Preparation method of azulene sulfonamide

Abstract

The invention provides a method for preparing azulene sulfonamide, which comprises the following steps: reacting sodium gualenate with concentrated sulfuric acid to generate azulene sulfonic acid, and reacting with phosphorus pentoxide to generate azulene sulfonic anhydride; the preparation method comprises the following steps: protecting p-phenylenediamine by BOC, then carrying out amidation reaction on p-phenylenediamine and azulene sulfonic anhydride, and adding 4-dimethylaminopyridine as a catalyst; and finally, removing a BOC protecting group by using trifluoroacetic acid, and purifying by column chromatography to obtain azulene sulfonamide. The method avoids the use of azulene sulfonyl chloride with high activity, reduces side reactions, improves the purity and yield of the product, and has the advantages of simplicity and convenience in operation, mild conditions and high yield.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical preparations, in particular to a method for preparing azulenesulfonamide by sodium azulenesulfonate. Background Art

[0002] Azulenesulfonamide, a compound derived from sodium azulenesulfonate, has a wide range of application potentials in the medical field. Its unique chemical structure gives it a variety of biological activities, including significant anti-inflammatory, antibacterial, antioxidant and anti-tumor effects. In the field of anti-inflammatory, azulenesulfonamide can effectively relieve inflammatory responses and fight inflammatory diseases; its antibacterial properties help treat infections caused by bacteria; at the same time, the antioxidant ability of azulenesulfonamide has a positive effect on removing excess free radicals in the body and protecting cells from oxidative damage; more noteworthy is its application prospects in the field of anti-cancer, showing a significant inhibitory effect on tumor cells.

[0003] However, despite the huge medical value of azulenesulfonamide, its synthesis process faces a series of technical challenges. CN111362844B describes a synthetic method of azulenesulfonamide, first reacting sodium azulenesulfonate with thionyl chloride in an organic solvent to generate an intermediate, then performing an amidation reaction with p-phenylenediamine protected with Boc anhydride to form protected azulenesulfonamide, and finally removing the Boc protecting group by trifluoroacetic acid to obtain the target product azulenesulfonamide. Although this method improves the yield, harmful reagents are used and the by-product treatment is complicated. For example, this method uses thionyl chloride as a key intermediate, and the reaction activity of this substance is high, and strict requirements are placed on equipment and operating conditions, which increases the complexity and cost in the production process. The intermediate azulenesulfonyl chloride obtained is also prone to decomposition during the amidation process, so that there are more by-products, which not only affects the yield and purity of azulenesulfonamide, but also makes the purification process of the product complicated and inefficient. And traditional purification techniques, such as repeated extraction and crystallization, are often time-consuming and labor-intensive, and it is difficult to achieve large-scale production. At the same time, these processes may also produce a large amount of chemical waste, causing secondary pollution to the environment.

[0004] Therefore, the existing synthesis of azulenesulfonamide faces technical problems such as harsh reaction conditions and many by-products. It is urgent to develop a method for synthesizing azulenesulfonamide with milder reaction conditions and higher purity of the target product to solve the problems existing in the prior art. Summary of the invention

[0005] In order to solve the problems in the prior art, the present invention reduces the generation of by-products and improves the yield and selectivity of the reaction by anhydriding sodium azulenesulfonate and using azulenesulfonic anhydride and protected p-phenylenediamine to carry out an amidation reaction in an organic solvent under mild conditions under the action of a specific catalyst.

