Cyclization preparation method of N-hydroxy-7-azabenzotriazole
Through the substitution reaction of sulfonyl chloride compounds with 2-nitro-3-hydroxypyridine and the ring-closed reaction, the problems of low yield and poor safety in the preparation of N-hydroxy-7-azabenzotriazole were solved, and efficient and safe industrial production was achieved.
Patent Information
- Application Number
- CN202510621524.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-05-14
- Publication Date
- 2025-08-19
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Abstract
Description
Technical Field
[0001] The present invention belongs to the technical field of compound preparation, and more specifically, relates to a cyclization preparation method of N-hydroxy-7-azabenzotriazole. Background Art
[0002] Amide bond formation is a crucial chemical reaction in organic chemistry, particularly medicinal chemistry. In medicinal chemistry, the most common bonding method used to construct small-molecule peptide drugs is the amide bond. In currently widely used combinatorial chemistry, whether solid-phase or liquid-phase synthesis, the most studied area is how to more quickly and efficiently assemble molecular fragments using amide bonds. The amide bond between two amino acids is called a peptide bond.
[0003] Traditional amide bond synthesis typically involves first activating the carboxyl group to form an acyl chloride, anhydride, mixed anhydride, azide, or active ester, followed by reaction with an amino compound, typically a two-step process. Low amidation yields are primarily due to steric hindrance and electrical effects at the substrate's reactive center. The presence of bulky or numerous substituents near the substrate's reactive center slows the reaction; reduced charge on the nitrogen atom can slow the reaction or prevent its completion.
[0004] Since the late 1970s, amide bond-forming promoters (also useful in the synthesis of chiral esters) have been discovered and rapidly adopted in both laboratory and industrial production. Three of these reagents are widely used: 1-hydroxybenzotriazole (HOBT), 6-chloro-1-hydroxybenzotriazole (6-C1-HOBT), and 1-hydroxy-7-azabenzotriazole (HOAT). In the synthesis of six dipeptides, Merck researchers found that using EDCI alone as a condensing agent resulted in yields below 50%, with 15%-30% of isomers produced. However, when an equivalent amount of 1-hydroxybenzotriazole (HOBT) or N-hydroxy-7-azabenzotriazole (HOAT) was added, the yield increased to over 93%, while the isomer content decreased to less than 0.3%.
[0005] Among them, N-hydroxy-7-azabenzotriazole (HOAT) is a new, highly efficient peptide condensing agent developed in recent years. It not only effectively inhibits racemization but also significantly increases reaction speed, making it particularly suitable for the synthesis of sterically hindered peptides. For example, in the condensation of a highly hindered amine with 2-phenylpropionic acid, HOAT essentially completes the condensation in 22 hours, while 1-hydroxybenzotriazole (HOBT) produces only a small amount of the target product under the same conditions.
[0006] The synthesis of traditional HOAT is shown in the following formula (1):
[0007]
[0008] Specifically, 2-nitro-3-methoxypyridine, hydrazine hydrate, and water are added to a reactor in a specific ratio. After heating under reflux in an oil bath for a specified period of time, a certain amount of water is added, and HCl is added dropwise to make the reaction system strongly acidic. The product is cooled and crystallized, and then dried under vacuum to obtain a crude product. The crude product is further refined to obtain the fine product N-hydroxy-7-azabenzotriazole (HOAT). However, this method generally yields around 30-50%, and the reaction requires a temperature close to 100°C. At such high temperatures, hydrazine hydrate easily decomposes and releases hydrogen, which is relatively dangerous. Summary of the Invention
[0009] In view of this, the object of the present invention is to provide a cyclization preparation method of N-hydroxy-7-azabenzotriazole with high experimental safety, simple operation, mild conditions and easy control, and suitable for industrial production.
[0010] In order to solve the above technical problems, the present invention adopts the following technical solutions:
[0011] The cyclization preparation method of N-hydroxy-7-azabenzotriazole according to an embodiment of the present invention comprises:
[0012] Step S1, using a sulfonyl chloride compound to cause a substitution reaction of the hydroxyl group of 2-nitro-3-hydroxypyridine to obtain an intermediate;
[0013] Step S2, allowing the intermediate to undergo a ring-closing reaction with hydrazine hydrate to obtain N-hydroxy-7-azabenzotriazole.
