Preparation method of 5-bromo-4-chloro-3-indolyl disodium phosphate
A series of mild chemical reaction steps were used to prepare disodium 5-bromo-4-chloro-3-indolyl phosphate in high yield, which solved the problems of low yield and high cost in the existing technology and realized an economical and efficient preparation method.
Patent Information
- Application Number
- CN202511180892.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-08-22
- Publication Date
- 2025-12-02
AI Technical Summary
The existing methods for preparing 5-bromo-4-chloro-3-indolyl phosphate disodium salt have low yields, high production costs, and use large amounts of toxic raw materials and waste liquids.
Compound a is generated by reacting indole with acetic anhydride. Compound a is then reacted with tert-butanol peroxide to generate compound b. Compound b is reacted with N-chlorosuccinimide and N-bromosuccinimide to generate compounds c and d. Compound d is reacted with phosphorus oxychloride to generate compound e. Finally, it is reacted with sodium hydroxide to generate disodium 5-bromo-4-chloro-3-indole phosphate.
The synthetic route is simple, the reaction conditions are mild, the overall yield is high, and the raw materials are cheap and readily available, which reduces the synthesis cost and is conducive to industrial production.
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Figure CN121045262A_ABST
Abstract
Description
Technical Field
[0001] This application relates to the field of organic synthesis, and in particular to a method for preparing disodium 5-bromo-4-chloro-3-indolyl phosphate. Background Technology
[0002] Disodium 5-bromo-4-chloro-3-indole phosphate (BCIP, or its sodium salt form BCIP-2Na) is a commonly used substrate for alkaline phosphatases. Under the catalysis of alkaline phosphatase, it hydrolyzes, releasing a phosphate group and generating 5-bromo-4-chloro-3-indole (BCI). The latter, after oxidation, combines with oxidants such as nitroblue tetrazolium (NBT) to form an insoluble blue, purple, or red precipitate, which can be detected by visible light or chemiluminescence. Therefore, it is widely used in the fields of biochemistry and molecular biology.
[0003] However, the existing methods for preparing 5-bromo-4-chloro-3-indole phosphate disodium salt have low yields, high production costs, and use a large amount of toxic raw materials and waste liquid. Therefore, a new method for preparing 5-bromo-4-chloro-3-indole phosphate disodium salt is needed. Summary of the Invention
[0004] To overcome the deficiencies in the prior art, this application discloses a method for preparing disodium 5-bromo-4-chloro-3-indolyl phosphate, comprising the following steps:
[0005] Step 1: React indole with acetic anhydride to generate compound a;
[0006] Step 2: React compound a with tert-butanol hydrogen peroxide to generate compound b;
[0007] Step 3: React compound b with N-chlorosuccinimide to generate compound c;
[0008] Step 4: React compound c with N-bromosuccinimide to generate compound d;
[0009] Step 5: React compound d with phosphorus oxychloride to generate compound e;
[0010] Step 6: React compound e with sodium hydroxide to generate disodium 5-bromo-4-chloro-3-indolyl phosphate;
[0011] The details are as follows:
[0012]
[0013] By adopting the above technical solution, this application provides a new method for preparing disodium 5-bromo-4-chloro-3-indolyl phosphate. The synthetic route of this application is simple, the reaction conditions are mild, the overall yield is high, the raw materials are cheap and readily available, the synthesis cost is reduced, and it is conducive to industrialization.
[0014] Preferably, the molar ratio of indole to acetic anhydride is 1:(6-7.5);
[0015] Preferably, in step 1, acetic anhydride and anhydrous sodium acetate are mixed and heated to 50-70°C, indole is added and the temperature is raised to 80-100°C. After the raw materials are dissolved, the temperature is further raised to 110-130°C and the reaction is carried out for 1-3 hours.
[0016] Preferably, the molar ratio of compound a to tert-butanol peroxide is 1:(1-2);
[0017] Preferably, in step 2, the reaction temperature is 70–80°C and the reaction time is 3–4 hours.
