KR101739728B1 - Synthetic method for moracin F using Sonogashira coupling reaction - Google Patents

Abstract

The present invention relates to a method for synthesizing a natural compound, moracin F having biological activity. The synthesis method of the present invention can efficiently synthesize the moracin F having biological activity by using Sonogashira coupling reaction as a key step from a commercially available starting material.

Description

[0002] Synthetic method for moracin F using Sonogashira coupling reaction using Sonogashira coupling reaction [

The present invention relates to a method for synthesizing morazin F, which is a natural benzofuran compound, and more particularly, to a method for synthesizing morazin F using a Sonogashira coupling reaction as a key step.

Heterocyclic compounds occupy more than half of the existing organic compounds and can play an important role in the chemical and drug discovery. The fused heterocyclic compound, benzofuran, is present in numerous natural products and occupies a prominent position among plant phenols in terms of medical and biological importance [1]. In particular, some natural and non-natural 2-substituted benzofurans exhibit important biological properties including anti-inflammatory, antioxidant, anticancer, antifungal, antimicrobial, antiplatelet and antiviral activity [2-8]. In addition, some derivatives have been studied as enzyme inhibitors [9] and as diagnostic imaging agents targeting amyloid plaques in Alzheimer's disease [10]. Some benzofuran compounds have been studied in the field of organic semiconductors [11]. In addition, these compounds are looking for applicability as brightening agents [12] and in agriculture as pesticides and pesticides [13].

The genus Morus belongs to the flowering family Moraceae and contains about 16 species that are widely distributed throughout the world. The genus Morus has received considerable attention due to its medicinal and economic value [14]. In a recent review, Naik et al. Emphasized the separation of benzofuran (morazin AZ) from the genus Morus, and summarized the different synthetic methods used to construct the structural framework [15]. Mora Shin F (Fig. 1) F. solani f. sp . mori , and the acetone extract of tubal tissues [16], but no synthesis has been reported.

R. J. Nevagi, S. N. Dighe, S. N. Dighe, Eur. J. Med. Chem. 2015, 97, 561-581. (a) K. M. Dawood, H. Abdel-Gawad, M. Ellithey, H. Mohamed, B. Hegazi, Arch. Pharm. Chem. Life Sci. 2006, 339, 133-140 (b) Y. -S. Xie, D. Kumar, V. D. V. Bodduri, P. S. Tarani, B. -X. Zhao, J. -Y. Miao, K. Jang, D. -S. Shin, Tetrahedron Lett. 2014, 55, 2796-2800. (a) J. Rangaswamy, H. Vijaykumar, S. T. Harini, N. Naik, J. Heterocyclic Chem. 2015, 52, 938-943. (b) Y. Chen, X. Wei, H. Xie, H. Deng, J. Nat. Prod. 2008, 71, 929-932. (a) O. M. Abdelhafez, K. M. Amin, H. I. Ali, M. M. Abdalla, E. Y. Ahmed, RSC Adv. 2014, 4, 11569-11579. (b) M. Choi, H. Jo, H. Park, AS Kumar, J. Lee, J. Yun, Y. Kim, SB Han, JK Jung, J. Cho, K. Lee, JH Kwak, Bioorg. Med. Chem. Lett. 2015, 25, 2545-2549. M. Masubuchi, H. Ebiike, K. Kawasaki, S. Sogabe, K. Morikami, Y. Shiratori, S. Tsujii, T. Fujii, K. Sakata, M. Hayase, H. Shindoh, Y. Aoki, T. Ohtsuka, N. Shimma, Bioorg. Med. Chem. 2003, 11, 4463-4478. H. Hiremathad, M. R. Patil, K. R. Chethana, K. Chand, M. A. Santos, R. S. Keri, RSC Adv. 2015, 5, 96809-96828. M. Ohno, M. Miyamoto, K. Hoshi, T. Takeda, N. Yamada, A. Ohtake, J. Med. Chem. 2005, 48, 5279-5294. W. -J. Wang, L. Wang, Z. Liu, R. -W. Jiang, Z. -W. Liu, M. -M. Li, Q. -W. Zhang, Y. Dai, Y. -L. Li, X. -Q. Zhang, W. -C. Ye, Phytochemistry 2016, 122, 238-245. (a) D. G. McGarry, J. R. Regan, F. A. Volz, C. Hulme, K. J. Moriarty, S. W. Djuric, J. E. Souness, B. E. Miller, J. J. Travis, D. M. Sweeney, Bioorg. Med. Chem. 1999, 7, 1131-1139. (b) J. S. Lazo, R. Nunes, J. J. Skoko, P. E. Q. de Oliveira, A. Vogt, P. Wipf. Bioorg. Med. Chem. 2006, 14, 5643-5640. M. Ono, H. Saji, Med. Chem. Commun. 2015, 6, 391-402. (a) J. -X. Qiu, Y.-X. Li, X.-F. Yang, Y. Nie, Z. -W. Zhang, Z. -H. Chen, G.-X. Sun, J. Mater. Chem. C, 2014, 2, 5954-5962. (b) X. H. Yang, S. J. Zheng, H. S. Chae, S. Li, A. Mochizuki, G. E. Jabbour, Org. Electron. 2013, 14, 2023-2028. (c) Z. Tang, B. Liu, A. Melianas, J. Bergqvist, W. Tress, Q. Bao, D. Qian, O. Ingan, F. Zhang, Adv. Mater. 2015, 27, 1900-1907. J. Habermann, S. V. Ley, R. Smits, J. Chem. Soc., Perkin Trans 1 1999, 2421-2423. J. A. Findlay, S. Buthelezi, G. Li, M. Seveck, J. Nat. Prod. 1997, 60, 1214-1215. S. Priya, J. Pharm. Res. 2012, 5, 3588-3596. R. Naik, D. S. Harmalkar, X. Xu, K. Jang, K. Lee, Eur. J. Med. Chem. 2015, 90, 379-393. M. Takasugi, S. Nagao, T. Masamune, A. Shirata, K. Takahashi. Tetrahedron Lett. 1978, 48, 4675-4678. (a) J. J. Lee, S. -R. Yun, J. -G. Jun, Bull. Korean Chem. Soc. 2014, 35, 3453-3458. (b) C. G. Kim, J. -G. Jun, Bull. Korean Chem. Soc. 2015, 36, 2278-2283. (c) H.-H. Yoon, J. -K. Kim, J. -G. Jun, Bull. Korean Chem. Soc. 2015, 36, 571-577. (d) K. Damodar, J. -K. Kim, J. -G. Jun, Tetrahedron Lett. 2016, 57, 1183-1186. (a) E. W. Colvin, B. J. Hamill, J. Chem. Soc., Chem. Commun. 1973, 151-152. (b) D. Habrant, V. Rauhala, A. M. P. Koskinen, Chem. Soc. Rev. 2010, 39, 2007-2017. M. Ono, H. Kawashima, A. Nonaka, T. Kawai, M. Haratake, H. Mori, M. -P. Kung, H. F. Kung, H. Saji, M. Nakayama, J. Med. Chem. 2006, 49, 2725-2730.

