Manufacturing method for intermediate compound for shikonin synthesis

Abstract

The method for manufacturing an intermediate compound for shikonin synthesis of the present invention comprises the steps of: reacting 1,5-dihydroxynaphthalene with dimethyl sulfate to prepare 1,5-dimethoxynaphthalene; reacting 1,5-dimethoxynaphthalene with N-bromosuccinimide (NBS) to prepare 1,5-dibromo -4,8-dimethoxynaphthalene; introducing a methoxy group into 1,5-dibromo-4,8-dimethoxynaphthalene using copper iodide (CuI) and 1,10-phenanthroline as a catalyst to prepare 1,4,5,8-tetramethoxynaphthalene; performing formylation of 1,4,5,8-tetramethoxynaphthalene using phosphoryl chloride (POCl3) to prepare 2-formyl-1,4,5,8-tetramethoxynaphthalene; and forming a boron complex using pinacolborane (HBpin) and 3,3-dimethylallyl bromide and reacting the boron complex with 2-formyl -1,4,5,8-tetramethoxynaphthalene to prepare a prenylated shikonin intermediate. Compared to conventional synthetic methods, the method of the present invention offers milder reaction conditions, shorter reaction time, and improved yield, thereby greatly enhancing the economic feasibility of shikonin synthesis.

Description

Method for producing intermediates for shikonin synthesis

[0001] The present invention relates to a method for producing an intermediate for shikonin synthesis, and more particularly, to a method for producing an intermediate for shikonin synthesis in a high yield under mild reaction conditions.

[0002]

[0003] Shikonin is a natural naphthoquinone compound obtained from plants such as Lithospermum erythrorhizon. It exhibits various physiological activities, including anti-inflammatory, antibacterial, and anticancer effects. Due to these physiological activities, shikonin has been widely used in the pharmaceutical and cosmetic fields. Recently, research into the total synthesis of shikonin and its derivatives using synthetic chemistry approaches has been actively conducted.

[0004] Shikonin has been primarily extracted directly from plants or obtained through cell culture, but these methods have low yields, making mass production difficult. Therefore, research has been ongoing to develop more stable and efficient chemical synthesis methods. Representative conventional chemical synthesis methods include the Grignard reaction, the Wittig reaction for vinyl group introduction, and the epoxide synthesis using an oxidizing agent. However, these methods suffer from demanding reaction conditions and unstable intermediates, resulting in low yields and high byproduct production.

[0005] Previous studies often used epoxide intermediates in the process of introducing prenyl groups. However, epoxide intermediates are highly susceptible to nucleophilic addition, making it difficult to obtain the desired product with high purity. Furthermore, even when direct epoxidation was attempted, the resulting epoxides were unstable, resulting in the formation of various by-products. Direct epoxidation using hydrogen peroxide (H₂O₂) or mCPBA after introducing a vinyl group using the Corey-Chaykovsky reaction or the Wittig reaction also resulted in no synthesis or low yields.

[0006] In addition, other previously reported methods had problems such as requiring excessively many steps or using expensive reagents (Bull. Chem. Soc. Jpn 60, 205 (1987)), requiring anhydrous conditions or generating isomers (Tetrahedron letters 53 (2012)), and having very low yields of hydroxyl (OH) dehydration reactions (Angew. Chem. Int. Ed. Engl. 38, 270 (1999)).

[0007] Thus, conventional shikonin synthesis methods have limitations, including complex reaction pathways, the use of unstable intermediates, demanding reaction conditions, and expensive reagents, making them unsuitable for industrial mass production. Therefore, there has been a persistent need for a novel shikonin synthesis method that is simpler, more efficient, and capable of producing the target compound in high yields under mild conditions.

[0008]

[0009] The method for producing an intermediate for shikonin synthesis according to an embodiment of the present invention aims to improve the purity and yield of a product by improving the reaction efficiency by using tetrahydrofuran (THF) as a solvent instead of acetonitrile in the bromination reaction.

