Preparation method of 6-ethynyl pyrazolo [1, 5-a] pyridine

Abstract

The invention discloses a preparation method of 6-ethynyl pyrazolo [1, 5-a] pyridine, which comprises the following steps: carrying out a sonogashira coupling reaction on 2, 5-dibromopyridine to obtain 2, 5-bis ((trimethylsilyl) ethynyl) pyridine; carrying out nitrogen amination reaction by using a nitrogen aminating agent, so as to obtain 1-amino-2, 5-bis ((trimethylsilyl) ethynyl) pyridine; and carrying out ring closing under the action of a catalyst, and carrying out a desilicication methyl reaction by using tetrabutylammonium fluoride to obtain the 6-ethynyl pyrazolo [1, 5-a] pyridine. According to the preparation method of the 6-ethynyl pyrazolo [1, 5-a] pyridine, low-cost raw materials are used, reaction conditions are easy to control, the reaction selectivity is high, byproducts are few, and the preparation method is suitable for large-scale production of the 6-ethynyl pyrazolo [1, 5-a] pyridine.

Description

Technical Field

[0001] The invention relates to the technical field of preparation and synthesis of organic compounds, and in particular to a method for preparing 6-ethynylpyrazolo[1,5-a]pyridine. Background Art

[0002] Nitrogen heterocycles are widely present in various natural products, bioactive compounds (including drugs and agrochemicals) and functional materials. Among them, pyrazolo[1,5-a]pyridine compounds have great prospects in drug design and development due to their broad-spectrum pharmacological activities. Therefore, the efficient synthesis of functionalized pyrazolo[1,5-a]pyridine derivatives has attracted great attention in recent years.

[0003] Pyrazolopyridine compounds have a conjugated π electron system and can be used as isoelectronics of similar compounds existing in the body; at the same time, since this type of aromatic five-ring and six-ring system has a large dipole moment and a certain number of nitrogen atoms, it can be used as an auxiliary structure of the drug to enhance the binding of the drug to the body and show a certain selectivity. According to the type of ring, pyrazolopyridine compounds can be mainly divided into the following categories: pyrazolo[3,4-b]pyridine, pyrazolo[4,3-c]pyridine, pyrazolo[1,5-a]pyridine. These isomers have extremely high biological activity, among which the most studied are pyrazolo[1,5-,a]pyridine compounds. At present, the research on this type of compound is mainly on the biological activity of its derivatives, including: 1. Adenosine A1 receptor antagonist; 2. CRF1 receptor inhibitor; 3. P38 kinase inhibitor; 4. Anti-herpes inhibitory activity.

[0004] According to many literatures and patent reports (such as Lett Drug Des Discov. 2024; 21(1): 71-87), compounds with the basic structure of pyrazolopyridine play a very important role in pharmacological research. Pharmacological studies have shown that this type of compound has many activities such as bactericidal, herbicidal, antifungal, anti-inflammatory, antiallergic, antimalarial, anxiolytic, antithrombotic, antihypotensive, antibacterial, analgesic, and antiplatelet activities, and is a class of compounds with high research value.

[0005] The prior art WO2011073172A1 reports the following method for synthesizing alkynylpyrazolo[1,5-a]pyridine compounds:

[0006]

[0007] This method has four steps of reaction, the process is relatively complicated, and includes a heating reaction, which consumes a lot of energy; at the same time, the total yield of the final preparation target is very low, only about 7-8%. Summary of the invention

[0008] [Technical issues]

[0009] Provided is a method for preparing 6-ethynylpyrazolo[1,5-a]pyridine, which has low raw material price, easily controllable reaction conditions (conducted at room temperature), few by-products, high yield and is suitable for factory-scale production.

