Process for the preparation of 6-ethynylpyrazolo[1,5-a]pyridines

Abstract

The application discloses a preparation method of 6-ethynylpyrazolo[1,5-a]pyridine, which comprises the following steps: 2,5-dibromopyridine is subjected to a sonogashira coupling reaction to obtain 2,5-di((trimethylsilyl)ethynyl)pyridine; a post-nitrogen amination agent is used for nitrogen amination reaction to obtain 1-amino-2,5-di((trimethylsilyl)ethynyl)pyridine; then, ring closing is carried out under the action of a post catalyst, and a tetrabutylammonium fluoride is used for desilylation to obtain 6-ethynylpyrazolo[1,5-a]pyridine. The preparation method of 6-ethynylpyrazolo[1,5-a]pyridine disclosed by the application has the advantages of low-cost raw materials, easy-to-control reaction conditions, high reaction selectivity, few by-products and suitability for large-scale production.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic compound preparation and synthesis, and particularly relates to a preparation method of 6-ethynylpyrazolo[1,5-a]pyridine. BACKGROUND

[0002] Aza rings 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, in recent years, there has been great concern about the efficient synthesis of functional pyrazolopyridine derivatives.

[0003] Pyrazolopyridine compounds have a conjugated π-electron system and can act as an isostere of similar compounds present in living organisms. At the same time, due to the large dipole moment and certain number of nitrogen atoms in the aromatic hetero five-ring and six-ring system, the compounds can act as an adjunct structure of drugs to enhance the binding of drugs to living organisms and show certain selectivity. According to the type of pyrazolopyridine compounds, they can be mainly divided into the following categories: pyrazolo[3,4-b]pyridine, pyrazolo[4,3-c]pyridine, and pyrazolo[1,5-a]pyridine. These isomers all have high biological activity, among which pyrazolo[1,5-a]pyridine compounds are the most studied. At present, the research on such compounds is mainly focused on the biological activity of their derivatives, including: 1. adenosine A1 receptor antagonists; 2. CRF1 receptor inhibitors; 3. P38 kinase inhibitors; 4. anti-bleomycin inhibitory activity.

[0004] According to multiple literature and patent reports (such as Lett Drug Des Discov.2024;21(1):71-87), compounds with a pyrazolopyridine basic structure play a very important role in pharmacological research. Pharmacological research shows that such compounds have bactericidal, herbicidal, antifungal, anti-inflammatory, anti-allergic, antimalarial, anxiolytic, antithrombotic, antihypotensive, antibacterial, analgesic, and anti-platelet activities, and many other activities, making them a highly valuable class of compounds.

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

[0006]

[0007] This method has four steps of reaction, the process is relatively complex, and contains a heating reaction, which consumes a large amount of energy. At the same time, the overall yield of the final target product is very low, only about 7-8%. SUMMARY

[0008] [TECHNICAL PROBLEM]

[0009] The application provides a preparation method of 6-ethynylpyrazolo[1,5-a]pyridine, which is low in raw material cost, easy to control reaction conditions (carried out at room temperature), low in by-products, high in yield and suitable for factory scale production.

[0010] [Technical scheme]

[0011] A preparation method of 6-ethynylpyrazolo[1,5-a]pyridine, a reaction route of which is shown in the following formula:

[0012]

[0013] The method comprises the following steps:

[0014] Step 1: 2,5-dibromopyridine and trimethylsilyl acetylene are used as substrates to carry out coupling to obtain 2,5-di((trimethylsilyl)ethynyl)pyridine;

[0015] Step 2: the obtained 2,5-di((trimethylsilyl)ethynyl)pyridine is subjected to amination reaction with an amination agent to obtain 1-amino-2,5-di((trimethylsilyl)ethynyl)pyridine;

[0016] Step 3: the obtained 1-amino-2,5-di((trimethylsilyl)ethynyl)pyridine is subjected to ring formation reaction in the presence of silver carbonate, and then tetrabutylammonium fluoride is added to carry out desilylation to obtain the target product 6-ethynylpyrazolo[1,5-a]pyridine.

