A method for preparing 1,4,5,8-tetramethoxynaphthalene compounds containing a side chain characteristic of baijacine and 6-fluoro derivatives thereof

Abstract

This invention relates to a method for preparing 1,4,5,8-tetramethoxynaphthalene compounds containing the characteristic side chain of shikonin and their 6-fluoro derivatives. The method uses 2-fluoro-1,4-dimethoxybenzene or 2,5-difluoro-1,4-dimethoxybenzene as starting materials. After cyclization, ring-opening, and O-methylation to construct the 1,4,5,8-tetramethoxynaphthalene core, an aldehyde group is introduced at the 2-position via Vilsmeier-Haack formylation. This is followed by addition with allyl magnesium bromide to obtain an allyl alcohol intermediate. Finally, a cross-metathesis reaction catalyzed by a Grubbs II catalyst is performed with 2-methyl-2-butene to construct the characteristic side chain of shikonin –CH(OH)CH2CH=C(CH3)2. This invention offers high yields, simple operation, avoids the use of highly toxic reagents, and successfully solves the problem of the difficulty in synthesizing 6-fluoro derivatives due to direct fluorination, providing a key intermediate for the development of novel naphthoquinone drugs.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis and medicinal chemistry, and relates to a method for preparing 1,4,5,8-tetramethoxynaphthalene compounds containing the characteristic side chain of shikonin and their 6-fluoro derivatives. Background Technology

[0002] Shikonin and its derivatives are a class of natural naphthoquinone compounds isolated from the traditional Chinese medicine Lithospermum erythrorhizon, exhibiting significant anti-inflammatory, antibacterial, antiviral, and antitumor activities. Their core structural feature is a 1,4-naphthoquinone core with an unsaturated side chain containing a secondary hydroxyl group attached at the C-2 position (–CH(OH)CH2CH=C(CH3)2). In recent years, studies have found that reducing naphthoquinone to the 1,4,5,8-tetramethoxynaphthalene skeleton while retaining this side chain can significantly improve the metabolic stability and selectivity of the compound, becoming an important direction for structural optimization.

[0003] However, existing synthetic routes have significant drawbacks. Traditional methods typically use 1,5-dihydroxynaphthalene as a starting material, involve multiple steps with harsh reaction conditions, result in low overall yields, and require the use of highly toxic reagents (such as dimethyl sulfate) and multiple column chromatography purifications, making it difficult to scale up the reaction.

[0004] More importantly, when introducing a fluorine atom at the 6-position of the naphthalene ring to regulate electronic effects and pharmacokinetic properties, conventional strategies attempt to directly electrophilically fluorinate the constructed 1,4,5,8-tetramethoxynaphthalene core. However, due to the electron-rich and symmetrical nature of this skeleton, the fluorination reaction is prone to over-substitution, oxidation, or tarring, making it difficult to obtain a single 6-fluorinated product. Therefore, developing a universal route that can efficiently construct shikonin side chains and is compatible with the synthesis of 6-fluorinated derivatives has been a long-standing technical challenge in this field. Summary of the Invention

[0005] To address the aforementioned technical problems, this invention provides a method for preparing 1,4,5,8-tetramethoxynaphthalene compounds containing the characteristic side chain of shikonin and their 6-fluoro derivatives. The method uses 2-fluoro-1,4-dimethoxybenzene or 2,5-difluoro-1,4-dimethoxybenzene as starting materials. After cyclization, ring-opening, and O-methylation to construct the 1,4,5,8-tetramethoxynaphthalene core, an aldehyde group is introduced at the 2-position via Vilsmeier-Haack formylation. This is followed by addition with allyl magnesium bromide to obtain an allyl alcohol intermediate. Finally, a cross-metathesis reaction catalyzed by a Grubbs II catalyst is performed with 2-methyl-2-butene to efficiently construct the characteristic side chain of shikonin –CH(OH)CH2CH=C(CH3)2. This invention offers high yields, simple operation, avoids the use of highly toxic reagents, and successfully solves the problem of the difficulty in synthesizing 6-fluoro derivatives due to direct fluorination, providing a key intermediate for the development of novel naphthoquinone drugs.

