KR101492225B1

KR101492225B1 - Method for Synthesizing 4-O-Methylhonokiol

Info

Publication number: KR101492225B1
Application number: KR1020100102491A
Authority: KR
Inventors: 정재경; 곽영신; 이희순; 곽재환; 조영애
Original assignee: 주식회사 바이오랜드
Priority date: 2010-10-20
Filing date: 2010-10-20
Publication date: 2015-03-09
Also published as: WO2012053832A3; WO2012053832A2; KR20120040959A

Abstract

The present invention relates to a process for synthesizing a useful active compound 4-O-methylhornokiol by a chemical method. According to the present invention, it is advantageous to mass-produce 4-O-methylhornokiol of high purity at a much higher yield than the conventional method of extracting 4-O-methylhornokiol from natural products.

Description

Method for Synthesizing 4-O-Methylhonokiol}

The present invention relates to a method for chemically synthesizing 4-O-methyl-honokiol.

4-O-methylhornokiol is a generic term for 3 ', 5-diallyl-4'-methoxybiphenyl-2-ol and has recently been isolated from Magnolia species, (1), (2), and (3). Korean Patent No. 10-932962, Korean Patent Publication No. 2009-94916, and Korean Patent Publication No. 2008-104760 disclose 4-O-methyl hornokiol extracted from the stem and leaves of Magnolia officinalis Rehd. Et Wils It is disclosed that the composition can be used for treatment of amyloid-related diseases, prevention of hair loss, promotion of hair growth, and skin whitening.

To date, the bark of roots and stems of Magnolia species have been used as traditional medicines for the treatment of various diseases and the main biologically active compounds belonging to Magnolia are honokiol, magnolol and obovatol, (2). These compounds are known as biphenyl-neo-lignan compounds. Interestingly, 4-O-methylhornokiol has a higher anti-inflammatory activity than honokiol and various other honokiol analogues, with an IC ₅₀ value for COX-2 of 0.06 μM (3). In addition, 4-O-methyl-honokiol has recently been shown to exhibit neuroprotective and memory-enhancing activity (4). The chemical structure of 4-O-methylnonochiol is asymmetric 5,3'-diallyl-biphenyl having a hydroxyl group at the C ₂ position of the A ring and a methoxy group at the C ₄ position of the B ring (Fig. 1 Reference).

However, despite the interesting biological activity of 4-O-methylhornokiol, the synthesis of homozygotes, honokiol and obovatol has been reported, while the synthesis of 4-O- Have not yet been reported in the industry (3, 5). Therefore, there is a demand for a method of synthesizing a useful active compound 4-O-methylhornokiol by a high yield chemical method.

Numerous papers and patent documents are referenced and cited throughout this specification. The disclosures of the cited papers and patent documents are incorporated herein by reference in their entirety to better understand the state of the art to which the present invention pertains and the content of the present invention.

The present inventors have made efforts to develop a chemical synthesis method capable of mass-synthesis at a high yield by replacing the method of extracting 4-O-methyl-hornokiol compounds having various skin diseases and skin whitening activity from natural products. As a result, 4-allyl-2-bromophenol was synthesized from 4-allylphenol, and potassium 3-allyl-4-methoxyphenyltrifluoroborate was synthesized from 2-allyl- Then, Suzuki-Miyaura coupling reaction of the synthesized 4-allyl-2-bromophenol and potassium 3-allyl-4-methoxyphenyltrifluoroborate was carried out to obtain 4- O-methyl-Hornokiol can be chemically synthesized, thereby completing the present invention.

Accordingly, it is an object of the present invention to provide a method for chemically synthesizing 4-O-methylhornokiol.

The objects and advantages of the present invention will become more apparent from the following detailed description of the invention, claims and drawings.