[0017] In an embodiment of the application, the method specifically comprises the following steps:

[0018] Step 1: 2,5-dibromopyridine is dissolved to obtain solution A, and then trimethylsilyl acetylene is added to solution A to carry out coupling reaction to obtain 2,5-di((trimethylsilyl)ethynyl)pyridine;

[0019] Step 2: 2,5-di((trimethylsilyl)ethynyl)pyridine is dissolved to obtain solution B, and an amination agent is added to solution B to carry out amination reaction to obtain 1-amino-2,5-di((trimethylsilyl)ethynyl)pyridine;

[0020] Step 3: 1-amino-2,5-di((trimethylsilyl)ethynyl)pyridine is dissolved to obtain solution C, silver carbonate is added to solution C to carry out ring formation reaction to obtain an intermediate, the intermediate is dissolved to obtain solution D, and tetrabutylammonium fluoride is added to solution D to carry out desilylation to obtain 6-ethynylpyrazolo[1,5-a]pyridine.

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

[0022] In an embodiment of the present application, in step 1, the coupling agent used in the coupling reaction includes any one or a combination of the following: cuprous iodide, cuprous bromide, cuprous chloride.

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

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

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

[0026] In an embodiment of the present application, in step 1, the catalyst used in the coupling reaction is specifically selected from dichlorobis(triphenylphosphine)palladium, tetrakis(triphenylphosphine)palladium, dichlorobis(diphenylphosphino) palladium.

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

[0028] In an embodiment of the present application, in step 1, the molar ratio of 2,5-dibromopyridine to trimethylsilyl acetylene group is 1:2-2.5.

[0029] In an embodiment of the present application, in step 1, the temperature of the coupling reaction is room temperature (20-30℃) and the time is 15-40h.

[0030] In an embodiment of the present application, in step 2, the nitrene agent is specifically selected from 2,4,6-trimethylbenzenesulfonyl hydroxylamine, diphenylphosphoryl hydroxylamine, hydroxylamine sulfonic acid, 2,4-dinitrophenyl hydroxylamine.

[0031] In an embodiment of the present application, in step 2, the equivalent ratio of 2,5-bis(trimethylsilyl acetylene) pyridine to the nitrene agent is 1:1.2-1.7.

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

[0033] In one embodiment of the present application, in step 2, the temperature of the amination reaction is room temperature (20-30℃), and the time is 15-40h.

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

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

[0036] In one embodiment of the present application, in step 3, the temperature of the ring-forming reaction is room temperature (20-30℃), and the time is 15-40h.

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

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

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

[0040] [Advantages]

[0041] The present application uses low-cost raw materials, easy-to-control reaction conditions, and has high reaction selectivity, less by-products, and simple product post-treatment, and obtains a relatively ideal product, and is suitable for large-scale industrial production. DETAILED DESCRIPTION

[0042] The technical solutions of the present application will be described in detail below with reference to the embodiments of the present application. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments of the present application, all other embodiments obtained by a person of ordinary skill in the art without creative labor fall within the scope of the present application. The 2,4,6-trimethylbenzenesulfonyl hydroxylamine involved in the present application can be prepared according to the existing literature, for example, literature: Org. Process Res. Dev. 2009, 13, 2, 263-267.

