Synthesis method of adarglasib intermediate
By simplifying the synthesis method of adagarate intermediates, using mild reaction conditions and appropriate catalysts, the problems of using highly toxic chemicals and low raw material utilization in existing technologies have been solved, enabling efficient and low-cost industrial production.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2026-01-28
- Publication Date
- 2026-05-12
AI Technical Summary
Existing methods for synthesizing adagarate intermediates have drawbacks, including the use of highly toxic chemicals, low raw material utilization, poor atom economy, and complex synthetic routes, making them unsuitable for industrial production.
By employing steps such as cyclization, coupling, and deprotection, and using mild reaction conditions and appropriate amounts of catalysts, alkaline auxiliaries, and solvents, the post-processing is simplified, high-temperature and high-pressure reactions are avoided, intermediate impurities are reduced, and product purification efficiency is improved.
This method enables the efficient synthesis of adagarate intermediates, simplifies the process, reduces production costs, and improves product purification efficiency, making it suitable for industrial production.
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Figure CN122010821A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of pharmaceutical synthesis, and in particular to a method for synthesizing an adagaracilb intermediate compound. Background Technology
[0002] Adagorazolidone is a highly selective, irreversible small molecule inhibitor of KRAS G12C. It effectively inhibits downstream oncogenic signaling pathways by covalently binding to and locking the KRAS G12C protein in an inactive state. This drug received accelerated approval from the US FDA in 2022 for the treatment of previously treated KRAS G12C-mutant non-small cell lung cancer (NSCLC), providing an important targeted therapy option for approximately 13% of NSCLC patients with this mutation. In addition to lung cancer, it has also shown therapeutic potential in other KRAS G12C-mutant solid tumors such as colorectal cancer and pancreatic cancer, and its indications are expected to continue to expand. Industry analysis indicates that the global KRAS inhibitor market is projected to grow rapidly to tens of billions of US dollars in the coming years, representing a promising market outlook.
[0003] The intermediate compound of adagaratesibu has the following chemical name: (S)-7-(8-chloronaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(1H)-one; its structural formula is... The molecular formula is: C 23 H 25 ClN4O2; molecular weight: 424.92; CAS Registry Number: 2408250-15-5.
[0004] The structural formula of Adagoras is as follows:
[0005] .
[0006] CAS Registry Number: 2326521-71-3, Molecular Formula: C 23 H 35 ClFN7O2.
[0007] Synthesis methods for this product have been reported in the literature, but these methods all have obvious drawbacks.
[0008] The synthetic route of the method in patent CN119072477A is as follows:
[0009] .
[0010] The route from compound to The compound undergoes a three-step reaction. The reaction also uses the highly toxic and dangerous chemical triphosgene, which poses a potential toxic gas risk and requires strict quenching and protection. Furthermore, triphosgene has a molecular weight as high as 296.75 g / mol, but its effective fraction (one carbonyl group) has a molecular weight of only 28 g / mol, resulting in low raw material utilization and poor atom economy. Summary of the Invention
[0011] In view of the shortcomings of the prior art described above, the purpose of this invention is to provide a method for synthesizing adagarate intermediate compounds, which is suitable for industrial production.
[0012] To achieve the above and other related objectives, the present invention is obtained through the following technical solution.
[0013] The first aspect of this invention provides a method for synthesizing an intermediate compound of adagograss, comprising a cyclization reaction of a compound with the structure shown in Formula III and a compound with the structure shown in Formula IV to obtain an adagograss intermediate compound with the structure shown in Formula V, wherein the reaction route is as follows:
[0014] .
[0015] Preferably, the molar ratio of compound III to compound IV is 1:(1.05-1.2), such as 1:1.05, 1:1.1, 1:1.15, or 1:1.2. If the ratio is too small, too much compound IV will remain, making subsequent separation and purification difficult; if the ratio is too large, the reaction will be incomplete, resulting in a decrease in the yield of the target product. More preferably, the ratio is 1:1.06.
[0016] Preferably, the cyclization reaction system further includes a basic auxiliary agent, which is selected from one or both of potassium tert-butoxide and sodium methoxide. The role of the basic auxiliary agent in the cyclization reaction is to provide a basic environment. More preferably, the basic auxiliary agent is sodium methoxide.