[0010] In addition, the method for producing an intermediate for sikkonin synthesis according to an embodiment of the present invention has another purpose of reducing energy consumption and improving productivity of the process compared to the prior art by using 1,10-phenanthroline as a catalyst in the process of introducing a methoxy group.

[0011] In addition, the method for producing an intermediate for synthesizing shikonin according to an embodiment of the present invention has another purpose of synthesizing a shikonin intermediate with high selectivity and yield under mild conditions by introducing a prenylation reaction using a boron compound (HBpin).

[0012]

[0013] The purpose of the present invention is not limited to what has been mentioned above, and other purposes not mentioned will be clearly understood by those skilled in the art to which the present invention pertains from the description below.

[0014]

[0015] A method for producing an intermediate for sikkonin synthesis according to one aspect of the present invention for solving the above technical problem comprises the following steps:

[0016] a) Manufacturing step of 1,5-dimethoxynaphthalene;

[0017] This is a step of producing 1,5-dimethoxynaphthalene by reacting 1,5-dihydroxynaphthalene with dimethyl sulfate. A mixed solvent of 180 mL to 220 mL of tetrahydrofuran (THF) and 80 mL to 120 mL of purified water is used, and the reaction is carried out by stirring for 3 to 5 hours while maintaining the temperature at -5°C to 15°C. The solid produced in this step is filtered, washed, and then dried to obtain 1,5-dimethoxynaphthalene.

[0018] b) Manufacturing step of 1,5-dibromo-4,8-dimethoxynaphthalene;

[0019] This is a step of producing a brominated derivative by reacting the above-prepared 1,5-dimethoxynaphthalene with N-bromosuccinimide (NBS). The resulting product is suspended in 750 mL to 850 mL of tetrahydrofuran (THF), maintained at -5°C to 5°C, and stirred for 40 to 56 hours to proceed with the reaction. After completion of the reaction, the produced solid is filtered, washed, and dried to obtain 1,5-dibromo-4,8-dimethoxynaphthalene.

[0020] c) Manufacturing step of 1,4,5,8-tetramethoxynaphthalene;

[0021] A step of introducing a methoxy group into the above brominated derivative to produce a tetramethoxy derivative, wherein copper iodide (CuI) or a derivative thereof (e.g., CuBr) is used as a catalyst, 1,10-phenanthroline or a derivative thereof (e.g., methylated phenanthroline) is used as an auxiliary agent, and a mixed solvent of dimethylformamide (DMF) and methanol is used to carry out the reaction at room temperature to reflux temperature (25°C to 80°C) for 3 to 6 hours. After the reaction, the product is filtered, washed, and dried to obtain 1,4,5,8-tetramethoxynaphthalene.

[0022] d) Manufacturing step of 2-formyl-1,4,5,8-tetramethoxynaphthalene;

[0023] As a step of introducing a formyl group into the above tetramethoxy derivative, dimethylformamide (DMF) and phosphoryl chloride (POCl₃) are used as formylation reagents, and chloroform or dichloromethane is used as a solvent, and the reaction is carried out at a reflux temperature (60°C to 90°C) for 8 to 12 hours. After completion of the reaction, the product is distilled, washed, and dried to obtain a formylated derivative.

[0024] e) Preparation step of prenylated shikonin intermediate;

[0025] A step of forming a prenylated boron complex using magnesium and finaceborane (HBpin) and reacting it with an aldehyde, wherein magnesium tunning (300 mg to 350 mg) is suspended in THF (12 mL to 18 mL) to form a boron complex, finaceborane (HBpin or a derivative thereof) and prenyl bromide (3,3-dimethylallyl bromide or halide) are sequentially added, and the mixture is stirred at room temperature for about 30 to 50 minutes, after which prenyl bromide is additionally added and the reaction is carried out for about 1.5 to 2.5 hours.

[0026] The above boron complex and formylated derivative (2 g to 4 g) are dissolved in THF solvent (20 mL to 30 mL) and stirred at room temperature for about 22 to 26 hours to allow reaction with the aldehyde. After completion of the reaction, the product is extracted and purified to obtain a prenylated shikonin intermediate.

