Patent Application
20080081025
a) Activation of OH Groups of a Poly(glycerol-b-propylene Oxide) by Mesylation
Poly(glycerol-b-propylene oxide) prepared according to Sunder, A.; Mulhaupt, R.; Frey, H. Macromolecules, 2000, 33, 309-314 was supplied from the Institute of Organic Chemistry of the University of Mainz, Germany. The Polyglycerol was characterized by 1H NMR and GPC to reveal a PO unit/OH group ratio of 1.25 and a Mn of 1060 g/mol with a polydispersity of 1.6.
Methanesulfonyl chloride (3.75 ml, 48.5 mmol) was added dropwise to a solution of poly(glycerol-b-propylene oxide) (5.0 g, 4.6 mmol, 37 mmol OH) and triethylamine (9.5 ml, 67.9 mmol) in DCM (dichloromethane) (75 mL) under Argon at 0° C. DMAP (dimethylaminopyridine) (20 mg) was added and the mixture stirred at room temperature for 12 h. Excess of methanesulfonyl chloride was hydrolyzed by addition of water (50 mL) at 0° C. and the organic layer extracted with 2N HCl (40 mL) and water (40 mL). The combined aqueous phases were extracted with DCM (3×50 mL). The combined organic extracts were dried over sodium sulfate and filtered. Evaporation under vacuo afforded 7.5 g mesylated poly(glycerol-b-propylene oxide). Total conversion of hydroxy groups to mesyl groups was proved by the absence of OH oscillation signal at 3500-3600 cm−1 using FT-IR analysis. The amount of mesyl groups was determined using 1H NMR, comparing the integration of the signals of mesyl CH3 at 3.04 ppm to trimethylolpropane CH3 at 0.87 ppm, to give an average of about 8 OH/polymer.
b) Preparation of a polymeric UV-filter by attaching 4-(1,3-benzoxazol-2-yl)-phenol to an activated Poly(glycerol-b-propylene oxide)
Cesium carbonate (16 g, 50 mmol) and potassium iodate (50 mg) were added to a solution of 4-(1,3-benzoxazol-2-yl)-phenol I (8.9 g, 42 mmol) (prepared according to Passerini, J. Chem. Soc. 1954, 2256-2257) in NMP (N-methylpyrolidon) (100 mL) and the mixture stirred under Argon at 80° C. for 20 min. A solution of mesylated poly(glycerol-b-propylene oxide) (7.48 g, 4.4 mmol, 35 mmol MsO) in NMP (60 mL) was added dropwise and the reaction mixture stirred at 80° C. for 12 h. Water and ethyl acetate were added (200 mL each), an orange precipitate was separated by filtration, and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic phases were washed with 2 N HCl (100 mL) and saturated bicarbonate solution (100 mL) and the combined aqueous layers extracted with ethyl acetate (100 mL). The combined organic phases were dried over sodium sulfate, filtered and evaporated under vacuo. The oily residue was purified by column chromatography (ethyl acetate/n-hexane, 1:2ethyl acetate) on silica to yield 4.82 g chromophore II. The amount of attached chromophore was determined using 1H NMR, comparing the integration of the signals of the phenol's aromatic protons at 6.99 and 8.12 ppm to trimethylolpropane CH3 at 0.87 ppm, to give an average of about 8 chromophores/polymer. The polymeric filter showed a E1/1/-value of 840 in CHCl3 at 309 nm, which corresponds to the theoretical chromophore content of 64% (w/w). The solubility in Tegosoft TN (C12-C15 alkylbenzoate) was determined to be at least 24% (w/w).
a) 4-Dicyanomethylene-2,6-dimethyl-1,4-dihydropyridine-N-ethane-2-ol
A 350 ml three necked reaction flask, equipped with a thermometer, a reflux condenser and an oil bath with a magnetic stirrer was charged with 4-dicyanomethylene-4H-pyran (25.8 g, 150 mmol, prepared according Helv. Chim. Acta 1962, 1908-1917) in ethanolamine (100 mL, Fluka) and heated to 80° C. for 30 Min. under Ar atmosphere. Shortly after the start, an exothermic reaction is observed. After cooling, the mixture is diluted with n-Butanol (100 mL) and filtered off. The filter residue was washed consecutively with cold water (2×10 mL) and Acetone (2×100 mL). After drying slightly yellowish crystals (17.5 g) were obtained. M.p. 267-268° C. UV (THF) 360 and 372 nm (26'305).