[0017] More preferably, the molar ratio of the alkaline auxiliary agent to the compound of formula III is (3-5):1. For example, it can be 3:1, 4:1, or 5:1. Preferably, it is 3:1.
[0018] Preferably, the reaction system for the cyclization reaction further includes a first organic solvent, which is one or both selected from methanol or tetrahydrofuran (THF); other solvents will result in poor solubility. More preferably, the first organic solvent is methanol.
[0019] Preferably, the cyclization reaction temperature is 20–65°C, such as 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, or 65°C. More preferably, the reaction temperature is 60–65°C. If the reaction temperature is too high (e.g., above 70°C), the product will contain more impurities; if the reaction temperature is below 50°C, the reaction will be very slow; if the reaction temperature is too low (e.g., below 10°C), the reaction will not proceed.
[0020] Preferably, the cyclization reaction takes 18 to 22 hours, such as 18 hours, 19 hours, 20 hours, 21 hours, or 22 hours. More preferably, the reaction time is 20 hours.
[0021] Preferably, the reaction further includes a post-processing step, which includes extraction, concentration, and purification. More preferably, the extraction involves adding water and methyl tert-butyl ether (MTBE), stirring, and then separating the organic phases. Those skilled in the art can determine the specific amounts of water and MTBE added based on actual extraction operations, as long as the reaction product system can be separated into layers to facilitate phase separation. For example, specifically, the volume of water added during extraction is at least 10 times the volume of the compound of formula III, such as 12, 14, 16, 18, or 20 times, and the volume of MTBE added is at least 4 times the volume of the compound of formula III, such as 6, 8, 10, or 12 times.
[0022] More preferably, the concentration is achieved by vacuum distillation of the organic phase; the purification involves adding ethyl acetate to dissolve the crude product after vacuum distillation of the organic phase, adding n-heptane dropwise, filtering, and drying at 50-60°C to obtain the target product. Those skilled in the art can set specific amounts of ethyl acetate and n-heptane based on actual purification operations, as long as the reaction product achieves the purpose of dissolving the crude product and purification. For example, specifically, the amount of ethyl acetate used is 1-2 mL per gram of crude product. The volume of n-heptane added dropwise is 1.5-3 times the volume of ethyl acetate used, such as 1.5 times, 2 times, 2.5 times, or 3 times.
[0023] The second aspect of this invention also discloses a method for obtaining a compound with the structure shown in Formula II by coupling reaction with 1-bromo-8-chloronaphthalene, wherein the reaction route is as follows:
[0024] .
[0025] Preferably, the molar ratio of compound II to 1-bromo-8-chloronaphthalene is 1:(1 to 1.1), such as 1:1, 1:1.05, or 1:1.1. If the molar ratio is too small, too much 1-bromo-8-chloronaphthalene will remain, complicating the separation and purification steps; if the molar ratio is too large, the reaction will be incomplete. A ratio of 1:1 is preferred.
[0026] Preferably, the coupling reaction system further includes a catalyst, which is one or both selected from palladium acetate or tris(dibenzylacetone)dipalladium(O) (abbreviated as DBA palladium). More preferably, the catalyst is DBA palladium, considering the need to suppress side reactions and increase the yield of the target compound.
[0027] More preferably, the molar ratio of the catalyst to the compound of formula II is (0.02-0.05):1. For example, it can be 0.02:1, 0.03:1, 0.04:1, or 0.05:1. Preferably, it is 0.02:1. The amount of catalyst used is the catalytically effective amount. If the amount of catalyst is too small, the reaction is very slow, and the raw material conversion is insufficient; if the amount of catalyst is too large, the reaction cost increases.
[0028] Preferably, the coupling reaction system further includes a basic auxiliary agent, which is selected from one or both of cesium carbonate and potassium tert-butoxide. The basic auxiliary agent provides an alkaline environment for the reaction and also neutralizes the hydrobromic acid produced during the reaction. More preferably, the basic auxiliary agent is cesium carbonate, considering the need to suppress side reactions and increase the yield of the target compound.
[0029] More preferably, the molar ratio of the alkaline auxiliary agent to the compound of formula II is (1~2):1. For example, it can be 1:1, 1.2:1, 1.4:1, 1.6:1, 1.8:1 or 2:1. Preferably, it is 1:1.
