Dimethoxy-dibenzoylmethane

[0040] To a mixture of 1.67g 4-methoxy benzoic acid methylester (10 mmole) and 0.86g potassium methoxide (12 mmole) in 10 ml toluene was added a solution of 1.52g 4-methoxyacetophenone (10 mmole) in 5ml toluene. The mixture 40 was boiled for 2h at 105°C-110°C resulting in a homogeneous mixture. The mixture was acidified with diluted hydrochloric acid, extracted with toluene and washed with water. The extract was evaporated and the residue crystallized from ethyl acetate yielding 2.02g (71%) 4,4’-dimethoxy-dibenzoylmethane

Example 7: 4-tert-butyl-4’-methoxydibenzoylmethane: variability of solvent 45 [0041] To a mixture of 20 ml solvent, 26 mmole potassium methylate (Fluka) and 4.04 g 4-tert.-butyl benzoic acid methylester (21 mmole) was added 3.00 g 4-methoxyacetophenone (20 mmole) and 6 ml solvent as indicated in table 6 at boiling temperature and distillation of solvent. The mixture was boiled for additional 2h and continued distillation (the solvent was replenished on occasion to maintain at least 20 ml volume). The mixture was cooled to ambient 50 temperature and acidified with 2M acetic acid. An aliquot was analyzed by HPLC to determine the chemical yield of 4- tert-butyl-4’-methoxydibenzoylmethane.

Table 6: No Solvent Yield [mole%] 55 1 Chlorobenzene 85 2 Benzene 90

7 EP 2 655 308 B1

(continued)

No Solvent Yield [mole%] 31,2-Diethoxyethane 83 5 4Octane 82

Claims 10 1. A process for the preparation of substituted dibenzoylmethane derivatives of formula (I)

20 wherein

1 2 R and R are independently selected from the group consisting of hydrogen, C 1 to C12 alkyl, C1 to C12 alkoxy, C3 to C12 alkenyloxy and C2 to C12 alkenyl; 25 characterized in that the 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

R1 and R2 are as defined above 3 40 R is hydrogen; 4 R is C1 to C12 alkyl and 5 R is C1 to C8 alkyl. with the proviso that at least one of R1 and R2 is not hydrogen and with the proviso that the potassium alkoxide is potassium methylate, potassium-isopropylate and/ or potassium tert.-butylate, the reaction tem- 45 perature is selected in the range of 80-150°C, the reaction is carried out in an inert solvent selected from the group of aromatic or hydrocarbon solvents as well as mixtures thereof and wherein the alcohols R 4OH and R5OH are removed continuously as formed.

2. The process according to claim 1 wherein 1R and R2 are independently selected from the group consisting of 50 hydrogen, C1 to C12 alkyl and C1 to C12 alkoxy.

3. The process according to claim 1 or 2 wherein R3 is hydrogen and R4 is methyl, ethyl or 1,1-dimethylethyl.

4. The process according to any one of claims 1 to 3 wherein the inert solvent is toluene and/ or xylene, preferably 55 toluene.

5. The process according to any one of claims 1 to 4 wherein the potassium alcoholate is potassium methylate and/ or potassium tert.-butylate, preferably potassium methylate.

8 EP 2 655 308 B1

6. The process according to any one of claims 1 to 5 wherein R 1 is methoxy, R 2 is 1,1-dimethylethyl and R4 is methyl, ethyl or 1,1-dimethylethyl.

7. The process according to any one of claims 1 to 6 wherein the molar ratio of the ketone of formula (II) to the ester 5 of formula (III) is selected in the range of 0.5 to 1.25, preferably in the range of 0.9 to 1.

8. The process according to any one of claims 1 to 6 wherein the molar ratio of the ketone of formula (II) to the potassium alcoholate is selected in the range of 0.5 to 1.1, preferably in the range of 0.8 to 1

10 9. The process according to any one of claims 1 to 8 wherein the solvent is toluene and the reaction temperature is selected in the range of 80° to 120°C.

