SYNTHESIS OF MORIN AND MORIN DERIVATIVES

Description

[0001] The dyer's mulberry tree (Maclura tinctoria or Morus tinctoria) The dyer's mulberry is a deciduous tree native to Central America, the Caribbean, East India, and tropical South America, reaching an average height of 20–30 m and a trunk diameter of 70–80 cm. The heartwood of the dyer's mulberry is commonly known as yellowwood and was used for dyeing textiles as far back as pre-Columbian times. The pigments in yellowwood are maclurin (also called maclurin or moringeric acid) and the pentahydroxyflavonol morin of the following formula I:

[0002] Morin (2,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-chromen-4-one) belongs to the group of flavonols, a subclass of flavonoids. The name of these mostly yellow plant pigments comes from the Latin word flavus, meaning yellow. Morin possesses five hydroxyl groups and three cyclic systems. The basic structure of flavonols, with the numbering of the framework atoms, along with the structurally similar aurone and the open-chain chalcones, can be seen in Fig. 1.

[0003] Morin has antioxidant and anti-inflammatory properties and is barely toxic. It thus fulfills an important requirement for pharmacological applications. The 3-hydroxylation of morin increases its antioxidant activity compared to flavones unsubstituted at the 3-position. Due to its low pKa value of 3.5 (3-OH group), morin exists in a deprotonated state under physiological conditions and, unlike other flavonoids, binds poorly to negatively charged DNA or RNA. Morin (1) is an excellent anionic ligand that complexes transition metal (e.g., a 2:1 complex with Zn²⁺) and lanthanide cations (e.g., a 3:1 complex with La³⁺) by deprotonating the 2'-OH or 3-OH group, respectively, and is used in the fluorimetric analysis of various metal ions. With Al 3+< a green fluorescent 3:1 complex is formed.

[0004] Even today, morin is isolated for commercial use from the extract of yellowwood. However, commercially available morin (both naturally and synthetically produced) exhibits a purity of only about 85%, often containing the minor component kaempferol(II) as an impurity, which morin lacks the 2'-hydroxyl group. Furthermore, it contains other impurities, typically a mixture of polyphenols and flavonoids. These impurities, which are extremely difficult or even impossible to remove, interfere with many applications, whether in pharmaceuticals, electroplating, or electroplating.

[0005] Therefore, there is a need to provide a process for the direct synthetic production of high-purity morin and morin derivatives. Furthermore, yellowwood is a tropical wood, the use of which is not without environmental concerns.

[0006] Two synthetic routes are described in the prior art for laboratory-scale synthesis. Although the structure of morin was elucidated by Perkin as early as 1896, and extensive literature exists on the synthesis of flavonoids in general, morin was only synthesized in 2013, using an Allan-Robinson condensation starting from 2-methoxy-1-(2,4,6-trihydroxyphenyl)ethan-1-one and 2,4-dimethoxybenzoyl chloride (CN 103342690 A). A similar route to morin has also been described, proceeding via the chalcone (E)-3-(2,4-dimethoxyphenyl)-1-(2-hydroxy-4,6-dimethoxyphenyl)prop-2-en-1-one (8) (CN 105985306). This approach utilizes the aldol condensation of the acetophenone derivative 1-(2-hydroxy-4,6-dimethoxyphenyl)ethan-1-one with 2,4-dimethoxybenzaldehyde. B. Vyas, M. Singh, M. Kaur, O. Silakari, MS Bahia, B. Singh, Med. Chem. Res. 2016, 25, 609-626 describe the design and screening of aldose reductase inhibitors, in which morin is also investigated as a reductase inhibitor.Furthermore, a method for the synthesis of morin is described that is intended to do without the methylation of the phenolic hydroxy groups.

[0007] Tetrahedron 73 (2017), 3485-3491 discloses the synthesis of Sanggenol-F starting from 2,4,6-trihydroxyacetophenone via 15 steps, in which morin is formed as an intermediate. Furthermore, a 7-step synthesis starting from naturally occurring morin is described.

[0008] The object of the present invention is to provide a process for the production of high-purity morin and morin derivatives based on readily available and inexpensive starting materials, as well as the provision of high-purity synthetically produced morin and morin derivatives, i.e., without the aforementioned impurities. The term morin derivatives is understood here to include derivatives directly obtainable from morin, as well as compounds of high purity that possess at least the carbon skeleton of morin, including its oxygenation pattern.

