Preparation method and application of sodium gualenate impurity
Through the reaction of guaifene oil hydrocarbons with bromination reagents and sulfonating agents, combined with alkali hydrolysis, a high-purity impurity compound of formula 1 was prepared, which solved the problem of inaccurate detection in the prior art and achieved sodium hyaluronic acid Accurate quantity detection of impurities in the preparation improves the quality and safety of the preparation.
Patent Information
- Application Number
- CN202310772273.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2023-06-27
- Publication Date
- 2024-12-27
AI Technical Summary
The prior art cannot accurately detect degraded impurities in sodium oxysulfonate tablets and sodium oxysulfonate compound particles, affecting the quality control of the preparation, and lacking high-purity impurity control products, resulting in inaccurate detection.
The guaiac oil hydrocarbon is reacted with bromination reagent, and then reacted with a sulfonating agent and a base to obtain a high-purity compound of impurity formula 1 by hydrolysis, and purified by silica gel chromatography to prepare impurity formula 1 with a content of nearly 98%. The compounds are used as reference materials for more accurate qualitative and quantitative detection.
By preparing high-purity impurity compound 1, the content of impurities in sodium oxysulfonate preparation can be effectively reduced, the quality of the preparation can be improved, more accurate quality control can be ensured, and the safety hazards of impurities can be reduced.
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Figure CN119192038A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the field of drug analysis, and particularly relates to a method for preparing sodium azulene sulfonate impurities and uses thereof. Background Art
[0002] Sodium azulene sulfonate is the active ingredient of chamomile flowers, also known as chamomile blue. It inhibits the release of histamine from inflammatory cells through local direct action; increases the synthesis of prostaglandin E2 in the mucosa, promotes granulation and epithelial cell regeneration; and reduces the activity of pepsin, thereby achieving strong anti-pepsin, anti-inflammatory, antibacterial, anti-allergic, and mucosal metabolism-promoting effects.
[0003] Sodium azulene sulfonate tablets are an anti-inflammatory and anti-ulcer drug developed by Nippon Shinyaku Co., Ltd. and launched in Japan in 1960. After its launch in Japan, it has not yet been launched in the United States and the European Union. In China, only sodium azulene sulfonate and its compound granules with L-glutamine, namely L-glutamine sodium guarenate granules, are available. The National Drug Administration's imported drug registration standard, standard number: JX20190025, contains a variety of impurities that need to be controlled in this compound preparation, including impurities with a chemical structure shown in Formula 1.
[0004]
[0005] The generation of this impurity was not found in the stability investigation of sodium azulene sulfonate raw material, but this impurity was found in the stability sampling process of sodium azulene sulfonate tablets and sodium glutamine azulene sulfonate compound granules, so impurity formula 1 is classified as degradation impurity. Degradation impurities have great hidden dangers to the safety of medication, and need to be studied in the quality control of preparations. However, at present, impurity formula 1 is mostly detected by liquid phase area normalization method due to the lack of reference substances, and the detection is not accurate enough, which affects the quality control of sodium azulene sulfonate preparations. It is necessary to study and develop a preparation method of high-purity impurity formula 1, and obtain purity that meets the requirements of reference substances, so that the impurity formula 1 in sodium azulene sulfonate tablets and sodium glutamine azulene sulfonate compound granules can be more accurately detected qualitatively and quantitatively, which is convenient for the control of impurity formula 1 in sodium azulene sulfonate preparations and improves product quality. Summary of the invention
[0006] To solve the above problems, the present invention provides a method for preparing a compound represented by Formula 1, which comprises the following steps:
[0007]
[0008] Step a, preparation of compound (i): guaiacyl oil reacts with a bromination reagent in a solvent to obtain compound (i);
[0009] Step b, preparation of compound (ii): compound (i) reacts with a sulfonating agent in a solvent to obtain compound (ii);
[0010] Step c, preparation of the compound of formula 1: Compound (ii) undergoes hydrolysis reaction with a base in a solvent to obtain a compound of formula 1.