[0006] The specific plan is as follows:

[0007] The present invention provides a method for preparing azulenesulfonamide, comprising the following steps:

[0008] a. reacting sodium azulenesulfonate with concentrated sulfuric acid in an organic solvent at 0-5°C to produce azulenesulfonic acid, then adding phosphorus pentoxide to the reactant, and continuing the reaction for 5-20 min to obtain azulenesulfonic anhydride;

[0009] b. dissolving p-phenylenediamine in a dry organic solvent, and adding Boc anhydride at 0-5°C, separating unreacted Boc anhydride and by-products by filtration or extraction to obtain Boc-protected p-phenylenediamine;

[0010] c. mixing azulenesulfonic anhydride and Boc-protected p-phenylenediamine in an organic solvent, adding 4-dimethylaminopyridine as a catalyst, and performing an amidation reaction;

[0011] d. adding trifluoroacetic acid to the reaction solution obtained in step c, reacting, and stirring at room temperature until the protecting group Boc is removed to form azulene sulfonamide;

[0012] e. Purify azulenesulfonamide by column chromatography using an eluent, collect fractions of the target compound, and dry them to obtain pure azulenesulfonamide.

[0013] In one embodiment, the molar ratio of sodium azulene sulfonate to concentrated sulfuric acid is 1:1 to 1:5, and the concentrated sulfuric acid is 75 wt % or more sulfuric acid.

[0014] In one embodiment, the molar ratio of sodium azulene sulfonate to phosphorus pentoxide is 1:1 to 1:2, wherein the water content of the phosphorus pentoxide is less than 0.5 wt %.

[0015] In one of the schemes, the amidation reaction in step c is carried out at room temperature with low-speed stirring of 50-100 rpm, and the reaction time is 2-8 hours.

[0016] In one embodiment, the organic solvent in step a, step b and step c is selected from dichloromethane, ethyl acetate or a mixture thereof.

[0017] In one embodiment, the amount of 4-dimethylaminopyridine used is 0.5 to 2.0 wt % based on the total weight of the amidation reaction mixture.

[0018] In one of the schemes, the molar ratio of the Boc-protected p-phenylenediamine to sodium azulene sulfonate in step c is 1:1 to 3:1.

[0019] In one embodiment, the amount of trifluoroacetic acid used is 1.1 to 1.5 times the molar amount of the protecting group Boc on the reactant obtained in step c.

[0020] In one embodiment, the eluent used for column chromatography purification in step e is a mixture of ethyl acetate and petroleum ether in a volume ratio of 4:1 to 2:1.

[0021] In one embodiment, the drying treatment in step e is carried out at a vacuum degree of 10 mmHg and a temperature range of room temperature to 60° C. for 2-10 hours.

[0022] Based on the above scheme, the present invention has the following beneficial effects:

[0023] First, by converting sodium azulenesulfonate into an azulenesulfonic anhydride intermediate, the method avoids the use of azulenesulfonyl chloride, which is too active and difficult to control, thereby reducing the possibility of side reactions and improving the selectivity of the reaction and the purity of the product. The stability and low reactivity of azulenesulfonic anhydride make it easier to react with p-phenylenediamine under mild conditions, thereby improving the synthesis efficiency and product quality.

[0024] Secondly, the present invention introduces 4-dimethylaminopyridine as a catalyst for the amidation reaction. When azulenesulfonic anhydride is used as a reaction intermediate, the activation energy required for the reaction can be significantly reduced, the reaction rate is accelerated, and the entire synthesis process is more efficient. The defect of insufficient reaction activity brought about by azulenesulfonic anhydride as an intermediate is made up. In addition, 4-dimethylaminopyridine is easily separated from the product and reused, thereby improving the utilization rate of the catalyst.

[0025] Finally, through the Boc protection of the p-phenylenediamine group and the subsequent deprotection step, the reaction selectivity was finely controlled to ensure that the specific functional groups of the target molecule were not affected by the side reactions, effectively avoiding unnecessary reactions of p-phenylenediamine in the amidation reaction, thereby increasing the yield of the target product. Mild reaction conditions also help maintain the stability of the reaction system, reduce the requirements for the environment and equipment, and make the entire synthesis process safer and more economical. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 The present invention is a synthetic route diagram of azulenesulfonamide. DETAILED DESCRIPTION

[0027] Although the present invention has been described to a certain extent, it is obvious that appropriate changes in various conditions can be made without departing from the spirit and scope of the present invention. It is understood that the present invention is not limited to the embodiments described, but belongs to the scope of the claims, which includes equivalent replacements of each factor described.