10. The process according to any one of claims 1 to 9 wherein the condensation step is followed by hydrolysis using an organic or mineral acid, preferably a mineral acid. 15 11. The process according to claim 10 wherein the mineral acid is sulfuric acid.

Patentansprüche 20 1. Verfahren zur Herstellung von substituierten Dibenzoylmethanderivaten der Formel (I)

30 wobei

1 2 R und R unabhängig aus der Gruppe bestehend aus Wasserstoff, C 1- bis C12-Alkyl, C1- bis C12-Alkoxy, C3- bis C12-Alkenyloxy und C2- bis C12-Alkenyl ausgewählt sind; dadurch gekennzeichnet, dass das Verfahren den Schritt des Bildens des Kaliumsalzes von (I) durch Kon- 35 densieren eines Ketons der Formel (II) mit einem Ester der Formel (III) in Gegenwart eines Kaliumalkoholats (IV) (Kondensationsschritt) umfasst

wobei

50 R1 und R2 wie oben definiert sind; R3 für Wasserstoff steht; 4 R für C1- bis C12-Alkyl steht und 5 R für C1- bis C8-Alkyl steht; mit der Maßgabe, dass mindestens eine der Variablen R1 und R2 nicht für Wasserstoff steht, und mit der 55 Maßgabe, dass es sich bei dem Kaliumalkoxid um Kaliummethylat, Kaliumisopropylat und/oder Kalium- tert-butylat handelt, die Reaktionstemperatur im Bereich von 80-150° C ausgewählt wird, die Umsetzung in einem inerten Lösungsmittel aus der Gruppe der aromatischen Lösungsmittel oder Kohlenwasserstoff- Lösungsmittel sowie Mischungen davon durchgeführt wird und die Alkohole R4OH und R5OH im Maße

9 EP 2 655 308 B1

ihrer Bildung kontinuierlich entfernt werden.

1 2 2. Verfahren nach Anspruch 1, bei dem R und R unabhängig aus der Gruppe bestehend aus Wasserstoff, C1- bis C12-Alkyl und C1- bis C12-Alkoxy ausgewählt sind. 5 3. Verfahren nach Anspruch 1 oder 2, bei dem R 3 für Wasserstoff steht und R 4 für Methyl, Ethyl oder 1,1-Dimethylethyl steht.

4. Verfahren nach einem der Ansprüche 1 bis 3, bei dem es sich bei dem inerten Lösungsmittel um Toluol und/oder 10 Xylol, vorzugsweise Toluol, handelt.

5. Verfahren nach einem der Ansprüche 1 bis 4, bei dem es sich bei dem Kaliumalkoholat um Kaliummethylat und/oder Kalium-tert-butylat, vorzugsweise Kaliummethylat, handelt.

15 6. Verfahren nach einem der Ansprüche 1 bis 5, bei dem R 1 für Methoxy steht, R2 für 1,1-Dimethylethyl steht und R4 für Methyl, Ethyl oder 1,1-Dimethylethyl steht.

7. Verfahren nach einem der Ansprüche 1 bis 6, bei dem das Molverhältnis von Keton der Formel (II) zu Ester der Formel (III) im Bereich von 0,5 bis 1,25, vorzugsweise im Bereich von 0,9 bis 1, ausgewählt wird. 20 8. Verfahren nach einem der Ansprüche 1 bis 6, bei dem das Molverhältnis von Keton der Formel (II) zu Kaliumalkoholat im Bereich von 0,5 bis 1,1, vorzugsweise im Bereich von 0,8 bis 1, ausgewählt wird.

9. Verfahren nach einem der Ansprüche 1 bis 8, bei dem es sich bei dem Lösungsmittel um Toluol handelt und die 25 Reaktionstemperatur im Bereich von 80 bis 120 °C ausgewählt wird.

10. Verfahren nach einem der Ansprüche 1 bis 9, bei dem auf den Kondensationsschritt eine Hydrolyse unter Verwen- dung einer organischen Säure oder Mineralsäure, vorzugsweise eine Mineralsäure, folgt.

30 11. Verfahren nach Anspruch 10, bei dem es sich bei der Mineralsäure um Schwefelsäure handelt.