[0009] The problem is solved by a method for producing a compound with the following formula (1), comprehensively the steps: i) Acetylation of a compound of the following formula (4) to form the acetophenone of formula (6), ii) Reaction of the acetophenone of formula (6) with a compound of the following formula (7) under basic conditions at room temperature to form the chalcone of the following formula (8), iii) Reaction of the chalcone of formula (8) under oxidizing conditions in a basic environment to form a flavonol with the following formula (9); and iv) Demethylation of the flavonol of formula (9), where R1<, R2<, R3<, R4<, R5< and R6< independently comprise a branched or unbranched C1-C8-alkyl, NO2, SO3H, NX2, where X is an ethyl or methyl group or hydrogen, CF3 is or hydrogen, preferably C1-C5-alkyl or hydrogen, most preferably C1-C3-alkyl or hydrogen, and R7< and R8< independently comprise a methyl, ethyl, tert-butyl, benzyl, methoxymethyl, p-Methoxybenzyl, benzyloxymethyl, triphenylmethyl, tetrahydropyranyl or allyl group.

[0010] The process relies on readily available raw materials and offers a high yield of the desired product. Furthermore, the product is obtained in a high purity, thus exhibiting higher activity than naturally occurring morin.

[0011] The procedure can additionally or alternatively include a step (ia) Methylation of a compound of the following formula (3) under acidic conditions to form a compound of formula (4) wherein R 1< , R 2< , R 3< , R 4< , R 5< and R 6< are defined as above.

[0012] This allows morin or morin derivatives to be synthesized from other, readily available starting materials, e.g., commercially available trimethoxybenzene, which can be used directly.

[0013] In a preferred embodiment, R3< is hydrogen. In a particularly preferred embodiment, R1<, R2<, R3<, R4<, R5< and R6< are hydrogen. Thus, the process according to the invention particularly preferably yields highly pure morin of formula I:

[0014] In step iii), the oxidizing conditions can preferably be prepared using tert-butyl hydroperoxide and the basic environment preferably using an alkali hydroxide. Suitable alkali hydroxides include LiOH, KOH, and NaOH. The use of tert.- Butyl hydroperoxide reduces the formation of unwanted byproducts with an auron backbone and also increases the yield.

[0015] In step ii), the basic conditions can be created using an alkali hydroxide. Additionally, the reaction can take place at room temperature.

[0016] In step i), the acetylation can be carried out using acetyl chloride in the presence of a Lewis acid and dichloromethane. The Lewis acids can preferably be boron trichloride, BBr₃, or AlCl₃, or mixtures thereof; AlCl₃ or boron trichloride is particularly preferred.

[0017] In step (ia), the acidic conditions can be created using an inorganic acid. Nitric acid, hydrochloric acid, or sulfuric acid are preferred in this context.

[0018] Furthermore, the problem is solved by providing a kaempferol-free compound with formula (1), obtainable by the method according to the invention. In a particularly preferred embodiment, R1, R2, R3, R4, R5, and R6 in the compound of formula (1) are hydrogen, i.e., the compound is kaempferol-free morin of formula (I). The morin according to the invention is characterized by very high purity; preferably, the purity is more than 85%, 90%, or, most preferably, more than 95%, and in particularly preferred embodiments, a purity of 99% is achieved. Purity in this context means that polyphenols or flavonoids are detectable only in the aforementioned amounts. In particular, as already mentioned, the morin according to the present invention is free of kaempferol impurities, i.e., free of kaempferol of formula (II) and / or its derivatives.In the present context, the term "free from" means that, within the usual measurement accuracy, kaempferol or its derivatives are present in a proportion of less than 0.5%, and in specific embodiments, less than 0.3%. In particularly preferred embodiments, kaempferol or its derivatives are undetectable within the measurement accuracy. The high-purity morin obtainable according to the present invention can, for example, be used directly without further purification in electrolytic tin or tin / lead deposition (e.g., according to EP 810303 A1 or DE 19623274 A1). It has been found that the activity of morin in Sn and Sn / Pb deposition does not correlate linearly with the morin content in the previously used natural product, which is due to the non-removable impurities, in particular kaempferol, polyphenols, and flavonoids.It is assumed that natural impurities, which are not yet technically removable, reduce the activity of morin. The pure synthetic product according to the present invention does not contain these natural impurities and therefore exhibits an activity that is 22.35% improved compared to the natural product. Improved activity within the meaning of the present invention means an increased coverage of a sheet with Sn or Sn / Pb by this percentage in an electroplating process called a hull cell, as described in detail in EP 810303 A1. Furthermore, the porosity of the tin or tin / lead layer obtained using the morin according to the invention (measured by moisture transport FSP, Diss. H. Künzel, Univ. Stuttgart 1994) is approximately 35% lower than in the comparative example produced using natural morin.It was found that, regardless of the source of natural morin tested (Sigma-Aldrich, Adooq Bioscience, Aurantika, Fisher-Scientific), the improved properties are always of the same order of magnitude (within the usual measurement tolerances).