[0006] The objective of this invention can be achieved through the following methods:

[0007] In a first aspect, the present invention provides a method for preparing 1,4,5,8-tetramethoxynaphthalene compounds containing the characteristic side chain of shikonin and their 6-fluoro derivatives, comprising the following steps: S1. Using 2-fluoro-1,4-dimethoxybenzene or 2,5-difluoro-1,4-dimethoxybenzene and 2-methoxyfuran as raw materials, an addition and cyclization reaction is carried out under the action of an organolithium reagent to obtain intermediate 1. S2. Intermediate 1 is subjected to an acidic hydrolysis ring-opening reaction to obtain phenolic intermediate 2; S3. Intermediate 2 is reacted with iodomethane in the presence of a base to undergo an O-methylation reaction to obtain 1,4,5,8-tetramethoxynaphthalene intermediate 3. S4. Intermediate 3 is subjected to Vilsmeier-Haack formylation reaction to introduce an aldehyde group at the 2 position to obtain aldehyde intermediate 4; S5. Intermediate 4 undergoes a Grignard addition reaction with allyl magnesium bromide to obtain allyl alcohol intermediate 5. S6. Intermediate 5 is subjected to a cross metathesis reaction with 2-methyl-2-butene in the presence of Grubbs II catalyst to obtain the target product; The intermediate 1 has the following structural formula: ; The intermediate 2 has the following structural formula: ; The intermediate 3 has the following structural formula: ; The intermediate 4 has the following structural formula: ; The intermediate 5 has the following structural formula: ; The target product has the following structural formula: ; R is selected from H or F.

[0008] In this invention, the structure of allyl alcohol intermediate 5 is 2-(1-hydroxybut-3-en-1-yl)-1,4,5,8-tetramethoxynaphthalene or its 6-fluoro derivative; the target product has the following structure: the naphthalene ring has methoxy substitutions at the 1, 4, 5, and 8-positions, a substituent at the 2-position is –CH(OH)CH2CH=C(CH3)2, and the 6-position is a hydrogen or fluorine atom. The reaction pathway is as follows: .

[0009] As one embodiment of the present invention, if the starting material used is 2-fluoro-1,4-dimethoxybenzene, the target product obtained is a non-fluorinated compound; if the starting material used is 2,5-difluoro-1,4-dimethoxybenzene, the target product obtained is a fluorinated compound.

[0010] In one embodiment of the present invention, in step S1, the organolithium reagent includes n-butyllithium.

[0011] In one embodiment of the present invention, in step S1, the temperature of the addition and cyclization reaction is -90 to -60°C, and the reaction time is 0.2 to 1 hour; then 2-methoxyfuran is added, the reaction temperature is raised to -10 to 10°C, and the reaction time is 2 to 4 hours.

[0012] As one embodiment of the present invention, in step S2, the ring-opening reaction is carried out in a closed container under reflux at 110~130°C; after the reaction is completed, the mixture is cooled and allowed to stand at -20~0°C for 4~12 hours to crystallize.

[0013] In one embodiment of the present invention, in step S3, the alkali includes sodium hydride.

[0014] As one embodiment of the present invention, in step S3, the O-methylation reaction specifically involves: first reacting intermediate 2 with a base at -10 to 10°C for 0.2 to 1 hour, then adding iodomethane dropwise, and raising the temperature to 10 to 40°C to continue the reaction for 12 to 24 hours.

[0015] As one embodiment of the present invention, in step S4, the Vilsmeier-Haack reagent used in the Vilsmeier-Haack formylation reaction is generated in situ from phosphorus oxychloride and N,N-dimethylformamide.