[0028] The synthetic route of azulenesulfonamide of the present invention is as follows Figure 1As shown, first, sodium azulenesulfonate and concentrated sulfuric acid are reacted in an organic solvent at 0-5°C to generate azulenesulfonic acid, and then phosphorus pentoxide is added to continue the reaction for 5-20 minutes to obtain azulenesulfonic anhydride; then, p-phenylenediamine is dissolved in a dry organic solvent, Boc anhydride is added at 0-5°C, and unreacted Boc anhydride and by-products are separated by filtration or extraction to obtain Boc-protected p-phenylenediamine; then, azulenesulfonic anhydride and Boc-protected p-phenylenediamine are mixed in an organic solvent, and 4-dimethylaminopyridine is added as a catalyst to perform an amidation reaction; next, trifluoroacetic acid is added to the reactant solution, and the reaction is stirred at room temperature until the protecting group Boc is removed to form azulenesulfonamide; finally, azulenesulfonamide is purified by column chromatography using an eluent, and the fractions of the target compound are collected and dried to obtain pure azulenesulfonamide.

[0029] In the azulenesulfonamide synthesis method of the present invention, the formation of azulenesulfonic anhydride is a key step, and strict control must be performed during the process to avoid the introduction of moisture. The presence of moisture may cause side reactions, affect the yield and purity of azulenesulfonic anhydride, and then affect the quality of the final product azulenesulfonamide. Therefore, all solvents and reagents used in the reaction process should be dry, and the reaction should be carried out under anhydrous conditions.

[0030] In the preparation process of azulenesulfonic anhydride, sodium azulenesulfonate is first reacted with concentrated sulfuric acid at 0-5°C to generate azulenesulfonic acid. In this step, the molar ratio of sodium azulenesulfonate to concentrated sulfuric acid is controlled between 1:1 and 1:5, and the concentration of concentrated sulfuric acid used should be above 75wt%. Excessive sulfuric acid can ensure that sodium azulenesulfonate is completely reacted, but at the same time, the ratio needs to be controlled to avoid excessive sulfuric acid affecting subsequent reactions and the purity of the product.

[0031] Subsequently, phosphorus pentoxide is added to the reactants to generate azulene sulfonic anhydride, and the duration of this step is about 5-20 minutes. The molar ratio of sodium azulene sulfonate to phosphorus pentoxide should be controlled between 1:1 and 1:2, and the water content of phosphorus pentoxide should be less than 0.5wt%. Phosphorus pentoxide is used as a dehydrating agent, and the control of its water content is crucial for the smooth progress of the reaction, because the introduction of water will cause the hydrolysis of azulene sulfonic anhydride, thereby reducing the purity of the product.

[0032] The Boc anhydride (di-tert-butyl dicarbonate) of the present invention has the chemical formula C 10 H 18O5 is a protective agent widely used in organic synthesis, which can react with a variety of nucleophilic reagents, including amines, phenols, thiols and carboxylic acids, to form corresponding Boc protected compounds. In the present invention, Boc anhydride is used to react with one end of p-phenylenediamine to obtain Boc protected p-phenylenediamine, so the molar ratio of p-phenylenediamine to Boc anhydride in step b is controlled at 1:1, ensuring that one end of p-phenylenediamine is protected and the other end participates in the subsequent amidation reaction. The Boc protecting group can be removed under mild conditions by using an acidic substance such as trifluoroacetic acid. In the present invention, Boc is also removed under mild conditions by trifluoroacetic acid after the amidation reaction is completed.

[0033] Regarding the Boc-protection of p-phenylenediamine, as described in the preparation of compound 2 in the specification of CN111362844B, it will not be described in detail here. Since azulenesulfonic anhydride with a catalyst is used, the amidation conversion rate is higher and the selectivity is better. Therefore, the amount of Boc-protected p-phenylenediamine used in step c is generally excessive compared to the raw material sodium azulenesulfonate, and the molar ratio is 1:1 to 3:1, preferably 1:1 to 1.5:1.