The present invention aims to provide a method for synthesizing a natural compound morasin F having biological activity as described above.

As a result of continuing interest in the synthesis and biological evaluation of benzofuran [17] as an anti-inflammatory agent, the present inventors have succeeded in synthesizing morphine F, which is natural benzofuran, by Sonogashira coupling, Suzuki coupling, ₂ O ₃ mediated cyclization and intramolecular Wittig reaction as main steps.

As a key reaction, compound 1 is synthesized using Sonogashira coupling reaction [17a] by protecting the 3,4-dimethoxyphenol (compound 2) with TBDMS-Cl ( tert- butyldimethylsilyl chloride) (FIG. 2). Position selective iodination of compound 3 using the I ₂ / AgSO ₄ system provides iodine compound 4 without TBS. The 3,5-dihydroxybenzaldehyde (Compound 5) was treated with EOM-Cl (chloromethyl ethyl ether) in the presence of K ₂ CO ₃ and the resulting aldehyde compound protected with the EOM group was identified by the Colvin rearrangement [18] Of alkyne. Next, the Sonogashira coupling between Compound 4 and Compound 7 produced benzofuran compound 8 protected with an EOM group, which was treated with Dowex ^® resin to obtain the target compound, morasin F (Compound 1).

Next, the synthesis of morasin F using the neutral Al ₂ O ₃ mediated cyclization as the main step [17c] began with the TBS-protection of 3,5-dihydroxyacetophenone (compound 9) (FIG. 3). Compound 10 thus obtained was converted to the corresponding phenacyl bromide compound 11 by using copper bromide (CuBr ₂ ).

Positively selective cyclization of compound 2 to compound 11 is facilitated by addition of neutral Al ₂ O ₃ , resulting in benzofuran compound 12 protected by TBS which is treated with 1.0 M TBAF (tetrabutylammonium fluoride) (THF solution) Compound 1 was obtained in high yield.

The synthesis of natural benzofuran compound 1 was also possible with other approaches disclosed in FIG. A key step in the benzofuran skeleton formation was achieved with intramolecular Wittig reaction between triphenylphosphonium salt compound 18 and 3,5-bis (allyloxy) benzoyl chloride compound 15 (FIG. 4). A preferred Wittig reagent compound 18 was prepared from PPh ₃ .HBr (triphenylphosphine hydrobromide) and benzyl alcohol compound 17, and compound 17 was obtained by reduction of the corresponding aldehyde compound. The acid chloride compound 15 was prepared by reacting the 3,5-dihydroxybenzoic acid compound 13 with an ally protecting gas-esterification, ester hydrolysis and chlorination. The Wittig reaction yielded benzofuran compound 19 protected with an allyl group, to which K ₂ CO ₃ and catalyst Pd (PPh ₃ ) ₄ were added to obtain target compound 1 at a yield of 86%.

Finally, the present inventors have identified a Suzuki coupling approach [17d] for the synthesis of Compound 1. This method started with the ramirez gem-dibromoolefination reaction of the aldehyde compound 16 (Fig. 5). The gem-dibromoolefin compound 20 obtained by this reaction produced 2-bromobenzofuran compound 21 by intramolecular cross coupling using an anhydrous K ₃ PO ₄ / CuI system. The corresponding boron ester coupling reagent 23 was obtained from commercially available 5-bromoresorcinol compound 22 [17b]. In a sealed tube _{(PPh 3) 4 (10 mmol} %) and as a base, using THF as aqueous 2.0 MK ₂ CO ₃ solution and the solvent is a benzofuran compound by performing the Suzuki coupling between compound 21 and compound 23 at 100 ℃ The yield was 10%. Next, PdCl ₂ (dppf) .CH ₂ Cl ₂ (dppf) in a DMF ( N, N- dimethylformamide) (5 mmol%) and anhydrous K ₃ PO ₄ as a base were reacted at 120 ° C. to obtain benzofuran compound 8 in 35% yield. Compound 1 was obtained from compound 8 as shown in FIG.