[0030] Preferably, the coupling reaction system further includes a ligand, which is selected from one or both of 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (abbreviated as XantPhos) or 2-(dicyclohexylphosphino)biphenyl. More preferably, the ligand is XantPhos, considering the suppression of side reactions and the improvement of the yield of the target compound. The ligand is a catalyst ligand, and it must be used in conjunction with a palladium metal catalyst to effectively catalyze the reaction; without the ligand, the palladium catalyst is easily deactivated or its catalytic efficiency is significantly reduced, causing the reaction to fail.
[0031] More preferably, the molar ratio of the ligand to the compound of formula II is (0.04 to 0.1):1. For example, it can be 0.04:1, 0.05:1, 0.06:1, 0.07:1, 0.08:1, 0.09:1 or 0.1:1. Preferably, it is 0.04:1.
[0032] Preferably, the reaction system of the coupling reaction further includes a second organic solvent, which is selected from one or more of toluene, N,N-dimethylformamide (abbreviated as DMF), and 1,4-dioxane; more preferably, the second organic solvent is 1,4-dioxane, based on the consideration of suppressing the occurrence of side reactions and improving the yield of the target compound.
[0033] Preferably, the coupling reaction temperature is 90–100°C, such as 90°C, 95°C, or 100°C. More preferably, the reaction temperature is 95–100°C. The reaction is very slow below 80°C; the reaction does not occur below 60°C.
[0034] Coupling reactions proceed stably along the target reaction pathway through the combined action of catalysts, basic auxiliaries, and solvents, while suppressing side reactions and thus increasing the yield of the target compound. Using other types of catalysts, basic auxiliaries, or solvents will increase the occurrence of side reactions, reduce the yield, and increase the difficulty of subsequent product separation and purification.
[0035] Preferably, the coupling reaction time is 18–22 hours, such as 18 hours, 19 hours, 20 hours, 21 hours, or 22 hours. More preferably, the reaction time is 20 hours.
[0036] Preferably, the coupling reaction further includes a post-processing step, which includes extraction and concentration. More preferably, the extraction involves adding water and MTBE, stirring, and then retaining the organic phase in layers. More preferably, the concentration involves vacuum distillation of the organic phase. Those skilled in the art can set specific amounts of water and MTBE added based on actual extraction operations, as long as the reaction product system can be separated into layers to facilitate phase separation. For example, specifically, the volume of water added during extraction is at least 10 times the volume of the compound of formula III, such as 12, 14, 16, 18, or 20 times. The volume of MTBE added is at least 4 times the volume of the compound of formula III, such as 6, 8, 10, or 12 times.
[0037] The third aspect of this invention also discloses a method for obtaining a compound with the structure shown in Formula I by undergoing a deprotection reaction, as shown in the following reaction route:
[0038] .
[0039] Preferably, the deprotection reaction system further includes an acidic auxiliary agent, which is selected from one or two of trifluoroacetic acid, p-toluenesulfonic acid, or ethyl hydrochloride; more preferably, the acidic auxiliary agent is ethyl hydrochloride. The acidic auxiliary agent provides an acidic environment for the reaction and simultaneously provides a sufficient proton concentration in the reaction system. By protonating the carbonyl oxygen of the BOC group, it drives its elimination cleavage, thereby efficiently and selectively removing the BOC group.
[0040] In the deprotection reaction, ethyl acetate plays a dual role in the reaction system; it is both an acidic auxiliary agent that provides protons and an organic solvent that dissolves the reactants and supports the reaction process. Therefore, when this solution is chosen as the acidic auxiliary agent, it itself satisfies the reaction system's requirements for an organic solvent, eliminating the need for additional solvents. This simplifies the operation and reduces reagent costs.
[0041] The structural formula of the ethyl hydrochloride is as follows: The concentration of hydrochloric acid is 1~7 mol / L; for example, it can be 1 mol / L, 2 mol / L, 3 mol / L, 4 mol / L, 5 mol / L, 6 mol / L, or 7 mol / L.
[0042] More preferably, the molar ratio of the acidic auxiliary agent to the compound of formula I is (4~6):1. For example, it can be 4:1, 5:1 or 6:1. Preferably, it is 5:1.
[0043] Preferably, the reaction system for the deprotection reaction further includes a third organic solvent, which is one or both selected from methanol or ethyl acetate; more preferably, the third organic solvent is ethyl acetate.