[0014] In a possible implementation of the present invention, the sulfonyl chloride compound includes methanesulfonyl chloride, p-toluenesulfonyl chloride, or a mixture thereof.
[0015] Furthermore, the sulfonyl chloride compound is methylsulfonyl chloride, and the intermediate is 2-nitro-3-methylsulfonylpyridine.
[0016] Furthermore, the sulfonyl chloride compound is p-toluenesulfonyl chloride, and the intermediate is 2-nitro-3-p-toluenesulfonylpyridine.
[0017] Furthermore, the substitution reaction is carried out in a first solvent in the presence of a first base, wherein the first solvent is one or more of dichloromethane, dichloroethane, tetrahydrofuran, dioxane, N,N'-dimethylformamide, N,N'-dimethylacetamide, dimethyl sulfoxide, and N-methylpyrrolidone, and the first base is one or more of triethylamine, diisopropylethylamine, pyridine, dimethylaminopyridine, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, and lithium hydroxide.
[0018] Furthermore, the molar ratio of the 2-nitro-3-hydroxypyridine:sulfonyl chloride compound:first base is 1:(1-1.5):(1-5.0); the reaction temperature is 0-30° C., and the reaction time is 1-40 hours.
[0019] In a possible implementation of the present invention, the ring-closure reaction is carried out in a second solvent under the action of a second base, wherein the second solvent is one or more of methanol, ethanol, isopropanol, N,N'-dimethylformamide, N,N'-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, dichloromethane, ethyl acetate, n-heptane, tetrahydrofuran, dioxane, petroleum ether, and diethyl ether, and the second solvent is 2-5 times the volume of the intermediate.
[0020] Furthermore, the second base is one or more of triethylamine, diisopropylethylamine, pyridine, dimethylaminopyridine, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, and lithium hydroxide.
[0021] Furthermore, the molar ratio of the intermediate: hydrazine hydrate: second base is 1: (1-1.5): (1-5.0), the reaction temperature of the ring-closure reaction is 0-30° C., and the reaction time is 1-40 hours.
[0022] In a possible implementation of the present invention, the preparation method further includes:
[0023] Step S3: After the ring-closure reaction is completed, the mixture is filtered and concentrated, and slurried with an ethyl acetate / n-heptane mixed solvent to obtain the N-hydroxy-7-azabenzotriazole.
[0024] The above technical solution of the present invention has at least one of the following beneficial effects:
[0025] According to the preparation method of an embodiment of the present invention, 2-nitro-3-hydroxypyridine is used instead of traditional 2-nitro-3-methoxypyridine as a starting raw material. First, a sulfonyl chloride compound is subjected to a substitution reaction with the hydroxyl group of 2-nitro-3-hydroxypyridine to generate an intermediate with a better leaving group; thereafter, the intermediate is subjected to a ring-closure reaction with hydrazine hydrate to generate N-hydroxy-7-azabenzotriazole. Since the intermediate of the present application has a better leaving group than the traditional 2-nitro-3-methoxypyridine, the ring-closure reaction is easier to carry out, does not require a high reaction temperature, the conditions are mild and easy to control, and the experimental safety is higher, and the yield is higher.
[0026] In addition, the preparation method of the present invention has a short synthesis route, cheap and easily available raw and auxiliary materials, low synthesis cost, mild and easy-to-control conditions, and is suitable for industrial production. DETAILED DESCRIPTION
[0027] To make the objectives, technical solutions, and advantages of the embodiments of the present invention more clear, the technical solutions of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the described embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field are within the scope of protection of the present invention.
[0028] The following describes in detail the cyclization preparation method of N-hydroxy-7-azabenzotriazole according to an embodiment of the present invention.
[0029] The cyclization preparation method of N-hydroxy-7-azabenzotriazole according to an embodiment of the present invention comprises:
[0030] Step S1, using a sulfonyl chloride compound to cause a substitution reaction of the hydroxyl group of 2-nitro-3-hydroxypyridine to obtain an intermediate;
[0031] Step S2, allowing the intermediate to undergo a ring-closing reaction with hydrazine hydrate to obtain N-hydroxy-7-azabenzotriazole.