In conclusion, the present inventors have used four different approaches employing Suzuki coupling, Sonogashira coupling, neutral Al ₂ O ₃ mediated cyclization and intracellular Wittig reaction as key steps to synthesize natural 2-arylbenzofuran compounds Morosa F (moracin F) was synthesized. All approaches have started with commercially available starting materials and have found that the Suzuki coupling approach is the most viable and feasible way of approaching other approaches.

The present invention relates to a process for the production of (a) 2-iodo-4,5-dimethoxyphenol represented by the formula (4) and 1,3-bis (ethoxy Ethoxymethoxy) -5-ethynylbenzene} was subjected to a Sonogashira coupling reaction to obtain 2- (3,5-bis (ethoxymethoxy) phenyl) -1,3- -5,6-dimethoxybenzofuran} {2- (3,5-Bis (ethoxymethoxy) phenyl) -5,6-dimethoxybenzofuran}; And

(B) treating the 2- (3,5-bis (ethoxymethoxy) phenyl) -5,6-dimethoxybenzofuran with a cation exchange resin to obtain a morphine F compound, F synthesis method.

≪ Formula 4 >

≪ Formula 7 >

(8)

The present invention also relates to a process for the preparation of 2-iodo-4,5-dimethoxyphenol

(a) 3,4-dimethoxyphenol represented by the formula (2) is protected by using TBS-Cl ( tert- butylsilyl chloride) to obtain tert -butyl (3,4-dimethoxyphenoxy ) Dimethylsilane { tert- Butyl (3,4-dimethoxyphenoxy) dimethylsilane}; And

(b) I ₂ / using AgSO ₄ wherein the tert - butyl (3,4-methoxyphenoxy) by regioselective iodination of 2-iodo-dimethyl silane to produce the 4,5-methoxyphenol Wherein the morphine F synthesis method is characterized by the following steps:

(2)

(3)

The present invention also relates to a process for preparing 1,3-bis (ethoxymethoxy) -5-ethynylbenzene

(A) 3,5-dihydroxybenzaldehyde represented by the formula (5) is treated with EOM-Cl (chloromethyl ethyl ether) in the presence of K ₂ CO ₃ to obtain 3,5-bis (ethoxymethoxy ) Benzaldehyde {3,5-Bis (ethoxymethoxy) -benzaldehyde}; And

(B) converting the 3,5-bis (ethoxymethoxy) benzaldehyde into 1,3-bis (ethoxymethoxy) -5-ethynylbenzene by rearrangement of the cholbin To a morphine F synthesis method.

≪ Formula 5 >

(6)

According to the present invention, morosin F having biological activity can be efficiently synthesized using Sonogashira coupling reaction from a commercially available starting material.

1 is a chemical structural formula of morphine F. Fig.
FIG. 2 is a chemical reaction formula showing one embodiment of morasin F synthesis method in which Sonogashira coupling reaction is a key step.
FIG. 3 is a chemical reaction formula showing an embodiment of the morasin F synthesis method in which the Al ₂ O ₃ mediator ring is a key step.
FIG. 4 is a chemical reaction formula showing one embodiment of morphine F synthesis method in which intracellular Wistig reaction is a key step.
5 is a chemical reaction formula showing one embodiment of morphine F synthesis method with Suzuki coupling reaction being a key step.

Hereinafter, the configuration of the present invention will be described in more detail with reference to specific embodiments. However, it is apparent to those skilled in the art that the scope of the present invention is not limited to the description of the embodiments.

All chemicals were used without purification as purchased unless otherwise noted. All the solvents used in the reaction were distilled under a nitrogen gas with an appropriate dehydrating agent. All solvents used in the chromatography were purchased and immediately used without further purification. ^{The 1} H-NMR spectra were recorded on a Varian Mercury at 300 MHz FT-NMR and ¹³ C at 75 MHz, chemical shifts (δ) were expressed in parts per million (ppm) relative to TMS, and CDCl ₃ / CD ₃ OD / CD ₃ COCD ₃ was used as a solvent and an internal standard. Mass spectra were recorded using an Agilent-5977E spectrometer. Melting points were measured on the MEL-TEMP II apparatus and not calibrated. Thin-film chromatography (TLC) was performed on plates coated with silica gel on a DC-Plasticfolien 60, F ₂₅₄ (Merck, 0.2 mm thick) plastic plate and observed with UV (254 nm) or with p- anisaldehyde And stained with phosphomolybdic acid (PMA). Chromatographic purification was performed using Kieselgel 60 (60-120 mesh, Merck).

tert - Butyl (3,4-dimethoxyphenoxy) dimethylsilane  { tert -Butyl (3,4-dimethoxyphenoxy) dimethylsilane} (Compound 3)