[0011] Further, in step a, the bromination reagent is N-bromosuccinimide, bromine, 1,3-dibromo-5,5-dimethylhydantoin and / or pyridinium tribromide, preferably N-bromosuccinimide;
[0012] and / or, the molar ratio of the guaiac oil hydrocarbon to the brominating agent is 1:0.5-1.5, preferably 1:1;
[0013] and / or, the solvent is tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, N,N-dimethylformamide, 1,4-dioxane, diethyl ether, ethylene glycol dimethyl ether, etc., preferably tetrahydrofuran;
[0014] And / or, the reaction temperature is 0°C to 25°C, preferably 10 to 15°C, and the reaction time is 5 to 60 min, preferably 15 to 30 min.
[0015] Furthermore, after the reaction in step a, sodium sulfite aqueous solution and ethyl acetate are added for extraction, and the organic layer is concentrated and purified to obtain compound (i).
[0016] Furthermore, the concentration is concentration under reduced pressure; the purification is purification by silica gel chromatography, and the eluent is petroleum ether and ethyl acetate in a volume ratio of 1:10.
[0017] Further, in step b, the sulfonating agent is sulfur trioxide, concentrated sulfuric acid and / or oleum, preferably concentrated sulfuric acid;
[0018] and / or, the molar ratio of the compound (i) to the sulfonating agent is 1:1 to 2, preferably 1:1;
[0019] And / or, the reaction temperature is -30°C to 0°C, preferably -15°C to -10°C, and the reaction time is 1h to 4h, preferably 4h;
[0020] And / or, the solvent is any one or more of acetic anhydride, a mixed solution of acetic anhydride and dichloromethane, a mixed solution of acetic anhydride and chloroform, a mixed solution of acetic anhydride and ethyl acetate, and a mixed solution of acetic anhydride and acetonitrile, preferably a mixed solution of acetic anhydride and dichloromethane in a volume ratio of 1:1.
[0021] Furthermore, after the reaction in step b, the temperature is raised to 0-5°C and the pH value is adjusted to 8-9, and the solid is purified by silica gel chromatography to obtain compound (ii).
[0022] Furthermore, the eluent used for the silica gel chromatography purification is dichloromethane and methanol in a volume ratio of 10:1.
[0023] Further, in step c, the base is NaOH, Na2CO3 or NaHCO3, preferably NaOH;
[0024] And / or, the solvent is water, a mixed solution of water and methanol, a mixed solution of water and ethanol, a mixed solution of water and N,N-dimethylformamide, or a mixed solution of water and 1,4-dioxane, preferably a mixed solution of water and methanol in a volume ratio of 1:1;
[0025] And / or, the reaction temperature is 10°C to 30°C, preferably 20°C to 25°C, and the reaction time is 4h to 10h, preferably 6h.
[0026] Furthermore, after the hydrolysis reaction in step c, the product is concentrated, and the concentrate is purified by silica gel chromatography to obtain the compound of formula 1.
[0027] Furthermore, the eluent used for the silica gel chromatography purification is dichloromethane and methanol in a volume ratio of 10:1.
[0028] The present invention also provides a compound represented by formula 1, which is prepared according to the above method.
[0029] Finally, the present invention provides a use of the compound represented by the aforementioned formula 1 in detecting sodium azulene sulfonate preparations.
[0030] Furthermore, the sodium azulene sulfonate preparation includes sodium azulene sulfonate tablets and L-glutamine sodium guarenate granules.
[0031] The "concentrated sulfuric acid" mentioned in the present invention is a sulfuric acid aqueous solution with a sulfuric acid mass fraction greater than or equal to 70%.
[0032] The invention discloses a method for preparing sodium azulene sulfonate impurities, which can obtain a compound represented by formula 1 with a content of nearly 98%, and use the compound as a reference substance to detect the content of the compound represented by formula 1 in a sodium azulene sulfonate preparation, thereby facilitating quality control in the pharmaceutical production of the sodium azulene sulfonate preparation, reducing the content of the impurity represented by formula 1, and improving the quality of the sodium azulene sulfonate preparation.
[0033] Obviously, according to the above contents of the present invention, in accordance with common technical knowledge and customary means in the art, without departing from the above basic technical ideas of the present invention, other various forms of modification, replacement or change may be made.
[0034] The above contents of the present invention are further described in detail below through specific implementation methods in the form of embodiments. However, this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS
[0035] Figure 1 The method for degrading the impurity compound of formula 1 by sodium azulene sulfonate1 HNMR spectrum.
[0036] Figure 2 The method for degrading the impurity compound of formula 1 by sodium azulene sulfonate 13 CNMR spectrum.