[0019] The invention is explained below by means of examples, Example 1 Production of 3,5-dimethoxyphenol (4)

[0020] Under an argon atmosphere, phloroglucinol (3) (80.0 g, 634 mmol, 1.0 eq.) was dissolved in methanol (400 mL). Sulfuric acid (95%, 46.3 mL, 825 mmol, 1.3 eq.) was added dropwise, and the reaction mixture was stirred under reflux at 80 °C for 26 h. Subsequently, 10% aqueous potassium carbonate solution (800 mL) and toluene (300 mL) were added. After separating the phases, the aqueous phase was extracted twice with toluene (300 mL each time). The aqueous phase was adjusted to pH < 2 with 2 M HCl solution and extracted three times with ethyl acetate (300 mL each time). The combined organic phases were dried over sodium sulfate, and the solvent was removed under high vacuum. After purification by fractional distillation, compound (4) (81.2 g, 527 mmol, 83%) was obtained as a colorless oil. Additionally, the byproduct (5) (4.71 g, 28.0 mmol, 4.4%) was obtained as a colorless oil. 3,5-Dimethoxyphenol (4): Boiling point: 139–141 °C (2.8 mbar). TLC [Petrol ether / Ethyl acetate (2:1)]:R f = 0.40. 1< H-NMR (400 MHz, CDCl 3 ): δ = 6.08 (t, J = 2.2 Hz, 1H, 4-CH), 6.03 (d, J = 2.2 Hz, 2H, 2-CH, 6-CH), 5.19 (s, 1H, OH), 3.75 (s, 6H, OC H 3 ). 13< C-NMR (100 MHz, CDCl 3 ): δ = 162.0 (2C, C Ph -OCH 3 ), 157.7 (C Ph -OH), 94.6 (2C, C-2, C-6), 93.5 (C-4), 55.7 (2C, O C H 3 ). IR (Diamant-ATR): ṽ = 3384 (m, br.),3003 (w), 2942 (w), 2842 (w), 1595 (s), 1500 (m), 1458 (m), 1433 (m), 1342 (m), 1294 (m), 1192 (s), 1139 (s), 1052 (s), 992 (m), 973 (m), 924 (m), 818 (s), 679 (m). UV (MeOH): λ max (lg ε) = 267 (2.79), 206 (4.60). MS (EI): m / z (%) = 69 [M - MeOC-CH-COH] +< (18), 125 [M - COH] +< (60), 154 [M] +< (100).

[0021] The product was obtained in a yield of 78%. This was primarily due to the second extraction of the aqueous phase after lowering the pH, which increased the product yield by an additional 23%. An increase in reaction time was necessary, especially for larger batches; it was increased from 21 h for 500 mg batches to 30 h for 20 g batches. The product characterization analyses were in line with expectations.

[0022] Two byproducts were found and isolated during the reaction. One of these is the monomethylated 5-methoxybenzene-1,3-diol, which was confirmed by <1H NMR and <13C NMR analyses. The yield was 15%. The other byproduct is the triply methylated 3,5-trimethoxybenzene, which occurred in a yield of 7%. Here, too, <1H NMR and <13C NMR analyses confirmed the structure. Byproduct 1,3,5-trimethoxybenzene (5)

