WO2005054169A1

WO2005054169A1 - Preparation method of 2-phenylacetophenone derivatives

Info

Publication number: WO2005054169A1
Application number: PCT/KR2004/000335
Authority: WO
Inventors: Jeong-Jae Lee; Chul-Bae Kim; Sung-Min Park; Bum-Chun Lee; Hyeong-Bae Pyo
Original assignee: Hanbul Cosmetic Co., Ltd.
Priority date: 2003-12-08
Filing date: 2004-02-19
Publication date: 2005-06-16

Abstract

Disclosed is a preparation method of 2-phenylacetophenone derivatives which are used as key intermediates in total syntheses of coumestans and isoflavonoids such as coumestrol, genistein and daidzein which are phytoestrogens contained in soybean and black soybean. By using Fries rearrangement in the production, the 2-phenylacetophenone derivatives can be produced with much more simplified synthetic steps than prior art methods. In addition, the time of production is reduced due to short reaction time and easy purification in every step, thereby making it possible to produce 2-phenylacetophenone derivatives with high yields.

Description

PREPARATION METHOD OF 2-PHENYLACETOPHENONE DERIVATIVES

Technical Field The present invention relates to a preparation method of 2-phenylacetophenone derivatives which are used as key intermediates in the total syntheses of various coumestans and isoflavonoids such as coumestrol, genistein and daidzein, which are phytoestrogens.

Background Art As a use of synthetic estrogen such as diethylstilbestrol (DES) which has potent estrogen effect in estrogen therapy for women in their climacteric, with low cost, was completely prohibited by US FDA, attentions have been made to natural phytoestrogens, as a replacing substance for the female hormone. However, the naturally-occurring phytoestrogens are present in only very small amount, thereby being difficult to obtain large quantity of phytoestrogens. Further, there has been no significant achievement in mass production of such substances over the last half century, due to lukewarm attitude on those development. Only there have been some reports concerning the development of synthetic methods for phytoestrogens, but they are only in the level of experiment. Therefore, mass production methods of such substances with ease has not been developed at all until the present. Coumestrol has been known as the most potent substance among phytoestrogens up to now, being a kind of isoflavonoids, generally found in seed, root and leaf of leguminosae and compositae and it is typically classified into coumestan compounds. Attentions have been made to coumestrol, as it has been found that when plants are externally damaged, a heavy concentration of coumestrol is secreted from the damaged area, to prevent an infection by providing antibacterial, antifungal and antiviral actions due to its antioxidative, anti-inflammatory and antitoxic activities (Darbarwar, M., et al, J. Sci. Incl. Res., 35, 297, 1982; Jeffrey, B. H., et al, Phytochemical Dictionary, Taylor & Francis, London, pp 418, 1933). The origin of such antibiotic activity of coumestrol is its phenolic structure which is fundamental as an antioxidant, thus blocking the entry of reactive oxygen species(ROS), thereby inhibiting the generation of peroxidized compounds. Estrogenic effect is evaluated based on the changes in the weight of uterus after oral administration of coumestrol to immature rats. In the evaluation test, it was specifically noted that coumestrol showed estrogenic effect in immature female rats, meanwhile showed no activity in mature male animals, and exhibited no toxicity at all (Darbarwar, M., et al, J. Sci. Ind. Res., 35, 297, 1982). Currently, commercially used natural coumestrol is marketed at high price, since only extremely small amount of natural coumestrol presents in black soybean and the like.

Due to such high price, researches have been intermittently made to obtain synthetic coumestrol, however, those synthetic methods are complicated and have many problems, thereby being difficult to be commercialized. It is also well known that genistein and daidzein which are isoflavonoids being mostly-contained, among leguminosae, in soybean, have estrogenic effect as excellent as coumestrol. However, in an aspect of their commercialization, they are in similar situation with coumestrol. Several synthetic methods for coumestrol which have been reported up to now are described below. It has been reported that coumestrol could be synthesized with a total yield of less than approximately 20 % by a preparation method comprising 7 subsequent steps suggested by Gadre, et al. (Gadre, S. Y., et al., Syn. Comm., 18(2), 157-166, 1988). This method, however, would be difficult to be commercialized in substantial, since the reaction control in critical 7* step where ethyl ether salt of coumestrol is prepared by oxidation of coumarin intermediates is difficult, due to its long reaction time in the above step, thereby being reported to show dramatic decrease in yield. While, Kappe, et al. suggested a more efficient 4-step synthetic method, with a total yield as high as around 30 %, however, there are some disadvantageous aspects for being substantially commercialized (Kappe, T., et al, Synthesis, 387-388, 1990) as follows. In this method, it is expected that the substantial yield would become less than 20 %, since starting materials such as 4-hydroxy-7-methoxycoumarin and diacetoxyiodobenzene should be first prepared. Further, this method needs to use stoichiometric amount of palladium catalyst which is very expensive, thereby it is not considered to be suitable for mass production. Recently, Kraus, et al. proposed a 5-step synthetic method starting from