[0016] As one embodiment of the present invention, in step S4, the Vilsmeier-Haack formylation reaction specifically involves reacting phosphorus oxychloride with N,N-dimethylformamide (DMF) at -10 to 10°C for 0.5 to 3 hours to form the Vilsmeier-Haack reagent; then adding intermediate 3 and refluxing at 45 to 55°C for 12 to 48 hours.

[0017] As one embodiment of the present invention, in step S5, the Grignard addition reaction specifically involves: dissolving intermediate 4, adding allyl magnesium bromide dropwise under nitrogen protection, and reacting at 25-35°C for 1.5-2.5 hours.

[0018] As one embodiment of the present invention, in step S6, the cross metathesis reaction specifically involves: dissolving intermediate 5 with Grubbs II catalyst, adding 2-methyl-2-butene, and reacting at 20-30°C for 15-20 hours under nitrogen protection.

[0019] Secondly, the present invention provides a 1,4,5,8-tetramethoxynaphthalene compound containing a characteristic side chain of shikonin obtained by the preparation method described above, and its 6-fluoro derivative.

[0020] Compared with the prior art, the present invention has the following beneficial effects: 1. This invention provides a high-yield and environmentally friendly method for synthesizing 1,4,5,8-tetramethoxynaphthalene-based shikonin derivatives, overcoming the bottleneck of difficulty in obtaining 6-fluoro derivatives due to direct fluorination, and achieving unified and efficient preparation of non-fluorinated and 6-fluoro target compounds.

[0021] 2. Highly efficient route: Non-fluorinated target compounds require only 6 reaction steps, with an overall yield of 38-51%, far exceeding the levels reported in the literature. This route innovatively bypasses the difficult-to-control Ullmann reaction, the unstable zinc bromine reagent reaction, and the high-risk HMPA reaction in existing technologies, fundamentally solving the problems of low yield, poor reproducibility, and low safety of traditional methods.

[0022] 3. Green and safe: Methylation uses iodomethane instead of highly toxic dimethyl sulfate, and the products from multiple steps can be directly extracted and separated without the need for column chromatography.

[0023] 4. Overcoming the fluorination bottleneck: By introducing fluorine atoms at the starting material stage (using 2,5-difluoro-1,4-dimethoxybenzene), the infeasibility of later fluorination was successfully avoided, and the controllable synthesis of 6-fluoroshikonin derivatives was achieved. Attached Figure Description

[0024] Other features, objects, and advantages of the present invention will become more apparent from the following detailed description of non-limiting embodiments with reference to the accompanying drawings: Figure 1 This invention provides a novel synthetic route for 1,4,5,8-tetramethoxynaphthalene compounds and their 6-fluoro derivatives. Figure 2 The hydrogen spectrum of 1,4,5,8-tetramethoxyshikonin in Example 2; Figure 3 The hydrogen spectrum of 6-fluoro-1,4,5,8-tetramethoxyshikonin in Example 4; Figure 4 The old synthetic route for the 1,4,5,8-tetramethoxynaphthalene compounds in Comparative Example 1; Figure 5 An attempt was made to use an electrophilic fluorinating agent in Comparative Example 2. Detailed Implementation

[0025] The present invention will now be described in detail with reference to the accompanying drawings and specific embodiments. The following examples are implemented under the premise of the technical solution of the present invention, providing detailed implementation methods and specific operating procedures, which will help those skilled in the art to further understand the present invention. It should be noted that the scope of protection of the present invention is not limited to the following embodiments; any adjustments and improvements made under the concept of the present invention are all within the scope of protection of the present invention.

[0026] Unless otherwise specified, the experimental methods used in the following examples are conventional methods, performed according to the techniques or conditions described in the literature in this field or according to the product instructions. Unless otherwise specified, the materials and reagents used in the following examples are commercially available.

[0027] The Grubbs II catalyst was purchased from Aladdin, catalog number G120500-1g.