[12] : Yield: 7%. TLC [Petrol ether / ethyl acetate (2:1)]: R f = 0.78. Sdp.: 135-137 °C (2.8 mbar). 1< H-NMR (400 MHz, CDCl 3 ): δ = 6.09 (s, 3H, Ph-H), 3.77 (s, 9H, OC H 3). 13<C-NMR (100 MHz, CDCl 3 ): δ = 161.6 (3C, C Ph -OCH 3 ), 92.9 (3C, C Ph ), 55.3 (3C, O C H 3 ). IR (Diamond ATR): ṽ= 3075 (w), 3004 (m), 2963 (m), 2940 (m), 2839 (m), 1591 (s), 1480 (m), 1456 (s) 1423 (m), 1339(m), 1322 (m), 1252 (w), 1209 (s), 1194 (m), 1147 (s), 1064 (s), 1034 (s), 990 (m), 942 (m), 916 (m), 847 (s), 822 (s), 779 (s), 686 (s), 640 (m), 616 (m), 591 (m), 537 (m). UV (MeOH): λ max (Ig ε) = 266 (2.62), 207 (4.47). MS (EI): m / z (%) = 69 [M - MeOC-CH-COMe] +< (83), 125 [M - COMe] +< (100), 167 [M] +< (100). Example 2 Preparation of 1-(2-Hydroxy-4,6-dimethoxyphenyl)ethan-1-one (6)

[0023] Under an argon atmosphere, boron trichloride (1 M in dichloromethane, 48.9 mL, 48.9 mmol, 1.0 eq.) was dissolved in dichloromethane (50 mL) and cooled to -10 °C. 3,5-Dimethoxyphenol (4) (7.54 g, 48.9 mmol, 1.0 eq.), pre-dissolved in dichloromethane (25 mL), was added dropwise. The reaction mixture was brought to room temperature and stirred for 30 min. Then, over 15 min, acetyl chloride (4.54 mL, 63.6 mmol, 1.3 eq.), pre-dissolved in dichloromethane (80 mL), was added dropwise. The reaction mixture was stirred under reflux for 3 h. After cooling, 1 M aqueous HCl solution (300 mL) was added. The phases were separated, and the aqueous phase was extracted three times with ethyl acetate (200 mL each time). The combined organic phases were dried over sodium sulfate and the solvent was removed under high vacuum. After column chromatographic purification on silica gel [petroleum ether / ethyl acetate (2:1)], the acetophenone derivative (6) (7.38 g, 37.6 mmol, 77%) was obtained as a colorless solid.TLC [petroleum ether / ethyl acetate (2:1)]: . R f = 0.73. Temp.: 79-82 °C. 1< H-NMR (400 MHz, DMSO- d 6): δ = 14.03 (s, 1H, OH), 6.06 (d, J = 2.4 Hz, 1H, 5-CH), 5.92 (d, J = 2.4 Hz, 1H, 3-CH), 3.85 (s, 3H, o -Ph-O C H 3 ), 3.82 (s, 3H, p -Ph-O C H 3 ), 2.61 (s, 3H, O=CC H 3). 13< C-NMR (100 MHz, DMSO- d 6 ): δ = 203.2 (C=O), 167.6 ( p - C Ph -OCH 3 ), 166.1 (o- C Ph -OCH 3 ), 162.9 (o- C Ph -OH), 106.0 ( C Ph -C=O), 93.5 (C-5), 90.75 (C-3), 55.5 (2C, O C H 3 ),32.9 ( C H 3 ). IR (Diamond-ATR): ṽ= 3103 (w, br.), 3008 (w), 2945 (w, br.), 2849 (w, br.), 2705 (w, br.),2599 (w, br.), 1613 (s), 1457 (m), 1441 (m), 1423 (m), 1389 (m), 1366 (m), 1325 (m), 1269 (s), 1220 (s),1205 (s), 1155 (s), 1112 (m), 1081 (m), 1045 (m), 1030 (m), 962 (m), 941 (m), 893 (m), 835 (s), 806 (m),744 (m), 715 (w), 690 (w), 657 (m), 628 (w), 596 (m), 557 (m), 531 (m). UV (MeOH): λ max (lg ε) = 286(4.26), 209 (4.21). MS (ESI): m / z (%) = 197 [M + H] +< (49), 219 [M + Na] +< (100). HRMS (ESI+): m / z = 219.06279 (0.1 ppm, ber.: 219.06278 [M+Na] +< ). Example 3 Preparation of 3-(2,4-Dimethoxyphenyl)-1-(2-hydroxy-4,6-dimethoxyphenyl)prop-2-en-1-one (8)