[0018] Preferably, the compound a reacts with hydrogen peroxide tert-butanol in a solvent, and the ratio of compound a to solvent is 1 mol: (400-500) mL.
[0019] Preferably, in step 3, the molar ratio of compound b to N-chlorosuccinimide is 1:(1-2);
[0020] Preferably, in step 3, the reaction temperature is 60–70°C and the reaction time is 6–7 h.
[0021] Preferably, in step 3, compound b reacts with N-chlorosuccinimide in a solvent, wherein the ratio of compound b to solvent is 1 mol: (1700–2000) mL.
[0022] Preferably, the solvent in step 2 and the solvent in step 3 are selected from one or more of petroleum ether, ethyl acetate, methanol, and ethanol.
[0023] Preferably, in step 4, the molar ratio of compound c to N-bromosuccinimide is 1:(1-2);
[0024] Preferably, in step 4, the reaction temperature is 30–40°C and the reaction time is 5–6 hours.
[0025] Preferably, in step 4, compound c reacts with N-bromosuccinimide in a solvent selected from one or more of ethyl acetate, methanol, ethanol, and glacial acetic acid, and the ratio of compound c to solvent is 1 mol: (2000-2300) mL.
[0026] Preferably, in step 5, the molar ratio of the compound d to phosphorus oxychloride is 1:(2-3);
[0027] Preferably, in step 5, compound d reacts with phosphorus oxychloride in a solvent selected from one or more of toluene, pyridine, ethanol, and petroleum ether, and the ratio of compound d to solvent is 1 mol: (4400-4600) mL.
[0028] Preferably, in step 5, after dissolving compound d in the solvent, the temperature is first raised to 60-70°C, phosphorus oxychloride is added dropwise, and the dropwise addition time is controlled to be 10-20 min. After the dropwise addition is completed, the temperature is raised to 109-115°C and refluxed for 30-40 min. Then pyridine is added dropwise, and the reaction continues for 3-5 h after the dropwise addition is completed.
[0029] Preferably, the molar ratio of compound d to pyridine is 1:(1-2).
[0030] By adopting the above technical solution, the preparation method disclosed in this application is relatively simple, the reaction conditions are relatively mild, and it is easy to operate, and can obtain a relatively high yield.
[0031] In summary, this application has the following beneficial effects:
[0032] 1. Preparation method provided in this application: The synthetic route of this application is simple, the reaction conditions are mild, the overall yield is high, the raw materials are cheap and readily available, which reduces the synthesis cost and is conducive to industrialization. Detailed Implementation
[0033] Example
[0034] The following examples illustrate the preparation method of disodium 5-bromo-4-chloro-3-indolyl phosphate, which proceeds along the following reaction route:
[0035]
[0036] Example 1
[0037] Step 1: Add 487.6 g of acetic anhydride to the reaction flask, then add 30.0 g of anhydrous sodium acetate and heat to 60°C. Add 80.0 g of indole. After the addition is complete, heat to 90°C until the starting material dissolves completely. Continue heating to 120°C and react for 2 hours. After the reaction is complete, pour the reaction solution directly into 2.5 L of ice water and stir for 15 minutes. A large amount of solid precipitates. Cool, filter, wash the filter cake once with water, and dry to obtain a wet product. Recrystallize the wet product from methanol, filter, and dry to obtain 98.7 g of compound a, with a yield of 90.8%.
[0038] Step 2: Add 225 mL of ethanol to the reaction flask, add 79.6 g of compound a while stirring, disperse, add 67.6 g of tert-butanol hydrogen peroxide, heat to 75 °C, and react for 3.5 h. After the reaction is complete, slowly pour the reaction solution into 1 L of ice water while stirring, stir for 15 min, keep the internal temperature below 20 °C, and a solid precipitates. Filter, wash the filter cake twice with water, and dry to obtain a wet product. Add 300 mL of ethyl acetate to the wet product, stir, add 30 g of activated carbon, heat to reflux, filter while hot to remove insoluble impurities, cool the filtrate to crystallize, filter, and then dry at 50 °C to obtain 84.6 g of compound b, with a yield of 96.6%.