3,4-dimethoxyphenol (Compound 2 ) (0.2 g, 1.30 mmol) and imidazole (0.221 g, 3.25 mmol) were dissolved in anhydrous DMF (6 ml) mL) and the stirred solution was added. The reaction mixture was stirred at 40 < 0 > C for four hours. After completion of the reaction, it was diluted with ether (20 mL), washed with water (3 x 25 mL), brine (3 x 25 mL), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The crude compound was purified by column chromatography (EtOAC / Hexane = 1/15) to obtain pure compound 3 (0.33 g, 94%) as a colorless liquid. _Rf = 0.48 (EtOAc / hexane = 1/15); ^{1 H NMR (300 MHz, CDCl} 3) δ 6.70 (1H, d, J = 8.1 Hz), 6.41 (1H, d, J = 2.4 Hz), 6.35 (1H, dd, J = 8.1, 2.4 Hz), 3.83 (3H, s), 3.82 (3H, s), 0.98 (9H, s), 0.18 (6H, s); ¹³ C NMR (75 MHz, CDCl ₃ ) 隆 149.6, 149.3, 143.5, 111.6, 110.5, 104.8, 56.3, 55.8, 25.8, 18.3,

2- Iodo -4,5- Dimethoxyphenol  (2- Iodo -4,5- dimethoxyphenol ) (Compound 4)

Molecular iodine (0.208 g, 0.84 mmol) and sulfuric acid silver (0.236 g, 0.84 mmol) were added to a stirred solution of compound 3 (0.2 g, 0.76 mmol) in ethanol (6 mL). The reaction mixture was stirred at room temperature for 48 hours. After completion of the reaction, the reaction mixture was diluted with a saturated sodium thiosulfate solution and the ethanol solvent was removed in vacuo. The compound was extracted with EtOAc (2 x 25 mL). Mixing the organic solvent layer is washed with brine (2 x 30 mL), dried over anhydrous Na ₂ SO _4, and concentrated in vacuo. The crude compound was purified by column chromatography (EtOAC / Hexane = 1/6) to obtain pure compound 4 as a brown liquid. _Rf = 0.28 (EtOAc / hexane = 1/2); ¹ H NMR (300 MHz, CDCl ₃ )? 7.02 (1H, s), 6.59 (1H, s), 5.25 (1H, s), 3.84 (3H, s), 3.80 (6H, s); ¹³ C NMR (75 MHz, CDCl ₃ )? 151.0, 149.8, 144.1, 119.9, 99.6, 71.8, 56.9, 56.3.

3,5- Bis (ethoxymethoxy) benzaldehyde  {3,5- Bis ( ethoxyMethane ) -benzaldehyde < / RTI > (Compound 6)

To the stirred solution of 3,5-dihydroxybenzaldehyde (0.138 g, 1.0 mmol) in anhydrous DMF (7 mL) was added K ₂ CO ₃ (0.553 g, 4.0 mmol) at room temperature under nitrogen atmosphere. After stirring for 15 minutes, chloromethyl ethyl ether (0.28 mL, 3.0 mmol) was added dropwise and stirred overnight at room temperature. After completion of the reaction, it was diluted with water (10 mL) and extracted with ether (3 x 30 mL). Mixing the organic solvent layer was washed successively with water (3 x 30 mL) and brine (3 x 30 mL), dried over anhydrous Na ₂ SO _4, and concentrated in vacuo. The crude compound was purified by column chromatography (EtOAc / hexane = 1/6) to give pure compound 6 (0.193 g, 76%) as a colorless liquid. R _f = 0.54 (EtOAc / hexane = 1/5); ^{1 H NMR (300 MHz, CDCl} 3) δ 9.89 (1H, s), 7.19 (2H, d, J = 2.4 Hz), 6.98 (1H, t, J = 2.4 Hz), 5.24 (4H, s), 3.73 (4H, q, J = 6.9 Hz), 1.23 (6H, t, J = 6.9 Hz); ^{13 C NMR (75 MHz, CDCl} 3) δ 191.8, 159.0, 138.6, 111.4, 110.6, 93.5, 64.8, 15.5

1,3- Bis ( Ethoxymethoxy ) -5- Ethynylbenzene  {1,3- Bis ( ethoxyMethane ) -5-ethynylbenzene} (Compound 7)

N- BuLi (2.0 M cyclohexane solution, 2.0 M cyclohexane solution) was added to a solution prepared by stirring (trimethylsilyl) diazomethane (2.0 M solution in diethyl ether, 0.75 mL, 1.5 mmol) in anhydrous THF 1.5 ml, 1.5 mmol) was added dropwise, followed by stirring for 30 minutes. To this was added dropwise a solution of compound 6 (0.127 g, 0.5 mmol) in anhydrous THF (3 ml) and the mixture was stirred for one hour. After completion of the reaction, a saturated aqueous NH ₄ Cl solution (1 mL) was slowly added and the temperature of the reaction mixture was raised to room temperature. The reaction mixture was extracted with EtOAc (2 x 20 mL). The combined organic solvent layers were washed with brine (2 x 15 mL), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The crude compound was purified by column chromatography (EtOAc: Hexane = 1: 8) to give pure compound 7 (0.099 g, 79%). ^{1 H NMR (300 MHz, CDCl} 3) δ 6.85 (2H, d, J = 2.4 Hz), 6.75 (1H, t, J = 2.4 Hz), 5.20 (4H, s), 3.73 (4H, q, J = 6.9 Hz), 3.06 (1H, s), 1.25 (6H, t, J = 6.9 Hz); ¹³ C NMR (75 MHz, CDCl ₃ )? 158.0, 123.3, 113.2, 106.2, 93.1, 83.3, 64.4, 15.2.

