Novel synthesis method of naphthazarin

Abstract

The invention discloses a novel synthetic method of naphthazarin, which comprises the following steps of: 1, reacting 1, 4, 5, 8-tetramethoxynaphthalene with boron tribromide or aluminum trichloride, crystallizing to obtain a high-purity product, and distilling a solvent under reduced pressure to obtain 5, 8-dihydroxy-2, 3-dihydronaphthalene-1, 4-diketone; 2, 5, 8-dihydroxy-2, 3-dihydronaphthalene-1, 4-diketone is added into another reaction kettle, an alkali solution is added, an oxygen micro-positive pressure (0.01-0.03 MPa) is performed for a reaction, and after the reaction is finished, high-purity 5, 8-dihydroxy-2, 3-dihydronaphthalene-1, 4-diketone salt is obtained through ethanol crystallization and filtration; and adding the salt of the 5, 8-dihydroxy-2, 3-dihydronaphthalene-1, 4-diketone into another reaction kettle, adding a hydrochloric acid ethyl acetate solution, heating and reacting, and then filtering and pulping to obtain a final product. The total preparation yield gt of naphthazarin; the HPLC purity is gt; the yield is 99.6%. The route is simple and convenient to operate and easy to implement, raw materials are cheap and easy to obtain, reaction conditions are mild, high-temperature and high-pressure reaction is not needed, and requirements on equipment are reduced. The whole route is safer to the environment, and green and pollution-free production can be realized.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a novel method for synthesizing naphthalene. Background Technology

[0002] Naphthoquinone, a natural naphthoquinone compound, is primarily used in the pharmaceutical and scientific research fields. In the pharmaceutical field: as an active naphthoquinone component, it inhibits tumor cells through oxidative stress and apoptosis pathways, showing potential, especially in the treatment of drug-resistant cholangiocarcinoma; nanomedicine carriers integrated into fully active nanomedicines (such as AFeC FANDs) enhance targeted therapy efficiency and reduce side effects. In the fragrance field: as a plant-based natural fragrance intermediate, benefiting from consumption upgrades, the Chinese plant fragrance market is projected to exceed 30 billion yuan by 2025, with a compound annual growth rate of 12.3%; high-purity (≥97%) products are used in the synthesis of dyes and pharmaceutical intermediates.

[0003] Currently, the methods for preparing naphthylazine reported both domestically and internationally have the following main shortcomings: Reference J. Am. Chem. Soc. 1917, 39, 2466 describes the preparation using 1,4-dimethoxybenzene as the starting material: The Friedel-Crafts reaction of 1,4-dimethoxybenzene with 2,3-dichloromaleic anhydride has significant drawbacks: The reaction conditions are harsh: requiring temperatures above 180℃, resulting in high energy consumption and significant safety hazards. Reagent toxicity: Uses highly sensitizing raw materials and low-cost tin reducing agents; The process is cumbersome: it requires multiple purification steps such as dehalogenation and oxidation, resulting in a low overall yield.

[0004] The literature, *Journal of Chemical Research*, 2011, vol. 35, #1, p. 24-25, describes the preparation using 1,4,5,8-tetramethoxynaphthalene as a raw material. The target molecule was obtained from the raw material 1,4,5,8-tetramethoxynaphthalene via electrochemical oxidation, but the reproducibility was poor. The second route in this literature was lengthy, inefficient, polluting, and required expensive reagents.

[0005] Currently, there is a lack of a simple, low-temperature, step-by-step method for synthesizing naphthalene, which requires green and safe reagents, is environmentally friendly, and inexpensive. Therefore, developing a new process that balances economy, safety, and environmental friendliness is key to overcoming the current technological bottleneck. Summary of the Invention

[0006] To address the shortcomings of existing technologies, the present invention aims to provide a novel synthetic method for naphthalassium suitable for green and safe synthesis, achieving the following objectives: ① using inexpensive and readily available starting materials; ② mild reaction conditions, eliminating the need for high-temperature and high-pressure equipment; ③ using green, safe, environmentally friendly, and low-cost reagents; ④ a simple number of steps; and ⑤ recyclable solvents, reducing emissions of waste.

[0007] The core idea of ​​this invention is as follows: using 1,4,5,8-tetramethoxynaphthalene as the starting material, reducing the methoxy group with boron tribromide or aluminum trichloride; then oxidizing with a strong base and finally freeing it with hydrochloric acid to obtain naphthalene.