b) Hyperbranched UV-A Filter
Potassium tert. butylate (2.3 g) were added to a solution of 4-Dicyanomethylene-2,6-dimethyl-1,4-dihydropyridine-N-ethane-2-ol (4.3 g, 20 mmol) in NMP (50 mL) and the mixture stirred under Argon at rt. for 10 min. A solution of mesylated poly(glycerol-b-propylene oxide) (4.5 g, 2.3 mmol) in NMP (20 mL) was added dropwise and the reaction mixture stirred at rt. for 6 days. 10% aq. NaHCO3 solution (150 ml) were added and extracted with ethyl acetate (3×100 mL), a precipitate was separated by filtration. The combined organic phases were washed with water (3×100 mL) and saturated NaCl solution (100 mL) and concentrated to yield 4 g of a red oil. This product was chromatographed in Ethylacetate/Ethanol=19:1 and the fractions were analyzed by GPC. A middle fraction of 390 mg showed an UV absorption in THF of E=477 at 370 nm. This corresponds to an average loading of 3.2 chromophores per molecule.
Preparation of a Brij Formulation Containing 5% (w/w) of Chromophore II as a O/W Sunscreen
The hyperbranched chromophore II (5.0 g, corresponding to 5% (w/w) UV-filter/sunscreen) was dissolved in Tegosoft TN at 80° C. and added to a mixture of Brij 72 (INCI: Steareth-2) (2.0 g), Brij 721 (INCI: Steareth-21) (2.0 g), Lanette O (cetearyl alcohol) (2.0 g), Estol GMM 3650 (glyceryl monomyristate) (2.0 g), BHT (butylhydroxytoluene) (0.05 g) and Phenonip (phenoxyethanol and methyl-, ethyl-, propyl-, butylparaben) (0.8 g). The mixture was shortly heated to 80° C. in order to melt solid emulsifiers. To the still warm mixture (70-80° C.) a preheated solution (˜80° C.) of glycerin (4.0 g) and EDTA BD (0.1 g) in water (62.95 g) and subsequently 10% aqueous KOH (0.1 g) as well as Sepigel 305 (polyacrylamide and C13-C14 isoparaffin and Laureth-7) (1.0 g) were added slowly under continuous stirring. The resulting emulsion was stirred until a temperature of about 40° C. was reached, homogenized with 24,000 rpm using a ULTRA-TURRAX®, and finally stirred for an additional hour. Determination of the photostability of the novel polymeric chromophore II was performed according to G. Berset et al. (International Journal of Cosmetic Science 1996, 18(3), 167-177) applying instead of a liquid film the prepared sunscreen. Thereby 96% of the chromophore II could have been recovered. In vitro SPF measurements were performed in comparison to a sunscreen containing 5% Parsol® MCX (2-ethylhexyl 4-methoxycinnamate) after application of 1.4 mg sunscreen per cm2 on PMMA plates (Helioscience, Marseille, FR) using the SPF-290S Analyzer System (Optometrics LLC, Chicago, US). Each in vitro SPF was determined in triplicate to give for chromophore II and Parsol® MCX an average of 6.6 (II) and 6.8, respectively.
Preparation of a Polymeric UV-Filter by Attaching 4-(dimethylamino)benzoyl Chloride to Hybrane® D2000
Hybrane200 D2000 (WO 99/16810) was supplied from DSM Hybrane (Geleen, The Netherlands) with a Mn of about 2000 g/mol as determined by GPC. Triethylamine (4.0 mL, 29.0 mmol) and DMAP (50 mg) were added to a solution of Hybrane® D2000 (5.0 g, 2.5 mmol, 20.0 mmol OH) in DCM (75 mL) under Argon at 0° C. Subsequently a solution of 4-(dimethylamino)benzoyl chloride (4.5 g, 24 mmol) in DCM (25 mL) was added dropwise keeping the temperature below 5° C. The reaction mixture was stirred at room temperature for 48 h. Excess acid chloride was hydrolyzed by addition of water (100 mL) and stirring for another 12 h at room temperature. The phases were separated and the aqueous phase was extracted with DCM (2×50 mL). The combined organic phases were washed with saturated bicarbonate solution (150 mL) and 2 N HCl (150 mL). Each organic phase was re-extracted with DCM (50 mL). The combined organic extracts were dried over sodium sulfate, filtered and evaporated under vacuo. The oily residue was purified by column chromatography (ethyl acetate/n-hexane, 1:2 ethyl acetate) on silica to yield 6.46 g chromophore III. Total conversion of hydroxy groups was confirmed by the absence of OH oscillation signal at 3500-3600 cm−1 using FT-IR analysis. The amount of attached chromophore was determined using 1H NMR, comparing the integration of the signals of the aromatic protons at 6.59 and 7.85 ppm to the CH3 of the aliphatic chain at 0.86 ppm, to give an average of about 8 chromophores/polymer. The polymeric filter showed a E1/1-value of 440 in CHCl3 at 311 nm, which corresponds to the theoretical chromophore content of 45% (w/w). The solubility in Tegosoft TN was determined to be at least 22% (w/w).