1,3-dimefhoxybenzene (Kraus, G. A. et al, J. Org. Chem., 65, 5644-5646, 2000). However, this method also has an only total yield of less than 5 %, thereby having low value in terms of commercialization. Finally, an 8-step method suggested by Bickoff has been reported to provide coumestrol with a total yield of approximately 17 %, through 8 synthetic steps (Bickoff, E. M., et al., J.A.C.S., 80, 4381, 1958). This method is quite advantageous in terms of commercialization due to its easiness in each step and high yield, even though this method has long synthetic process. Meanwhile, a major problem of this method is in the 5^th step, the critical step of the method, wherein α-(2,4-dimethoxyphenyl)-2,4-dihydroxyacetophenone is produced by using Houben-Hoesch condensation, reportedly with an yield of approximately 50 %. The step has to be carried out in ethereal solution saturated with hydrogen chloride gas under an anhydrous condition, then a reaction is conducted in refrigerator at 0°C for more than 5 days, moreover, when the reactants being 20 g or more, the time required for saturation with hydrogen chloride gas is more than 6 hours or more. Furthermore, after completion of the reaction, an excessive amount of hydrogen chloride gas should be handled for recovery of the resulting product. It means that dangerous and complicated procedures are accompanied to its separation and purification process, thereby taking a considerable period of time. Moreover, many times of repeating the reaction in 20 g-scale is required to obtain desired amount of product, since the expansion of the reaction scale is very difficult. In addition, the practical yield is shown to lower than the one being reported by Bickoff. Such low yield also has been reported in Boyd, J., et al, J. Chem. Soc, 174,

1948, wherein the same reaction of Bickoff was conducted. As another problem of the method, a reactant 2,4-dimethoxyphenylacetonitrile which is required for carrying out the 5 step should be prepared through a separate 4-step method, since the reactant is not commercialized. The total preparation yield for the reactant is reported to be approximately 62 %, as it has been inspected by the inventors of the present application.

Meanwhile, for preparing 100 g or more of the reactant, considerable amount of time is required in the reaction and purification. Although such problems and disadvantages described so far, attentions were made by the present inventors to the methods of Bickoff and Boyd et al. among the listed methods, since 2-phenylacetophenone derivatives comprising a key intermediate α-(2,4-dimethoxyphenyl)-2,4-dihydroxyacetophenone, which are commonly used in the methods of Bickoff and Boyd, are multi-purpose key intermediates having a high commercial value. As long as the derivatives are conveniently secured, it may be much easy to prepare coumestans including coumestrol as well as their corresponding isoflavonoids. Preparation methods for isoflavonoids including genistein and daidzein have been developed and reported by various researchers up to now, however, most of the methods use 2-phenylacetophenone derivatives as a key intermediate. Meanwhile, the preparation of 2-phenylacetophenone derivatives is difficult, thereby its synthesis being only carried out at a lab scale or being limitative to a certain range of compounds (Mitter, P. C. et al, J. Ind. Chern. Soc, 13, 236, 1936; Baker et al, J. Chem. Soc, 214, 1933; Mahal et al, J. Chem. Soc, 1769, 1934; Baker et al, J. Chem. Soc, 1852, 1953; Baker et al, J. Chem. Soc, 3115, 1928; Narasimhachari, J. Sci. Ind. Res., 12, 287, 1953; Krishnamurty, H. G.,