According to one aspect of the present invention, the present invention provides a process for the synthesis of 4-O-methylhornokiol comprising the steps of: (a) introducing bromine (Br) at the ortho position of 4- To thereby synthesize 4-allyl-2-bromophenol; (b) synthesizing potassium 3-allyl-4-methoxyphenyltrifluoroborate from 2-allyl-4-bromo-1-anisole; (c) reacting the 4-allyl-2-bromophenol synthesized in the step (a) and the potassium 3-allyl-4-methoxyphenyltrifluoroborate synthesized in the step (b) (Suzuki-Miyaura Coupling Reaction) to synthesize 4-O-methyl-honokiol.

According to a preferred embodiment of the present invention, the present invention relates to a process for preparing 2-allyl-4-bromo-1-anisole of the above step (b) Reacting bromophenol with allyl bromide to synthesize 2-allyl-4-bromophenol; And (b) reacting the 2-allyl-4-bromophenol with methyl iodide (MeI) to synthesize 2-allyl-4-bromo-1-anisole.

Hereinafter, the synthesis method of the present invention will be described in detail in each step.

Step (a): Synthesis of 4-allyl-2-bromophenol from 4-allylphenol

4-allylphenol is reacted with 1,3-dibromo-5,5-dimethylhydantoyl and a base in a suitable organic solvent for 4 to 24 hours to obtain 4-substituted 4-allylphenol with one bromine group at the ortho position of the phenolic hydroxyl group - allyl-2-bromophenol. The ratio of the 4-allylphenol, 1,3-dibromo-5,5-dimethylhydantoin and base may be used in an equivalent ratio of 0.9-1.1: 0.5: 1. As the organic solvent, solvents such as ether, isopropyl ether, hexane and heptane may be used alone or in combination. As the base, isopropyl magnesium chloride ( i- PrMgCl) may be used.

Step (b): Synthesis of potassium 3-allyl-4-methoxyphenyltrifluoroborate from 2-allyl-4-bromo-

Allyl-4-bromo-1-anisole, butyllithium, triisopropylborate and potassium bifluoride in a suitable organic solvent for up to 2 hours to obtain potassium 3-allyl-4-methoxyphenyltrifluoroborate Synthesized. The ratio of the 2-allyl-4-bromo-1-anisole, butyllithium, triisopropylborate and potassium bifluoride can be used in an equivalent ratio of 0.9 - 1.2: 1.2: 1.2: 2. The organic solvent used in the above reaction may be a solvent such as tetrahydrofuran, ether, isopropyl ether, hexane, heptane or pentane.

On the other hand, the starting material 2-allyl-4-bromo-1-anisole of the reaction of step (b) can be synthesized by the following reaction: (i) Reaction of 4-bromophenol with allyl bromide Synthesizing 2-allyl-4-bromophenol; And (ii) synthesizing 2-allyl-4-bromo-1-anisole by reacting 2-allyl-4-bromophenol synthesized in step (i) with methyl iodide (MeI).

(I) reacting 4-bromophenol with allyl bromide to synthesize 2-allyl-4-bromophenol

4-Bromophenol and allyl bromide are added to a suitable organic solvent and reacted under reflux for a maximum of 5 hours to produce 2-allyl-4-bromophenol. As the organic solvent, a conventional organic solvent may be used, and for example, acetone may be used.

( Ii) synthesizing 2-allyl-4-bromo-1-anisole by reacting 2-allyl-4-bromophenol with methyl iodide (MeI)

4-bromo-1-anisole (2-allyl-4-methoxyphenol) was added to a suitable organic solvent and stirred, followed by addition of methyl iodide (MeI) Bromo-1-methoxybenzene). As the organic solvent, a conventional container solvent may be used, for example, acetone may be used.