[0008] To achieve the above objectives, the present invention adopts the following technical solution: A novel synthetic method for naphthylazine, the synthetic route is as follows: The specific synthesis process is as follows: (1) Add solvent to the reaction vessel, start stirring, add 1,4,5,8-tetramethoxynaphthalene (purity ≥98%), stir until completely dissolved, cool to 0~5℃, add boron tribromide or aluminum trichloride to react, after the reaction is complete (1,4,5,8-tetramethoxynaphthalene residue ≤0.5%), recover the solvent by vacuum distillation (recovery rate ≥90%), and obtain the high-purity product 5,8-dihydroxy-2,3-dihydronaphthalene-1,4-dione (purity ≥90%) by crystallization. (2) Add the 5,8-dihydroxy-2,3-dihydronaphthyl-1,4-dione, water and KOH obtained in step (1) to another reaction vessel, dissolve until there is no solid residue, stir under slight positive pressure with oxygen until the reaction is complete, after the reaction is complete (5,8-dihydroxy-2,3-dihydronaphthyl-1,4-dione ≤ 1.0%), obtain high purity 5,8-dihydroxypotassium-1,4-naphthoquinone by ethanol crystallization filtration; (3) Add 5,8-dihydroxypotassium-1,4-naphthoquinone and solvent to another reaction vessel, add ethyl acetate hydrochloride solution, stir the reaction at 35~40℃, monitor the endpoint by HPLC (naphthoquinone>95%), and after the reaction is completed, obtain high-purity naphthoquinone (purity≥99%) by filtration and pulping.

[0009] Further, in step (1), the molar ratio of 1,4,5,8-tetramethoxynaphthalene to boron tribromide is 1:(2~3), the reaction temperature of 1,4,5,8-tetramethoxynaphthalene with boron tribromide is 0~5℃, and the concentration of 1,4,5,8-tetramethoxynaphthalene in the solvent is 0.4~0.5mol / L; the molar ratio of 1,4,5,8-tetramethoxynaphthalene to aluminum trichloride is 1:(2~4), and the reaction temperature of 1,4,5,8-tetramethoxynaphthalene with aluminum trichloride is 20~30℃.

[0010] Further, in step (2), the molar ratio of 5,8-dihydroxy-2,3-dihydronaphthyl-1,4-dione to KOH is 1:(7~9), and the concentration of 5,8-dihydroxy-2,3-dihydronaphthyl-1,4-dione in water is 0.5~0.6mol / L.

[0011] Furthermore, in step (2), the pressure of the oxygen micro-positive pressure is 0.01~0.03MPa, and the temperature of the oxygen micro-positive pressure reaction is 20~40℃.

[0012] Further, in step (3), the molar ratio of 5,8-dihydroxypotassium-1,4-naphthoquinone to hydrochloric acid in the ethyl acetate hydrochloride solution is 1:(2~4), the molar concentration of hydrochloric acid in the ethyl acetate hydrochloride solution is 1~3 mol / L, the temperature is controlled at 10~15℃ when the ethyl acetate hydrochloride solution is added, and the concentration of 5,8-dihydroxypotassium-1,4-naphthoquinone in the solvent is 0.4~0.5 mol / L.

[0013] Further, in step (1), after the reaction is complete, the reaction solution is poured into ice water, stirred for 20-40 minutes, the solvent is removed under reduced pressure, filtered, and the filter cake is dried at 40-60℃. After drying, it is dissolved in a mixed solvent of MeOH and ethyl acetate in a volume ratio of 1:(1-3). After dissolution, it is poured into a mixed solvent of ethyl acetate and petroleum ether in a volume ratio of 1:(4-6), filtered, and the filtrate is concentrated to obtain the final product. The volume ratio of the reaction solution to ice water is 1:(1.5-2). The volume ratio of the mixed solvent of MeOH and ethyl acetate to the mixed solvent of ethyl acetate and petroleum ether is 1:(3-10).

[0014] Further, in step (2), after the reaction is complete, add 2 to 4 times the volume of ethanol to the reaction solution, filter, wash the filter cake with ethanol, and dry at 45 to 50°C to obtain the final product.

[0015] Further, in step (3), the reaction solution is filtered, and the filter cake is washed with ethyl acetate; the filtrate is concentrated to 1 / 2 to 2 / 3 of its original volume by rotary evaporation at 40~45℃; petroleum ether is added and stirred for 0.5~1 hour; the filter cake is dried at 45~50℃ to obtain the final product.

[0016] Furthermore, in steps (1) and (3), the solvent used is at least one of ethyl acetate, THF, dichloromethane, and acetone.