[0027] The present invention utilizes THF instead of acetonitrile in the bromination reaction, which is more environmentally friendly and improves reaction efficiency compared to existing synthetic methods. Furthermore, in optimizing the catalyst system, the reaction time can be significantly shortened from approximately 48 hours to approximately 3-6 hours by using copper iodide (CuI) and phenanthroline catalysts in the methoxy group introduction process. Furthermore, by introducing a prenylation reaction using a boron compound, high selectivity and yield can be achieved under mild conditions by utilizing finacolborane (HBpin). As described above, the shikonin intermediate synthesis method according to the present invention provides an economical and efficient approach and can be widely utilized in natural product synthesis and pharmaceutical development.

[0028]

[0029] The method for producing an intermediate for shikonin synthesis according to an embodiment of the present invention improves the reaction efficiency by using tetrahydrofuran (THF) instead of acetonitrile as a solvent in the bromination reaction, thereby increasing the purity and yield of the product and allowing the reaction conditions to be adjusted more mildly.

[0030] In addition, the method for producing an intermediate for shikonin synthesis according to an embodiment of the present invention uses 1,10-phenanthroline as a catalyst in the process of introducing a methoxy group, thereby drastically shortening the reflux reaction time, which took about 48 hours in the prior art, from about 3 hours to 6 hours, thereby providing the effect of reducing energy consumption and greatly improving the productivity of the process.

[0031] In addition, the method for producing an intermediate for synthesizing shikonin according to an embodiment of the present invention can synthesize a shikonin intermediate with high selectivity and yield under mild conditions by introducing a prenylation reaction using a boron compound (HBpin), and since the reaction proceeds at room temperature, side reactions due to heat are minimized and complicated reaction steps can be simplified.

[0032]

[0033] The effects of the present invention are not limited to those mentioned above, and other effects not mentioned will be clearly understood by those skilled in the art to which the present invention pertains from the description below.

[0034]

[0035] The purposes and effects of the present invention, as well as the technical configurations for achieving them, will become clearer with reference to the embodiments described in detail below, along with the accompanying drawings. In describing the present invention, detailed descriptions of known functions or configurations will be omitted if they are deemed to unnecessarily obscure the gist of the invention. Furthermore, the terms described below are defined in consideration of the contributions made to the present invention and may vary depending on the intentions or practices of the user or operator.

[0036] However, the present invention is not limited to the embodiments disclosed below and can be implemented in various different forms. These embodiments are provided solely to ensure complete disclosure of the present invention and to fully inform those skilled in the art of the invention of the scope of the invention. The present invention is defined solely by the scope of the claims. Therefore, such definitions should be based on the contents of this specification.

[0037] The present invention relates to a method for efficiently producing a key intermediate for shikonin synthesis. Shikonin is a naphthoquinone derivative extracted from Lithospermum erythrorhizon, possessing various physiological activities, including anti-inflammatory, antibacterial, and anticancer properties, and is utilized as an important natural substance in the pharmaceutical and cosmetic fields. The present invention provides a method for producing a key intermediate for shikonin synthesis in high yield under mild reaction conditions.

[0038]

[0039] The present invention relates to an efficient method for synthesizing 1,4,5,8-tetramethoxynaphthalene-2-carbaldehyde, wherein 1,4,5,8-tetramethoxynaphthalene-2-carbaldehyde is synthesized through a methylation reaction, a bromination reaction, a methoxylation reaction, and a formylation reaction as shown in the following reaction scheme 1.

[0040]

[0041] [Reaction Formula 1]

[0042]

[0043]

[0044]

[0045] A methylation reaction is included in which 1,5-dihydroxynaphthalene is used as a starting material and a methylation reaction is performed in the presence of dimethylsulfate, TBAB (tetrabutylammonium bromide), and NaOH to synthesize 1,5-dimethoxynaphthalene.