[0039] Step 3: Add 570 mL of ethyl acetate to a three-necked reaction flask, then add 52.6 g of compound b while stirring. After dispersing, add 60.1 g of N-chlorosuccinimide and react at 65 °C for 6.5 h. After the reaction is complete, filter directly and dry under vacuum to obtain the wet product. Add 250 mL of methanol to the wet product, heat to 60 °C, stir for 1 h, then hot filter, dry under vacuum, and then dry at 50 °C to obtain 52.4 g of compound c, with a yield of 93.3%.
[0040] Step 4: Add 420 mL of ethyl acetate to a three-necked reaction flask, then add 41.9 g of compound c while stirring. After dispersing, add 53.3 g of N-bromosuccinimide and react at 35 °C for 5.5 h while stirring. After the reaction is complete, filter directly, collect the filtrate, and remove insoluble matter. Remove the solvent from the filtrate by vacuum distillation, place the residue in a freezer, cool to 0 °C, and crystallize for 2 h. Filter to collect the solid, wash once with 200 mL of petroleum ether, dry under vacuum, and dry the solid at 50 °C to obtain 47.2 g of compound d, with a yield of 91.8%.
[0041] Step 5: Add 675 mL of toluene to the reaction flask, then add 43.3 g of compound d. While stirring, heat to 65 °C and add 57.5 g of phosphorus oxychloride dropwise over 15 minutes. After the addition is complete, heat to 112 °C and reflux for 35 minutes. Then, slowly add 17.8 g of pyridine dropwise. The reaction is exothermic, producing a large amount of white fumes. Add the pyridine dropwise over 10 minutes, then reflux for 4 hours. After the reaction is complete, discharge the hot mixture and cool to room temperature. Filter to remove salts, evaporate the filtrate to dryness, and cool to 0 °C to form crude compound e. Proceed directly to step 6.
[0042] Step 6: Add 500g of pure water to the reaction flask, then add 25.0g of sodium hydroxide, stir to dissolve, cool to 20℃, and add the crude compound e in batches, completing the addition in about 0.5h. After the addition is complete, maintain the internal temperature at 20-25℃ for 5h. After the reaction is complete, adjust the pH to 9.0-10.0 with glacial acetic acid, add 20g of activated carbon, stir to decolorize, and let it sit overnight. Filter the next day. Decolorize again with 20g of activated carbon overnight, filter, the filtrate is pale yellow, filter once more through a filter membrane, collect the filtrate, remove the solvent by vacuum distillation in a water bath at 70℃, add 300g of anhydrous ethanol to disperse, then stir magnetically for 1h, filter, dry under vacuum at 40℃ for 3h, to obtain 44.8g of disodium 5-bromo-4-chloro-3-indolyl phosphate, yield 80.6%.
[0043] Example 2
[0044] Step 1: Add 417.9 g of acetic anhydride to the reaction flask, then add 40.0 g of anhydrous sodium acetate and heat to 50°C. Add 80.0 g of indole. After the addition is complete, heat to 80°C until the starting material dissolves completely. Continue heating to 110°C and react for 3 hours. After the reaction is complete, pour the reaction solution directly into 2.5 L of ice water and stir for 15 minutes. A large amount of solid precipitates. Cool, filter, wash the filter cake once with water, and dry to obtain a wet product. Recrystallize the wet product from methanol, filter, and dry to obtain 95.9 g of compound a, with a yield of 88.2%.