[0028] Example 1: Preparation of 1,4,5,8-Tetramethoxynaphthalene refer to Figure 1 The synthetic route shown involves placing 5.0 g (32 mmol) of 2-fluoro-1,4-dimethoxybenzene in a dry double-necked flask, adding 100 mL of anhydrous THF under nitrogen protection, and cooling to -78 °C. Then, 20 mL (35.2 mmol) of 1.6 M inhexane was added dropwise, and the mixture was stirred for 30 minutes. Next, 4.4 mL (48 mmol) of 2-methoxyfuran was added. Stirring continued for another 30 minutes, and the mixture was slowly raised to 0 °C and reacted for 3 hours. The reaction mixture was quenched with saturated NH4Cl solution, and the pH was adjusted to neutral with 1 M HCl. The mixture was extracted with ethyl acetate (3 × 50 mL), and the organic phases were combined, washed successively with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain crude intermediate 1. This crude intermediate was used directly in the next step without column chromatography.

[0029] The crude intermediate 1 (containing approximately 32 mmol) was dissolved in methanol (350 mL), and 9 M HCl (100 mL) was slowly added. The mixture was refluxed at 120 °C under sealed conditions for 3 hours. After cooling to room temperature, it was allowed to stand overnight at -20 °C. The precipitate was carefully adjusted to neutral with solid NaHCO3, methanol was removed by rotary evaporation, the residue was extracted with ethyl acetate, washed with saturated NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain crude intermediate 2, which was used directly in the next step without column chromatography.

[0030] The crude intermediate 2 (containing approximately 32 mmol) was dissolved in anhydrous DMF (71 mL), and NaH (60% in oil, 1.6 g, 40 mmol) was added under nitrogen protection. The mixture was stirred at 0 °C for 30 minutes. Iodomethane (2.5 mL, 40 mmol) was then added dropwise, and the reaction was continued at 25 °C for 18 hours. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with saturated NaCl, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to give a white solid intermediate 3 (1,4,5,8-tetramethoxynaphthalene), 6.2 g. The overall yield of the three steps was calculated to be 78.5%.

[0031] Example 2: Preparation of non-fluorinated target compounds 2.1 Vilsmeier formylation reaction Intermediate 3 (1,4,5,8-tetramethoxynaphthalene, 3.0 g, 12.8 mmol) was dissolved in dichloromethane (30 mL). Separately, POCl3 (3.4 mL, 38.4 mmol) was slowly added dropwise to DMF (3.1 mL, 42.2 mmol) under ice bath conditions, and the mixture was stirred for 2 hours to form Vilsmeier's reagent. The dichloromethane solution of intermediate 3 was then added to the above reagent, and the mixture was refluxed at 50 °C for 48 hours. After cooling, the solvent was removed by rotary evaporation, and the residue was poured into ice water, stirred for 1 hour, and filtered. The filter cake was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to give 2.8 g of yellow needle-like crystals intermediate 4 (1,4,5,8-tetramethoxy-2-carboxaldehyde), in a yield of 83.8%.

[0032] To investigate the effect of temperature, the following preferred examples are set up: Preferred Example 2-1a: Except for changing the reaction temperature to 40°C, the rest of the operation was the same as in Example 2.1. The reaction time was 48 hours, and the yield was 74.9%.

[0033] Preferred Example 2-1b: Except for changing the reaction temperature to 60°C, the rest of the operation was the same as in Example 2.1. The reaction time was 36 hours, and the yield was 73.5%.

[0034] 2.2 Grignard addition reaction Intermediate 4 (0.98 g, 3.55 mmol) was dissolved in anhydrous THF (10 mL), and allyl magnesium bromide (1.0 M in THF, 7.1 mL, 7.1 mmol) was added dropwise under nitrogen protection. The reaction mixture was reacted at 30 °C for 2 hours. The reaction solution was quenched with saturated NH4Cl solution, extracted with ethyl acetate, washed with saturated NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give intermediate 5 (allyl alcohol adduct), a yellow oily compound, 1.04 g, yield 94.2% (racemic mixture).