The same product was obtained, when a mixture of Dodecenyl succinic anhydride (26.6 g, 100 mmol), Diisopropanolamine (17.2 g, 129 mmol) and 4-(N,N-Dimethylamino)-benzoic acid (25.2 g, 153 mmol) was heated under mechanical stirring in an inert atmosphere to 70° C. and then with vacuum to 170° C. during 6 hours. The reaction water was distilled off to get this Polymer as a residue.
Preparation of a Brij Formulation Containing 5% (w/w) of Chromophore III as a O/W Sunscreen
The sunscreen was assembled exactly in the same way as in Example 3 by using the hyperbranched polymeric chromophore III (5.0 g, corresponding to 5% (w/w) UV-filter/sunscreen) instead of chromophore II. The in vitro SPF was determined as described in Example 3 to give 5.8.
Preparation of a Polymeric Broadband UV-Filter by Attaching 4-(dimethylamino)benzoic Acid and 2-(4-Diethylamino-2-hydroxybenzoyl)benzoic Acid to Hybrane® D2000
Hybrane® D2000 (WO 99/16810) was supplied from DSM Hybrane (Geleen, The Netherlands) with a Mn of about 2000 g/mol as determined by GPC. 2 g (=8 meq. of OH groups) of Hybrane D2000, 0.63 g (2 mmol) of 2-(4-Diethylamino-2-hydroxybenzoyl)benzoic acid (TCI Europe nv; CAS 5809-23-4) and 1.24 g (6 mmol) of N,N′-Dicyclohexylcarbodiimide (DCC) is dissolved in 20 ml of DMF at room temperature. The reaction is traced by HPLC. After one hour, 0.54 g (2 mmol) of 4-(dimethylamino)benzoic acid, dissolved in 5 ml of DMF is slowly added and stirring is continued with heating to 65° C. for 18 hours. The solvent is evaporated at the Rotavap using high vacuum and the residue is dissolved in Ethylacetate/Hexane=1:1, washed twice with water, dried over Sodium sulfate, filtered and concentrated to form a honey like material. This is chromatographed over Silica starting with Ethylacetate/Hexane=1:2 and ending with pure Ethylacetate. 0.95 g of a brown, honey like product is obtained.
Preparation of a Polymeric Broadband UV-Filter by Attaching 4-(dimethylamino)benzoic Acid Chloride to the UV-A Filter Obtained in Example 2
170 mg (˜0.1 mmol) of the hyperbranched UV-A filter of example 2b and two drops of DMAP are dissolved in 5 ml of dry Pyridine and 150 mg (ca. 0.8 mmol) of 4-(dimethylamino) benzoyl chloride are added to this solution. This mixture is stirred under Argon at 0° C. for two hours and then heated to 45° C. for another 18 hours. Two drops of distilled water is added, and the stirring is continued for further 60 minutes. The crude mixture is diluted with 50 ml of Ethylacetate and washed twice with 50 ml of sat. aq. Na2CO3 solution followed by 2×50 ml of 1 n HCl and finally with 50 ml of aq. NaCl solution. The combined organic phase is dried over Na2SO4 and concentrated at the Rotavap. The brown, honey like residue is chromatographed over Silica using EtOAc/EtOH=18:2 as eluent to obtain after high vacuum drying a dark yellow foam of the desired product.
Preparation of a Polymeric Lipophilic and Easily Soluble UV-A Filter by Attaching 2-Ethyl Hexoic Acid Chloride to the Product of Example 2
The same procedure as in example 7 is carried out except that the 4-(dimethylamino) benzoyl chloride is replaced by 2-Ethyl hexoic acid chloride. The product is chromatographed over Silica using Hexane/EtOAc=1:1 as eluent to obtain after high vacuum drying a redish oil of the desired product.
Preparation of a Polymeric, Lipophilic UV-Filter by Attaching 4-(1,3-benzoxazol-2-yl)-phenol to an Activated Poly(glycerol-b-propylene Oxide) Followed by Ethoxylation
The same reaction is carried out as in example 1b, but only 5.5 g (26 mmol) of 4-(1,3-benzoxazol-2-yl)-phenol is applied instead of 8.9 g. The reaction mixture is heated for five hours to 80° C., cooled to room temperature and a solution of 2.7 g (40 mmol) of dry Sodium ethylate in 10 ml NMP is slowly added. The reaction is again heated to 80° C. for two hours and then worked up and chromatographed as described before to yield 3.3 g of the desired product.
| Number | Date | Country | Kind |
|---|---|---|---|
| 04007201.9 | Mar 2004 | EP | regional |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/EP05/03117 | 3/23/2005 | WO | 00 | 10/17/2006 |