[0044] Preferably, the deprotection reaction temperature is 10–40°C, such as 10–20°C, 20–30°C, or 30–40°C. More preferably, the reaction temperature is 20–30°C. If the reaction temperature is too high (e.g., above 50°C), side reactions will increase, producing impurities; if the reaction temperature is below 10°C, the reaction will be very slow; if the reaction temperature is too low (e.g., below 0°C), the reaction will essentially not occur.
[0045] Preferably, the deprotection reaction time is 18 to 22 hours, such as 18 hours, 19 hours, 20 hours, 21 hours or 22 hours. More preferably, the reaction time is 20 hours.
[0046] Preferably, the deprotection reaction further includes a post-processing step, which is filtration and purification. More preferably, the filtration involves filtering the reaction solution, washing the filter cake with ethyl acetate, and drying the filter cake at 50°C. The purification involves dissolving the dried filter cake in water, adjusting the pH to 9-10 with a 5% sodium carbonate solution, filtering, and drying the filter cake at 50-60°C. Those skilled in the art can determine the specific amount of water added based on actual purification operations, as long as it ensures the crude product is completely dissolved. For example, specifically, the amount of water used is 3-10 mL per gram of crude product.
[0047] The fourth aspect of this invention also discloses the use of a palladium salt and ligand combination as a catalyst system in the reaction of a compound with the structure shown in Formula II with 1-bromo-8-chloronaphthalene to generate a compound with the structure shown in Formula III.
[0048] Preferably, the palladium salt is selected from one or both of palladium acetate or tris(dibenzylacetone)dipalladium(O) (abbreviated as DBA palladium). More preferably, the catalyst is DBA palladium.
[0049] Preferably, the ligand is selected from one or both of 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (abbreviated as XantPhos) or 2-(dicyclohexylphosphino)biphenyl. More preferably, the ligand is XantPhos. The ligand is a catalyst ligand that needs to be used in conjunction with a palladium metal catalyst to effectively catalyze the reaction; without the use of the ligand, the palladium catalyst is prone to deactivation or a significant reduction in catalytic efficiency, resulting in the reaction failing to proceed smoothly.
[0050] This invention provides a method for synthesizing an intermediate compound of adagaratesib. The synthesis steps of this method involve simple processes and mild reaction conditions, without high temperature (above 100°C) or high pressure reactions. The intermediates formed in each synthesis step have few impurities, and the products are easy to purify without the need for silica gel column separation and purification, or cumbersome post-processing operations. This avoids complicated separation and purification steps, prevents waste of raw materials, and reduces production costs.
[0051] The method for synthesizing adagarate intermediate compounds provided by this invention is suitable for industrial production. Attached Figure Description
[0052] Figure 1 This is a flowchart illustrating the preparation route of compound II in Example 1.
[0053] Figure 2 This is a flowchart illustrating the preparation route of compound III in Example 2.
[0054] Figure 3 This is a flowchart illustrating the preparation route of compound V in Example 3.
[0055] Figure 4 This is a complete flowchart of the synthesis process.
[0056] Figure 5 The above is an HPLC spectrum of the compound with the structure of formula V prepared in the examples. Detailed Implementation
[0057] The following specific examples illustrate the implementation of the present invention. Those skilled in the art can easily understand other advantages and effects of the present invention from the content disclosed in this specification. The present invention can also be implemented or applied through other different specific embodiments, and various details in this specification can also be modified or changed based on different viewpoints and applications without departing from the spirit of the present invention.
[0058] Furthermore, it should be understood that the one or more method steps mentioned in this invention do not preclude the existence of other method steps before or after the combined steps, or the insertion of other method steps between these explicitly mentioned steps, unless otherwise stated; moreover, unless otherwise stated, the numbering of each method step is merely a convenient tool for identifying each method step, and not for limiting the order of the method steps or limiting the scope of the invention. Changes or adjustments to their relative relationships, without substantially altering the technical content, should also be considered as within the scope of the invention.
[0059] The room temperature in this application is 25℃±5℃.