[0024] Under an argon atmosphere, the acetophenone derivative (6) (4.80 g, 24.5 mmol, 1.0 eq.) and 2,4-dimethoxybenzaldehyde (7) (6.01 g, 36.7 mmol, 1.5 eq.) were dissolved in ethanol (150 mL). A solution of NaOH (8.80 g, 220 mmol, 9.0 eq.) in distilled water (38 mL) was added dropwise. The reaction mixture was stirred at room temperature for 117 h. Subsequently, 1 M aqueous HCl solution (350 mL) was added and stirred for a further 15 min. The solution was extracted three times with ethyl acetate (250 mL each time). The combined organic phases were dried over sodium sulfate, and the solvent was removed under high vacuum. After column chromatographic purification on silica gel [petroleum ether / ethyl acetate (3:1 → 1:1)], the chalcone (8) (5.87 g, 17.0 mmol, 70%) was obtained as a yellow solid. TLC [petroleum ether / ethyl acetate (4:1)]: R f = 0.32. mp: 126-129 °C. 1< H-NMR (400 MHz, CDCl 3 ) δ = 14.54 (s, 1H, 2'-OH), 8.10 (d, J = 15.7 Hz, 1H, β-H), 7.90 (d, J = 15.7 Hz, 1H, α-H ), 7.54 (d, J = 8.6 Hz, 1H, 6-H), 6.53 (dd, J = 8.6, 2.4 Hz, 1H, 5-H), 6.47 (d, J = 2.4 Hz, 1H, 3-H), 6.10 (d, J = 2.4 Hz, 1H, 3'-H), 5.95 (d, J = 2.4 Hz, 1H, 5'-H), 3.90 (s, 3H, 6'-OC H 3 ), 3.89 (s, 3H, 2-OC H 3 ), 3.85 (s, 3H, 4- OC H 3 ),3.83 (s, 3H, 4'-OC H 3 ). 13< C-NMR (100 MHz, CDCl 3 ): δ = 193.0 ( C =O), 168.3 ( C -6'), 165.8 ( C -4'), 162.8 ( C -4), 162.4 ( C -2'), 160.2 (C-2), 138.3 ( C -β), 130.4 ( C- 6), 125.3 ( C -α), 117.8 (C-1), 106.5 ( C -1'), 105.5 (C-5), 98.4 ( C -3), 93.8 (C-5'), 91.1 (C-3'), 55.7 (2'-O C H 3 ), 55.5 (2- O C H 3 ), 55.5 (4'-O C H 3 ), 55.4 (4- O C H 3 ). IR (Diamant-ATR): ṽ= 3120 (w, br.), 3082 (w, br.), 3000 (w), 2942 (m, br.), 2840 (w, br.), 1604 (s), 1547 (s), 1502 (s), 1451 (m), 1437 (m), 1414 (m), 1343 (m), 1315 (m), 1293 (m), 1268 (s), 1206 (s), 1158 (s), 1106 (s), 1057 (m), 1028 (s), 980 (m), 940 (m), 867 (m), 849 (m), 814 (s), 795 (s), 767 (m), 720 (m), 697 (m), 674 (m),648 (m), 621 (m), 604 (m), 582 (m), 563 (m). UV (MeOH): λ max (Ig ε) = 379 (4.52), 251 (3.95), 207 (4.60).MS (EI): m / z (%) = 345 [M + H] +< (47), 367 [M + Na] +< (67), 711 [2M + Na] +< (100). HRMS (ESI+): m / z = 711.24176 (0.1 ppm, calc.: 711.24120 [2M+Na] +< ). Example 4 Preparation of 2-(2,4-Dimethoxyphenyl)-3-hydroxy-5,7-dimethoxy-4 H -chromen-4-one (9)