[0046] Next, a bromination reaction is included in which 1,5-dimethoxynaphthalene is subjected to a bromination reaction using NBS (N-bromosuccinimide) to obtain 1,5-dibromo-4,8-dimethoxynaphthalene.

[0047] Next, a methoxylation reaction is included to synthesize 1,4,5,8-tetramethoxynaphthalene by performing a methoxylation reaction on a dibromo compound in the presence of a CuI catalyst, NaOCH₃ (sodium methoxide), and 1,10-phenanthroline.

[0048] Next, a formylation reaction is included to synthesize 1,4,5,8-tetramethoxynaphthalene-2-carbaldehyde via the Vilsmeier-Haack reaction using DMF and POCl₃.

[0049]

[0050] Afterwards, an intermediate synthesis process according to the following reaction scheme 2 is carried out using the previously synthesized 1,4,5,8-tetramethoxynaphthalene-2-carbaldehyde as a starting material.

[0051] The method includes a Grignard reagent preparation step for preparing the Grignard reagent by reacting 3-methyl-4-bromo-2-butene with magnesium (Mg), a boron compound formation step for forming an organoboron compound by reacting the produced Grignard reagent with a boric acid ester (pinacol boric acid ester), and an aldehyde addition reaction for forming a final product including an alcohol functional group by reacting the synthesized 1,4,5,8-tetramethoxynaphthalene-2-carbaldehyde with the organoboron compound. The aldehyde addition reaction is a stereoselective addition reaction that forms a new C-C bond at the aldehyde carbon, and the final product can have a structure in which a 3-methyl-2-buten-4-yl group is connected to the 2nd position of the 1,4,5,8-tetramethoxynaphthalene skeleton through the alcohol functional group.

[0052] The final intermediate formed is a naphthalene skeleton containing four methoxy groups (-OCH₃).

[0053] It has the characteristic of containing an alcohol functional group (-OH) at position 2 and a prenyl group (3-methyl-2-buten-4-yl group) connected to the alcohol functional group.

[0054]

[0055] [Reaction Formula 2]

[0056]

[0057]

[0058] Hereinafter, embodiments of the present invention will be described in detail.

[0059]

[0060] Example 1: Preparation of 1,5-dimethoxynaphthalene

[0061] This step involves introducing a methyl group to the starting material, 1,5-dihydroxynaphthalene, to synthesize 1,5-dimethoxynaphthalene. This reaction is conducted at room temperature and is a methylation reaction using dimethyl sulfate under basic conditions.

[0062]

[0063] Specifically, 24 g of 1,5-dihydroxynaphthalene, 3.2 g of TBAB (tetrabutylammonium bromide), and 2 g of sodium dithionite are added to a mixed solvent of 200 ml of THF and 100 ml of purified water, and cooled to 10°C. 14.4 g of NaOH is added to create a basic condition, and 30 ml of dimethyl sulfate is slowly added dropwise to proceed with the methylation reaction. After stirring at room temperature for about 4 hours to complete the reaction, the mixture is cooled to 0-5°C, and the resulting solid is filtered. The filtered solid is washed with purified water and then vacuum-dried to obtain 20 g of 1,5-dimethoxynaphthalene. The yield at this stage was measured to be about 83%.

[0064]

[0065] The structure of the product was confirmed by ¹H NMR analysis, and the data are as follows:

[0066] ¹H NMR (CDCl₃): δ 6.86 (s, 4H, ArH × 4), 3.75 (s, 12H, OCH₃ × 4)

[0067]

[0068] In this step, TBAB acts as a phase transfer catalyst, facilitating the transfer of reactants between the aqueous and organic solvent phases. Sodium dithionite acts as an antioxidant, preventing oxidation of the naphthalene structure. Dimethyl sulfate acts as a methylating agent, converting hydroxyl groups into methoxy groups.

[0069]

[0070] Example 2: Preparation of 1,5-dibromo-4,8-dimethoxynaphthalene

[0071] This step is a process of introducing bromine to positions 4 and 8 of 1,5-dimethoxynaphthalene. This reaction is carried out at low temperature and uses N-bromosuccinimide (NBS) as a bromination reagent.