[0017] The advantages and positive effects of this invention are as follows: The novel synthetic method for naphthylazine provided by this invention is simple to operate, easy to implement, and operates under mild reaction conditions, avoiding the use of hazardous reagents and high-temperature, high-pressure equipment. The entire process is safe and environmentally friendly. The purity of the final product, naphthylazine, can reach 99.6%. Attached Figure Description

[0018] Figure 1 It is the 5,8-dihydroxy-2,3-dihydronaphthalene-1,4-dione obtained in the examples. 1 H-NMR spectrum; Figure 2 It is the final product obtained from the examples. 1 H-NMR spectrum; Figure 3 This is the HPLC chromatogram of the final product obtained in the examples. Detailed Implementation

[0019] To further illustrate the content and features of the present invention, the following description is provided in conjunction with embodiments.

[0020] Example 1 A novel method for synthesizing naphthylazine, the process of which is as follows: (1) Preparation of 5,8-dihydroxy-2,3-dihydronaphthalene-1,4-dione: Method 1: Add 5 L of dichloromethane (DCM) to a 10 L reactor, add 600 g (2.4 mol) of 1,4,5,8-tetramethoxynaphthalene, rinse with 1 L of DCM, and purge with nitrogen three times. Cool to 0°C, add 1.5 kg (6 mol) of boron tribromide, and react at 0°C for 1 hour. The intermediate content should be ≤0.5% as controlled by the system. Pour the reaction solution into 9 L of ice water, stir for 0.5 h, remove DCM under reduced pressure and recover DCM, filter, dry the filter cake at 50°C, and dissolve it in 600 mL of MeOH / EA (ethyl acetate) = 1 / 2 (volume ratio). After dissolution, pour the solution into 1.8 L of EA / PE (petroleum ether) = 1 / 5 (volume ratio), filter, and concentrate the filtrate to obtain 300 g of pale yellow solid. 1 H-NMR spectrum as follows Figure 1 As shown, 1 H-NMR (400 MHz, DMSO- d 6): 11.92 (s, 2H), 7.26 (s, 2H), 3.02 (s, 4H). Yield: 65%, Purity: ≥93.0%. Method 2: Add 2 L of DCM to a 5 L reactor, add 100 g (0.4 mol) of 1,4,5,8-tetramethoxynaphthalene, rinse with 100 mL of DCM, and purge with nitrogen three times. Cool to 0°C, add 161 g of aluminum trichloride (1.2 mol), and react at 20-25°C for 16 hours. The intermediate content should be ≤0.5% as monitored. Pour the reaction solution into 5 L of ice water, stir for 0.5 h, remove DCM under reduced pressure and recover DCM, filter, dry the filter cake at 50°C, dissolve in 100 mL of MeOH / EA = 1 / 2 (volume ratio), pour into 1 L of EA / PE = 1 / 5 (volume ratio), filter, and concentrate the filtrate to obtain 60 g of pale yellow solid. Yield: 70%, purity: ≥90%.

[0021] (2) Preparation of naphthalene: A 3L stainless steel reactor was equipped with a mechanical stirrer, an oxygen inlet, a thermometer, and a pressure gauge; 0.5 L of water was added to the reactor, stirring was started, and 116.7 g (2.0 mol) of KOH was added and dissolved until no solid residue remained; 50.0 g of KOH was slowly added. (0.26 mol) 5,8-dihydroxy-2,3-dihydronaphthyl-1,4-dione, controlling the feeding rate to avoid agglomeration; close the reactor, introduce oxygen to a pressure of 0.05 MPa, maintain for 5 minutes and then vent, repeat 3 times; stir for 5 hours at 25-30℃ under a slight positive pressure of oxygen (0.03-0.05 MPa), and monitor with HPLC until 5,8-dihydroxy-2,3-dihydronaphthyl-1,4-dione ≤1.0%; slowly add the reaction solution to 1.5 L of ethanol, controlling the addition rate to avoid local overconcentration; filter using a Buchner funnel, wash the filter cake with 50 mL of ethanol, and dry under vacuum at 45-50℃ to obtain 63.4 g of blue solid (yield 91.5%).

[0022] (3) A 2L glass reaction flask is equipped with a mechanical stirrer, a thermometer, and a dropping funnel; 63.4g (0.238mol) of blue solid and 0.5L of ethyl acetate are added to the reaction flask; the temperature of the reaction solution is lowered to 10-15℃ using an ice bath; 325mL of 2M HCl-ethyl acetate solution is slowly added dropwise, controlling the dropping rate to avoid a sudden temperature rise; after the addition is complete, the temperature is raised to 35-40℃ and stirred for 1 hour; the mixture is filtered using a glass frit funnel, and the filter cake is washed with 100mL of ethyl acetate; the filtrate is concentrated to one-third of its volume by rotary evaporation at 40-45℃; 150mL of petroleum ether is added, and the mixture is stirred for 0.5-1 hour; the mixture is filtered using a Buchner funnel, and the filter cake is vacuum dried at 45-50℃ to obtain 31.5g of dark red solid. The HPLC chromatogram is shown below. Figure 3 As shown, the purity is 99.1% and the yield is 63.7%. 1 H-NMR spectrum as follows Figure 2 As shown, 1H-NMR (400 MHz, CDCl3): 12.40 (s, 2H), 7.14 (s, 4H).