[0035] To investigate the effect of temperature, the following preferred examples are set up: Preferred Example 2-2a: Except for changing the reaction temperature to 20°C, the other operations were the same as in Example 2.2. The reaction time was 4 hours, and the yield was 82.0%.

[0036] Preferred Example 2-2b: Except for changing the reaction temperature to 40°C, the other operations were the same as in Example 2.2. The reaction lasted for 1 hour, with a yield of 91.7%.

[0037] 2.3 Alkene Metathesis Reactions Intermediate 5 (0.76 g, 2.38 mmol) and Grubbs II catalyst (0.1 g, 0.119 mmol) were dissolved in anhydrous dichloromethane (8 mL), and 2-methyl-2-butene (39 mL, 367 mmol) was added. The reaction was carried out at 25 °C for 16 hours under nitrogen protection. The solvent was removed by rotary evaporation, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to give 0.69 g of the target compound (I) as a yellow oil, in 83% yield. The overall yield of the three steps from intermediate 3 to the target compound was calculated to be 65.5%.

[0038] Preferred Example 2-3a: Except for changing the reaction temperature to 35°C, the rest of the operation was the same as in Example 2.3. The reaction time was 12 hours, and the yield was 80.1%.

[0039] Preferred Example 2-3b: Except for changing the reaction temperature to 15°C, the rest of the operation was the same as in Example 2.3. The reaction time was 24 hours, and the yield was 81.4%.

[0040] The proton NMR spectrum of the 1,4,5,8-tetramethoxynaphthalene compounds is shown below. Figure 2 As shown, its proton spectrum data is as follows: 1H NMR (400 MHz, Chloroform-d) δ 7.01 (s, 1H), 6.80 (d, J = 1.4 Hz,2H), 5.28 – 5.20 (m, 2H), 3.93 (d, J = 6.6 Hz, 6H), 3.88 (s, 3H), 3.74 (s,3H), 2.52 (s, 2H), 2.49 – 2.37 (m, 1H), 1.71 (d, J = 1.6 Hz, 3H), 1.64 (d, J= 1.5 Hz, 3H). Example 3: Preparation of 6-fluoro-1,4,5,8-tetramethoxynaphthalene 2,5-Difluoro-1,4-dimethoxybenzene (5.0 g, 28.7 mmol) was placed in a dry two-necked flask, and anhydrous THF (100 mL) was added under nitrogen protection. The mixture was cooled to -78°C. Butyllithium (2.5 M in hexane, 11.5 mL, 28.7 mmol) was added dropwise, and the mixture was stirred for 30 minutes. Then, 2-methoxyfuran (4.0 mL, 43.1 mmol) was added. The mixture was stirred for another 30 minutes, and the temperature was slowly raised to 0°C. The reaction mixture was reacted for 3 hours. The reaction solution was quenched with saturated NH4Cl solution, and the pH was adjusted to neutral with 1 M HCl. The mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed successively with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give crude intermediate 1 (6.3 g, used directly in the next step).

[0041] The crude intermediate 1 (6.3 g, 28.7 mmol) was dissolved in methanol (1025 mL), and 9 M HCl (315.7 mL) was slowly added. The mixture was refluxed at 120 °C under sealed conditions for 3 hours. After cooling to room temperature, it was allowed to stand overnight at -20 °C. The precipitate was carefully adjusted to neutral with solid NaHCO3, methanol was removed by rotary evaporation, the residue was extracted with ethyl acetate, washed with saturated NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give intermediate 2 (7.2 g), a mixture of 7-fluoro-4,5,8-trimethoxynaphthol and 6-fluoro-4,5,8-trimethoxynaphthol, which was used directly in the next step.