2- (3,5- Bis (ethoxymethoxy) phenyl ) -5,6- Dimethoxybenzofuran  {2- (3,5-Bis (ethoxymethoxy) phenyl) -5,6-dimethoxybenzofuran} (Compound 8)

Compound 4 (0.072 g, 0.26 mmol), compound 7 (0.080 g, 0.32 mmol) and triethylamine (0.11 mL, 0.78 mmol) were placed in a sealed tube and anhydrous DMF was added. _{Pd (PPh 3) 4 (0.011} g, 0.02 mmol) and was added CuI (0.003 g, 0.02 mmol) to the mixture for 2 minutes to remove gas. The reaction mixture was stirred at 80 < 0 > C for 15 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (EtOAC / Hexane = 1/8) to give pure compound 8 (0.026 g, 20%) as a brown liquid. _Rf = 0.28 (EtOAc / hexane = 1/3); ^{1 H NMR (300 MHz, CDCl} 3) δ 7.13 (2H, d, J = 1.8 Hz), 7.11, (1H, s), 7.01 (1H, s), 6.93 (1H, s), 6.72 (1H, t , J = 2.1 Hz), 5.26 (4H, s), 3.94 (3H, s), 3.92 (3H, s), 3.76 (4H, q, J = 6.9 Hz), 1.25 (6H, t, J = 6.9 Hz ); ^{13 C NMR (75 MHz, CDCl} 3) δ 158.5, 154.4, 149.5, 148.0, 146.4, 132.4, 120.8, 105.6, 104.5, 102.0, 95.2, 93.2, 93.1, 64.4, 56.3, 56.2, 15.2 [ Note: compound 8 PdCl ₂ (dppf). CH ₂ Cl _{2 /} anhyd.K ₃ PO ₄ system can also be synthesized from compounds 21 and 23 by Suzuki coupling reaction ^17b .

5- (5,6- Dimethoxybenzofuran Yl) benzene-1,3- Diol  {5- (5,6- Dimethoxy  benzofuran-2-yl) benzene-1,3-diol} (morazine F) (Compound 1)

Compound was added to 8 (0.025 g, 0.06 mmol) in anhydrous methanol (2 mL) Dowex ^® 50X2-100 resin (0.025 g) in a nitrogen atmosphere to a stirred solution into a. The mixture was stirred at room temperature for 12 hours. After completion of the reaction, the resin was filtered and washed with EtOAc (15 mL). The filtrate was concentrated in vacuo. The crude compound was purified by column chromatography (EtOAc / hexane = 1/1) to obtain pure compound 1 (0.013 g, 75%) which was a white solid. _Rf = 0.32 (EtOAc / hexane = 1/1); mp 186-188 [deg.] C; ^{1 H NMR (300 MHz, CD} 3 OD) δ 7.15 (1H, s), 7.08 (1H, s), 6.92 (1H, s), 6.74 (2H, d, J = 1.2 Hz), 6.21 (1H, t , J = 1.2 Hz), 3.88 (3H, s), 3.86 (3H, s); ¹³ C NMR (75 MHz, CD ₃ OD)? 158.7, 155.4, 149.7, 148.4, 146.9, 132.5, 121.5, 103.0, 102.7, 102.3, 101.3, 95.4, 55.9, 55.7; EI-MS m / z 286 (M ^< ^{+ >} , base), 271, 257.

1- (3,5- Bis (( tert - butyl dimethylsilyl) oxy) phenyl ) Ethanone  {1- (3,5-Bis (( tert -butyldimethylsilyl) oxy) phenyl) ethanone} (Compound 10)

(0.026 g, 0.5 mmol), TBSCl (0.226 g, 1.5 mmol) and imidazole (0.17 g, 2.5 mmol) were reacted in anhydrous DMF (6 mL) for 4.5 hours Compound 10, a colorless liquid, was synthesized in the same manner as in the synthesis of Compound 3. _{^{1 H NMR (300MHz, CDCl 3}} ) δ 7.01 (2H, d, J = 2.1 Hz), 6.51 (1H, t, J = 2.1 Hz), 2.53 (3H, s), 0.98 (18H, s), 0.21 ( 12H, s); ¹³ C NMR (75 MHz, CDCl ₃ )? 197.7, 156.8, 139.2, 117.0, 113.5, 27.1, 26.0, 18.6, -4.0.