[0010] [Technical solution]

[0011] A method for preparing 6-ethynylpyrazolo[1,5-a]pyridine, the reaction route of which is as follows:

[0012]

[0013] The steps include:

[0014] Step 1, using 2,5-dibromopyridine and trimethylsilyl acetylene as substrates, coupling to obtain the product 2,5-bis((trimethylsilyl)ethynyl)pyridine;

[0015] Step 2, the obtained 2,5-bis((trimethylsilyl)ethynyl)pyridine is subjected to a nitrogen amination reaction with a nitrogen aminating agent to obtain 1-amino-2,5-bis((trimethylsilyl)ethynyl)pyridine;

[0016] Step 3: The obtained 1-amino-2,5-bis((trimethylsilyl)ethynyl)pyridine is first subjected to a cyclization reaction under the action of silver carbonate, and then tetrabutylammonium fluoride is added to carry out a desilylation methylation reaction to obtain the target 6-ethynylpyrazolo[1,5-a]pyridine.

[0017] In one embodiment of the present invention, the method specifically comprises the following steps:

[0018] Step 1, dissolving 2,5-dibromopyridine to obtain solution A, and then adding trimethylsilyl acetylene to solution A to carry out a coupling reaction to obtain 2,5-bis((trimethylsilyl)ethynyl)pyridine;

[0019] Step 2, dissolving 2,5-bis((trimethylsilyl)ethynyl)pyridine to obtain solution B, adding a nitrogen amination agent to solution B for nitrogen amination reaction to obtain 1-amino-2,5-bis((trimethylsilyl)ethynyl)pyridine;

[0020] Step 3, dissolving 1-amino-2,5-bis((trimethylsilyl)ethynyl)pyridine to obtain solution C, adding silver carbonate to solution C to carry out cyclization reaction to obtain an intermediate, dissolving the intermediate to obtain solution D, adding tetrabutylammonium fluoride to solution D to carry out desilylation methylation reaction to obtain 6-ethynylpyrazolo[1,5-a]pyridine.

[0021] In one embodiment of the present invention, in step 1, the solvent in the solution A is tetrahydrofuran or N,N-dimethylformamide.

[0022] In one embodiment of the present invention, in step 1, the coupling agent used in the coupling reaction includes any one or more of the following combinations: cuprous iodide, cuprous bromide, and cuprous chloride.

[0023] In one embodiment of the present invention, in step 1, the base used in the coupling reaction is any one or more of the following combinations: triethylamine, diisopropylamine, diisopropylethylamine, potassium carbonate.

[0024] In one embodiment of the present invention, in step 1, the molar ratio of the 2,5-dibromopyridine to the base is 1:1.5-3.

[0025] In one embodiment of the present invention, in step 1, the molar ratio of the 2,5-dibromopyridine to the coupling agent is 1:0.05-0.2.

[0026] In one embodiment of the present invention, in step 1, the catalyst used in the coupling reaction may be bistriphenylphosphine palladium dichloride, tetrakistriphenylphosphine palladium, or 1,1-bis(diphenylphosphine)ferrocene palladium dichloride.

[0027] In one embodiment of the present invention, in step 1, the molar ratio of the 2,5-dibromopyridine to the catalyst is 1:0.02-0.1.

[0028] In one embodiment of the present invention, in step 1, the molar ratio of the 2,5-dibromopyridine to the trimethylsilylethynyl group is 1:2-2.5.

[0029] In one embodiment of the present invention, in step 1, the coupling reaction temperature is room temperature (20-30° C.) and the time is 15-40 hours.

[0030] In one embodiment of the present invention, in step 2, the nitrogen aminating agent may be 2,4,6-trimethylbenzenesulfonylhydroxylamine, diphenylphosphonylhydroxylamine, hydroxylamine sulfonic acid, or 2,4-dinitrophenylhydroxylamine.

[0031] In one embodiment of the present invention, in step 2, the equivalent ratio of the 2,5-bis((trimethylsilyl)ethynyl)pyridine to the nitrogen aminating agent is 1:1.2-1.7.

[0032] In one embodiment of the present invention, in step 2, the solvent used in solution B is dichloromethane (DCM), N,N-dimethylformamide, or N-methylpyrrolidone.

[0033] In one embodiment of the present invention, in step 2, the temperature of the nitrogen amination reaction is room temperature (20-30° C.) and the time is 15-40 hours.

[0034] In one embodiment of the present invention, in step 3, the molar ratio of 1-amino-2,5-bis((trimethylsilyl)ethynyl)pyridine to silver carbonate is 1:0.02-0.10.