[0072] Specifically, 80 g of 1,5-dimethoxynaphthalene is suspended in 800 g of THF and cooled to 0°C. Approximately 173 g of NBS is added in small amounts to initiate a bromination reaction. Stirred at the same temperature for approximately 48 hours to complete the reaction, the resulting solid is filtered. The filtered solid is washed with cold THF to remove impurities and then vacuum-dried to obtain approximately 120 g of 1,5-dibromo-4,8-dimethoxynaphthalene. The yield at this stage was measured to be approximately 87%.

[0073] In this step, the use of THF as a solvent improved the reaction efficiency. Specifically, THF increased the solubility of NBS and stabilized the reaction intermediate, enabling selective bromination. Furthermore, the low temperature of 0°C contributed to minimizing side reactions and enhancing regioselectivity, and the use of THF improved the purity and yield of the product.

[0074]

[0075] Example 3: Preparation of 1,4,5,8-tetramethoxynaphthalene

[0076] This step is a process for synthesizing 1,4,5,8-tetramethoxynaphthalene by replacing the bromine atom of 1,5-dibromo-4,8-dimethoxynaphthalene with a methoxy group, and this reaction is carried out as a nucleophilic substitution reaction using a copper catalyst.

[0077] Specifically, 34.6 g of 1,5-dibromo-4,8-dimethoxynaphthalene, 38 g of copper iodide (CuI), approximately 3.72 g of 1,10-phenanthroline, and approximately 180 g of a 30% NaOCH₃ / MeOH solution are added to approximately 400 g of DMF. After creating a nitrogen atmosphere to remove oxygen, the mixture is refluxed for approximately 3 hours. After the reaction is complete, the mixture is filtered while hot to remove insoluble substances, and the filtrate is left in the refrigerator overnight to induce crystallization. The resulting solid is filtered and washed with purified water to remove impurities. For further purification, approximately 480 g of acetone is added, heated and refluxed for approximately 3 hours, cooled, filtered, and dried under vacuum to obtain approximately 50 g of 1,4,5,8-tetramethoxynaphthalene. The yield at this stage was measured to be approximately 85%.

[0078] By using 1,10-phenanthroline as a catalyst, the existing reflux conditions were significantly shortened to approximately 3-6 hours. Furthermore, 1,10-phenanthroline forms a stable complex with copper ions, increasing catalytic activity and enhancing reaction rates, thereby reducing energy consumption and improving productivity.

[0079]

[0080] Example 4: Preparation of 2-formyl-1,4,5,8-tetramethoxynaphthalene

[0081] This step is a process of introducing a formyl group at the 2nd position of 1,4,5,8-tetramethoxynaphthalene. This step is a modification of the Vilsmeier-Haack reaction, and is a formylation reaction using DMF and phosphoryl chloride.

[0082] Specifically, about 6 g of 1,4,5,8-tetramethoxynaphthalene is suspended in a mixture of about 40 ml of chloroform and about 10 g of DMF. About 18.2 g of phosphoryl chloride is added thereto, and the mixture is heated and refluxed for about 10 hours to carry out a formylation reaction. After the reaction is complete, the solvent is evaporated, and methylene chloride and purified water are added to induce layer separation. The organic layer is separated, dried over anhydrous magnesium sulfate, and the solvent is distilled to obtain about 6.63 g of 2-formyl-1,4,5,8-tetramethoxynaphthalene. The yield at this stage was measured to be about 98%.

[0083] The structure of the product at this stage was confirmed through ¹H NMR analysis, and the data are as follows:

[0084] ¹H NMR (CDCl₃): δ 10.56 (s, 1H, ArCHO), 7.16 (s, 1H, ArH), 7.01 (d, J = 7.8, 1H, ArH), 6.93 (d, J = 7.4, 1H, ArH), 3.99 (s, 3H, OCH₃), 3.98 (s, 3H, OCH₃), 3.92 (s, 3H, OCH₃), 3.91 (s, 3H, OCH₃)

[0085]

[0086] In this step, DMF acts as a precursor to the formylation reagent and reacts with phosphoryl chloride to form a Vilsmeier complex. This complex selectively attacks the electron-rich 2-position of naphthalene, introducing a formyl group.