Step (c): 4-Allyl-2-bromophenol and potassium 3-allyl-4-methoxyphenyltrifluoroborate to synthesize 4-O-

In step (c), 4-allyl-2-bromophenol synthesized in step (a) is reacted with potassium 3-allyl-4-methoxyphenyltrifluoroborate synthesized in step (b) O-methyl-Hornokiol. Allyl-2-bromophenol and potassium 3-allyl-4-methoxyphenyltrifluoroborate were mixed with a palladium (Pd) catalyst and a ligand and a base to prepare a Suzuki-Miya (Suzuki-Miyaura Coupling) reaction to synthesize 4-O-methylhornokiol. In this reaction, the palladium (Pd) catalyst and the ligand are selected from the group consisting of Pd (PPh ₃ ) ₄ , Pd ₂ (dba) ₃ , Pd (OAc) ₂ , PdCl ₂ (dppf) CH ₂ Cl ₂ , PdCl ₂ OAc) ₂ / RuPhos, or Pd (OAc) ₂ / XPhos can be used. As the base, potassium carbonate (K ₂ CO ₃ ) or cesium carbonate (Cs ₂ CO ₃ ) can be used. Organic solvents such as dimethyl ether (DME), methanol (MeOH), toluene, or water (H ₂ O) may be used alone or in combination. Preferably, the palladium (Pd) catalyst and the ligand may be PdCl ₂ (dppf) 揃 CH ₂ Cl ₂ , Pd (OAc) ₂ / RuPhos, or Pd (OAc) ₂ / XPhos, A mixture of toluene and water, or a mixture of dimethyl ether and water can be used. More preferably a combination of palladium (Pd) catalyst and a ligand, a base and an organic solvent in the reaction (ⅰ) PdCl ₂ (dppf) and CH ₂ Cl _2, cesium carbonate, methanol, (ⅱ) Pd (OAc) 2 / RuPhos, potassium carbonate, toluene and water mixture, (ⅲ) Pd (OAc) to ₂ / RuPhos, potassium carbonate, dimethyl ether and water mixture _{(ⅳ) Pd (OAc) 2} / XPhos, potassium carbonate, toluene and water mixture is a combination of Can be used. The reaction may be carried out at room temperature or at a high temperature, preferably at a high temperature of 50 to 160 ° C, more preferably at 60 to 150 ° C, more preferably at 70 to 140 ° C, Lt; RTI ID = 0.0 > 80 C < / RTI >

Figure 1 shows representative neo-lignans isolated from Magnolia species.

Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are only for describing the present invention in more detail and that the scope of the present invention is not limited by these embodiments in accordance with the gist of the present invention .

Example

Example 1: Preparation of 2-allyl-4-bromophenol

After adding 150 g (1.1 mol) of anhydrous potassium carbonate, 30 g (0.17 mol) of 4-bromophenol and 40 g (0.33 mol) of allyl bromide to 300 ml of acetone, the mixture was stirred in a reflux condenser for 5 hours. Concentrate, add 500 mL of water, and extract twice with 200 mL of hexane. The hexane layer was washed twice with 200 mL of 10% sodium hydroxide solution, and the water of the organic layer was removed with sodium sulfate. The solvent was removed by concentration, and the solution was heated to 190 DEG C for 6 hours in a round flask, dissolved in 300 mL of 10% sodium hydroxide solution And washed twice with 200 mL of hexane. The aqueous layer was neutralized with hydrochloric acid and extracted twice with 200 mL of methylene chloride. The organic layer was collected, and water was removed with sodium sulfate and concentrated under reduced pressure. 25 g (yield: 67%) of the title compound was obtained by column chromatography (hexane: ethyl acetate = 8: 1).

^{1 H NMR (500 MHz, CDCl} 3) δ 7.23 (s, 1H), 7.73 (d, J = 14 Hz, 1H), 6.70 (d, J = 14 Hz, 1H), 5.98 (m, 1H), 5.17 (m, 2 H), 3.37 (d, J = 6.4 Hz, 2 H)

Example 2: Preparation of 2-allyl-4-bromo-1-anisole

4.2 g (0.03 mol) of anhydrous potassium carbonate and 3.2 g (0.015 mmol) of 2-allyl-4-bromophenol were placed in 30 ml of acetone, stirred for 30 minutes, and then methyl iodide (MeI) was added at room temperature. After 4 hours, the solvent was removed by concentration under reduced pressure, 15 mL of water was added, and extracted three times with 20 mL of ether. The organic layer was collected and washed with 10 mL of water, then water was removed with sodium sulfate, and the filtrate was concentrated under reduced pressure. 2.4 g (the yield: 70%) of the title compound was obtained by column chromatography (hexane).