Tetrahedron Lett., 3071, 1977). Therefore, when convenient and easy synthetic techniques are secured for 2-phenylacetophenone derivatives, it would be widely applicable to syntheses of various compounds which employ the derivatives as a synthetic intermediate, including the above-mentioned coumestans and isoflavonoids. 2-phenylacetophenone derivatives such as α-(2,4-dimethoxyphenyl)-2,4-dihydroxyacetophenone can be obtained by typical Friedel-Crafts acylation between acyl chloride of the corresponding phenylacetic acid derivatives and benzene derivatives, in the presence of an aluminum chloride catalyst (Christopher, P. M., et al, U.S. Pat. 6,589,980B2). The method is more efficient compared to Houben-Hoesch condensation reaction, however, when hydroxy groups are present in the phenylacetic acid derivatives and benzene derivatives to be employed, protecting groups which are not affected by inorganic acids such as hydrochloric acid or aluminum chloride, or Lewis acids, are must be attached, hence, deprotecting step should be essentially required after reacting the rather unstable phenylacetic acid derivatives with thionyl chloride for acyl chlorination, then Friedel-Crafts acylation, making the total synthetic procedure longer, thereby having disadvantageous such as risks involved in the method and dramatic reduction in yield in mass production.

Disclosure of the Invention Under the above-mentioned technical circumstances, a novel synthetic method for

2-phenylacetophenone derivatives comprising α-(2,4-dimethoxyphenyl)-2,4-dihydroxyacetophenone using Fries rearrangement which is a much easier synthetic route compared to the one of above Houben-Hoesch condensation or Friedel-Craft acylation, has been developed by the present inventors. The present invention relates to a convenient and efficient preparation method with high value of commercialization for coumestans and isoflavonoids comprising coumestrol, genistein and daidzein, specifically intends to provide a remarkable synthetic method for coumestans and isoflavonoids in which 2-phenylacetophenone derivatives comprising α-(2,4-dimethoxyphenyl)-2,4-dihydroxyacetophenone, which had been prepared through 5 steps in each method of Bickoff, Mitter, Boyd and Krishnamurty, etc. (Bickoff, E. M., et al., J.A.C.S, 80, 4381, 1958; Mitter P. C, et al, J. Indian Chem. Soc, 13, 236, 1936; Boyd, J., et al, J. Chem. Soc, \1A, 1948; Krishnamurty, H. G., Tetrahedron

Lett., 3071, 1977) can be simply prepared with high efficiency through 2 steps using Fries rearrangement The preparation method of the present invention is comprised of total 2 steps, each step being carried out for a short period of reaction time and being easy to separate and purify, thereby securing high synthetic yield. For achieving the above object, the present inventors have prepared 2-phenylacetophenone derivatives by the novel synthetic method of the present invention. Particularly, the present invention relates to a preparation method for

2-phenylacetophenone derivatives comprising: a step of carrying out esterification between phenol derivatives and phenylacetic acid derivatives to obtain phenyl phenylacetate derivatives; and a step of subjecting the phenyl phenylacetate derivatives to Fries rearrangement with aluminum chloride to obtain 2-phenylacetophenone derivatives. The present invention is further characterized in that the phenol derivatives are resorcinol, hydroquinone or phloroglucinol. The present invention is further characterized in that the phenylacetic acid derivatives are 4-methoxyphenylacetic acid or 2,4-dimethoxyphenylacetic acid. Moreover, the present invention is characterized in that the 2-phenylacetophenone derivatives are α-(4-methoxyphenyl)-2,4-dihydroxyacetophenone, α-(4-methoxyphenyl)-2,5-dihydroxyacetophenone, α-(4-methoxyphenyl)-2,4,6-trihydroxyacetophenone, α-(2,4-dimethoxyphenyl)-2,4-dihydroxyacetophenone, α-(2,4-dimethoxyphenyl)-2,5-dihydroxyacetophenone or α-(2,4-dimethoxyphenyl)-2,4,6-trihydroxyacetophenone. The general formula 1 below represents a chemical structure of 2-phenylacetophenone derivatives .

Formula 1

where Ri, R₂, R₃, j are -H or -OH or -OCH₃, and R₅, R₆, R_7, R₈, R₉ are -H or -OCH₃.