1- (3,5- Bis (( tert - butyl dimethylsilyl) oxy) phenyl )-2- Bromoethanone  {1- (3,5-Bis (( tert -butyldimethylsilyl) oxy) phenyl) -2-bromoethanone} (Compound 11)

Copper (II) bromide (0.279 g, 1.25 mmol) was added at room temperature to a solution of the substituted acetophenone compound 10 (0.19 g, 0.5 mmol) in EtOAc (5 mL) and the mixture was refluxed for 2.5 hours. After cooling to room temperature, the mixture was filtered through a pad of Celite® and washed with EtOAc (10 mL). The filtrate was concentrated in vacuo. The crude compound was purified by short column (EtOAc / hexane = 1/15) to give pure compound 11 as a light yellow liquid (0.2 g, 87%). R f = 0.64 (EtOAc / Hexane = 1/10); _{1H NMR (300 MHz, CDCl 3} ) δ 7.12 (2H, s), 6.56 (1H, s), 4.37 (2H, s), 0.98 (18H, s), 0.22 (12H, s); ^{13 C NMR (75 MHz, CDCl} 3) δ 189.1, 160.8, 133.8, 114.2, 110.9, 34.7, 25.3, 14.3, -4.20.

((5- (5,6-dimethoxybenzofuran-2-yl) -1,3- Phenylene ) Bis (oxy) bis tert -part Tiladimethylsilane) {((5- (5,6- Dimethoxybenzofuran -2- yl ) -1,3- henylene ) bis (oxy)) bis ( tert -butyldimethylsilane)} (Compound 12)

A mixture of compound 2 (0.068 g, 0.44 mmol), alpha -bromoacetophenone compound 11 (0.2 g, 0.44 mmol) and neutral aluminum oxide (0.156 g, 1.53 mmol) was added in xylene (3 mL) Lt; / RTI > The reaction was filtered through a Celite pad and evaporated. The residue was purified by column chromatography on silica gel using ethyl acetate / hexane as eluant to afford the corresponding benzofuran (0.018 mg, 8%) as a brown liquid. _Rf = 0.22 (EtOAc / hexane = 1/3); ^{1 H NMR (300 MHz, CDCl} 3) δ 7.09 (1H, s), 6.98 (1H, s), 6.89 (2H, d, J = 1.8 Hz), 6.85 (1H, s), 6.28 (1H, t, J = 1.8 Hz), 3.94 (3H, s), 3.92 (3H, s), 1.00 (18H, s), 0.23 (12H, s); ¹³ C NMR (75 MHz, CDCl ₃ ) 隆 157.0, 154.9, 149.8, 148.2, 146.7, 132.5, 121.2, 112.1, 109.8, 102.3, 102.0, 95.5, 56.6, 56.5, 26.1, 18.6,

5- (5,6- Dimethoxybenzofuran Yl) benzene-1,3- Diol  {5- (5,6-Dimethoxybenzofuran-2-yl) benzene-1,3-diol} ( Mora  F) (Compound 1)

1.0 M TBAF (0.07 mL, 0.07 mmol) was added to TBS-protected benzofuran compound 12 (0.015 g, 0.029 mmol) in anhydrous THF and stirred at room temperature for 4 hours. After completion of the reaction, the solvent was removed in vacuo. The crude compound was purified by column chromatography (EtOAc / hexane = 1/1) to obtain pure compound 1 (0.008 g, 90%) which was a white solid.

3,5- Bis (allyloxy) benzoic acid  {3,5- Bis (allyloxy) benzoic  acid} (Compound 14)

To a suspension of 3,5-dihydroxybenzoic acid (Compound 13 ) (0.2 g, 1.298 mmol) and K ₂ CO ₃ (0.897 g, 6.489 mmol) in anhydrous DMF (8 mL) was added allyl bromide (0.34 mL, 3.793 mmol) was gradually added to the room temperature in a nitrogen atmosphere. The reaction mixture was stirred for three hours. After completion of the reaction, the reaction mixture was filtered through a Celite pad and washed with ether (30 mL). The filtrate was washed with water (3 x 15 mL) and brine (3 x 15 mL), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The crude compound was purified by column chromatography (EtOAc / hexane = 1/2) to obtain colorless liquid allyl 3,5-bis (allyloxy) benzoate (0.327 g, 92%). _Rf = 0.80 (EtOAc / hexane = 1/2); ^{1 H NMR (300 MHz, CDCl} 3) δ 7.20 (2H, d, J = 2.4 Hz), 6.68 (1H, t, J = 2.4 Hz), 6.02 (3H, m), 5.40 (3H, dd, J = 17.1, 1.5 Hz), 5.28 ( 3H, dd, J = 10.2, 1.5 Hz), 4.80 (2H, dt, J = 5.4, 1.5 Hz), 4.54 (4H, dt, J = 4.8, 1.5 Hz); ¹³ C NMR (75 MHz, CDCl ₃ )? 166.0, 159.7, 133.0, 132.3, 132.1, 118.4, 118.1 108.5, 107.3, 69.4, 66.0. 1.0 N NaOH (1.91 mL) was added to the stirred solution of the ester (0.175 g, 0.638 mmol) in methanol (5 mL) and refluxed for two hours. The mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The approximate pH was adjusted to 2 with 1N HCl and extracted with EtOAc (2 x 25 mL). Mixing the organic solvent layer is washed with brine (2 x 30 mL), and concentrated after drying over anhydrous Na ₂ SO ₄ vacuo. An unrefined white solid acid compound 14 (0.127 g, 85%) was obtained which was used in the next step without further purification. Melting point 64-66 ° C; ^{1 H NMR (300 MHz, CDCl} 3) δ 7.28 (2H, d, J = 2.4 Hz), 6.70 (1H, t, J = 2.4 Hz), 6.06 (2H, m), 5.44 (2H, dd, J = 17.1, 1.5 Hz), 5.32 (2H, dd , J = 10.5, 1.5 Hz), 4.58 (4H, dt , J = 5.5, 1.5 Hz); ^{13 C NMR (75 MHz, CDCl} 3) δ 172.0, 159.6, 132.7, 131.0, 118.1, 108.6, 108.0, 69.1