[0032] According to the preparation method of an embodiment of the present invention, 2-nitro-3-hydroxypyridine is used instead of traditional 2-nitro-3-methoxypyridine as a starting raw material. First, a sulfonyl chloride compound is subjected to a substitution reaction with the hydroxyl group of 2-nitro-3-hydroxypyridine to generate an intermediate with a better leaving group; thereafter, the intermediate is subjected to a ring-closure reaction with hydrazine hydrate to generate N-hydroxy-7-azabenzotriazole. Since the intermediate of the present application has a better leaving group than the traditional 2-nitro-3-methoxypyridine, its ring-closure reaction is easier to carry out, does not require a high reaction temperature, the conditions are mild and easy to control, and the experimental safety is higher, and the yield is higher.
[0033] Examples of sulfonyl chloride compounds include methanesulfonyl chloride, p-toluenesulfonyl chloride, or mixtures thereof. These compounds can easily undergo substitution reactions with hydroxyl groups and can be easily removed during the ring-closure reaction, making them simple and easy to operate.
[0034] According to some embodiments of the present invention, the sulfonyl chloride compound is methylsulfonyl chloride. In this case, the intermediate is 2-nitro-3-methylsulfonylpyridine.
[0035] At this time, the entire synthetic route is shown in the following formula (2):
[0036]
[0037] According to other embodiments of the present invention, the sulfonyl chloride compound is p-toluenesulfonyl chloride. In this case, the intermediate is 2-nitro-3-p-toluenesulfonylpyridine.
[0038] At this time, the entire synthetic route is shown in the following formula (3):
[0039]
[0040] Both sulfonyl chlorides have the advantage of high activity, and the intermediate formed is easier to remove the group from the sulfonyl chloride during the ring-closure reaction. Among them, methanesulfonyl chloride is more preferred due to its high reaction conversion rate and high yield.
[0041] The following describes in detail the substitution reaction (i.e., step S1) and the ring-closure reaction (i.e., step S2) in the preparation method.
[0042] (1) Substitution reaction
[0043] As described above, according to the preparation method of the present invention, 2-nitro-3-hydroxypyridine is used as the starting material, and a sulfonyl chloride compound is first subjected to a substitution reaction with a hydroxyl group to generate an intermediate having a good leaving group.
[0044] In some embodiments of the present invention, the substitution reaction is carried out in the first solvent in the presence of a first base, that is, the substitution reaction is carried out in a solution under the catalysis of a base.
[0045] The first solvent may be, for example, one or more of dichloromethane, dichloroethane, tetrahydrofuran, dioxane, N,N'-dimethylformamide, N,N'-dimethylacetamide, dimethyl sulfoxide, and N-methylpyrrolidone. 2-Nitro-3-hydroxypyridine and sulfonyl chloride compounds dissolve well in these solvents. Dichloromethane is preferred for ease of post-processing such as concentration.
[0046] In addition, as the first base, for example, it can be one or more of triethylamine, diisopropylethylamine, pyridine, dimethylaminopyridine, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, and lithium hydroxide. Under the catalytic action of these bases, the hydroxyl group is more likely to be separated, thereby promoting the substitution reaction. Among them, triethylamine or diisopropylethylamine is preferred, as the yield is 5-20% higher than that of other bases. From the perspective of cost and atom economy, triethylamine is more preferred.
[0047] In some embodiments of the present invention, the molar ratio of 2-nitro-3-hydroxypyridine:sulfonyl chloride compound:first base is 1:(1-1.5):(1-5.0).
[0048] That is to say, compared with 2-nitro-3-hydroxypyridine, using a sulfonyl chloride compound in an amount slightly higher than the chemical equivalent and a base in an amount slightly higher than the chemical equivalent is more conducive to promoting the reaction, improving the yield and reaction rate, and at the same time will not cause a large amount of excess and waste of raw materials.
[0049] Preferably, the first base is triethylamine, and the molar ratio of 2-nitro-3-hydroxypyridine:sulfonyl chloride compound:triethylamine is 1:1.05:1.2. Under this condition, the yield, reaction rate, and production cost can be balanced.