Revendications

35 1. Procédé de préparation de dérivés de dibenzoylméthane substitué de formule (I)

45 dans laquelle 1 2 R et R sont indépendamment choisis dans le groupe constitué d’hydrogène, alkyle en C1 à C12, alcoxy en C1 à C12, alcényloxy en C3 à C12 et alcényle en C2 à C12 ; caractérisé en ce que le procédé comprend l’étape de formation du sel de potassium de (I) par condensation d’une cétone de formule (II) avec un ester de formule (III) en présence d’un alcoolate de potassium (IV) (étape de condensation) 50

10 EP 2 655 308 B1

dans lequel

R1 et R2 sont tels que définis ci-dessus ; R3 est hydrogène ; 5 4 R est alkyle en C1 à C12 et 5 R est alkyle en C1 à C8, à condition qu’au moins l’un de R 1 et R2 ne soit pas hydrogène et à condition que l’alcoxyde de potassium soit le méthylate de potassium, l’isopropylate de potassium et/ou le tert-butylate de potassium, la température de réaction est choisie dans la plage de 80 à 150 °C, la réaction est conduite dans un solvant inerte choisi dans 10 le groupe de solvants aromatique ou hydrocarbures ainsi que des mélanges de ceux-ci et dans lequel les alcools R4OH et R5OH sont enlevés en continu au fur et à mesure qu’ils sont formés.

2. Procédé selon la revendication 1 dans lequel R1 et R2 sont indépendamment choisis dans le groupe constitué d’hydrogène, alkyle en C1 à C12 et alcoxy en C1 à C12. 15 3. Procédé selon la revendication 1 ou 2 dans lequel R 3 est hydrogène et R 4 est méthyle, éthyle ou 1,1-diméthyléthyle.

4. Procédé selon l’une quelconque des revendications 1 à 3 dans lequel le solvant inerte est le toluène et/ou le xylène, de préférence le toluène. 20 5. Procédé selon l’une quelconque des revendications 1 à 4 dans lequel l’alcoolate de potassium est le méthylate de potassium et/ou le tert-butylate de potassium, de préférence le méthylate de potassium.

6. Procédé selon l’une quelconque des revendications 1 à 5 dans lequel R 1 est méthoxy, R 2 est 1,1-diméthyléthyle et 25 R4 est méthyle, éthyle ou 1,1-diméthyléthyle.

7. Procédé selon l’une quelconque des revendications 1 à 6 dans lequel le rapport molaire de la cétone de formule (II) à l’ester de formule (III) est choisi dans la plage de 0,5 à 1,25, de préférence dans la plage de 0,9 à 1.

30 8. Procédé selon l’une quelconque des revendications 1 à 6 dans lequel le rapport molaire de la cétone de formule (II) à l’alcoolate de potassium est choisi dans la plage de 0,5 à 1,1, de préférence dans la plage de 0,8 à 1.

9. Procédé selon l’une quelconque des revendications 1 à 8 dans lequel le solvant est le toluène et la température de réaction est choisie dans la plage de 80 °C à 120 °C. 35 10. Procédé selon l’une quelconque des revendications 1 à 9 dans lequel l’étape de condensation est suivie d’une hydrolyse au moyen d’un acide organique ou minéral, de préférence un acide minéral.

11. Procédé selon la revendication 10 dans lequel l’acide minéral est l’acide sulfurique. 40

11 EP 2 655 308 B1

REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description

• DE 2945125 [0003] • DE 4427512 [0004] • US 6278025 B [0003] • US 5344992 A [0005] • US 6410795 B [0004] • US 2009246156 A [0010]

Non-patent literature cited in the description

• NANDURKAR et al. Synthetic Communications, • FRANEK et al. Monatshefte fuer Chemie, 1996, vol. 2007, vol. 37 (13), 4111-15 [0006] 127 (8/9), 895-907 [0008] • GUOQING et al. Journal of the American Chemical • ISHIDA et al. Bioorg. & Med. Chem, 2002, vol. 10, Society, 2010, vol. 132 (7), 2160-2 [0007] 3481-87 [0009]