2-( Hydroxymethyl ) -4,5- Dimethoxyphenol  {2-( Hydroxymethyl ) -4,5-dimethoxyphenol} (Compound 17)

To a stirred solution of 2-hydroxy-4,5-dimethoxybenzaldehyde (Compound 16 ) (0.1 g, 0.54 mmol) in ethanol (3 mL) was added sodium borohydride (0.021 g, 0.55 mmol ) At 0 < 0 > C. The reaction mixture was stirred at room temperature for one hour. After removal of the solvent, aqueous 1N HCl solution (4 mL) was added to the residue and extracted with CH ₂ Cl ₂ (2 x 20 mL). The organic solvent layer was dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated to obtain a clear liquid alcohol compound 17 (0.09 g, 90%). _Rf = 0.20 (EtOAc / hexane = 1/2); ^{1 H NMR (300 MHz, CDCl} 3) δ 6.74 (1H, s), 5.93 (1H, s), 5.82 (1H, br s), 4.58 (2H, br d, J = 4.5 Hz), 4.15 (1H, br s), 3.86 (3H, s), 3.83 (3H, s); ¹³ C NMR (75 MHz, CDCl ₃ )? 159.8, 159.0, 147.9, 129.4, 108.2, 107.3, 60.0, 59.0, 56.8

2-(( Bromotriphenylphosphoranyl ) methyl ) -4,5- Dimethoxyphenol  {2 - ((Bromotriphenylphosphoranyl) methyl) -4,5-dimethoxyphenol} (Compound 18)

Triphenylphosphine hydrobromide (0.145 g, 0.41 mmol) was added to a stirred solution of compound 17 (0.076 g, 0.41 mmol) in acetonitrile (3 mL) and the mixture was refluxed for one hour . After completion of the reaction, the reaction mixture was cooled to room temperature, filtered, washed with acetonitrile (8 mL) and dried to obtain solid compound 18 (0.2 g, 95%). ^{1 H NMR (300 MHz, CDCl} 3) δ 7.78-7.39 (15H, m), 6.89 (1H, s), 6.37 (1H, s), 5.39 (1H, s), 4.49 (2H, d, J = 12.0 Hz), 3.71 (3H, s), 3.68 (3H, s).

2- (3,5- Bis (allyloxy) phenyl ) -5,6- Dimethoxybenzofuran  {2- (3,5-Bis (allyloxy) phenyl) -5,6-dimethoxybenzofuran} (Compound 19)

Thionyl chloride (0.07 mL, 0.96 mmol) was added to the above acid compound 14 (0.150 g, 0.64 mmol) and refluxed for two hours. The mixture was cooled to room temperature and excess thionyl chloride was removed under reduced pressure to obtain an acid chloride compound. ^{1 H NMR (300 MHz, CDCl} 3) δ 7.24 (2H, d, J = 2.1 Hz), 6.77 (1H, t, J = 2.1 Hz), 6.03 (2H, m), 5.42 (2H, dd, J = 17.1, 0.9 Hz), 5.31 ( 2H, dd, J = 10.8, 0.9 Hz), 4.56 (4H, d, J = 5.4 Hz) 13 C NMR (75 MHz, CDCl 3) δ 167.9, 159.5, 134.7, 132.2, 118.2, 109.8, 109.1, 69.2. Wittig salt 18 (0.3 g, 0.58 mmol), trimethylamine (0.25 mL) and toluene (10 mL) were added to the hydrochloric acid and refluxed for three hours. It was cooled to room temperature and the precipitate was filtered and washed with EtOAc (10 mL). The filtrate was concentrated in vacuo. The crude compound was purified by column chromatography (EtOAc / hexane = 1/7) to obtain pure benzofuran compound 19 (0.033 g, 15%) as a clear liquid. _Rf = 0.28 (EtOAc / hexane = 1/4); ^{1 H NMR (300 MHz, CDCl} 3) δ 7.07 (1H, s), 6.99 (1H, s), 6.96 (2H, d, J = 2.1 Hz), 6.88 (1H, s), 6.46 (1H, t, J = 2.4 Hz), 6.07 ( 2H, m), 5.44 (2H, dd, J = 17.1, 1.2 Hz), 5.31 (2H, dd, J = 10.2, 1.2 Hz), 4.58 (4H, dt, J = 5.4 Hz), 3.94 (3H, s), 3.93 (3H, s); ¹³ C NMR (75 MHz, CDCl ₃ )? 159.7, 154.5, 149.3, 147.3, 146.3, 132.8, 132.2, 120.7, 117.6, 103.2, 101.9, 101.7, 101.5, 95.0, 68.8, 56.2, 56.1

5- (5,6- Dimethoxybenzofuran Yl) benzene-1,3- Diol  {5- (5,6-Dimethoxybenzofuran-2-yl) benzene-1,3-diol} ( Mora  F) (Compound 1)

To a suspension of compound 19 (0.025 g, 0.068 mmol) and K ₂ CO ₃ (0.056 g 0.408 mmol) in methanol (3 mL) was added Pd (PPh ₃ ) ₃ (0.002 g, 2 mmol%) in a nitrogen atmosphere He said. The mixture was stirred at 60 < 0 > C for three hours. The supernatant cooled at room temperature was removed under reduced pressure. The crude compound was neutralized with IN HCl and extracted with CH ₂ Cl ₂ (2 x 15 mL). Mixing the organic solvent layer is washed with brine (2 x 10 mL), dried under anhydrous Na ₂ SO _4, and concentrated in vacuo. The crude compound was purified by column chromatography (EtOAc / hexane = 1/2) to obtain pure benzofuran compound 1 as a white solid (0.017 g, 86%).