[0045] Step 2: Add 200 mL of ethanol to the reaction flask, add 80.0 g of compound a while stirring, disperse, add 45.1 g of tert-butanol hydrogen peroxide, heat to 70 °C, and react for 4 h. After the reaction is complete, slowly pour the reaction solution into 1 L of ice water while stirring, stir for 15 min, keep the internal temperature below 20 °C, and a solid precipitates. Filter, wash the filter cake twice with water, and dry to obtain a wet product. Add 300 mL of ethyl acetate to the wet product, stir, add 30 g of activated carbon, heat to reflux, filter while hot to remove insoluble impurities, cool the filtrate to crystallize, filter, and then dry at 50 °C to obtain 82.7 g of compound b, with a yield of 94.5%.
[0046] Step 3: Add 510 mL of ethyl acetate to a three-necked reaction flask, then add 52.6 g of compound b while stirring. After dispersing, add 40.1 g of N-chlorosuccinimide and react at 60 °C for 7 h. After the reaction is complete, filter directly and dry under vacuum to obtain the wet product. Add 250 mL of methanol to the wet product, heat to 60 °C, stir for 1 h, then hot filter, dry under vacuum, and then dry at 50 °C to obtain 57.4 g of compound c, with a yield of 91.2%.
[0047] Step 4: Add 400 mL of ethyl acetate to a three-necked reaction flask, and add 41.9 g of compound c while stirring. After dispersing, add 35.6 g of N-bromosuccinimide and react at 30 °C for 6 h while stirring. After the reaction is complete, filter directly, collect the filtrate, and remove insoluble matter. Remove the solvent from the filtrate by vacuum distillation, and place the residue in a freezer to cool to 0 °C. Crystallize for 2 h, filter and collect the solid. Wash the solid once with 200 mL of petroleum ether, dry under vacuum, and dry the solid at 50 °C to obtain 51.3 g of compound d, with a yield of 88.9%.
[0048] Step 5: Add 660 mL of toluene to the reaction flask, then add 43.3 g of compound d. While stirring, heat to 60 °C and add 47.5 g of phosphorus oxychloride dropwise, controlling the addition over 10 minutes. After the addition is complete, heat to 109 °C and reflux for 30 minutes. Then, slowly add 11.9 g of pyridine dropwise. The reaction is exothermic, producing a large amount of white fumes. Continue adding the pyridine dropwise over 10 minutes, then reflux for 3 hours. After the reaction is complete, discharge the hot mixture and cool to room temperature. Filter to remove salts. Dry the filtrate by rotary evaporation and cool to 0 °C to form crude compound e, which is then directly used in step 6.
[0049] Step 6: Add 500g of pure water to the reaction flask, then add 25.0g of sodium hydroxide, stir to dissolve, cool to 20℃, and add the crude compound e in batches, completing the addition in about 0.5h. After the addition is complete, maintain the internal temperature at 20-25℃ for 5h. After the reaction is complete, adjust the pH to 9.0-10.0 with glacial acetic acid, add 20g of activated carbon, stir to decolorize, and let it sit overnight. Filter the next day. Decolorize again with 20g of activated carbon overnight, filter, the filtrate is pale yellow, filter once more through a filter membrane, collect the filtrate, remove the solvent by vacuum distillation in a water bath at 70℃, add 300g of anhydrous ethanol to disperse, then stir magnetically for 1h, filter, dry under vacuum at 40℃ for 3h, to obtain 38.1g of disodium 5-bromo-4-chloro-3-indolyl phosphate, yield 78.5%.
[0050] Example 3
[0051] Step 1: Add 522.4 g of acetic anhydride to the reaction flask, then add 30.0 g of anhydrous sodium acetate and heat to 70°C. Add 80.0 g of indole. After the addition is complete, heat to 100°C until the starting material dissolves completely. Continue heating to 130°C and react for 1 hour. After the reaction is complete, pour the reaction solution directly into 2.5 L of ice water and stir for 15 minutes. A large amount of solid precipitates. Cool, filter, wash the filter cake once with water, and dry to obtain a wet product. Recrystallize the wet product from methanol, filter, and dry to obtain 96.5 g of compound a, with a yield of 88.8%.