[0035] In one embodiment of the present invention, in step 3, the solvent used in solution C is ethanol (EtOH), methanol, or N,N-dimethylformamide.

[0036] In one embodiment of the present invention, in step 3, the temperature of the cyclization reaction is room temperature (20-30° C.) and the time is 15-40 hours.

[0037] In one embodiment of the present invention, in step 3, the molar ratio of 1-amino-2,5-bis((trimethylsilyl)ethynyl)pyridine to tetrabutylammonium fluoride is 1:2.0-4.0.

[0038] In one embodiment of the present invention, in step 3, the solvent used in solution D is tetrahydrofuran (THF), N,N-dimethylformamide, or dimethyl sulfoxide.

[0039] In one embodiment of the present invention, in step 3, the temperature of the desilylation reaction is room temperature (20-30° C.) and the time is 15-40 hours.

[0040] [Beneficial Effects]

[0041] The invention uses low-cost raw materials, easy-to-control reaction conditions, high reaction selectivity, few by-products, and relatively simple product post-processing, thereby obtaining relatively ideal products and being suitable for large-scale industrial production. DETAILED DESCRIPTION

[0042] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solution of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention. The 2,4,6-trimethylbenzenesulfonylhydroxylamine involved in the present invention can be prepared by itself according to existing documents, such as the document: Org.Process Res.Dev.2009,13,2,263-267.

[0043] The synthesis path of the present invention is:

[0044]

[0045] The preparation method thereof comprises the following steps:

[0046] Step 1, dissolving 2,5-dibromopyridine to obtain solution A, and then adding trimethylsilyl acetylene to solution A to carry out a coupling reaction to obtain 2,5-bis((trimethylsilyl)ethynyl)pyridine;

[0047] Step 2, dissolving 2,5-bis((trimethylsilyl)ethynyl)pyridine to obtain solution B, adding a nitrogen amination agent to solution B to carry out a nitrogen amination reaction to obtain 1-amino-2,5-bis((trimethylsilyl)ethynyl)pyridine;

[0048] Step 3, dissolving 1-amino-2,5-bis((trimethylsilyl)ethynyl)pyridine to obtain solution C, adding silver carbonate to solution C to carry out cyclization reaction to obtain an intermediate, dissolving the intermediate to obtain solution D, adding tetrabutylammonium fluoride to solution D to carry out desilylation methylation reaction to obtain 6-ethynylpyrazolo[1,5-a]pyridine.

[0049] The following is a specific embodiment to illustrate the technical solution of the present invention:

[0050] Example 1

[0051] Step 1. Synthesis of 2,5-bis((trimethylsilyl)ethynyl)pyridine

[0052]

[0053] 2,5-dibromopyridine (118g, 500mmol), bistriphenylphosphine palladium dichloride (7.58g, 10mmol), cuprous iodide (4.76g, 25mmol) were used to replace argon in a reaction flask, and N,N-dimethylformamide (400mL), N,N-diisopropylethylamine (193.86g, 1.5mol), and trimethylethynylsilane (122.77g, 1.25mol) treated by bubbling degassing were injected into the reaction flask in turn, and stirred at room temperature for 24h. After the reaction was completed, the reaction solution was diluted with ethyl acetate (800mL), washed with water (300mL×3), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, filtered on silica gel, and the filtrate was concentrated to obtain 128.72g 5-bis((trimethylsilyl)ethynyl)pyridine, with a yield of 95%. 1 H NMR (400MHz, Chloroform-d) δ (ppm) 8.62 (s, 1H), 7.68 (d, J = 8.1Hz, 1H), 7.38 (d, J = 8.1Hz, 1H), 0.26 (d, J = 3.3Hz, 18H).