[0042] Intermediate 2 (7.2 g, 28.7 mmol) was dissolved in anhydrous DMF (64 mL), and NaH (60% in oil, 1.4 g, 35.6 mmol) was added under nitrogen protection. The mixture was stirred at 0 °C for 30 minutes. Iodomethane (2.2 mL, 35.6 mmol) was then added dropwise, and the reaction was continued at 25 °C for 18 hours. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with saturated NaCl, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to give 6.1 g of a white solid 6-fluoro-1,4,5,8-tetramethoxynaphthalene (intermediate 3), with an overall yield of 74.4% for the three steps.

[0043] Example 4: Preparation of the 6-fluorinated target compound 4.1 Vilsmeier formylation reaction 6-Fluoro-1,4,5,8-Tetramethoxynaphthalene (intermediate 3, 1.0 g, 3.76 mmol) was dissolved in dichloromethane (10 mL). Separately, POCl3 (1.0 mL, 11.3 mmol) was slowly added dropwise to DMF (0.9 mL, 11.3 mmol) under ice bath conditions, and the mixture was stirred for 2 hours to form Vilsmeier's reagent. The dichloromethane solution of intermediate 3 was then added to the above reagent, and the mixture was refluxed at 50 °C for 8 hours. After cooling, the solvent was removed by rotary evaporation, and the residue was poured into ice water, stirred for 1 hour, and filtered. The filter cake was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to give 0.92 g of yellow needle-like crystals of 6-fluoro-1,4,5,8-tetramethoxy-2-carboxaldehyde (intermediate 4), yield 88.4%.

[0044] To investigate the effect of temperature, the following preferred examples are set up: Preferred Example 4-1a: Except for changing the reaction temperature to 40°C, the other operations were the same as in Example 2.1. The reaction time was 72 hours, and the yield was 81.7%.

[0045] Preferred Example 4-1b: Except for changing the reaction temperature to 60°C, the rest of the operation was the same as in Example 2.1. The reaction time was 38 hours, with a yield of 86.5%, but TLC showed a slight increase in by-product spots.

[0046] 4.2 Grignard addition reaction Intermediate 4 (0.36 g, 1.23 mmol) was dissolved in anhydrous THF (5.05 mL), and allyl magnesium bromide (1.0 M in THF, 2.45 mL, 2.46 mmol) was added dropwise under nitrogen protection. The reaction mixture was reacted at 30 °C for 2 hours. The reaction solution was quenched with saturated NH4Cl solution, extracted with ethyl acetate, washed with saturated NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a yellow oily allyl alcohol adduct (intermediate 5), 0.39 g, yield 92.8% (racemic mixture).

[0047] To investigate the effect of temperature, the following preferred examples are set up: Preferred Example 4-2a: Except for changing the reaction temperature to 20°C, the other operations were the same as in Example 2.2. The reaction time was 3 hours, and the yield was 89.2%.

[0048] Preferred Example 4-2b: Except for changing the reaction temperature to 40°C, the other operations were the same as in Example 2.2. The reaction lasted for 1 hour, with a yield of 88.5%.

[0049] 4.3 Olefin Metathesis Reactions Intermediate 5 (0.383 g, 1.14 mmol) and Grubbs II catalyst (0.05 g, 0.057 mmol) were dissolved in anhydrous dichloromethane (3 mL), and 2-methyl-2-butene (20.8 mL, 175.7 mmol) was added. The reaction was carried out at 25 °C for 16 hours under nitrogen protection. The solvent was removed by rotary evaporation, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to give 0.31 g of the target compound (formula (I)) (6-fluoro-1,4,5,8-tetramethoxynaphthalene), with a yield of 81.1%. The overall yield from intermediate 3 to the target compound was 66.0%.

[0050] Preferred Example 4-3a: Except for changing the reaction temperature to 35°C, the rest of the operation was the same as in Example 2.3. The reaction time was 10 hours, and the yield was 79.8%.