^{1 H NMR (500 MHz, CDCl} 3) δ 7.29 (dd, J = 8.6, 2.5 Hz, 1H), 7.24 (ds, J = 2.5 Hz, 1H), 6.2 (d, J = 8.6 Hz, 1H), 5.94 (m, IH), 5.06 (m, IH), 3.80 (s, 3H), 3.34 (d, J =

Example 3: 4-Allyl-2- Bromophenol Produce

(1 mmol) of isopropylmagnesium chloride ( i- PrMgCl) was added to 134 mg (1 mmol) of 4-allylphenol dissolved in ether and stirred vigorously at -78 째 C for 30 minutes in a stream of nitrogen. After raising the temperature to room temperature, 143 mg (0.5 mmol) of 1,3-dibromo-5,5-dimethylhydantoin was added after 10 minutes, and the mixture was stirred for 2.5 hours. 10 mL of a saturated ammonium chloride solution was added, stirred for 10 minutes, and extracted twice with 20 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 115 mg (yield: 54%) of the title compound was obtained by column chromatography (hexane: ether = 10: 1).

^{1 H NMR (400 MHz, CDCl} 3) δ 7.28 (ds, J = 2.0 Hz, 1H), 7.04 (dd, J = 8.3, 2.0 Hz, 1H), 6.95 (d, J = 8.3 Hz, 1H), 5.91 (m, IH), 5.10 (m, 2H), 3.30 (d, J = 6.7 Hz, 2H)

Example 4: Preparation of potassium 3-allyl-4-methoxyphenyltrifluoroborate salt

720 mg (3.2 mmol) of 2-allyl-4-bromo-1-anisole obtained in Example 2 and 620 mg (3.2 mmol) of triisopropylborate were dissolved in 30 ml of tetrahydrofuran, Lithium 2.0 mL (1.6 M nucleic acid solution, 3.2 mmol) was slowly added under a stream of nitrogen for 20 minutes. After stirring vigorously for 1 hour, the temperature was raised to room temperature and stirred for 40 minutes. After the reaction was terminated, 9.0 mL (9.0 mmol) of 1N potassium biporide was added, and the mixture was stirred for 30 minutes. After concentrating under reduced pressure for 3 hours and drying, the white solid was dissolved in 15 mL of anhydrous acetone and filtered through celite. The remaining filtrate was concentrated and dried, and then recrystallized using acetone and ether to obtain 460 mg (yield: 57%) of the title compound as a white solid.

^{1 H NMR (400 MHz, Aceton} -d 6) δ 7.29 (d, J = 7.95 Hz, 1H), 7.27 (s, 1H), 6.70 (d, J = 7.95 Hz, 1H), 5.98 (m, 1H) , 5.00 (m, IH), 4.91 (m, IH), 3.75 (s, 3H), 3.31 (d, J = 6.64 Hz,

¹³ C NMR (100 MHz, Aceton-d ₆ ) ? 155.39, 138.44, 133.41, 130.56, 125.25, 113.43, 108.75, 54.55, 34.62

Example 5: Preparation of 4-O-methylhornokiol

(1) Suzuki - Miyaura Catalyst of reaction Ligand And solvent conditions

Allyl-2-bromophenol obtained in Example 3 and the potassium 3-allyl-4-methoxyphenyltrifluoroborate obtained in Example 4 were subjected to Suzuki-Miyaura Cross Coupling Reaction (Suzuki-Miyaura Cross Coupling Reaction ) Was carried out to establish the optimum catalyst and solvent conditions for the production of 4-O-methylhornokiol. The results of the experiment are shown in Table 1 below.