[0025] Under an argon atmosphere, the chalcone (8) (1.00 g, 2.90 mmol, 1.0 eq.) was dissolved in ethanol (40 mL). A solution of tertα-Butyl hydroperoxide (70% in H₂O, 4.0 mL, 29.0 mmol, 10 eq.) and NaOH (1.74 g, 43.6 mmol, 15 eq.) in distilled H₂O (4 mL) were added and stirred at room temperature for 23 h. Aqueous HCl solution (1.0 M, 100 mL) was then added and extracted three times with ethyl acetate (80 mL each time). The combined organic phases were dried over sodium sulfate and the solvent was removed under high vacuum. After column chromatographic purification on silica gel [petroleum ether / ethyl acetate (1:4)], the flavonol (9) (395 mg, 1.10 mmol, 38%) was obtained as a yellowish solid, in addition to the auron (10) (44 mg, 0.13 µmol, 4.5%). The hydroxylated auron derivative (11) was also obtained (118 mg, 329 µmol, 11%). TLC [petrol ether / ethyl acetate (1:4)]: R f = 0.45. mp: 110-112 °C. 1< H-NMR (600 MHz, CDCl 3 ): δ = 7.50(d, J = 8.4 Hz, 1H, 6'-CH), 6.78 (s, 1H, OH), 6.61 (dd, J = 8.4, 2.4 Hz, 1H, 5'-CH), 6.58 (d, J = 2.3 Hz, 1H, 3'-CH), 6.48 (d,J = 2.3 Hz, 1H, 8-CH), 6.34 (d, J = 2.3 Hz, 1H, 6-CH), 3.97 (s, 3H, 4'-OC H 3 ), 3.87 (s, 6H, 2'-OCH3, 7-OC H 3 ), 3.84 (s, 3H, 5-OC H 3 ). 13< C-NMR (150 MHz, CDCl 3 ): δ = 172.0 ( C -4), 164.1 (C-7), 162.7 ( C -4'), 160.6 ( C -5), 159.6 (8C- C -1O), 158.8 ( C -2'), 142.7 ( C -2), 138.6 ( C -3), 131.9 ( C -6'), 112.4 (C-1'), 106.8(4C-C-5C), 104.8 (C-5'), 99.2 (C-3'), 95.6 (C-6), 92.6 ( C -8), 56.4 (4'- O C H 3 ), 55.9 (5-O C H 3 ), 55.8 (2'- O C H 3 ),55.5 (7- O C H 3 ). IR (Diamant-ATR): ṽ= 3204 (m, br.), 3006 (w), 2961 (m), 2938 (m), 2840 (w), 1728 (m),1658 (m), 1601 (s), 1499 (m), 1461 (m), 1435 (m), 1414 (m), 1373 (m), 1317 (m), 1299 (m), 1281 (m),1252 (m), 1206 (s), 1161 (s), 1120 (m), 1092 (m), 1024 (m), 1002 (m), 967 (m), 936 (m), 918 (m), 873(m), 814 (m), 742 (w), 677 (w), 639 (m), 599 (m), 552 (m). UV (MeOH): λ max (lg ε) = 338 (4.07), 286(3.89), 246 (4.32), 203 (4.64). MS (ESI): m / z (%) = 359 [M + H] +< (40), 381 [M + Na] +< (56), 739 [2M + Na] +< (100). HRMS (ESI+): m / z = 739.20013 (0.02 ppm, ber.: 739.20028 [2M+Na] +< ).

[0026] Nebenprodukt 2-(2,4-Dimethoxybenzyliden)-4,6-dimethoxybenzofuran-3(2H)-on (10): DC [Petrolether / Ethylacetat (1:4)]: R f = 0.44. 1< H-NMR (400 MHz, CDCl 3 ): δ = 8.19 (d, J = 8.7 Hz, 1H, 6'-H), 7.27 (s, 1H, 2C=CH), 6.58 (dd, J = 8.7, 2.4 Hz, 1H, 5'-H), 6.45 (d, J = 2.4 Hz, 1H, 3'-H), 6.36 (d, J = 1.9 Hz, 1H,7H), 6.11 (d, J = 1.9 Hz, 1H, 5H), 3.94 (s, 3H, 4-OC H 3 ), 3.90 (s, 3H, 6-OC H 3 ), 3.87 (s, 3H, 2'-OC H 3 ),3.86 (s, 3H, 4'-OC H 3 ). 13< C-NMR (100 MHz, CDCl 3 ): δ = 180.6 (C-3),168.6 (7-C- C -10), 168.4 (C-6), 162.2 (C-4'), 160.1 ( C -2'), 159.3 (C-4), 146.8 (C-2), 132.8 (C-6'), 114.7 (C-1'), 105.7 (3C-C-4C), 105.5 (C-5'), 105.3 (2C=C), 98.0 ( C -3'), 93.8 ( C -5), 89.1 (C-7), 56.2 (4-O C H 3 ), 56.0 (6-O C H 3 ), 55.6 (2'-O C H 3 ), 55.4 (4'-O C H 3 ). IR (Diamant-ATR): ṽ= 2975 (w, br.), 2945 (w, br.), 2836 (w, br.), 1689 (m), 1648 (m), 1590 (s, br.), 1503 (m), 1447 (m), 1419 (m), 1362 (m), 1350 (m), 1321 (m),1289 (m), 1243 (s), 1217 (s), 1201 (s), 1155 (s), 1087 (s), 1033 (s), 946 (m), 917 (m), 890 (m), 815 (s),788 (s), 720 (m), 695 (m), 674 (m), 633 (m), 589 (m), 548 (m). UV (MeOH): λ max (lg ε) = 403 (4.43), 252(3.93), 203 (4.53). MS (ESI): m / z (%) = 343 [M + H] +< (61), 365 [M+ Na] +< (100), 707 [2M + Na] +< (97). HRMS (ESI+): m / z = 365.09975 (0.5 ppm, ber.: 365.09956 [M+Na] +< ).