[0034] The catalyst 4-dimethylaminopyridine (DMAP) of the amidation reaction of the present invention has a molecular formula of C7H 10 N2 can promote nucleophilic substitution reactions and significantly catalyze the acylation / esterification reactions of alcohols and amines / acids with high steric hindrance and low reactivity. This is due to the resonance between the electron-donating dimethylamino group and the parent ring (pyridine ring) in its structure, which strongly activates the nitrogen atom on the ring for nucleophilic substitution, and has a catalytic activity that is more than 100 times higher than that of traditional pyridine catalysts. The present invention uses DMAP for catalysis, so that the azulenesulfonic anhydride, which has a lower activity than azulenesulfonyl chloride, can improve the reaction yield under mild reaction conditions, and highly selectively carry out the amidation reaction, reducing the generation of by-products, thereby facilitating the efficient formation of the target product azulenesulfonamide with higher purity. The amount of DMAP used is 0.5 to 2.0wt% of the total weight of the amidation reaction mixture, and more preferably 0.8-1.2wt%.

[0035] The eluent used in step e is based on the polarity difference between the target product and the by-product, and a mixture of ethyl acetate and petroleum ether with a volume ratio of 4:1 to 2:1 is selected. Within this ratio range, the elution effect can be optimized to ensure the effective separation of the target compound while reducing the interference of the by-product. The higher polarity of ethyl acetate helps to elute the by-products with greater polarity, while the low polarity of petroleum ether can effectively elute non-polar or weakly polar compounds. In order to prevent the occurrence of side reactions in the azulene sulfonamide during the purification stage, it is preferably dried for 2-10 hours under a vacuum degree of 10 mmHg and a temperature range of room temperature to 60°C under mild conditions.

[0036] The following is a detailed description of the azulenesulfonamide synthesis method provided by the present invention in conjunction with the examples, but they should not be construed as limiting the scope of protection of the present invention. In addition, if no specific conditions are specified in the examples of the present invention, the process is carried out according to conventional conditions or conditions recommended by the manufacturer; if the manufacturer of the reagents or instruments is not specified, they are all conventional products that can be purchased commercially.

[0037] Preparation of Boc-protected p-phenylenediamine (homemade):

[0038] Add 10.39 g of p-phenylenediamine, 62.88 g of BOC anhydride and 200 mL of dichloromethane into a 500 mL flask, stir at 25 ° C for 10 h, monitor the reaction by TLC, add 50 mL of 2 mol / L hydrochloric acid to wash three times, take the water layer, add 100 mL of dichloromethane to the aqueous phase, adjust the pH value of the solution to 8 with 2 mol / L NaOH solution, take the organic layer, and concentrate under reduced pressure to recover dichloromethane to obtain pure Boc-protected p-phenylenediamine.

[0039] Embodiment 1:

[0040] 30 g (0.1 mol) of sodium azulenesulfonate and 36.78 g (0.3 mol) of 80 wt% concentrated sulfuric acid were placed in 200 ml of dichloromethane solvent and ice-bathed at 0°C for 20 minutes, and then 42.3 g (0.15 mol) of phosphorus pentoxide was added to the reactants and the reaction was continued for 10 minutes to obtain azulenesulfonic anhydride. (theoretical 25.6 g, 0.05 mol);

[0041] 20.8 g (0.1 mol) of Boc-protected p-phenylenediamine and the reactant azulenesulfonic anhydride were mixed in dichloromethane solvent, 0.46 g of DMAP was added as a catalyst, and amidation reaction was carried out at room temperature with low-speed stirring at 60 rpm for 5 h; 13.69 g (0.12 mol) of trifluoroacetic acid was added to the obtained reactant solution, and stirred at room temperature for 1 h until the protecting group Boc was removed;

[0042] After the dichloromethane solvent was recovered under reduced pressure, a solid substance was obtained, and a mixture of ethyl acetate and petroleum ether in a volume ratio of 3:1 was selected for column chromatography purification, and dried at room temperature for 5 hours under a vacuum degree of 10 mmHg to obtain 30.89 g (0.089 mol, i.e., a yield of 89%) of a blue final product, azulenesulfonamide.