[0060] The HPLC analytical method in this application embodiment is as follows:
[0061] Instrument: waters2695
[0062] Column: DIKMA SILVERSIL C18
[0063] Detection wavelength: 214 nm
[0064] Mobile phases: Phase A: 0.05% trifluoroacetic acid (TFA) / water (H2O) Phase B: 0.05% trifluoroacetic acid (TFA) / acetonitrile (ACN)
[0065] Sample solution preparation: Dissolve 1 mg of sample in 1 mL of acetonitrile
[0066] Flow rate: 1 mL / min
[0067] Column temperature: 35℃
[0068] Injection volume: 5 μL
[0069] Washing process
[0070]
[0071] Example 1
[0072] This embodiment is as follows: Figure 1 The synthetic route shown is for the preparation of compounds with structures as shown in Formula II.
[0073] Ethyl hydrochloride (50 L) was added to a mechanically stirred 100 L reactor. Compound I (10 kg, 38.9 mol) was added in portions at room temperature, and the reaction was carried out at room temperature (25 °C) for 20 h. The reaction solution was filtered, and the filter cake was washed with ethyl acetate (5 L). After washing, the filter cake was dried at 50 °C. The dried filter cake was dissolved in water (20 L), and the pH was adjusted to 9-10 by adding 5% sodium carbonate solution. The mixture was then filtered, and the filter cake was dried at 50 °C to obtain 5.5 kg of compound II product, with a yield of 90%.
[0074] The NMR and mass spectrometry data of the prepared compound of formula II are as follows: ¹H NMR (400 MHz, CDCl₃): 4.87 (s, 2H), 3.72 (s, 3H), 3.70 (t, 1H), 2.78 (t, 2H), 1.65 (t, 2H). MS: m / z = 158.2 (M+H) + .
[0075] Example 2
[0076] This embodiment is as follows: Figure 2 The synthetic route shown is for the preparation of compounds with the structural formula shown in Formula III.
[0077] Compound II (3 kg, 19.1 mol), 1-bromo-8-chloronaphthalene (4.6 kg, 19.1 mol), cesium carbonate (6.2 kg, 19.1 mol), and 1,4-dioxane (15 L) were added to a mechanically stirred 100 L reactor. Nitrogen gas was purged for 2 h. DBA palladium (350 g, 0.382 mol) and XantPhos (442 g, 0.764 mol) were added. The reaction was carried out at 95 °C for 20 h. After cooling to room temperature, water (30 L) and MTBE (15 L) were added to the reaction solution. After stirring for 15 min, the organic phase was separated and concentrated under vacuum to obtain 5 kg of compound III product, with a yield of 82%.
[0078] The NMR and mass spectrometry data of the prepared compound of formula III are as follows: ¹H NMR (400 MHz, CDCl₃): 7.87 (dd, 2H), 7.58 (dd, 1H), 7.33 (dd, 1H), 7.31 (dd, 1H), 6.80 (dd, 1H), 5.73 (s, 2H), 3.72 (s, 3H), 3.70 (t, 1H), 3.33 (t, 2H), 1.65 (t, 2H). MS: m / z = 318.8 (M+H) + .
[0079] Example 3
[0080] This embodiment is as follows: Figure 3 The synthetic route shown is for the preparation of the Adagarasib intermediate compound.
[0081] Compound III (3 kg, 9.4 mol), methanol (15 L), and compound IV (3.3 kg, 10 mol) were added to a 100 L mechanically stirred reactor. Sodium methoxide (1.5 kg, 28.2 mol) was added in portions at 20–25 °C. After the addition was complete, the temperature was raised to 60 °C and reacted for 20 h. The temperature was then lowered to room temperature, and water (30 L) was added dropwise. MTBE (15 L) was then added and stirred for 15 min. The organic phase was separated, concentrated under vacuum, and the crude product was dissolved in 4 L of ethyl acetate. 8 L of n-heptane was added dropwise, filtered, and dried at 50 °C to obtain 3.2 kg of the adagarate intermediate compound product, with a yield of 80% and a purity of 99.07%.
[0082] The NMR and mass spectrometry data of the prepared compound of formula V are as follows: ¹H NMR (400 MHz, CDCl₃): 7.87 (dd, 2H), 7.58 (dd, 1H), 7.33 (dd, 1H), 7.31 (dd, 1H), 6.80 (dd, 1H), 5.53 (s, 1H), 4.17 (s, 2H), 3.52 (d, 2H), 3.36 (m, 1H), 3.33 (t, 2H), 2.85 (t, 2H), 2.72 (t, 2H), 2.27 (s, 3H), 1.90 (m, 2H), 1.74 (m, 2H). MS: m / z = 426.1 (M+H) + .