In Table 1, the reaction did not occur at Entry 1-8, and no satisfactory level of product was produced. This is presumably because the binding reaction is inhibited by the unprotected phenol of 4-allyl-2-bromophenol. On the other hand, the reaction (entry 5) in PdCl ₂ (dppf) CH ₂ Cl ₂ , Cs ₂ CO ₃ , and methanol solvent showed a yield of about 12%. Next, reaction conditions using Pd (OAc) ₂ , K ₂ CO ₃ and Buchwald's phosphine (RuPhos and XPhos) were performed. Surprisingly, when the reaction was conducted at 130 ° C. using a mixture of dimethyl ether and water as a solvent, 72% A satisfactory yield was obtained (entry 11).

(2) Preparation of 4-O-methylhornokiol

214 mg (1.0 mmol) of 4-allyl-2-bromophenol obtained in Example 3, 254 mg (1.0 mmol) of potassium 3-allyl-4-methoxyphenyltrifluoroborate obtained in Example 4, (2 mmol) of potassium carbonate (22 mg, 10 mmol%), RuPhos 94 mg (2-dicyclohexylphosphino-2 ', 6'-diisopropoxybiphenyl, 20 mol% Was sealed and 20 mL of a 5: 1 mixture of dimethyl ether and water was injected into the syringe. And the mixture was reacted in a microwave apparatus at 130 캜. After confirming that the reaction was terminated by TLC, it was cooled to room temperature. The organic layer was washed with 20 mL of water and 20 mL of brine. The organic layer was washed with 100 mL of ethyl acetate and the insoluble material was removed by filtration through a pad of silica gel. The organic layer was collected and dried over anhydrous magnesium sulfate, and then subjected to column chromatography to obtain 204 mg (yield: 72%) of the title compound as yellow oil.

^{1 H NMR (400 MHz, CDCl} 3) δ 7.30 (d, J = 8.4 Hz, 1H), 7.25 (m, 1H), 7.05 (m, 2H), 6.97 (d, J = 8.4 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 6.08-5.93 (m, 2H), 5.13-5.05 (m, 4H), 3.89 (s, 3H), 3.44 (d, J = 6.8 Hz, 1H), 3.36 ( d, J = 6.6 Hz, 2H)

^{13 C NMR (100 MHz, CDCl} 3) δ 157.2, 151.0, 138.0, 136.7, 132.4, 130.7, 130.4, 130.0, 129.2, 129.0, 128.1, 128.0, 116.1, 115.8, 115.7, 111.1, 55.7, 39.6, 64.5

LRMS (FAB) m / z 280 (M < + >) [

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the same is by way of illustration and example only and is not to be construed as limiting the scope of the present invention. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.

references

1. Rao, K. V .; Davis T. L. Plant Med. 1982, 45, 57-59.

2. (a) Lee, Y. K .; Yuk, D. Y .; Kim, T. I .; Kim, Y. H., Kim, K. T .; Kim, K. H .; Lee, B. J .; Nam, S.-Y .; Hong, J. T. J. Nat. Med. 2009, 63, 274-282. (b) Schiffly, W .; Khan, S. I .; Fischer, N. H. Inflammopharmacology 2009, 17, 106-110. (c) Oh, J. H .; Kang, L. L .; Ban, J. O .; Kim, Y. H .; Kim, K. H .; Han, S. B .; Hong, J. T. Chem. Biol. Interact. 2009, 180, 506-514. (d) Lee, Y. K .; Choi, I. S .; Kim, Y. H .; Kim, K. H .; Nam, S. Y .; Yun, Y. W .; Lee, M. S .; Oh, K. W .; Hong, J. T. Neurochem. Res. 2009, 34, 2251-2260. (e) Lee, J. W .; Lee, Y. K .; Lee, B. J .; Nam, S. Y .; Lee, S. I .; Kim, Y. H .; Kim, K. H .; Oh, K. W .; Hong, J. T. Pharmacol. Biochem. Behav. 2010, 95, 31-40. (f) Lee, Y. K .; Choi, I. S .; Ban, J. O .; Lee, H. J .; Lee, U. S .; Han, S. B .; Jung, J.-K .; Kim, Y. H .; Kim, K. H .; Oh, K. W .; Hong, J. T. J. Nutr. Biochem. 2010, 21, in press.