[0043] Example 2

[0044] 30 g (0.1 mol) of sodium azulenesulfonate and 61.3 g (0.5 mol) of 80 wt% concentrated sulfuric acid were placed in 300 ml of dichloromethane solvent and placed in an ice bath at 0°C for 10 minutes. Then 56.4 g (0.2 mol) of phosphorus pentoxide was added to the reactants and the reaction was continued for 20 minutes to obtain azulenesulfonic anhydride. (theoretical 25.6 g, 0.05 mol);

[0045] 62.4 (0.3 mol) of Boc-protected p-phenylenediamine and the reactant azulenesulfonic anhydride were mixed in dichloromethane solvent, 1.76 g of DMAP was added as a catalyst, and amidation reaction was carried out at room temperature with low-speed stirring at 50 rpm for 2 h; 11.41 g (0.1 mol) of trifluoroacetic acid was added to the obtained reactant solution, and stirred at room temperature for 1 h until the protecting group Boc was removed;

[0046] After the dichloromethane solvent was recovered under reduced pressure, a solid substance was obtained, and a mixture of ethyl acetate and petroleum ether in a volume ratio of 4:1 was selected for column chromatography purification, and dried at 60° C. for 2 h under a vacuum degree of 10 mmHg to obtain a blue final product, azulenesulfonamide 28.11 (0.081 mol, i.e., a yield of 81%).

[0047] Example 3

[0048] 30 g (0.1 mol) of sodium azulenesulfonate and 12.26 g (0.1 mol) of 80 wt% concentrated sulfuric acid were reacted in 200 ml of dichloromethane solvent at 0°C in an ice bath for 20 minutes, and then 28.2 g (0.1 mol) of phosphorus pentoxide was added to the reactant and the reaction was continued for 5 minutes to obtain azulenesulfonic anhydride. (theoretical 25.6 g, 0.05 mol);

[0049] 20.8 g (0.1 mol) of Boc-protected p-phenylenediamine and the reactant azulenesulfonic anhydride were mixed in dichloromethane solvent, 0.24 g of DMAP was added as a catalyst, and amidation reaction was carried out at room temperature with low-speed stirring at 100 rpm for 8 h; 17.11 g (0.15 mol) of trifluoroacetic acid was added to the obtained reactant solution, and stirred at room temperature for 1.55 h until the protecting group Boc was removed;

[0050] After the dichloromethane solvent was recovered under reduced pressure, a solid substance was obtained, and a mixture of ethyl acetate and petroleum ether in a volume ratio of 2:1 was selected for column chromatography purification, and dried at room temperature for 8 hours under a vacuum degree of 10 mmHg to obtain 29.50 g (0.085 mol, i.e., a yield of 85%) of a blue final product, azulenesulfonamide.

[0051] Comparative Example 1 is Example 1 of CN111362844B, specifically:

[0052] A method for synthesizing azulenesulfonamide comprises: step 1, wherein the molar ratio of sodium azulenesulfonate to thionyl chloride is 1:1; sodium azulenesulfonate (12 g, 0.04 mol) and thionyl chloride (2.9 mL, 0.04 mol) are added to a flask containing 50 mL of dichloromethane solvent, and reacted for 2 h under an ice bath condition of 0° C. to obtain a solution containing compound 1;

[0053] Step 2, the molar ratio of the compound 2 to the sodium azulene sulfonate is 1:1; 0.04 mol of the compound 2 is added to the dichloromethane solution containing the compound 1. After reacting for 8 h, a solution containing compound 3 was obtained;

[0054] Step 3, the molar ratio of sodium azulenesulfonate to trifluoroacetic acid is 1:1; 0.04 mol of trifluoroacetic acid is added to the solution of compound 3 and the reaction is carried out for 1 hour, and the dichloromethane solvent is recovered under reduced pressure. After column chromatography separation in a solvent with a volume ratio of V ethyl acetate: V petroleum ether = 3:1, a blue final product compound 4, i.e., azulenesulfonamide, is obtained, and the yield of compound 4 is 64%.