[0023] Its LCMS (ESI) plot shows: m / z 191.0 [M+H] + .

[0024] The above embodiments are merely illustrative of the present invention and are not intended to limit the scope of the present invention. All equivalent implementations of the present invention should be included within the scope of the claims of the present invention.

Claims

1. A novel method for synthesizing naphthylazine, characterized in that, The synthesis route is as follows: The specific synthesis process is as follows: (1) Add solvent to the reaction vessel, start stirring, add 1,4,5,8-tetramethoxynaphthalene, stir until completely dissolved, cool to 0~5℃, add boron tribromide or aluminum trichloride to react, and after the reaction is complete, obtain the high-purity product 5,8-dihydroxy-2,3-dihydronaphthalene-1,4-dione by crystallization. (2) Add the 5,8-dihydroxy-2,3-dihydronaphthyl-1,4-dione, water and KOH obtained in step (1) to another reaction vessel, dissolve until there is no solid residue, stir under slight positive pressure with oxygen until the reaction is complete, and after the reaction is complete, obtain high-purity 5,8-dihydroxypotassium-1,4-naphthoquinone by ethanol crystallization and filtration. (3) Add 5,8-dihydroxypotassium-1,4-naphthoquinone and solvent to another reaction vessel, add ethyl acetate hydrochloride solution, stir at 35~40℃ until the reaction is complete, and obtain high-purity naphthoquinone by filtration and pulping.

2. The novel synthetic method of naphthylazine according to claim 1, characterized in that, In step (1), the molar ratio of 1,4,5,8-tetramethoxynaphthalene to boron tribromide is 1:(2~3), and the reaction temperature of 1,4,5,8-tetramethoxynaphthalene with boron tribromide is 0~5℃; the molar ratio of 1,4,5,8-tetramethoxynaphthalene to aluminum trichloride is 1:(2~4), and the reaction temperature of 1,4,5,8-tetramethoxynaphthalene with aluminum trichloride is 20~30℃.

3. The novel synthetic method of naphthylazine according to claim 1, characterized in that, In step (2), the molar ratio of 5,8-dihydroxy-2,3-dihydronaphthalene-1,4-dione to KOH is 1:(7~9).

4. The novel synthetic method of naphthylazine according to claim 1, characterized in that, In step (2), the pressure of the oxygen micro-positive pressure is 0.01~0.03MPa, and the temperature of the oxygen micro-positive pressure reaction is 20~40℃.

5. The novel synthetic method of naphthylazine according to claim 1, characterized in that, In step (3), the molar ratio of 5,8-dihydroxypotassium-1,4-naphthoquinone to hydrochloric acid in the ethyl hydrochloride solution is 1:(2~4), the molar concentration of hydrochloric acid in the ethyl hydrochloride solution is 1~3 mol / L, and the temperature is controlled at 10~15℃ when adding the ethyl hydrochloride solution.

6. The novel synthetic method of naphthylazine according to claim 1, characterized in that, In step (1), after the reaction is complete, the reaction solution is poured into ice water and stirred for 20-40 minutes. The solvent is removed under reduced pressure, filtered, and the filter cake is dried at 40-60°C. After drying, it is dissolved in a mixed solvent of MeOH and ethyl acetate in a volume ratio of 1:(1-3). After dissolution, it is poured into a mixed solvent of ethyl acetate and petroleum ether in a volume ratio of 1:(4-6), filtered, and the filtrate is concentrated to obtain the final product.

7. The novel synthetic method of naphthylazine according to claim 1, characterized in that, In step (2), after the reaction is complete, add 2 to 4 times the volume of ethanol to the reaction solution, filter, wash the filter cake with ethanol, and dry at 45 to 50°C to obtain the final product.

8. The novel synthetic method of naphthylazine according to claim 1, characterized in that, In step (3), the reaction solution is filtered, and the filter cake is washed with ethyl acetate; the filtrate is concentrated to 1 / 2 to 2 / 3 of its original volume by rotary evaporation at 40~45℃; petroleum ether is added and stirred for 0.5~1 hour; the filter cake is dried at 45~50℃ to obtain the final product.

9. The novel synthetic method of naphthylazine according to claim 1, characterized in that, In steps (1) and (3), the solvent used is at least one of ethyl acetate, THF, dichloromethane and acetone.

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