[0043] The synthesis path of the present application is as follows:

[0044]

[0045] The preparation method comprises the following steps:

[0046] Step 1, 2, 5-dibromopyridine is dissolved to obtain solution A, then trimethylsilyl acetylene is added to solution A to carry out a coupling reaction, and 2, 5-di((trimethylsilyl)ethynyl)pyridine is obtained;

[0047] Step 2, 2, 5-di((trimethylsilyl)ethynyl)pyridine is dissolved to obtain solution B, and a nitrogen amination agent is added to solution B to carry out a nitrogen amination reaction, and 1-amino-2, 5-di((trimethylsilyl)ethynyl)pyridine is obtained;

[0048] Step 3, 1-amino-2, 5-di((trimethylsilyl)ethynyl)pyridine is dissolved to obtain solution C, silver carbonate is added to solution C to carry out a cyclization reaction, and an intermediate is obtained, the intermediate is dissolved to obtain solution D, and tetrabutylammonium fluoride is added to solution D to carry out a desilylation reaction, and 6-ethynylpyrazolo[1, 5-a]pyridine is obtained.

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

[0050] Example 1

[0051] Step 1, synthesis of 2, 5-di((trimethylsilyl)ethynyl)pyridine

[0052]

[0053] 2, 5-dibromopyridine (118 g, 500 mmol), dichlorobis(triphenylphosphine)palladium (7.58 g, 10 mmol), and cuprous iodide (4.76 g, 25 mmol) were replaced with argon in a reaction bottle, N, N-dimethylformamide (400 mL) treated with bubble degassing, N, N-diisopropyl ethylamine (193.86 g, 1.5 mol), and trimethylacetylenylsilane (122.77 g, 1.25 mol) were successively injected into the reaction bottle, and stirring was carried out at room temperature for 24 h. After the reaction was completed, the reaction solution was diluted with ethyl acetate (800 mL), washed with water (300 mL x 3), saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, filtered through silica gel, and the filtrate was concentrated to obtain 128.72 g of 5-di((trimethylsilyl)ethynyl)pyridine, with a yield of 95%. 1 H NMR (400 MHz, Chloroform-d) δ (ppm) 8.62 (s, 1H), 7.68 (d, J = 8.1 Hz, 1H), 7.38 (d, J = 8.1 Hz, 1H), 0.26 (d, J = 3.3 Hz, 18H).

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

[0055]

[0056] MSH (160.50 g, 750 mmol) was dissolved in dichloromethane (200 mL) at 0 °C, stirred for 5 min, added dropwise to 5-bis((trimethylsilyl)ethynyl)pyridine (135.50 g, 500 mmol) in dichloromethane (200 mL), 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, filtered to give 160.38 g of 1-amino-2,5-bis((trimethylsilyl)ethynyl)pyridine, yield 66%. 1 H NMR (400 MHz, Chloroform-d) d (ppm) 9.31 (s, 1H), 7.81 (dd, J = 8.4, 1.5 Hz, 1H), 7.65 (d, J = 8.3 Hz, 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), silver carbonate (6.89 g, 25 mmol) was added, stirred at room temperature, after 24 h, the reaction solution was concentrated under reduced pressure, filtered with silica gel, the filtrate was concentrated under reduced pressure to give a crude product. The crude product was dissolved in tetrahydrofuran (1.25 L), tetrabutylammonium fluoride trihydrate (209.60 g, 750 mmol) was added, stirred at room temperature for 24 h, after the reaction was completed, the reaction solution was concentrated under reduced pressure, the obtained crude product was purified by column chromatography (petroleum ether: ethyl acetate = 20:1) to give 27.69 g of 6-ethynylpyrazolo[1,5-a]pyridine, yield 78%. 1 H NMR (400 MHz, Chloroform-d) d (ppm) 8.65 (d, J = 1.2 Hz, 1H), 7.99 (d, J = 2.3 Hz, 1H), 7.49 (dd, J = 9.1, 1.0 Hz, 1H), 7.13 (dd, J = 9.1, 1.4 Hz, 1H), 6.54 (d, J = 2.9 Hz, 1H), 3.11 (s, 1H).