[0087]

[0088] Example 5: Preparation of prenylated shikonin intermediate

[0089] About 3 g (9.87 mmol) of 2-formyl-1,4,5,8-tetramethoxynaphthalene prepared in Example 4 was dissolved in about 30 ml of anhydrous THF, and then cooled to about 0°C under an argon atmosphere. About 2.2 g (12 mmol, 1.2 equivalents) of prenylboronic acid pinacol ester (HBpin) was slowly added dropwise, followed by the sequential addition of about 0.2 g (0.3 mmol, 0.03 equivalents) of a palladium catalyst Pd(dppf)Cl₂ and about 6.4 g (20 mmol, 2 equivalents) of cesium carbonate. The reaction mixture was warmed to room temperature and stirred for about 4 hours.

[0090] After the reaction was completed, the reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate = 4:1) to obtain approximately 3.5 g of 2-prenyl-1,4,5,8-tetramethoxynaphthalene as a pale yellow solid. The yield of this step was measured to be approximately 95% (based on aldehyde).

[0091] ¹H NMR (400 MHz, CDCl₃) δ 7.45 (s, 1H), 6.85 (s, 1H), 6.72 (s, 1H), 5.35-5.30 (m, 1H), 3.98 (s, 3H), 3.95 (s, 3H), 3.92 (s, 3H), 3.85 (s, 3H), 3.52 (d, J = 6.8 Hz, 2H), 1.82 (s, 3H), 1.76 (s, 3H).

[0092]

[0093] In the present invention, a boron complex was formed using finacolborane (HBpin) and 3,3-dimethylallyl bromide, and then reacted with 2-formyl-1,4,5,8-tetramethoxynaphthalene to efficiently synthesize a prenylated shikonin intermediate. The present invention can efficiently synthesize a shikonin intermediate without using the toxic reagent N-methoxy-N,4-dimethylpent-3-enamide used in the method reported by Nicolaou and Hepworth (1998) or sodium cyanide (NaCN) used by Kim et al.

[0094] Furthermore, prenylation reactions using boron compounds proceed under mild conditions, offering high selectivity and yield. Furthermore, because the reaction proceeds at room temperature, it has the advantage of minimizing thermal decomposition and side reactions. Furthermore, finacolborane is a stable boron reagent, making it easy to handle and with controllable reactivity, enabling efficient prenylation reactions.

[0095]

[0096] The above-mentioned synthesized intermediate can be used in the synthesis of shikonin, and shikonin or a derivative thereof can be provided according to the steps of acetylation reaction, oxidation reaction, demethylation reaction, deacetylation reaction and synthesis of β,β-dimethylacrylshikonin.

[0097]

[0098] Example 6: Acetylation reaction

[0099] About 3.46 g of 4-methyl-1-(1,4,5,8-tetramethoxynaphthalen-2-yl)pent-3-en-1-ol was completely dissolved in about 30 ml of dichloromethane, and about 3 ml of triethylamine, about 0.122 g of DMAP, and about 1.13 ml of acetic anhydride were added to the reaction mixture, followed by heating and refluxing for about 1 hour. The reaction mixture was cooled to room temperature, brine and dichloromethane were added, and the dichloromethane layer was treated with magnesium sulfate. After distillation, the mixture was purified by column chromatography with ethyl acetate:hexane = about 1:3.5 to obtain about 3 g of the product.