[0052] Step 2: Add 250 mL of ethanol to the reaction flask, add 80.0 g of compound a while stirring, disperse the mixture, add 90.1 g of tert-butanol hydrogen peroxide, heat to 80 °C, and react for 3 h. After the reaction is complete, slowly pour the reaction solution into 1 L of ice water while stirring, stir for 15 min, keep the internal temperature below 20 °C, and a solid will precipitate. Filter the solid, wash the filter cake twice with water, and dry it to obtain a wet product. Add 300 mL of ethyl acetate to the wet product, stir, add 30 g of activated carbon, heat to reflux, filter while hot to remove insoluble impurities, cool the filtrate to allow crystallization, filter again, and then dry at 50 °C to obtain 83.4 g of compound b, with a yield of 95.2%.
[0053] Step 3: Add 600 mL of ethyl acetate to a three-necked reaction flask, and add 52.6 g of compound b while stirring. After dispersing, add 80.1 g of N-chlorosuccinimide and react at 70 °C for 6 h. After the reaction is complete, filter directly and dry under vacuum to obtain the wet product. Add 250 mL of methanol to the wet product, heat to 60 °C, stir for 1 h, hot filter, dry under vacuum, and then dry at 50 °C to obtain 57.6 g of compound c, with a yield of 91.6%.
[0054] Step 4: Add 460 mL of ethyl acetate to a three-necked reaction flask, then add 41.9 g of compound c while stirring. After dispersing, add 71.2 g of N-bromosuccinimide and react at 40 °C for 5 h while stirring. After the reaction is complete, filter directly, collect the filtrate, and remove insoluble matter. Remove the solvent from the filtrate by vacuum distillation, place the residue in a freezer, cool to 0 °C, and crystallize for 2 h. Filter to collect the solid, wash once with 200 mL of petroleum ether, dry under vacuum, and dry the solid at 50 °C to obtain 51.7 g of compound d, with a yield of 89.6%.
[0055] Step 5: Add 690 mL of toluene to the reaction flask, then add 43.3 g of compound d. While stirring, heat to 70 °C and add 69.0 g of phosphorus oxychloride dropwise over 20 minutes. After the addition is complete, heat to 115 °C and reflux for 40 minutes. Then, slowly add 23.7 g of pyridine dropwise. The reaction is exothermic, producing a large amount of white fumes. Add the pyridine dropwise over 10 minutes, then reflux for 5 hours. After the reaction is complete, discharge the hot mixture and cool to room temperature. Filter to remove salts, evaporate the filtrate to dryness, and cool to 0 °C to form crude compound e. Proceed directly to step 6.
[0056] Step 6: Add 500g of pure water to the reaction flask, then add 25.0g of sodium hydroxide, stir to dissolve, cool to 20℃, and add the crude compound e in batches, completing the addition in about 0.5h. After the addition is complete, maintain the internal temperature at 20-25℃ for 5h. After the reaction is complete, adjust the pH to 9.0-10.0 with glacial acetic acid, add 20g of activated carbon, stir to decolorize, and let it sit overnight. Filter the next day. Decolorize again with 20g of activated carbon overnight, filter, the filtrate is pale yellow, filter once more through a filter membrane, collect the filtrate, remove the solvent by vacuum distillation in a water bath at 70℃, add 300g of anhydrous ethanol to disperse, then stir magnetically for 1h, filter, dry under vacuum at 40℃ for 3h, to obtain 44.0g of disodium 5-bromo-4-chloro-3-indolyl phosphate, yield 79.1%.