[0060] Example 2

[0061] Step 1, synthesis of 2,5-di((trimethylsilyl)ethynyl)pyridine

[0062] A reaction bottle was replaced with argon, 2,5-dibromopyridine (118 g, 500 mmol), dichlorobis(triphenylphosphine)palladium (7.58 g, 10 mmol), cuprous iodide (4.76 g, 25 mmol) were added, and then bubbled degassed N,N-dimethylformamide (400 mL), N,N-diisopropylethylamine (193.86 g, 1.5 mol), trimethylsilyl acetylene (122.77 g, 1.25 mol) were injected into the reaction bottle, and stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was diluted with ethyl acetate (800 mL), washed with water (300 mL x 3), saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, filtered with silica gel, and the filtrate was concentrated to obtain 130.08 g of 5-di((trimethylsilyl)ethynyl)pyridine at a yield of 96%.

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

[0064] MSH (160.50 g, 750 mmol) was dissolved in dichloromethane (200 mL) at 0℃, stirred for 5 min, and then added dropwise to 5-di((trimethylsilyl)ethynyl)pyridine (135.50 g, 500 mmol) dissolved in dichloromethane (200 mL), and 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-di((trimethylsilyl)ethynyl)pyridine at a yield of 67%.

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

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

[0067] Example 3

[0068] Step 1, synthesis of 2,5-di((trimethylsilyl)ethynyl)pyridine

[0069] Argon gas was purged in a reaction flask with 2,5-dibromopyridine (118 g, 500 mmol), bis(triphenylphosphine)palladium dichloride (7.58 g, 10 mmol), and cuprous iodide (4.76 g, 25 mmol). Then, N,N-dimethylformamide (400 mL), N,N-diisopropylethylamine (193.86 g, 1.5 mol), and trimethylethynylsilane (122.77 g, 1.25 mol), which had been degassed by bubbling, was injected sequentially into the flask. The mixture was stirred at room temperature for 24 h. After the reaction was complete, the reaction solution was diluted with ethyl acetate (800 mL), washed with water (300 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, filtered through silica gel, and the concentrated filtrate yielded 130.12 g of 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) and stirred for 5 min. The solution was then 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 for 24 h. After the reaction was completed, the solution was concentrated under reduced pressure and filtered through silica gel. The filtrate was concentrated under reduced pressure to obtain the 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 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] 1-Amino-2,5-bis((trimethylsilyl)ethynyl)pyridine was prepared according to steps 1 and 2 of Example 1.

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

[0077] Dissolve 1-amino-2,5-bis((trimethylsilyl)ethynyl)pyridine (121.50 g, 250 mmol) in ethanol (2.5 L), and add silver carbonate (137.87 g, 500 mmol). Stir at room temperature for 24 h, and then concentrate the reaction solution under reduced pressure. Filter the solution through silica gel, and concentrate the filtrate under reduced pressure to obtain the crude product. Dissolve the crude product in tetrahydrofuran (1.25 L), and add tetrabutylammonium fluoride trihydrate (139.74 g, 500 mmol). Stir at room temperature for 24 h, and then concentrate the reaction solution under reduced pressure. Purify the obtained crude product 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] Effects of Examples

[0079] As can be seen from Examples 1-3, the total yield of the method of the present application is more than 49%, which is significantly better than the reported preparation methods.

[0080] As can be seen from Examples 1-3 and Comparative Example 1, the amount of silver carbonate is very critical in the process of ring formation and desilylmethylation in step 3. In Examples 1-3, 0.02-0.1 eq of silver carbonate is used, and the ring formation product is obtained with a yield of more than 78%; however, if 2 eq of silver carbonate is used as shown in Comparative Example 1, only a trace amount of the target product is generated. The applicant speculates that the excess silver ions combine with the pyrazole ring to form various types of complexes that are difficult to dissociate, resulting in only a trace amount of product being generated. When a catalytic amount of silver carbonate is introduced to catalyze the reaction, the reaction condition is significantly improved. The silver carbonate not only reduces the amount of product lost due to the formation of complexes, but also ensures that the reaction can be maintained at a relatively ideal rate.