[0027] Nebenprodukt ( E )-2-((2,4-Dimethoxyphenyl)(hydroxy)methylen)-4,6-dimethoxybenzofuran-3(2 H )-on (11): DC [Petrolether / Ethylacetat (1:4)]: R f = 0.63. Schmp.: 177-180 °C. 1< H-NMR (400 MHz, CDCl 3 ): δ = 9.47 (s, OH), 7.19 (d, J = 7.3 Hz, 6'-H), 6.57 (dd, J = 7.3, 2.1 Hz, 5'-H), 6.56 (d, J = 2.1 Hz, 3'-H), 6.53 (d, J =2.3 Hz, 7- H ), 6.36 (d, J = 2.3 Hz, 4-H), 3.99 (s, 3H, 3-COC H 3 ), 3.86 (s, 3H, 5- COC H 3 ),3.83 (s, 3H, 4'- COC H 3 ), 3.79 (s, 3H, 2'- COC H 3 ). 13< C-NMR (100 MHz, CDCl 3 ): δ = 170.72 (3-C), 162.87 (6-C), 161.80 (2-C), 160.85 (4'-C), 158.67 (2'-C), 157.01 (4- C), 155.80 (7-C- C -1-0), 132.46 (6'-C), 112.98 (C-OH), 104.70 (5'-C), 100.41 (1'-C), 99.15 (3'- C), 99.09 (3-C-C-4-C),95.37 (5-C), 94.26 (7-C), 56.86 (4-C- C H 3 ), 55.86 (6-C- C H 3 ), 55.77 (2'-C- C H 3 ), 55.68 (4'-C- C H 3 ). IR (Diamant-ATR): ṽ= 3319 (m, br.), 3211 (w, br.), 3004 (m), 2951 (m, br.), 2841 (m), 2678 (w, br.), 1703(m), 1603 (s), 1576 (s), 1510 (m), 1446 (m), 1368 (m), 1281 (m), 1256 (m), 1204 (s), 1155 (s), 1110 (s), 1027 (s), 935 (m), 817 (m), 750 (m), 686 (m), 636 (m), 617 (m). UV (MeOH): λ max (lg ε) = 621 (1.71), 314(3.71), 295 (3.72), 253 (3.86), 206 (4.39), 203 (4.39). MS (ESI): m / z (%) = 381 [M + Na] +< (100), 739 [2M+ Na] +< (42). HRMS (ESI+): m / z = 381.09460 (1.10 ppm, ber.: 381.09502 [M+Na] +< ). Example 5 Preparation of 2-(2,4-Dihydroxyphenyl)-3,5,7-trihydroxy-4H-chromen-4-one (1, Morin)