2- (2,2- Dive Vinyl Vinyl ) -4,5- Dimethoxyphenol  {2- (2,2- Dibromovinyl ) -4,5-dimethoxyphenol} (Compound 20)

Compound 20 was prepared from compound 16 according to the method described in reference 17b. ^17b Yield: 49%; Brown liquid; _Rf = 0.23 (EtOAc / hexane = 1/1); ^{1 H NMR (300 MHz, CDCl} 3) δ 7.51 (1H, s), 7.10 (1H, s), 6.43 (1H, s), 4.80 (1H, s), 3.87 (3H, s), 3.86 (3H, s); ¹³ C NMR (75 MHz, CDCl ₃ )? 150.4, 147.3, 143.0, 132.0, 113.8, 111.5, 100.6, 90.7, 56.7

2- Bromo -5,6- Dimethoxybenzofuran  (2- Bromo -5,6- dimethoxybenzofuran ) (Compound 21)

Compound 21 was prepared from compound 20 according to the method described in reference 17b. ^17b Yield: 81%; Brown liquid; _Rf = 0.64 (EtOAc / hexane = 1/1); ¹ H NMR (300 MHz, CDCl ₃ )? 6.99 (1H, s), 6.92 (1H, s), 6.60 (1H, s), 3.90 (6H, s); ¹³ C NMR (75 MHz, CDCl ₃ )? 150.3, 150.3, 146.7, 125.2, 120.5, 108.0, 101.2, 95.0, 56.4, 56.2

2- (3,5- Bis (ethoxymethoxy) phenyl ) -4,4,5,5- Tetramethyl -1,3,2- Dioxabololan  {2- (3,5- Bis (ethoxymethoxy) phenyl ) -4,4,5,5- tetramethyl -1,3,2-dioxaborolane} (Compound 23)

Compound 23 was prepared from compound 22 according to the method described in reference 17b. ^{17b 1 H NMR (300MHz, CDCl} 3) δ 7.08 (2H, d, J = 2.4 Hz), 6.82 (1H, t, J = 2.4 Hz), 5.21 (4H, s), 3.72 (4H, q, J = 6.9 Hz), 1.32 (12H, s), 1.22 (6H, t, J = 6.9 Hz); ^{13 C NMR (75 MHz, CDCl} 3) δ 157.8, 115.3, 108.2, 93.1, 83.8, 64.3, 24.9, 15.2.

Claims (3)

(A) 2-Iodo-4,5-dimethoxyphenol represented by the general formula (4) and 1,3-bis (ethoxymethoxy) - PdCl ₂ (PPh ₃ ) ₂ and CuI were added to 5-ethynylbenzene {1,3-bis (ethoxymethoxy) -5-ethynylbenzene}, triethylamine and anhydrous DMF were added, and the mixture was subjected to Sonogashira coupling 2- (3,5-Bis (ethoxymethoxy) phenyl) -5,6-dimethoxybenzofuran, represented by the formula (8) 6-dimethoxybenzofuran}; And
(B) treating the 2- (3,5-bis (ethoxymethoxy) phenyl) -5,6-dimethoxybenzofuran with a cation exchange resin to obtain a morasin F compound, F synthesis method.
≪ Formula 4 >

≪ Formula 7 >

(8)

The method according to claim 1,
The 2-iodo-4, 5-dimethoxyphenol
(a) 3,4-dimethoxyphenol represented by the formula (2) is protected by using TBS-Cl ( tert- butylsilyl chloride) to obtain tert -butyl (3,4-dimethoxyphenoxy ) Dimethylsilane { tert- Butyl (3,4-dimethoxyphenoxy) dimethylsilane}; And
(b) I ₂ / using AgSO ₄ wherein the tert - butyl (3,4-methoxyphenoxy) by regioselective iodination of 2-iodo-dimethyl silane to produce the 4,5-methoxyphenol Wherein the morphine F synthesis method comprises:
(2)

(3)

The method according to claim 1,
The 1,3-bis (ethoxymethoxy) -5-ethynylbenzene
(A) 3,5-dihydroxybenzaldehyde represented by the formula (5) is treated with EOM-Cl (chloromethyl ethyl ether) in the presence of K ₂ CO ₃ to obtain 3,5-bis (ethoxymethoxy ) Benzaldehyde {3,5-Bis (ethoxymethoxy) -benzaldehyde}; And
(B) converting the 3,5-bis (ethoxymethoxy) benzaldehyde into 1,3-bis (ethoxymethoxy) -5-ethynylbenzene by rearrangement of the cholbin To obtain morphine F synthesis method.
≪ Formula 5 >

(6)

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