[0081] The above examples are not intended to limit the scope of the present application, and the described steps are not intended to limit the execution order. Those skilled in the art can make obvious improvements to the present application based on the existing common knowledge, and such improvements also fall within the protection scope defined by the claims of the present application.

Claims

1. A process for the preparation of 6-ethynylpyrazolo[l,5-a]pyridines, characterized in that, The reaction route is as follows: The method comprises the following steps: Step 1, using 2,5-dibromopyridine and trimethylsilyl acetylene as substrates, coupling to obtain product 2,5-di((trimethylsilyl)ethynyl)pyridine; Step 2, the obtained 2,5-di((trimethylsilyl)ethynyl)pyridine is subjected to amination reaction with a nitrogen amine agent to obtain 1-amino-2,5-di((trimethylsilyl)ethynyl)pyridine; Step 3, the obtained 1-amino-2,5-di((trimethylsilyl)ethynyl)pyridine is first subjected to a ring formation reaction in the presence of silver carbonate, and then subjected to a desilylation reaction in the presence of tetrabutylammonium fluoride to obtain the target product 6-ethynylpyrazolo[1,5-a]pyridine; In step 3, the molar ratio of the 1-amino-2,5-di((trimethylsilyl)ethynyl)pyridine to the silver carbonate is 1:0.02-0.

10.

2. The method of claim 1, wherein, In step 1, the coupling agent used for the coupling is any one or a combination of the following: cuprous iodide, cuprous bromide, cuprous chloride; the molar ratio of the 2,5-dibromopyridine to the coupling agent is 1:0.05-0.

2.

3. The method of claim 1, wherein, In step 1, a base is further added during the coupling, and the base is any one or a combination of the following: triethylamine, diisopropylamine, diisopropyl ethylamine, potassium carbonate; the molar ratio of the 2,5-dibromopyridine to the base is 1:1.5-3.

4. The method of claim 1, wherein, In step 1, a catalyst is further added during the coupling, and the catalyst is selected from the group consisting of dichlorobis(triphenylphosphine)palladium, tetrakis(triphenylphosphine)palladium, 1,1-bis(diphenylphosphino)ferrocene dichloropalladium; the molar ratio of the 2,5-dibromopyridine to the catalyst is 1:0.02-0.

1.

5. The method of claim 1, wherein, In step 1, the molar ratio of the 2,5-dibromopyridine to the trimethylsilyl acetylene is 1:2-2.

5.

6. The method of claim 1, wherein, In step 2, the nitrogen amine agent is selected from the group consisting of 2,4,6-trimethylbenzenesulfonyl hydroxylamine, diphenylphosphine hydroxylamine, hydroxylamine sulfonic acid, 2,4-dinitrophenyl hydroxylamine; the equivalent ratio of the 2,5-di((trimethylsilyl)ethynyl)pyridine to the nitrogen amine agent is 1:1.2-1.

7.

7. The method of claim 1, wherein, In step 3, the molar ratio of the 1-amino-2,5-di((trimethylsilyl)ethynyl)pyridine to the tetrabutylammonium fluoride is 1:2.0-4.

0.

8. The method according to any one of claims 1-7, wherein in step 1, the coupling is carried out in a solvent environment of tetrahydrofuran or N,N-dimethylformamide; In step 2, the amination reaction is carried out in a solvent environment of dichloromethane, N,N-dimethylformamide, N-methylpyrrolidone; In step 3, the ring formation reaction is carried out in a solvent environment of ethanol, methanol, N,N-dimethylformamide; the desilylation reaction is carried out in a solvent environment of tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide.

9. The method according to any one of claims 1-7, wherein in step 1, the temperature of the coupling is room temperature, and the time is 15-40 h; In step 2, the temperature of the amination reaction is room temperature, and the time is 15-40 h; ​ ​ In step 3, the temperature of the ring formation reaction is room temperature, and the time is 15-40 h; the temperature of the desilylation reaction is room temperature, and the time is 15-40 h.

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