[0054] Step 2, Synthesis of 1-amino-2,5-bis((trimethylsilyl)ethynyl)pyridine

[0055]

[0056] At 0°C, MSH (160.50 g, 750 mmol) was dissolved in dichloromethane (200 mL), stirred for 5 min, and added dropwise to dichloromethane (200 mL) containing 5-bis((trimethylsilyl)ethynyl)pyridine (135.50 g, 500 mmol). The mixture was stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, washed with methyl tert-butyl ether, and filtered to obtain 160.38 g of 1-amino-2,5-bis((trimethylsilyl)ethynyl)pyridine, with a yield of 66%. 1 H NMR (400MHz, Chloroform-d) δ (ppm) 9.31 (s, 1H), 7.81 (dd, J = 8.4, 1.5Hz, 1H), 7.65 (d,J=8.3Hz,1H),6.81(s,2H),2.69(s,6H),2.22(s,3H),0.35(s,9H),0.27(s,9H).

[0057] Step 3: Synthesis of 6-ethynylpyrazolo[1,5-a]pyridine

[0058]

[0059] 1-Amino-2,5-bis((trimethylsilyl)ethynyl)pyridine (121.50 g, 250 mmol) was dissolved in ethanol (2.5 L), and silver carbonate (6.89 g, 25 mmol) was added. The mixture was stirred at room temperature. After 24 h, the reaction solution was concentrated under reduced pressure, filtered through silica gel, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was dissolved in tetrahydrofuran (1.25 L), and tetrabutylammonium fluoride trihydrate (209.60 g, 750 mmol) was added. The mixture was stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain 27.69 g of 6-ethynylpyrazolo[1,5-a]pyridine with a yield of 78%. 1 H NMR(400MHz,Chloroform-d)δ(ppm)8.65(d,J=1.2Hz,1H),7.99(d,J=2.3Hz,1H),7.49( dd,J=9.1,1.0Hz,1H),7.13(dd,J=9.1,1.4Hz,1H),6.54(d,J=2.9Hz,1H),3.11(s,1H).

[0060] Example 2

[0061] Step 1. Synthesis of 2,5-bis((trimethylsilyl)ethynyl)pyridine

[0062] 2,5-dibromopyridine (118g, 500mmol), bistriphenylphosphine palladium dichloride (7.58g, 10mmol), cuprous iodide (4.76g, 25mmol) were used to replace argon in a reaction flask, and N,N-dimethylformamide (400mL), N,N-diisopropylethylamine (193.86g, 1.5mol), and trimethylethynylsilane (122.77g, 1.25mol) treated by bubbling degassing were injected into the reaction flask in turn, and stirred at room temperature for 24h. After the reaction was completed, the reaction solution was diluted with ethyl acetate (800mL), washed with water (300mL×3), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, filtered on silica gel, and the filtrate was concentrated to obtain 130.08g 5-bis((trimethylsilyl)ethynyl)pyridine, with a yield of 96%.

[0063] Step 2, Synthesis of 1-amino-2,5-bis((trimethylsilyl)ethynyl)pyridine

[0064] At 0°C, MSH (160.50 g, 750 mmol) was dissolved in dichloromethane (200 mL), stirred for 5 min, and added dropwise to dichloromethane (200 mL) containing 5-bis((trimethylsilyl)ethynyl)pyridine (135.50 g, 500 mmol). The mixture was stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, washed with methyl tert-butyl ether, and filtered to obtain 162.81 g of 1-amino-2,5-bis((trimethylsilyl)ethynyl)pyridine with a yield of 67%.

[0065] Step 3: Synthesis of 6-ethynylpyrazolo[1,5-a]pyridine

[0066] 1-Amino-2,5-bis((trimethylsilyl)ethynyl)pyridine (121.50 g, 250 mmol) was dissolved in ethanol (2.5 L), and silver carbonate (3.44 g, 12.5 mmol) was added. The mixture was stirred at room temperature. After 24 h, the reaction solution was concentrated under reduced pressure, filtered through silica gel, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was dissolved in tetrahydrofuran (1.25 L), and tetrabutylammonium fluoride trihydrate (209.60 g, 750 mmol) was added. The mixture was stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain 28.75 g of 6-ethynylpyrazolo[1,5-a]pyridine, with a yield of 81%.