[0050] In addition, the reaction temperature of the substitution reaction can be set to 0-30°C, and the reaction time is 1-40 hours. Preferably, the reaction temperature is room temperature and the reaction time is 2 hours. Excessively high temperature and prolonged reaction time will increase the production of by-products. Moreover, the reaction conditions of this reaction are mild and controllable.
[0051] In some embodiments of the present invention, after the reaction is completed, the following steps may be further performed: washing with brine, drying, and evaporating the first solvent to obtain a crude intermediate; and further processing the crude intermediate by slurrying (preferably using dichloromethane and n-heptane in a ratio of 1:10 to 1:20). This post-treatment step can remove unreacted sulfonyl chloride compounds, avoid the introduction of unnecessary byproducts and difficult-to-remove impurities in the subsequent ring-closure reaction, and further improve the yield.
[0052] (2) Ring closure reaction
[0053] That is, after the hydroxyl group is substituted to form an intermediate, the intermediate is used to undergo a ring-closure reaction with hydrazine hydrate to obtain the target product.
[0054] In some embodiments of the present invention, the ring-closure reaction is carried out in a second solvent under the action of a second base.
[0055] The second solvent may be, for example, one or more of methanol, ethanol, isopropanol, N,N'-dimethylformamide, N,N'-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, dichloromethane, ethyl acetate, n-heptane, tetrahydrofuran, dioxane, petroleum ether, and diethyl ether. Methanol is preferably used, as the use of a protic solvent facilitates the ring-closure reaction. Furthermore, the volume of methanol is 2-5 times the volume of the intermediate, preferably 3 times the volume.
[0056] In addition, as the second base, one or more of triethylamine, diisopropylethylamine, pyridine, dimethylaminopyridine, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, and lithium hydroxide can be selected. Inorganic bases make the reaction system heterogeneous, and higher temperatures are required when amplifying the reaction. The product is unstable under high-temperature strong alkaline conditions, so an organic base is preferably used. Further, considering the yield, triethylamine or diisopropylethylamine is preferred. Compared to other organic bases, the yield can be 5-20% higher. From the perspective of cost, alkalinity strength, and atom economy, triethylamine is more preferred.
[0057] In some embodiments of the present invention, the molar ratio of intermediate: hydrazine hydrate: second base is 1: (1-1.5): (1-5.0). That is, using a slightly higher than chemically equivalent amount of hydrazine hydrate and a slightly higher than chemically equivalent amount of the second base relative to the intermediate is more conducive to promoting the reaction, improving the yield and reaction rate, while also preventing excessive use and waste of raw materials. Preferably, the molar ratio of intermediate: hydrazine hydrate: triethylamine is 1: 1.5: 2.0.
[0058] In addition, the reaction temperature of the ring-closure reaction can be set to, for example, 0 to 30°C, and the reaction time is 1 to 40 hours. Moreover, the reaction conditions of the reaction are mild and controllable. The reaction temperature is carried out at room temperature and the reaction time is 8 hours. Excessively high temperatures and extended reaction times will increase the production of by-products and cause unnecessary production costs.
[0059] In some embodiments of the present invention, the preparation method further comprises:
[0060] Step S3: After the ring-closure reaction is completed, the mixture is filtered and concentrated, and slurried with an ethyl acetate / n-heptane mixed solvent to obtain the N-hydroxy-7-azabenzotriazole.
[0061] That is to say, the preparation method of the present invention is more convenient for post-processing. After filtration and concentration, 3 times the solvent is added for pulping, filtered and then dried to obtain a qualified product. The preferred solvent is ethyl acetate and n-heptane, with a volume ratio of 1 / 2 to 1 / 10.
[0062] The cyclization preparation method of N-hydroxy-7-azabenzotriazole of the present invention is further described in detail below through specific examples.
[0063] Example 1
[0064] (1) Preparation of intermediate 2-nitro-3-methylsulfonylpyridine
[0065] In a three-necked flask, 14 g of 2-nitro-3-hydroxypyridine was dissolved in 60 mL of dichloromethane, 12 g of triethylamine was added, and 12 g of methanesulfonyl chloride was added dropwise at 0-5°C. After the addition was complete, the temperature was naturally raised to room temperature and the reaction was carried out for 5 h.