[0057] Example 4
[0058] Step 1: Add 348.2 g of acetic anhydride to the reaction flask, then add 30.0 g of anhydrous sodium acetate and heat to 60°C. Add 80.0 g of indole. After the addition is complete, heat to 90°C until the starting material dissolves completely. Continue heating to 120°C and react for 2 hours. After the reaction is complete, pour the reaction solution directly into 2.5 L of ice water and stir for 15 minutes. A large amount of solid precipitates. Cool, filter, wash the filter cake once with water, and dry to obtain a wet product. Recrystallize the wet product from methanol, filter, and dry to obtain 87.2 g of compound a, with a yield of 80.2%.
[0059] Step 2: Add 300 mL of ethanol to the reaction flask, add 70.0 g of compound a while stirring, disperse, add 99.1 g of tert-butanol hydrogen peroxide, heat to 75 °C, and react for 3.5 h. After the reaction is complete, slowly pour the reaction solution into 1 L of ice water while stirring, stir for 15 min, keep the internal temperature below 20 °C, and a solid precipitates. Filter, wash the filter cake twice with water, and dry to obtain a wet product. Add 300 mL of ethyl acetate to the wet product, stir, add 30 g of activated carbon, heat to reflux, filter while hot to remove insoluble impurities, cool the filtrate to crystallize, filter, and then dry at 50 °C to obtain 69.7 g of compound b, with a yield of 90.5%.
[0060] Step 3: Add 570 mL of ethyl acetate to a three-necked reaction flask, then add 52.6 g of compound b while stirring. After dispersing, add 100.1 g of N-chlorosuccinimide and react at 55 °C for 8.5 h. After the reaction is complete, filter directly and dry under vacuum to obtain the wet product. Add 250 mL of methanol to the wet product, heat to 60 °C, stir for 1 h, then hot filter, dry under vacuum, and then dry at 50 °C to obtain 52.5 g of compound c, with a yield of 83.5%.
[0061] Step 4: Add 380 mL of ethyl acetate to a three-necked reaction flask, then add 41.9 g of compound c while stirring. After dispersing, add 89.0 g of N-bromosuccinimide and react at 50 °C for 3.5 h while stirring. After the reaction is complete, filter directly, collect the filtrate, and remove insoluble matter. Remove the solvent from the filtrate by vacuum distillation, place the residue in a freezer, cool to 0 °C, and crystallize for 2 h. Filter to collect the solid, wash once with 200 mL of petroleum ether, dry under vacuum, and dry the solid at 50 °C to obtain 46.9 g of compound d, with a yield of 81.3%.
[0062] Step 5: Add 700 mL of toluene to the reaction flask, then add 40.0 g of compound d (288.5250, 0.1386 mol). While stirring, heat to 50 °C and add 85.0 g of phosphorus oxychloride (153.332, 0.5545 mol) dropwise over 25 min. After the addition is complete, heat to 103 °C and reflux for 25 min. Then slowly add 27.4 g of pyridine (79.100). The reaction is exothermic, producing a large amount of white fumes. Add the pyridine dropwise over 10 min and reflux for 2 h. After the reaction is complete, discharge the hot mixture and cool to room temperature. Filter to remove salts. Dry the filtrate by rotary evaporation and cool to 0 °C to form crude compound e, which is then directly reacted in Step 6.
[0063] Step 6: Add 500g of pure water to the reaction flask, then add 25.0g of sodium hydroxide, stir to dissolve, cool to 20℃, and add the crude compound e in batches, completing the addition in about 0.5h. After the addition is complete, maintain the internal temperature at 20-25℃ for 5h. After the reaction is complete, adjust the pH to 9.0-10.0 with glacial acetic acid, add 20g of activated carbon, stir to decolorize, and let it sit overnight. Filter the next day. Decolorize again with 20g of activated carbon overnight, filter, the filtrate is pale yellow, filter once more through a filter membrane, collect the filtrate, remove the solvent by vacuum distillation in a water bath at 70℃, add 300g of anhydrous ethanol to disperse, then stir magnetically for 1h, filter, dry under vacuum at 40℃ for 3h, to obtain 31.0g of disodium 5-bromo-4-chloro-3-indolyl phosphate, yield 70.3%.