Table 1

Best Mode for Carrying Out the Invention Now, the present invention is described further in detail with reference to Examples below, however, they are provided in only exemplary way, by no means limitative of the scope of the invention. <Example: Syntheses of 2-phenylacetophenone derivatives >

Reaction Scheme 1

A B

I II 1) Syntheses of phenyl phenylacetate derivatives (Compound I)

1000 ml of methylene chloride was added to phenol derivatives (A, 0.75mol), phenylacetic acid derivatives (B, 0.25 mol), 1,3-dicyclohexylcarbodiimide (DCC, 0.28 mol) and 4-dimethylaminopyridine (DMAP, 0.05 mol), then stirred at room temperature for 4 hours. After completion of the reaction, white precipitates were removed by filtration, and the filtrates were concentrated under reduced pressure. To the concentrates, 1000 ml of 10 % aqueous solution of K₂CO₃ was added, then the mixture was extracted with 1000 ml of ethyl acetate, and washed 3 times with distilled water. The ethyl acetate layer was washed with a saturated aqueous solution of NaCl, then dried over magnesium sulfate, and concentrated to obtain a yellow viscous compound in liquid form. The obtained compound was dissolved into a mixed solution of hexane-ethylacetate (2:1 v/v), and filtrated through SiO₂ to obtain a colorless transparent viscous compound in liquid form (Compound I, phenyl phenylacetate derivatives). Yield: 95 % or higher. NMR data of the obtained phenyl phenylacetate derivatives (Compound I from the Reaction scheme 1) are shown below in Table 2.

Table 2

2) Syntheses of 2-phenylacetophenone derivatives (Compound II) by Fries rearrangement Phenyl phenylacetate derivatives (Compound I, 0.20 mol) and aluminum chloride (0.7 mol) were charged into a reactor equipped with a condenser having a calcium chloride trap, heated to 100°C in an oil bath and maintained at the temperature for 30 minutes. Then, the temperature was elevated to 130 °C over 30 minutes, and maintained the reaction at the temperature for 1 hour. Again, the temperature was elevated to 150 ^°C over 30 minutes, and maintained for another 1 hour. After completing the reaction, the mixture was cooled to room temperature, then thereto, 400 ml of iced water was added, and 1000 ml of dilute aqueous solution of hydrochloric acid was slowly added. The mixed solution was transferred to a separation funnel and extracted with an equivalent amount of ethyl acetate, and the organic layer was washed 3 times with distilled water. The ethyl acetate layer was washed with saturated aqueous solution of NaCl, then dried over magnesium sulfate and concentrated. The concentrated compound was dissolved into a mixed solution of hexane-ethyl acetate (1 :1, v/v), and filtrated through SiO₂ to obtain a liquid compound. The compound was recrystallized in toluene to obtain a platelet crystal (Compound II, 2-phenylacetophenone derivatives). Yield: 55-65%. NMR data of the obtained 2-phenylacetophenone derivatives (Compound II from the Reaction scheme 1) are shown below in Table 3. Table 3

Industrial Applicability As it has been shown above, the present invention provides a greatly efficient preparation method for key intermediates used in preparation of phytoestrogens comprising coumestans and isoflavonoids such as coumestrol, genistein and daidzein found in leguminosae such as soybean or black soybean. Since the present invention provides a preparation method for 2-phenylacetophenone derivatives with high yield, being comprised of total 2 steps, the each steps being carried out for a short period of reaction time, and being easy in separation and purification, the present invention can maximize the total synthetic yields of the above-mentioned natural phytoestrogens, as well as be broadly applicable to syntheses of various compounds in which adopt 2-phenylacetophenone derivatives as synthetic intermediates.

Claims

What is Claimed is:

1. A preparation method of 2-phenylacetophenone derivatives comprising: carrying out esterification between phenol derivatives and phenylacetic acid derivatives to obtain phenyl phenylactate derivatives; and subjecting the phenyl phenylacetate derivatives to Fries rearrangement with aluminum chloride to obtain 2-phenylacetophenone derivatives.

2. The preparation method of 2-phenylacetophenone derivatives according to claim 1 , wherein the phenol derivatives are resorcinol, hydroquinone or phloroglucinol.

3. The preparation method of 2-phenylacetophenone derivatives according to claim 1, wherein the phenylacetic acid derivatives are 4-methoxyphenylacetic acid or 2,4-dimethoxyphenylacetic acid.

4. The preparation method of 2-phenylacetophenone derivatives according to any one of claims 1 to 3, wherein the 2-phenylacetophenone derivatives are α-(4-methoxyphenyl)-2,4-dihydroxyacetophenone, α-(4-methoxyphenyl)-2,5-dihydroxyacetophenone, α-(4-methoxyphenyl)-2,4,6-trihydroxyacetophenone, α-(2,4-dimethoxyphenyl)-2,4-dihydroxyacetophenone, α-(2,4-dimethoxyphenyl)-2,5-dihydroxyacetophenone or α-(2,4-dimethoxyphenyl)-2,4,6-trihydroxyacetophenone.