[0028] Under an argon atmosphere, flavonol (9) (400 mg, 1.12 mmol, 1.0 eq.) was dissolved in acetic acid (99%, 10 mL) and HBr (48% in H₂O, 50 mL) was added. The mixture was then heated to reflux for 24 h. The crude product was largely freed from the solvent and reconstituted in ethanol (2 mL). After the addition of petroleum ether (100 mL), filtration, and drying of the residue under high vacuum, morin ((1), 220 mg, 728 µmol, 65%) was obtained as a dark red solid. RP-TLC [water / methanol (1:1)]: R f = 0.35. mp:> 250 °C. 1< H-NMR (400 MHz, DMSO- d 6 ): δ = 12.64 (s, 5-C-OH, 1H), 10.72 (s, COH, 1H), 9.79 (s, 4'- COH, 1H), 9.35 (s, COH, 1H), 8.89 (s, COH, 1H), 7.24 (d, J = 8.4 Hz, 6'-CH, 1H), 6.41 (d, J = 2.1 Hz, 3'-CH, 1H),6.36 (dd, J = 8.5, 2.3 Hz, 5'-CH, 1H), 6.30 (d, J = 2.1 Hz, 8-CH, 1H), 6.18 (d, J = 2.0 Hz, 6-CH, 1H). 13< C-NMR (100 MHz, DMSO- d6 ): δ = 176.2 (C-4), 163.7 (C-7), 160.9 (C-5), 160.4 (C-4'), 156.8 (2C, C-2', C-8a), 149.0 (C-2), 136.2 (C-3), 131.7 (C-6'), 109.3 (C-1'), 106.8 (C-5'), 103.6 (C-4a), 103.0 (C-2'), 98.0 (C-6), 93.4 (C-8). IR (Diamant-ATR): ṽ = 3212 (m, br.), 2731 (m, br.), 2341 (m, br.), 2116 (w, br.), 1995 (w, br.), 1920(w, br.), 1655 (m), 1626 (m), 1594 (m), 1570 (m), 1515 (m), 1480 (m), 1412 (m), 1365 (m), 1311 (m),1263 (m), 1224 (m), 1167 (s), 1102 (m), 1080 (m), 1011 (m), 983 (m), 969 (m), 874 (m), 833 (m), 805(m), 793 (m), 730 (m), 703 (m), 689 (m), 651 (m), 635 (m), 618 (m), 579 (m), 566 (m), 543 (m). UV (MeOH): λ max (lg ε) = 372 (4.12), 263 (4.25), 205 (4.59). MS (ESI): m / z (%) = 301 [M - H]- (100), 303 [M+ H]+ (24), 325 [M + Na] +< (100), 627 [2M + Na] +< (23), 739 [2M + Na] +< (100). HRMS (ESI+): m / z = 325.03212 (0.92 ppm, ber.: 325.03242 [M+Na] +< ).

Claims

1. A method for producing a compound represented by the following formula (1), comprising the steps of: i) acetylating a compound of the following formula (4) to form the acetophenone of formula (6), ii) reacting the acetophenone of formula (6) with a compound of the following formula (7) under basic conditions at room temperature to form the chalcone of the following formula (8), iii) Reacting the chalcone of formula (8) under oxidizing conditions in a basic medium to form a flavonol of the following formula (9); iv) and demethylating the flavonol with formula (9), where R1, R2, R3, R4, R5 and R6 are a branched or unbranched C1-C8-alkyl, NO2, SO3H, NX2 , wherein X is an ethyl or methyl radical or hydrogen, CF3 or hydrogen, preferably C1-C5 alkyl or hydrogen, most preferably C1-C3 alkyl or hydrogen, and R7 and R8 independently represent a methyl, ethyl, t-butyl, benzyl, methoxymethyl, p-methoxybenzyl, benzyloxymethyl, triphenylmethyl, tetrahydropyranyl, or allyl group.

2. The method according to claim 1, further comprising step (i-a): (i-a) Methylation of a compound of the following formula (3) under acidic conditions to a compound of formula (4), wherein R1, R2, R3, R4, R5 and R6 are as defined in claim 1.

3. Method according to any one of claims 1 to 2, wherein R3 is hydrogen.

4. Method according to any one of claims 1 to 3, wherein R1 , R2 , R3 , R4 , R6 and R6 are hydrogen.

5. Method according to any one of claims 1 to 4, wherein in step iii) the oxidizing conditions are established using tert-butyl hydroperoxide and the basic environment is established using an alkali hydroxide.

6. Method according to one of claims 1 to 5, wherein in step ii) the basic conditions are established with the aid of an alkali hydroxide and the reaction takes place at room temperature.

7. Method according to one of claims 1 to 6, wherein in step i) the acetylation is carried out using acetyl chloride in the presence of a Lewis acid and dichloromethane.

8. Methode according to one of claims 1 to 7, wherein in step (i-a) the acidic conditions are established with the aid of an inorganic acid.

9. Compound of formula (1) obtainable by a method according to one of claims 1 to 8, which has less than 0.5% kaempferol and / or its derivatives.

10. Compound according to claim 9, wherein R1, R2, R3, R4, R5 and R6 are hydrogen.