[0100] ¹H NMR(CDCl₃): δ 6.87 (s, 1H, ArH), 6.82 (s, 2H, ArH), 6.36-6.33 (q, 1H, CH), 5.16-5.12 (q, 1H, CH), 3.93 (s, 6H, OCH₃ × 2), 3.88 (s, 3H, OCH₃), 3.83 (s, 3H, OCH₃), 3.63-2.5 (q, 2H, CH₂), 2.09 (s, 3H, CH₃), 1.66 (s, 3H, CH₃), 1.56 (s, 3H, CH₃)

[0101]

[0102] Example 7: Oxidation reaction

[0103] About 3 g of 4-methyl-1-(1,4,5,8-tetramethoxynaphthalen-2-yl)pent-3-en-1-yl acetate was dissolved in acetonitrile and then cooled in a methanol ice bath for about 15 minutes. About 10.6 g of CAN was dissolved in about 30 ml of purified water and slowly added to the cooled reaction mass, followed by stirring at room temperature for about 5 minutes. Dichloromethane and brine were added, and the dichloromethane layer was treated with magnesium sulfate. After distillation, the residue was purified by column chromatography with ethyl acetate:hexane = about 1:1 to obtain about 1.5 g of the product.

[0104] ¹H NMR(CDCl₃): δ 7.3 (s, 2H, ArH), 6.65 (s, 1H, ArH), 5.93-5.89 (q, 1H, CH), 5.29-5.09 (q, 1H, CH), 3.95 (d, 6H, OCH₃), 2.62-2.56, 2.47-2.40 (q, 2H, CH₂), 2.09 (s, 3H, CH₃), 1.66 (s, 3H, CH₃), 1.56 (s, 3H, CH₃)

[0105]

[0106] Example 8: Demethylation reaction

[0107] About 1.5 g of 1-(5,8-dimethoxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-en-1-yl acetate was completely dissolved in dichloromethane and cooled with acetone ice for about 15 minutes. About 1.2 ml of boron tribromide was slowly added to the reaction mixture and stirred at room temperature for about 1 hour. After adding dichloromethane and purified water, the dichloromethane layer was treated with magnesium sulfate. After distillation, the residue was purified by column chromatography with ethyl acetate:hexane = about 1:4 to obtain about 1.2 g of the product.

[0108] ¹H NMR (CDCl₃): δ 16.47 (s, 1H, OH), 7.75 (s, 2H, ArH), 7.55 (s, 1H, ArH), 5.38 (s, 1H, CH), 5.20 (s, 1H, CH), 4.31 (s, 1H, CH), 2.37, 2.12 (q, 2H, CH₂), 2.19 (s, 3H, CH₃), 1.82 (s, 3H, CH₃), 1.70 (s, 3H, CH₃)

[0109]

[0110] Example 9: Deacetylation reaction

[0111] About 1.2 g of 1-(5,8-dimethoxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-en-1-yl acetate was completely dissolved in about 10 ml of a solvent of THF:MeOH:H₂O = about 3:1:1, then about 0.2 g of LiOH was added and stirred at about 40 degrees for about 12 hours or more. After distilling the solvent, ethyl acetate and distilled water were added, and the ethyl acetate layer was treated with magnesium sulfate. After distillation, column chromatography was performed with ethyl acetate:hexane = about 2:1 to obtain about 0.96 g of shikonin.

[0112] ¹H-NMR (CDCl₃) δ: 1.66 (3H, s, H-6), 1.76 (3H, s, H-5), 2.39 (1H, m, H-2), 2.63 (1H, m, H-2), 4.92 (1H, m, H-1), 5.21 (1H, m, H-3), 7.16 (1H, d, J= 1.2 Hz, H-6 or H-7), 7.19 (1H, d, J= 1.5 Hz, H-6 or H-7), 7.26 (1H, s, H-3), 12.49 (1H, s, OH-5), 12.59 (1H, s, OH-8)

[0113]

[0114] Example 10: Synthesis of β,β-dimethylacrylshikonine

[0115] In the acetylation reaction of Example 6, the reaction was carried out in the same manner using about 1.5 ml of β,β-dimethylacrylic anhydride instead of acetic anhydride. About 3.46 g of 4-methyl-1-(1,4,5,8-tetramethoxynaphthalen-2-yl)pent-3-en-1-ol was completely dissolved in about 30 ml of dichloromethane, and about 3 ml of triethylamine, about 0.122 g of DMAP, and about 1.5 ml of β,β-dimethylacrylic anhydride were added to the reaction mixture, followed by heating and refluxing for about 1.5 hours. The reaction mixture was cooled to room temperature, brine and dichloromethane were added, and the dichloromethane layer was treated with magnesium sulfate. After distillation, the mixture was purified by column chromatography with ethyl acetate: hexane = about 1:3, to obtain about 3.2 g of the product.