[0066] The reaction of the raw material was complete as monitored by TLC. The reaction solution was filtered, washed twice with 100 mL of water, dried over anhydrous sodium sulfate, concentrated, slurried with ethyl acetate / n-heptane = 1:20, filtered, and dried over the filter cake to obtain 20.7 g of 2-nitro-3-methylsulfonylpyridine in a yield of 95%.
[0067] The nuclear magnetic resonance experimental data of the obtained intermediate are as follows:
[0068] 1 H NMR (400MHz, CDCl3) δ8.52 (d, J = 4.4 Hz, 1H), 8.06 (d, J = 8.2 Hz, 1H), 7.75 (dd, J = 8.3, 4.6 Hz, 1H), 3.39 (s, 3H).
[0069] The test results were consistent with the structure of 2-nitro-3-methylsulfonylpyridine.
[0070] (2) Preparation of N-hydroxy-7-azabenzotriazole
[0071] In a three-necked flask, 20.7 g of 2-nitro-3-methylsulfonylpyridine prepared in (1) above was dissolved in a mixed solvent of 100 mL of methanol, and then 324 g of hydrazine hydrate was added. The atmosphere was replaced with nitrogen, and the temperature was raised to room temperature for reaction for 8 hours.
[0072] After TLC indicated completion of the reaction, the pH was adjusted to 3-4 with hydrochloric acid, concentrated, and then water was added. The reaction solution was washed with 100 mL of water, filtered, and then washed twice with 50 mL of water. The crude product of N-hydroxy-7-azabenzotriazole (HOAT) was obtained. The product was then slurried with ethyl acetate / n-heptane (1 / 2) to obtain 9 g of N-hydroxy-7-azabenzotriazole (HOAT), with a yield of 70%.
[0073] The NMR experimental data of the obtained product are as follows:
[0074] 1H NMR (400MHz, DMSO) δ13.18 (s, 1H), δ8.78 (dd, J = 4.4, 1.1 Hz, 1H), 8.54 (dd, J = 8.4, 1.1 Hz, 1H), 7.53 (dd, J = 8.4, 4.4 Hz, 1H).
[0075] The detection results were consistent with the target product HOAT.
[0076] Example 2
[0077] (1) Preparation of reaction intermediate 2-nitro-3-toluenesulfonylpyridine
[0078] In a three-necked flask, 14 g of 2-nitro-3-hydroxypyridine was dissolved in 60 mL of dichloromethane, 12 g of triethylamine was added, and 20 g of p-toluenesulfonyl chloride was added dropwise at 0-5°C. After the addition was complete, the temperature was naturally raised to room temperature and the reaction was carried out for 5 h.
[0079] The reaction of the raw material was complete as monitored by TLC. The reaction solution was filtered, washed twice with 100 mL of water, dried over anhydrous sodium sulfate, concentrated, slurried with ethyl acetate / n-heptane = 1:20, filtered, and dried over the filter cake to obtain 27 g of 2-nitro-3-toluenesulfonylpyridine in a yield of 92%.
[0080] The nuclear magnetic resonance experimental data of the obtained intermediate are as follows:
[0081] 1 H NMR (400MHz, CDCl3) δ8.45(d,J=4.5Hz,1H),8.01(d,J=8.3Hz,1H),7.74(d,J=8.3Hz,2H),7.67(dd,J=8.3,4.6Hz,1H),7.37(d,J=8.2Hz,2H),2.48(s,3H).
[0082] The test results were consistent with the structure of 2-nitro-3-toluenesulfonylpyridine.
[0083] (2) Preparation of N-hydroxy-7-azabenzotriazole (HOAT)
[0084] In a three-necked flask, 27 g of 2-nitro-3-toluenesulfonylpyridine obtained in (1) above was added and dissolved in a mixed solvent of 100 mL of methanol. Then, 19 g of triethylamine and 7 g of hydrazine hydrate were added. The atmosphere was replaced with nitrogen and the mixture was reacted at room temperature for 8 hours.