[0083] Figure 5 The above is an HPLC spectrum of the compound with the structure of formula V prepared in the examples.
[0084] The above embodiments are merely illustrative of the principles and effects of the present invention and are not intended to limit the invention. Any person skilled in the art can modify or alter the above embodiments without departing from the spirit and scope of the present invention. Therefore, all equivalent modifications or alterations made by those skilled in the art without departing from the spirit and technical concept disclosed in the present invention should still be covered by the claims of the present invention.
Claims
1. The use of a palladium salt and ligand combination as a catalyst system in the reaction of a compound with the structure shown in Formula II with 1-bromo-8-chloronaphthalene to generate a compound with the structure shown in Formula III.
2. A method for preparing a compound of formula III, characterized in that, The compound with the structure shown in Formula II was prepared by coupling reaction with 1-bromo-8-chloronaphthalene. The reaction route is as follows: 。 3. The synthesis method according to claim 2, characterized in that, The molar ratio of compound II to 1-bromo-8-chloronaphthalene is 1:(1 to 1.1). And / or, the reaction system of the coupling reaction also includes a catalyst, said catalyst being one or both selected from palladium acetate or palladium DBA; And / or, the reaction system of the coupling reaction also includes a basic auxiliary agent, wherein the basic auxiliary agent is one or both selected from cesium carbonate or potassium tert-butoxide; And / or, the reaction system of the coupling reaction also includes a ligand, which is one or both selected from XantPhos or 2-(dicyclohexylphosphino)biphenyl; And / or, the reaction system of the coupling reaction further includes a second organic solvent, which is one or more selected from toluene, DMF, and 1,4-dioxane; And / or, the reaction temperature for the coupling reaction is 90~100℃; And / or, after the coupling reaction is complete, post-processing steps such as extraction and concentration are also included.
4. The synthesis method according to claim 3, characterized in that, The molar ratio of the catalyst to the compound of formula II is (0.02–0.05):1; And / or, the molar ratio of the alkaline auxiliary agent to the compound of formula II is (1-2):1; And / or, the molar ratio of the ligand to the compound of formula II is (0.04–0.1):1; And / or, the extraction is performed by adding water and MTBE, stirring, and then separating the organic phase. And / or, the concentration is a vacuum distillation organic phase.
5. The synthesis method according to claim 2, characterized in that, The compound with the structure shown in Formula II was prepared by deprotection reaction of the compound with the structure shown in Formula I, and the reaction route is as follows: 。 6. The synthesis method according to claim 5, characterized in that, The deprotection reaction system also includes an acidic auxiliary agent, which is one or more of trifluoroacetic acid, p-toluenesulfonic acid, or ethyl hydrochloride. And / or, the reaction system for the deprotection reaction also includes a third organic solvent, which is one or both selected from methanol or ethyl acetate; And / or, the reaction temperature for the deprotection reaction is 10~40℃; And / or, after the deprotection reaction is completed, a post-processing step is included, which is filtration and purification.
7. The synthesis method according to claim 6, characterized in that, The molar ratio of the acidic auxiliary agent to the compound of formula I is (4-6):
1.
8. A method for synthesizing an adagarate intermediate compound, comprising a cyclization reaction of a compound with the structure shown in Formula III and a compound with the structure shown in Formula IV to obtain an intermediate compound with the structure shown in Formula V, wherein the reaction route is as follows: 。 9. The synthesis method according to claim 8, characterized in that, The molar ratio of compound III to compound IV is 1:(1.05–1.2). And / or, the reaction system of the cyclocondensation reaction also includes a basic auxiliary agent, which is one or both selected from potassium tert-butoxide or sodium methoxide; And / or, the reaction system of the cyclization reaction further includes a first organic solvent, which is one or both selected from methanol or THF; And / or, the reaction temperature for cyclocondensation is 20–65 °C; And / or, the cyclization reaction may also include extraction, concentration and purification.
10. The method according to claim 9, characterized in that, The molar ratio of the alkaline auxiliary agent to the compound of formula III is (3-5):1; And / or, the extraction is performed by adding water and MTBE, stirring, and then separating the organic phase. And / or, the concentration is a vacuum distillation organic phase; And / or, the purification involves adding ethyl acetate to dissolve the crude product, adding n-heptane dropwise, filtering, and drying.