[0037] Figure 3 The MS spectrum of the compound of formula 1 degraded from sodium azulene sulfonate.
[0038] Figure 4 The HPLC spectrum of the compound of formula 1 degraded from sodium azulene sulfonate.
[0039] Figure 5 It is the accelerated June spectrum of glutamine azulene sulfonic acid compound granules.
[0040] Figure 6 It is sodium azulene sulfonate accelerated 6 month spectrum. DETAILED DESCRIPTION
[0041] Example 1 Preparation of Compound (i)
[0042] Synthesis route:
[0043]
[0044] Specific preparation method ①:
[0045] Take 8.00 g (40.3 mmol) of guaiacyl hydrocarbon and 80.0 mL of tetrahydrofuran, stir and dissolve, add 7.17 g (40.3 mmol) of N-bromosuccinimide in batches at 10°C to 15°C, keep warm and react for 30 minutes, add 70.0 mL of 10% sodium sulfite aqueous solution and 40.0 mL of ethyl acetate, separate and collect the organic layer, extract the water layer with 40.0 mL of ethyl acetate, combine the organic phases and concentrate under reduced pressure to obtain a black viscous substance. Separate and purify by silica gel column chromatography (petroleum ether PE: ethyl acetate EA = 1:10) to obtain 2.18 g of compound (i), with a yield of 19.5%, LCMS: 276.1 [M] + , 1 HNMR (400MHz, DMSO-d6): 8.10-8.14(m,2H),7.71(m,1H),7.59(d,m,2H),2.58(s,6H),1.60(s,6H).
[0046] Specific preparation method ②:
[0047] Take 8.00 g (40.3 mmol) of guaiacyl hydrocarbon and 80.0 mL of tetrahydrofuran and stir to dissolve, add 10.75 g (60.45 mmol) of N-bromosuccinimide in batches at 10°C to 15°C, keep warm for 60 minutes, add 70.0 mL of 10% sodium sulfite aqueous solution and 40.0 mL of ethyl acetate, separate and collect the organic layer, extract the aqueous layer with 40.0 mL of ethyl acetate, combine the organic phases and concentrate under reduced pressure to obtain a black viscous substance. Separate and purify by silica gel column chromatography (PE:EA=1:10) to obtain 1.68 g of compound (i), with a yield of 15.1%.
[0048] Specific preparation method ③:
[0049] Take 8.00g (40.3mmol) of guaiacyl hydrocarbon and 80.0mL of dichloromethane and stir to dissolve, add 11.52g (40.3mmol) of 1,3-dibromo-5,5-dimethylhydantoin in batches at 5℃~10℃, keep warm for 45min, add 70.0mL of 10% sodium sulfite aqueous solution and 40.0mL of ethyl acetate, separate and collect the organic layer, extract the water layer with 40.0mL of ethyl acetate, combine the organic phases and concentrate under reduced pressure to obtain a black viscous substance. Separate and purify by silica gel column chromatography (PE:EA=1:10) to obtain 1.06g of compound (i), with a yield of 9.5%.
[0050] Specific preparation method ④:
[0051] Take 8.00g (40.3mmol) of guaiacyl hydrocarbon and 80.0mL of dichloromethane and stir to dissolve, add 2.82g (40.3mmol) of bromine in batches at 0℃~5℃, keep warm for 15min, add 70.0mL of 10% sodium sulfite aqueous solution and 40.0mL of ethyl acetate, separate and collect the organic layer, extract the water layer with 40.0mL of ethyl acetate, combine the organic phases and concentrate under reduced pressure to obtain a black viscous substance. Separate and purify by silica gel column chromatography (PE:EA=1:10) to obtain 0.64g of compound (i), with a yield of 5.8%.
[0052] Example 2 Preparation of Compound (ii)
[0053] Synthesis route:
[0054]
[0055] Specific preparation method ①:
[0056] Take 2.00 g (7.2 mmol) of compound (i) prepared in Example 1, 5.0 mL of dichloromethane and 5.0 mL of acetic anhydride, cool to -15°C, slowly add 0.72 g (7.2 mmol) of concentrated sulfuric acid, react at -15°C to -10°C for 4 h, then heat to 0 to 5°C and add sodium hydroxide aqueous solution to adjust the pH to 8 to 9, a large amount of dark blue solid precipitates, the filter cake is collected by suction to obtain a crude compound (ii), which is separated and purified by silica gel column chromatography (eluent dichloromethane DCM: methanol MeOH = 10:1) to obtain 2.22 g of compound (ii), with a yield of 81.6%. LCMS=356.0[M-Na]-, 1HNMR (400MHz, D2O): 1.59 (s, 6H), 2.47 (s, 3H), 3.18 (s, 3H), 7.41 (d, 1H), 7.79-7.84 (m, 1H), 8.10 (s, 1H), 8.62 (d, 1H).