3. (a) Maruyama, Y .; Kuribara, H. CNS Drug Rev. 2000, 6, 35-44. (b) Fukuyama, Y .; Otoshi, Y .; Miyoshi, K .; Nakamura, K .; Kodama, M .; Nagasawa, M .; Hasegawa, T .; Okazaki, H .; Sugawara, H. Tetrahedron 1992, 48, 377-392. (c) Chen, C. M .; Liu, Y.C. Tetrahedron Lett. 2009, 50, 1151-1152 and references cited therein.

4. Schilly, W .; H ㆌ fner, A .; Pferschy-Wenzig, E. M .; Prettner, E .; Adams, M .; Bodensieck, A .; Kunert, O .; Oluwemimo, A .; Haslinger, E .; Bauer, R. Bioorg. Med. Chem. 2009, 17, 4459.

5. (a) Tekeya, T .; Okubo, T .; Tobinaga, S. Chem. Pharm. Bull. 1986, 34, 2066-2070. (b) Kwak, J.-H .; In, J.-K .; Lee, M.-S .; Choi, E.-H .; Lee, H .; Hong, JT; Yun, YP; Lee, SJ; Seo, S.-Y .; Suh, Y.-G .; Jung, J.-K. Arch. Pharm. Res. 2008, 31, 1559-1563.

Claims

A process for the synthesis of 4-O-methylhornokiol comprising the steps of:
(a) synthesizing 4-allyl-2-bromophenol by substituting bromine (Br) at the ortho position of 4-allylphenol;
(b) synthesizing potassium 3-allyl-4-methoxyphenyltrifluoroborate from 2-allyl-4-bromo-1-anisole; And
(c) reacting the 4-allyl-2-bromophenol synthesized in the step (a) and the potassium 3-allyl-4-methoxyphenyltrifluoroborate synthesized in the step (b) (Suzuki-Miyaura Coupling Reaction) to synthesize 4-O-methylhornokiol.

2. A process according to claim 1, wherein the 2-allyl-4-bromo-1-anisole of step (b) is prepared by a process comprising the steps of:
(a) reacting 4-bromophenol with allyl bromide to synthesize 2-allyl-4-bromophenol; And
(b) synthesizing 2-allyl-4-bromo-1-anisole by reacting 2-allyl-4-bromophenol synthesized in step (a) with methyl iodide (MeI).

The method of claim 1, wherein the step (a) is performed by using ether, isopropyl ether, hexane, heptane, or a mixture thereof as a solvent.

The method according to claim 1, wherein the step (b) is performed by using tetrahydrofuran, ether, isopropyl ether, hexane, heptane, pentane or a mixture thereof as a solvent.

The method according to claim 1, wherein the step (c) is performed by using dimethyl ether, methanol, toluene, water or a mixture thereof as a solvent.

The method of claim 1, wherein the step (c) comprises the steps of: Pd (PPh ₃ ) ₄ , Pd ₂ (dba) ₃ , Pd (OAc) ₂ , PdCl ₂ (dppf) 揃 CH ₂ Cl ₂ , PdCl ₂ (Pd) catalyst and a ligand selected from the group consisting of (OAc) ₂ / RuPhos and Pd (OAc) ₂ / XPhos.

The method according to claim 1, wherein the step (c) is carried out using a base of potassium carbonate (K ₂ CO ₃ ) or cesium carbonate (Cs ₂ CO ₃ ).