[0085] TLC indicated the reaction was complete. The pH was adjusted to 3-4 with hydrochloric acid, and the mixture was concentrated, slurried with 100 mL of water, filtered, and washed twice with 50 mL of water. The mixture was then oven-dried to obtain crude N-hydroxy-7-azabenzotriazole (HOAT). The crude product was then slurried with ethyl acetate / n-heptane (1 / 2) to obtain 8 g of N-hydroxy-7-azabenzotriazole (HOAT), with a yield of 63%.
[0086] The NMR experimental data of the obtained product are as follows:
[0087] 1 H NMR (400MHz, DMSO) δ13.18 (s, 1H), δ8.78 (dd, J = 4.4, 1.1 Hz, 1H), 8.54 (dd, J = 8.4, 1.1 Hz, 1H), 7.53 (dd, J = 8.4, 4.4 Hz, 1H).
[0088] The detection results were consistent with the target product HOAT.
[0089] It can be seen from the above examples that the preparation method of N-hydroxy-7-azabenzotriazole (HOAT) of the present invention has the advantages of simple operation, short route, low cost and high yield.
[0090] In summary, the cyclization preparation method of N-hydroxy-7-azabenzotriazole of the present invention has the advantages of being easier to carry out the ring-closure reaction, not requiring a high reaction temperature, being mild and easily controllable, having higher experimental safety, and having a higher yield. In addition, the preparation method of the present invention has a short synthetic route, inexpensive and readily available raw and auxiliary materials, low synthesis cost, mild and easily controllable conditions, and is suitable for industrial production.
[0091] The above is a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as within the scope of protection of the present invention.
Claims
1. A cyclization preparation method of N-hydroxy-7-azabenzotriazole, characterized in that: include: Step S1, using a sulfonyl chloride compound to cause a substitution reaction of the hydroxyl group of 2-nitro-3-hydroxypyridine to obtain an intermediate; Step S2, allowing the intermediate to undergo a ring-closing reaction with hydrazine hydrate to obtain N-hydroxy-7-azabenzotriazole.
2. The method according to claim 1, characterized in that The sulfonyl chloride compound includes methanesulfonyl chloride, p-toluenesulfonyl chloride, or a mixture thereof.
3. The method according to claim 2, characterized in that The sulfonyl chloride compound is methylsulfonyl chloride, and the intermediate is 2-nitro-3-methylsulfonylpyridine.
4. The method according to claim 2, characterized in that The sulfonyl chloride compound is p-toluenesulfonyl chloride, and the intermediate is 2-nitro-3-p-toluenesulfonylpyridine.
5. The method according to claim 2, characterized in that The substitution reaction is carried out in a first solvent in the presence of a first base, Wherein, the first solvent is one or more of dichloromethane, dichloroethane, tetrahydrofuran, dioxane, N,N'-dimethylformamide, N,N'-dimethylacetamide, dimethyl sulfoxide, and N-methylpyrrolidone, The first base is one or more of triethylamine, diisopropylethylamine, pyridine, dimethylaminopyridine, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, and lithium hydroxide.
6. The method according to claim 5, characterized in that The molar ratio of the 2-nitro-3-hydroxypyridine:sulfonyl chloride compound:first base is 1:(1-1.5):(1-5.0); the reaction temperature is 0-30° C., and the reaction time is 1-40 hours.
7. The method according to claim 1, characterized in that The ring-closure reaction is carried out in a second solvent under the action of a second base, The second solvent is one or more of methanol, ethanol, isopropanol, N,N'-dimethylformamide, N,N'-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, dichloromethane, ethyl acetate, n-heptane, tetrahydrofuran, dioxane, petroleum ether, and diethyl ether, and the volume of the second solvent is 2-5 times that of the intermediate.
8. The method according to claim 7, characterized in that The second base is one or more of triethylamine, diisopropylethylamine, pyridine, dimethylaminopyridine, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, and lithium hydroxide.
9. The method according to claim 8, characterized in that The molar ratio of the intermediate: hydrazine hydrate: the second base is 1: (1-1.5): (1-5.0), the reaction temperature of the ring-closure reaction is 0-30° C., and the reaction time is 1-40 hours.
10. The method according to claim 1, characterized in that Also includes: Step S3: After the ring-closure reaction is completed, the mixture is filtered and concentrated, and slurried with an ethyl acetate / n-heptane mixed solvent to obtain the N-hydroxy-7-azabenzotriazole.