[0057] Specific preparation method ②:
[0058] Take 2.00 g (7.2 mmol) of compound (i) prepared in Example 1, 5.0 mL of dichloromethane and 5.0 mL of acetic anhydride, cool to -30°C, slowly add 1.44 g (14.4 mmol) of concentrated sulfuric acid, react at -30°C to -20°C for 2 h, then heat to 0 to 5°C and add sodium hydroxide aqueous solution to adjust the pH to 8 to 9, a large amount of dark blue solid precipitates, the filter cake is collected by suction to obtain a crude compound (ii), which is separated and purified by silica gel column chromatography (eluent DCM:MeOH=10:1) to obtain 2.34 g of compound (ii), with a yield of 85.9%.
[0059] Specific preparation method ③:
[0060] Take 2.00 g (7.2 mmol) of compound (i) prepared in Example 1 and 5.0 mL of acetic anhydride, cool to -30°C, slowly add 0.72 g (7.2 mmol) of concentrated sulfuric acid, react at -30°C to -20°C for 2 h, then heat to 0 to 5°C and add aqueous sodium hydroxide to adjust the pH to 8-9, a large amount of dark blue solid precipitates, the filter cake is collected by suction to obtain a crude compound (ii), which is separated and purified by silica gel column chromatography (eluent DCM:MeOH=10:1) to obtain 2.25 g of compound (ii), with a yield of 82.3%.
[0061] Specific preparation method ④:
[0062] Take 2.00 g (7.2 mmol) of compound (i) prepared in Example 1, 2.0 mL of ethyl acetate and 2.0 mL of acetic anhydride, cool to -15°C, slowly add 0.72 g (7.2 mmol) of concentrated sulfuric acid, react at -20°C to -10°C for 3 h, then heat to 0 to 5°C and add aqueous sodium hydroxide to adjust the pH to 8 to 9, a large amount of dark blue solid precipitates, the filter cake is collected by suction to obtain a crude compound (ii), which is separated and purified by silica gel column chromatography (eluent DCM:MeOH=10:1) to obtain 1.96 g of compound (ii), with a yield of 71.9%.
[0063] Specific preparation method⑤:
[0064] Take 2.00 g (7.2 mmol) of compound (i) prepared in Example 1, 2.0 mL of acetonitrile and 2.0 mL of acetic anhydride, cool to -15°C, slowly add 0.72 g (7.2 mmol) of concentrated sulfuric acid, react at -10°C to 0°C for 2 h, then heat to 0 to 5°C and add aqueous sodium hydroxide to adjust the pH to 8 to 9, a large amount of dark blue solid precipitates, the filter cake is collected by suction to obtain a crude compound (ii), which is separated and purified by silica gel column chromatography (eluent DCM:MeOH=10:1) to obtain 2.00 g of compound (ii), with a yield of 73.3%.
[0065] Example 3 Preparation of the compound of formula 1
[0066] Synthesis route:
[0067]
[0068] Specific preparation method ①
[0069] Take 1.00 g (2.6 mmol) of compound (ii) prepared in Example 2, 0.31 g (7.8 mmol) of sodium hydroxide, 3.0 mL of water and 3 mL of methanol. Keep the reaction at 20°C to 25°C for 6 hours, and concentrate under reduced pressure to dryness to obtain a blue viscous substance. Separate and purify by silica gel column chromatography (eluent DCM: MeOH = 10: 1) to obtain 0.52 g of compound 1, with a yield of 63.2% and a HPLC purity of 97.7%. LCMS = 292.8 [M-Na] - , 1 HNMR(400MHz,D2O):1.58(s,6H),2.49(s,3H),3.20(s,3H),7.33(d,1H),7.75-7.79(m,1H),7.98(s,1H),8.58(d,1H). 13CNMR (400MHz, D2O): 160.9, 149.1, 142.5, 139.6, 137.9, 135.0, 132.6, 130.4, 125.3, 124.3, 73.9, 30.6, 26.8, 11.8. For detailed spectrum, see Figures 1 to 4 .