[0051] Preferred Example 4-3b: Except for changing the reaction temperature to 15°C, the rest of the operation was the same as in Example 2.3. After 24 hours of reaction, there was still a residue of raw material, with a yield of 72.3%.

[0052] The proton NMR spectrum of the 6-fluoro-1,4,5,8-tetramethoxynaphthalene compound is shown below. Figure 3 As shown, its proton spectrum data is as follows: 1 H NMR (400 MHz, CDCl3) δ 7.04 (s, 1H), 6.74 (d, J = 12.3 Hz, 1H), 5.34– 5.18 (m, 2H), 3.97 (d, J = 7.4 Hz, 6H), 3.87 (s, 3H), 3.75 (s, 3H), 2.51 (t, J = 7.0 Hz, 2H), 2.25 (s, 1H), 1.74 (d, J = 1.6 Hz, 3H), 1.71 – 1.56 (m, 5H). Comparative Example 1: Old Synthetic Method for 1,4,5,8-Tetramethoxynaphthalene Compounds refer to Figure 4The synthetic route shown uses 1,5-dihydroxynaphthalene as the starting material. First, it undergoes O-methylation with dimethyl sulfate under basic conditions to obtain 1,5-dimethoxynaphthalene. Then, it undergoes selective bromination with N-bromosuccinimide (NBS) to obtain 1,5-dimethoxy-4,8-dibromonaphthalene. Next, two additional methoxy groups are introduced through a Ullmann-type methoxylation reaction to obtain 1,4,5,8-tetramethoxynaphthalene. This intermediate is then subjected to Vilsmeier-Haack formylation to obtain an aldehyde. Finally, a shikonin-type side chain is introduced through a zinc-mediated alkenylation reaction.

[0053] This route requires the use of highly toxic dimethyl sulfate, and each step requires column chromatography or recrystallization purification, which is cumbersome, generates a large amount of waste, and has a low yield.

[0054] Comparative Example 2: An attempt to directly fluorinate 1,4,5,8-tetramethoxynaphthalene using an electrophilic fluorinating agent. refer to Figure 5 The synthetic route shown is illustrated. To verify the necessity of the technical solution of this invention, an attempt was made to fluorinate 1,4,5,8-tetramethoxynaphthalene at the C-6 position using a commonly used electrophilic fluorination strategy in the art. Specifically, the following three conditions were explored: Conventional solution method: 1,4,5,8-Tetramethoxynaphthalene was dissolved in anhydrous dichloromethane, and Selectfluor or NFSI (1.2 equiv) was added, respectively. The mixture was stirred at room temperature for 24 hours. TLC monitoring showed that the starting material was not converted and the target monofluorinated product was not detected.

[0055] Solvent-free heating method: Referring to the solvent-free strategy reported in the literature, 1,4,5,8-tetramethoxynaphthalene was first ground and mixed thoroughly with Selectfluor or NFSI (1.2 equiv) in a mortar, and then reacted at 80°C for 20 hours. TLC showed that the starting material was completely consumed, but no target product was formed; instead, a large number of byproduct spots of different polarities were produced. The reaction mixture was dark brown and tar-like, and could not be separated and purified. Moreover, the system showed obvious signs of discoloration during the grinding and mixing stage.

[0056] Mechanical ball milling: Further attempts were made to promote the reaction through high-energy ball milling, but this resulted in the complete degradation of the raw materials, complete carbonization and blackening of the system, and no formation of any target product.

[0057] The above experimental results show that direct electrophilic fluorination of 1,4,5,8-tetramethoxynaphthalene is difficult to achieve under various conditions, including room temperature solution, solvent-free heating, and high-energy mechanochemical conditions. It is prone to side reactions or substrate degradation, which proves the necessity of the technical route adopted in this invention.