[0067] Example 3

[0068] Step 1. Synthesis of 2,5-bis((trimethylsilyl)ethynyl)pyridine

[0069] 2,5-dibromopyridine (118g, 500mmol), bistriphenylphosphine palladium dichloride (7.58g, 10mmol), cuprous iodide (4.76g, 25mmol) were used to replace argon in a reaction flask, and N,N-dimethylformamide (400mL), N,N-diisopropylethylamine (193.86g, 1.5mol), and trimethylethynylsilane (122.77g, 1.25mol) treated by bubbling degassing were injected into the reaction flask in turn, and stirred at room temperature for 24h. After the reaction was completed, the reaction solution was diluted with ethyl acetate (800mL), washed with water (300mL×3), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, filtered on silica gel, and the filtrate was concentrated to obtain 130.12g 5-bis((trimethylsilyl)ethynyl)pyridine, with a yield of 96%.

[0070] Step 2, Synthesis of 1-amino-2,5-bis((trimethylsilyl)ethynyl)pyridine

[0071] At 0°C, MSH (160.50 g, 750 mmol) was dissolved in dichloromethane (200 mL), stirred for 5 min, and added dropwise to dichloromethane (200 mL) containing 5-bis((trimethylsilyl)ethynyl)pyridine (135.50 g, 500 mmol). The mixture was stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, washed with methyl tert-butyl ether, and filtered to obtain 157.95 g of 1-amino-2,5-bis((trimethylsilyl)ethynyl)pyridine with a yield of 65%.

[0072] Step 3: Synthesis of 6-ethynylpyrazolo[1,5-a]pyridine

[0073] 1-Amino-2,5-bis((trimethylsilyl)ethynyl)pyridine (121.50 g, 250 mmol) was dissolved in ethanol (2.5 L), and silver carbonate (1.37 g, 5 mmol) was added. The mixture was stirred at room temperature. After 24 h, the reaction solution was concentrated under reduced pressure, filtered through silica gel, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was dissolved in tetrahydrofuran (1.25 L), and tetrabutylammonium fluoride trihydrate (139.74 g, 500 mmol) was added. The mixture was stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain 28.04 g of 6-ethynylpyrazolo[1,5-a]pyridine, with a yield of 79%.

[0074] Comparative Example 1

[0075] Referring to steps 1 and 2 in Example 1, 1-amino-2,5-bis((trimethylsilyl)ethynyl)pyridine was prepared.

[0076] Referring to step 3 in Example 1, only the amount of silver carbonate added is adjusted, and the other factors remain unchanged. The specific process is as follows:

[0077] 1-Amino-2,5-bis((trimethylsilyl)ethynyl)pyridine (121.50 g, 250 mmol) was dissolved in ethanol (2.5 L), and silver carbonate (137.87 g, 500 mmol) was added. The mixture was stirred at room temperature. After 24 h, the reaction solution was concentrated under reduced pressure, filtered through silica gel, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was dissolved in tetrahydrofuran (1.25 L), and tetrabutylammonium fluoride trihydrate (139.74 g, 500 mmol) was added. The mixture was stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain 1.06 g of 6-ethynylpyrazolo[1,5-a]pyridine, with a yield of 3%.

[0078] Embodiment Function and Effect

[0079] It can be seen from Examples 1-3 of the present invention that the total yield of the method of the present invention is above 49%, which is significantly better than the existing reported preparation method.

[0080] Combining Examples 1-3 and Comparative Example 1, it can be seen that in the process of cyclization-desilylation involved in step 3, the dosage of silver carbonate is very critical. In Examples 1-3, 0.02 to 0.1 eq of silver carbonate are used to obtain cyclization products superior to , and the yield can reach more than 78%; but if 2 eq of silver carbonate shown in Comparative Example 1 is used, only trace amounts of the target product are generated. The applicant speculates that excess silver ions will combine with the pyrazole ring to form various types of complexes that are difficult to dissociate, resulting in only trace amounts of product generation being detected. When a catalytic amount of silver carbonate is introduced to catalyze the reaction, the reaction conditions are significantly improved. Silver carbonate not only reduces the amount of product lost due to complex formation, but also ensures that the reaction can be maintained at a more ideal rate.