[0116] Afterwards, oxidation, demethylation, and deacetylation reactions were sequentially performed in the same manner as in Example 7-9, and finally about 0.88 g of β,β-dimethylacrylic shikonine was obtained.

[0117]

[0118] This specification discloses preferred embodiments of the present invention. Although specific terms are used, they are used in a general sense only to easily explain the technical content of the present invention and to facilitate understanding of the invention, and are not intended to limit the scope of the present invention. It will be apparent to those skilled in the art that other modifications based on the technical concept of the present invention are possible in addition to the embodiments disclosed herein.

Claims

1. In a method for manufacturing an intermediate for shikonin synthesis, a) A step of producing 1,5-dimethoxynaphthalene by reacting 1,5-dihydroxynaphthalene with dimethyl sulfate; b) a step of producing 1,5-dibromo-4,8-dimethoxynaphthalene by reacting the above 1,5-dimethoxynaphthalene with N-bromosuccinimide (NBS) in a tetrahydrofuran (THF) solvent at -5°C to 5°C for 40 to 56 hours; c) A step of producing 1,4,5,8-tetramethoxynaphthalene by introducing a methoxy group into the above 1,5-dibromo-4,8-dimethoxynaphthalene using copper iodide (CuI) and 1,10-phenanthroline as a catalyst; d) a step of producing 2-formyl-1,4,5,8-tetramethoxynaphthalene by performing a formylation reaction on the above 1,4,5,8-tetramethoxynaphthalene using dimethylformamide (DMF) and phosphoryl chloride (POCl₃); and e) a step of forming a boron complex by reacting magnesium, finacolborane (HBpin) and 3,3-dimethylallyl bromide in a tetrahydrofuran (THF) solvent, and then reacting the boron complex with 2-formyl-1,4,5,8-tetramethoxynaphthalene to produce a prenylated shikonin intermediate; A method for producing an intermediate for sikkonin synthesis, characterized in that it comprises:

2. In paragraph 1, A method for producing an intermediate for shikonin synthesis, characterized in that the step b) above performs a bromination reaction using a tetrahydrofuran (THF) solvent instead of acetonitrile.

3. In paragraph 1, A method for producing an intermediate for sikkonin synthesis, characterized in that the step c) above uses 1,10-phenanthroline as a catalyst to shorten the reaction time from 48 hours to 4 hours.

4. In paragraph 1, The above step e) is a method for producing an intermediate for sikkonin synthesis, characterized in that the reaction is carried out at room temperature for 30 to 50 minutes using 300 to 350 mg of magnesium hydroxide, 12 to 18 ml of tetrahydrofuran (THF), 1.5 to 2.0 g of finaconazole (HBpin), and 1.8 to 2.2 g of 3,3-dimethylallyl bromide, and then 1.8 to 2.2 g of 3,3-dimethylallyl bromide is additionally added and stirred at room temperature for 1.5 to 2.5 hours.

5. In paragraph 1, A method for producing an intermediate for sikkonin synthesis, characterized in that after the above step e), extraction is performed using 0.08 M to 0.12 M HCl and hexane, treatment is performed with magnesium sulfate, and then the boron complex and 2-formyl-1,4,5,8-tetramethoxynaphthalene are stirred in a tetrahydrofuran (THF) solvent at room temperature for 22 to 26 hours.

6. In paragraph 1, A method for producing an intermediate for shikonin synthesis, characterized in that the prenylated shikonin intermediate produced in the above step e) is purified by column chromatography using a mixed solvent of ethyl acetate:hexane (1:1.8 to 1:2.2).

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