[0058] The specific embodiments of the present invention have been described above. It should be understood that the present invention is not limited to the specific embodiments described above, and those skilled in the art can make various modifications or variations within the scope of the claims, which do not affect the essence of the present invention.

Claims

1. A process for the preparation of 1,4,5,8-tetramethoxynaphthalene derivatives containing a side chain characteristic of shikonin and their 6-fluoro derivatives, characterized in that, The method comprises the following steps: S1, using 2-fluoro-1,4-dimethoxybenzene or 2,5-difluoro-1,4-dimethoxybenzene and 2-methoxyfuran as raw materials, and adding an organic lithium reagent to perform addition and cyclization reactions to obtain an intermediate 1; S2, performing acid hydrolysis and ring-opening reaction on the intermediate 1 to obtain a phenolic intermediate 2; S3, performing O-methylation reaction on the intermediate 2 and methyl iodide in the presence of a base to obtain a 1,4,5,8-tetramethoxynaphthalene intermediate 3; S4, performing Vilsmeier-Haack formylation reaction on the intermediate 3 to introduce an aldehyde group at the 2-position to obtain an aldehyde intermediate 4; S5, performing Grignard addition reaction on the intermediate 4 and allyl magnesium bromide to obtain an allyl alcohol intermediate 5; S6, performing cross-metathesis reaction on the intermediate 5 and 2-methyl-2-butene in the presence of Grubbs II catalyst to obtain a target product; The intermediate 1 has the following structural formula: ； The intermediate 2 has the following structural formula: ； The intermediate 3 has the following structural formula: ； The intermediate 4 has the following structural formula: ； The intermediate 5 has the following structural formula: ； The target product has the following structural formula: ； Wherein, R is selected from H or F.

2. The production method according to claim 1, characterized by, In step S1, the organic lithium reagent comprises n-butyllithium.

3. The production method according to claim 1, characterized by, In step S1, the temperature of the addition and cyclization reaction is -90~ -60℃, and the reaction time is 0.2~1 hour; then 2-methoxyfuran is added, the reaction temperature is raised to -10~10℃, and the reaction time is 2~4 hours.

4. The method of claim 1, wherein, In step S2, the ring-opening reaction is performed in a closed container at 110~130℃ under reflux; after the reaction is completed, cooling is performed, and the mixture is placed at -20~0℃ for 4~12 hours for crystallization.

5. The method of claim 1, wherein, In step S3, the base comprises sodium hydride; and the O-methylation reaction specifically comprises: first, reacting the intermediate 2 and the base at -10~10℃ for 0.2~1 hour, then adding methyl iodide, and continuing to react at 10~40℃ for 12~24 hours.

6. The method of claim 1, wherein, In step S4, the Vilsmeier-Haack formylation reaction uses Vilsmeier-Haack reagent generated in situ from phosphorus oxychloride and N,N-dimethylformamide.

7. The preparation method according to claim 1, characterized in that, In step S4, the Vilsmeier-Haack formylation reaction specifically comprises: reacting phosphorus oxychloride and N,N-dimethylformamide at -10~10℃ for 0.5~3 hours to form Vilsmeier-Haack reagent; then adding the intermediate 3, and refluxing at 45~55℃ for 12~48 hours.

8. The method of claim 1, wherein, In step S5, the Grignard addition reaction specifically comprises: dissolving the intermediate 4, adding allyl magnesium bromide dropwise under nitrogen protection, and reacting at 25~35℃ for 1.5~2.5 hours.

9. The production method according to claim 1, characterized by, In step S6, the cross-metathesis reaction specifically comprises: dissolving the intermediate 5 and Grubbs II catalyst, adding 2-methyl-2-butene, and reacting at 20~30℃ for 15~20 hours under nitrogen protection.

10. A 1,4,5,8-tetramethoxynaphthalene compound with a side chain characteristic of shikonin and its 6-fluoro derivative, obtainable by the process according to any one of claims 1 to 9.

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