[0064] In addition to the above embodiments, the solvent in step 1 may also be selected from one or more of glacial acetic acid, anhydrous sodium acetate, methanol, and ethanol, which will not be elaborated here.
[0065] The solvents in step 2 and step 3 can also be selected from one or more of petroleum ether, ethyl acetate, methanol, and ethanol, which will not be elaborated here.
[0066] The solvent in step 4 can also be selected from one or more of ethyl acetate, methanol, ethanol, and glacial acetic acid, which will not be elaborated here.
[0067] The solvent in step 5 can also be selected from one or more of toluene, pyridine, ethanol, and petroleum ether, which will not be elaborated here.
[0068] This specific embodiment is merely an explanation of this application and is not intended to limit it. After reading this specification, those skilled in the art can make modifications to this embodiment without contributing any inventive step, but such modifications are protected by patent law as long as they fall within the scope of the claims of this application.
Claims
1. A method for preparing disodium 5-bromo-4-chloro-3-indolyl phosphate, characterized in that, Includes the following steps: Step 1: React indole with acetic anhydride to generate compound a; Step 2: React compound a with tert-butanol hydrogen peroxide to generate compound b; Step 3: React compound b with N-chlorosuccinimide to generate compound c; Step 4: React compound c with N-bromosuccinimide to generate compound d; Step 5: React compound d with phosphorus oxychloride to generate compound e; Step 6: React compound e with sodium hydroxide to generate disodium 5-bromo-4-chloro-3-indolyl phosphate; The details are as follows:
2. The preparation method according to claim 1, characterized in that, In step 1, the molar ratio of indole to acetic anhydride is 1:(6-7.5).
3. The preparation method according to claim 1, characterized in that, In step 2, the molar ratio of compound a to tert-butanol peroxide is 1:(1-2); Preferably, in step 2, the reaction temperature is 70–80°C and the reaction time is 3–4 hours.
4. The preparation method according to claim 1, characterized in that, In step 2, compound a reacts with hydrogen peroxide tert-butanol in a solvent, wherein the ratio of compound a to solvent is 1 mol: (400-500) mL.
5. The preparation method according to claim 1, characterized in that, In step 3, the molar ratio of compound b to N-chlorosuccinimide is 1:(1-2); Preferably, in step 3, the reaction temperature is 60–70°C and the reaction time is 6–7 h.
6. The preparation method according to claim 1, characterized in that, In step 3, compound b reacts with N-chlorosuccinimide in a solvent, wherein the ratio of compound b to solvent is 1 mol: (1700-2000) mL.
7. The preparation method according to claim 4 or 6, characterized in that, The solvents in step 2 and step 3 are selected from one or more of petroleum ether, ethyl acetate, methanol, and ethanol.
8. The preparation method according to claim 1, characterized in that, In step 4, the molar ratio of compound c to N-bromosuccinimide is 1:(1-2); Preferably, in step 4, the reaction temperature is 30–40°C and the reaction time is 5–6 hours.
9. The preparation method according to claim 1, characterized in that, In step 5, the molar ratio of the compound d to phosphorus oxychloride is 1:(2-3); Preferably, in step 5, compound d reacts with phosphorus oxychloride in a solvent selected from one or more of toluene, pyridine, ethanol, and petroleum ether, and the ratio of compound d to solvent is 1 mol: (4400-4600) mL.
10. The preparation method according to claim 9, characterized in that, In step 5, after dissolving compound d in the solvent, the temperature is first raised to 60-70°C, and phosphorus oxychloride is added dropwise, with the addition time controlled at 10-20 min. After the addition is complete, the temperature is raised to 109-115°C and refluxed for 30-40 min, and then pyridine is added dropwise. After the addition is complete, the reaction continues for 3-5 h. Preferably, the molar ratio of compound d to pyridine is 1:(1-2).