[0055] Instruments and reagents

[0056] Examples 1-3 and Comparative Example 1 all used the following instruments and reagents:

[0057] UV-210A ultraviolet spectrophotometer; silica gel GF254 high-efficiency plate (Yantai Jiangyou Silica Gel Development Co., Ltd.), and other reagents were of analytical grade.

[0058] Experimental verification

[0059] (1) Melting point test

[0060] Melting point determination was performed using a SGW-4 microscopic melting point apparatus produced by Shanghai Precision Scientific Instrument Co., Ltd., according to the prior art standards, and the melting points of the final products obtained from experimental groups 1 to 3 and control group 1 of the present invention were tested. The test results are detailed in Table 1:

[0061]

[0062]

[0063] (2) 1 H-NMR test

[0064] The experimental groups 1 to 3 and the control group 1 of the present invention were analyzed by using an Agilent-400 (frequency 400 MHz) nuclear magnetic resonance spectrometer with internal standard tetramethylsilane (TMS) and solvent deuterated dimethyl sulfoxide (DMSO-d6). 1 H-NMR analysis, the analysis results are shown in Table 2:

[0065]

[0066] Here 1.31 (d, J = 6.4 Hz, 6H): indicates that there is a doublet (d) at 1.31 ppm, the coupling constant (J) is 6.4 Hz, and the integral curve indicates that there are 6 hydrogen atoms. 2.49 (s, 3H): indicates that there is a singlet (s) at 2.49 ppm, and the integral curve indicates that there are 3 hydrogen atoms. 3.17 (q, J = 6.8 Hz, 1H): indicates that there is a quartet (q) at 3.17 ppm, the coupling constant is 6.8 Hz, and the integral curve indicates that there is 1 hydrogen atom. 3.30 (s, 3H): indicates that there is a singlet (s) at 3.30 ppm, and the integral curve indicates that there are 3 hydrogen atoms. 4.84 (s, 2H, NH2): indicates that there is a singlet (s) at 4.84 ppm, and the integral curve indicates that there are 2 hydrogen atoms, which belong to the amino group (NH2). 6.37 (d, J = 8.0 Hz, 2H, PhH): Indicates that there is a doublet (d) at 6.37 ppm, the coupling constant is 8.0 Hz, and the integral curve indicates that there are 2 hydrogen atoms, which belong to the benzene ring (PhH). 6.78 (d, J = 8.0 Hz, 2H, PhH): Similar to the previous one, it is also a hydrogen atom on the benzene ring. 7.44 (d, J = 10.8 Hz, 1H): Indicates that there is a doublet at 7.44 ppm, the coupling constant is 10.8 Hz, and the integral curve indicates that there is 1 hydrogen atom. 7.73 (d, J = 10.4 Hz, 1H): Indicates that there is a doublet at 7.73 ppm, the coupling constant is 10.4 Hz, and the integral curve indicates that there is 1 hydrogen atom. 7.92 (s, 1H): Indicates that there is a singlet at 7.92 ppm, and the integral curve indicates that there is 1 hydrogen atom. 8.30 (s, 1H): There is a single peak at 8.30 ppm, and the integral curve shows that there is one hydrogen atom, which corresponds to the structure of the target product azulenesulfonamide.