[0070] The HPLC method is:
[0071] According to the self-control method, a chromatographic column with porous bonded silica gel as filler is used, the column temperature is 20-40°C, the flow rate is 0.8-1.5 ml / min, the detection wavelength is 220-290 nm, the injection volume is 10-50 μl, the aqueous phase is a buffer solution, the organic phase is a mixed solution of a certain proportion of buffer solution and organic solvent, and the gradient elution program is:
[0072] Time (minutes) Water phase (vol.%) Organic phase (vol.%) 0 60～80 40～20 15 50～70 50～30 20 50～70 50～30 25 40～60 60～40 35 40～60 60～40 40 60～80 40～20 50 60～80 40～20
[0073] Specific preparation method ②
[0074] Take 1.00 g (2.6 mmol) of compound (ii) prepared in Example 2, 0.42 g (10.4 mmol) of sodium hydroxide, 3.0 mL of water and 3 mL of methanol. Keep the mixture at 25°C to 30°C for 6 h, and concentrate under reduced pressure to dryness to obtain a blue viscous substance, which is separated and purified by silica gel column chromatography (eluent DCM:MeOH=10:1) to obtain 0.44 g of compound 1, with a yield of 53.8% and a purity of 97.3%.
[0075] Specific preparation method ③
[0076] Take 1.00 g (2.6 mmol) of compound (ii) prepared in Example 2, 0.31 g (7.8 mmol) of sodium hydroxide, 3.0 mL of water and 3.0 mL of ethanol. Keep the mixture at 10°C to 15°C for 10 h, and concentrate under reduced pressure to dryness to obtain a blue viscous substance, which is separated and purified by silica gel column chromatography (eluent DCM:MeOH=10:1) to obtain 0.50 g of compound 1, with a yield of 60.1% and a purity of 97.6%.
[0077] Specific preparation method ④
[0078] Take 1.00 g (2.6 mmol) of compound (ii) prepared in Example 2, 0.31 g (7.8 mmol) of sodium hydroxide, 3.0 mL of water and 3.0 mL of 1,4-dioxane. Keep the mixture at 15°C to 20°C for 4 h, and concentrate under reduced pressure to dryness to obtain a blue viscous substance, which is separated and purified by silica gel column chromatography (eluent DCM:MeOH=10:1) to obtain 0.40 g of compound 1, with a yield of 48.5% and a purity of 97.5%.
[0079] The beneficial effects of the present invention are described below by experimental examples:
[0080] Experimental Example 1 Application Study of Compound 1
[0081] 1. Methods
[0082] The impurity compound of formula 1 obtained by the specific preparation method ① in Example 3 was used for the accelerated stability quality study of sodium azulene sulfonate tablets and sodium glutamine azulene sulfonate compound granules;
[0083] The specific method is: placing the sodium azulene sulfonate tablets provided by Chengdu Aqi Biopharmaceutical Technology Co., Ltd. and the commercially available sodium glutamine azulene sulfonate compound granules in an environment of 40±2°C and RH75%±5% for 6 months, and detecting them by high performance liquid chromatography, calculating by the self-control method, using a chromatographic column with porous bonded silica gel as the filler, the column temperature is 20-40°C, the flow rate is 0.8-1.5ml / min, the detection wavelength is 220-290nm, the injection volume is 10-50μl, the aqueous phase is a buffer solution, the organic phase is a mixed solution of a certain proportion of buffer solution and organic solvent, and the gradient elution program is:
[0084] Time (minutes) Water phase (vol.%) Organic phase (vol.%) 0 60～80 40～20 15 50～70 50～30 20 50～70 50～30 25 40～60 60～40 35 40～60 60～40 40 60～80 40～20 50 60～80 40～20
[0085] 2. Results
[0086] The accelerated stability data are shown in Table 1 and the specific spectra are shown in Figures 5-6 .