[0081] The embodiments provided above are not intended to limit the scope of the present invention, and the steps described are not intended to limit the execution order thereof. Those skilled in the art may make obvious improvements to the present invention in combination with existing common knowledge, which also fall within the scope of protection defined by the claims of the present invention.

Claims

1. A method for preparing 6-ethynylpyrazolo[1,5-a]pyridine, characterized in that: The reaction route is as follows: The steps include: Step 1, using 2,5-dibromopyridine and trimethylsilyl acetylene as substrates, coupling to obtain the product 2,5-bis((trimethylsilyl)ethynyl)pyridine; Step 2, the obtained 2,5-bis((trimethylsilyl)ethynyl)pyridine is subjected to a nitrogen amination reaction with a nitrogen aminating agent to obtain 1-amino-2,5-bis((trimethylsilyl)ethynyl)pyridine; Step 3: The obtained 1-amino-2,5-bis((trimethylsilyl)ethynyl)pyridine is first subjected to a cyclization reaction under the action of silver carbonate, and then tetrabutylammonium fluoride is added to carry out a desilylation methylation reaction to obtain the target 6-ethynylpyrazolo[1,5-a]pyridine.

2. The method according to claim 1, characterized in that In step 1, the coupling agent used for coupling is any one or more of the following combinations: cuprous iodide, cuprous bromide, cuprous chloride; the molar ratio of 2,5-dibromopyridine to the coupling agent is 1:0.05-0.

2.

3. The method according to claim 1, characterized in that In step 1, a base is also added during the coupling process, and the base is any one or more of the following combinations: triethylamine, diisopropylamine, diisopropylethylamine, potassium carbonate; the molar ratio of 2,5-dibromopyridine to the base is 1:1.5-3.

4. The method according to claim 1, characterized in that: In step 1, a catalyst is also added during the coupling process, and the catalyst is selected from bistriphenylphosphine palladium dichloride, tetrakistriphenylphosphine palladium, and 1,1-bis(diphenylphosphine)diferroni palladium dichloride; the molar ratio of 2,5-dibromopyridine to the catalyst is 1:0.02-0.

1.

5. The method according to claim 1, characterized in that In step 1, the molar ratio of the 2,5-dibromopyridine to the trimethylsilylethynyl group is 1:2-2.

5.

6. The method according to claim 1, characterized in that In step 2, the nitrogen aminating agent is selected from 2,4,6-trimethylbenzenesulfonylhydroxylamine, diphenylphosphonylhydroxylamine, hydroxylaminesulfonic acid, and 2,4-dinitrophenylhydroxylamine; and the equivalent ratio of 2,5-bis((trimethylsilyl)ethynyl)pyridine to the nitrogen aminating agent is 1:1.2-1.

7.

7. The method according to claim 1, characterized in that In step 3, the molar ratio of 1-amino-2,5-bis((trimethylsilyl)ethynyl)pyridine to silver carbonate is 1:0.02-0.

10.

8. The method according to claim 1, characterized in that In step 3, in step 3, the molar ratio of 1-amino-2,5-bis((trimethylsilyl)ethynyl)pyridine to tetrabutylammonium fluoride is 1:2.0-4.

0.

9. The method according to any one of claims 1 to 8, characterized in that: In step 1, the coupling is carried out in the following solvent environment: tetrahydrofuran or N,N-dimethylformamide; In step 2, the nitrogen amination reaction is carried out in the following solvent environment: dichloromethane, N,N-dimethylformamide, N-methylpyrrolidone; In step 3, the cyclization reaction is carried out in the following solvent environment: ethanol, methanol, N,N-dimethylformamide; the desilylation reaction is carried out in the following solvent environment: tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide.

10. The method according to any one of claims 1 to 8, characterized in that: In step 1, the coupling temperature is room temperature and the time is 15-40h; In step 2, the temperature of the nitrogen amination reaction is room temperature and the time is 15-40 hours; In step 3, the temperature of the cyclization reaction is room temperature and the time is 15-40 hours; the temperature of the desilylation reaction is room temperature and the time is 15-40 hours.

Images