[0067] (3) Mass spectrometry test

[0068] The mass spectra of Examples 1-3 of the present invention and Comparative Example 1 were performed using an LCQ ADVANTAGE MAX mass spectrometer. The analysis results are detailed in Table 3:

[0069] sample Solvents <![CDATA[ 1 H-NMR]]> Example 1 Methanol (chromatographic grade) <![CDATA[369.49[M+H] + ]]> Example 2 Methanol (chromatographic grade) <![CDATA[369.49[M+H] + ]]> Example 3 Methanol (chromatographic grade) <![CDATA[369.49[M+H] + ]]> Comparative Example 1 Methanol (chromatographic grade) <![CDATA[369.49[M+H] + ]]>

[0070] It can be seen that Examples 1-3 of the present invention can also obtain the target product azulenesulfonamide, and have a higher yield than Comparative Example 1, and the reaction conditions are milder and more efficient.

[0071] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present application, rather than to limit it. Although the present application has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present application.

Claims

1. A method for preparing azulenesulfonamide, characterized in that: The following steps are involved: a. reacting sodium azulenesulfonate with concentrated sulfuric acid in an organic solvent at 0-5°C to produce azulenesulfonic acid, then adding phosphorus pentoxide to the reactant, and continuing the reaction for 5-20 min to obtain azulenesulfonic anhydride; b. dissolving p-phenylenediamine in a dry organic solvent, and adding Boc anhydride at 0-5°C, separating unreacted Boc anhydride and by-products by filtration or extraction to obtain Boc-protected p-phenylenediamine; c. mixing azulenesulfonic anhydride and Boc-protected p-phenylenediamine in an organic solvent, adding 4-dimethylaminopyridine as a catalyst, and performing an amidation reaction; d. adding trifluoroacetic acid to the reaction solution obtained in step c, reacting, and stirring at room temperature until the protecting group Boc is removed to form azulene sulfonamide; e. Purify azulenesulfonamide by column chromatography using an eluent, collect fractions of the target compound, and dry them to obtain pure azulenesulfonamide.

2. The method for preparing azulenesulfonamide according to claim 1, characterized in that: The molar ratio of the sodium azulene sulfonate to the concentrated sulfuric acid is 1:1 to 1:5, and the concentrated sulfuric acid is more than 75 wt % sulfuric acid.

3. The method for preparing azulenesulfonamide according to claim 1, characterized in that: The molar ratio of the sodium azulene sulfonate to the phosphorus pentoxide is 1:1 to 1:2, wherein the water content of the phosphorus pentoxide is less than 0.5 wt %.

4. The method for preparing azulenesulfonamide according to claim 1, characterized in that: The amidation reaction in step c is carried out at room temperature with low-speed stirring at 50-100 rpm, and the reaction time is 2-8 hours.

5. The method for preparing azulenesulfonamide according to claim 1, characterized in that: The organic solvents in step a, step b and step c are all selected from dichloromethane, ethyl acetate or a mixture thereof.

6. The method for preparing azulenesulfonamide according to claim 1, characterized in that: The amount of 4-dimethylaminopyridine used is 0.5 to 2.0 wt % based on the total weight of the amidation reaction mixture.

7. The method for preparing azulenesulfonamide according to claim 1, characterized in that: In step c, the molar ratio of the Boc-protected p-phenylenediamine to the sodium azulene sulfonate is 1:1 to 3:

1.

8. The method for preparing azulenesulfonamide according to claim 1, characterized in that: The amount of trifluoroacetic acid used is 1.1 to 1.5 times the molar amount of the protecting group Boc on the reactant obtained in step c.

9. The method for preparing azulenesulfonamide according to claim 1, characterized in that: The eluent used for column chromatography purification in step e is a mixture of ethyl acetate and petroleum ether in a volume ratio of 4:1 to 2:

1.

10. The method for preparing azulenesulfonamide according to claim 1, characterized in that: The drying treatment in step e is carried out at a vacuum degree of 10 mmHg and a temperature range of room temperature to 60° C. for 2-10 hours.

Images