[0087]
[0088] From the above results, it can be seen that in the accelerated test, the preparations of sodium glutamine azulene sulfonate compound granules and sodium azulene sulfonate tablets both produced degradation impurity formula 1 compounds, and the degradation impurities (formula 1) of sodium azulene sulfonate tablets produced by Chengdu Aqi Biopharmaceutical Technology Co., Ltd., especially the total impurity content, were lower than those of sodium glutamine azulene sulfonate compound granules. Using the compound of formula 1 prepared by the present invention as a reference substance, the degradation impurity compound of formula 1 can be effectively detected by HPLC method, and can be accurately quantified.
[0089] In summary, the present invention can obtain a compound represented by formula 1 with a content of nearly 98%, and use it as a reference substance to detect the content of the compound of formula 1 in the sodium azulene sulfonate preparation, which can facilitate the quality control of the sodium azulene sulfonate preparation in the pharmaceutical production, reduce the content of the impurity formula 1, and improve the quality of the sodium azulene sulfonate preparation.
Claims
1. A method for preparing a compound represented by formula 1, characterized in that: It includes the following steps: Step a, preparation of compound (i): guaiacyl oil reacts with a bromination reagent in a solvent to obtain compound (i); Step b, preparation of compound (ii): compound (i) reacts with a sulfonating agent in a solvent to obtain compound (ii); Step c, preparation of the compound of formula 1: Compound (ii) undergoes hydrolysis reaction with a base in a solvent to obtain a compound of formula 1.
2. The preparation method according to claim 1, characterized in that: In step a, the bromination reagent is N-bromosuccinimide, bromine, 1,3-dibromo-5,5-dimethylhydantoin and / or pyridinium tribromide, preferably N-bromosuccinimide; and / or, the molar ratio of the guaiac oil hydrocarbon to the brominating agent is 1:0.5-1.5, preferably 1:1; and / or, the solvent is tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, N,N-dimethylformamide, 1,4-dioxane, diethyl ether, ethylene glycol dimethyl ether, etc., preferably tetrahydrofuran; And / or, the reaction temperature is 0°C to 25°C, preferably 10 to 15°C, and the reaction time is 5 to 60 min, preferably 15 to 30 min.
3. The preparation method according to claim 1 or 2, characterized in that: After the reaction in step a, sodium sulfite aqueous solution and ethyl acetate are added for extraction, and the organic layer is concentrated and purified to obtain compound (i).
4. The preparation method according to claim 1, characterized in that: In step b, the sulfonating agent is sulfur trioxide, concentrated sulfuric acid and / or oleum, preferably concentrated sulfuric acid; and / or, the molar ratio of the compound (i) to the sulfonating agent is 1:1 to 2, preferably 1:1; And / or, the reaction temperature is -30°C to 0°C, preferably -15°C to -10°C, and the reaction time is 1h to 4h, preferably 4h; And / or, the solvent is any one or more of acetic anhydride, a mixed solution of acetic anhydride and dichloromethane, a mixed solution of acetic anhydride and chloroform, a mixed solution of acetic anhydride and ethyl acetate, and a mixed solution of acetic anhydride and acetonitrile, preferably a mixed solution of acetic anhydride and dichloromethane in a volume ratio of 1:
1.
5. The preparation method according to claim 1 or 4, characterized in that: After the reaction in step b, the temperature is raised to 0-5°C and the pH value is adjusted to 8-9. The solid is purified to obtain compound (ii).
6. The preparation method according to claim 1, characterized in that: In step c, the base is NaOH, Na2CO3 or NaHCO3, preferably NaOH; And / or, the solvent is water, a mixed solution of water and methanol, a mixed solution of water and ethanol, a mixed solution of water and N,N-dimethylformamide, or a mixed solution of water and 1,4-dioxane, preferably a mixed solution of water and methanol in a volume ratio of 1:1; And / or, the reaction temperature is 10°C to 30°C, preferably 20°C to 25°C, and the reaction time is 4h to 10h, preferably 6h.
7. The preparation method according to claim 1 or 6, characterized in that: After the hydrolysis reaction in step c, the concentrate is concentrated and purified to obtain the compound of formula 1.
8. A compound represented by formula 1, characterized in that: The invention is prepared according to the method described in any one of claims 1 to 7.
9. Use of the compound of formula 1 according to claim 8 in detecting sodium azulene sulfonate preparations.
10. The use according to claim 9, characterized in that: The sodium azulene sulfonate preparation comprises sodium azulene sulfonate tablets and L-glutamine sodium guarenate granules.