Synthesis method of furadiazole [3, 4-d] fluorescent uridine and thiadiazole [3, 4-d] fluorescent uridine

Abstract

The invention discloses a synthesis method of furadiazole [3, 4-d] fluorescent uridine and thiadiazole [3, 4-d] fluorescent uridine, and belongs to the field of organic chemistry. According to the method, 4-amino-2, 6-dihydroxy-5-nitroso pyrimidine is taken as a raw material, and a synthetic route of furadiazole [3, 4-d] fluorescent uridine and thiadiazole [3, 4-d] fluorescent uridine is synthesized after reaction. The target product is directly generated, and the method has the characteristics of relatively simple and controllable reaction conditions, no generation of byproducts, high yield and the like. The experiment has the characteristics of convenience, sensitivity, rapidness, no radioactivity and repeatability.

Description

Technical Field

[0001] This invention relates to the field of fluorescent uridine synthesis technology, and in particular to a method for synthesizing furadiazole[3,4-d] fluorescent uridine and thiadiazole[3,4-d] fluorescent uridine. Background Technology

[0002] Fluorescence-based tools have revolutionized modern science. Advances in instrumentation and technology have expanded the scope of this phenomenon from basic spectroscopic exploration to incredible imaging tools. The advent of powerful light sources, miniaturization, and greater computing power have driven impressive achievements, but all technologies and applications fundamentally rely on suitable chromophores. It is clear how fluorescent proteins have transformed the landscape of biology. The evolution, characteristics, and limitations of low-molecular-weight fluorophores, particularly in the field of nucleic acid biophysics, are less apparent.

[0003] The photophysics of RNA and DNA is unique among biomolecules containing chromophore components. Unlike proteins containing intrinsically fluorescent amino acids (such as Trp), classical nucleosides, which exhibit maximum absorption between 250 and 270 nm, are practically non-emitting. This results in a very short excited-state lifetime (τ = 0.2–0.7 ps) compared to common organic fluorescent groups, and therefore an extremely low fluorescence quantum yield under neutral conditions. Consequently, these key building blocks are practically “dark” for most standard applications.

[0004] Nucleosides modified by base isomorphism, such as As relatively small chromophores with limited charge transfer properties in the ground state, isomorphically extended nucleoside analogs absorb near the high-energy end of the visible spectrum. This photophysical characteristic often limits their biological and imaging practicality. Therefore, exploring their multiphoton-induced emission requires meticulous attention. Steven Magennis discovered that thiophene-containing pyrimidines exhibit exceptionally high cross-sections under two-photon excitation, with single-molecule brightness an order of magnitude higher than any fluorescent base analog.

[0005] Heterocyclic modified nucleosides, such as Paul Ludford and Seth Cohen screened over 300 metal-binding pharmacophores and identified novel inhibitory motifs. Adenosine deaminase (ADAT) was involved in the process. m RNA editing and tRNA maturation also involves similar transformations in different oligomeric environments. Editing sites for GluR and BmRNAR / G modified by ADAR2 were also evaluated. RNA rapidly deamination yields a thiophene-containing product chain, and this process can be monitored by fluorescence changes in the modified RNA. ADAR2 showed a higher deamination rate compared to ADA, likely due to its insensitivity to N7 modification. The suitability of other emission nucleosides and nucleotides as potential substrates for metabolic enzymes was also evaluated using two hydrolases: guanine deaminase (GDA) and cytidine deaminase (CDA). Marcela Bucardo demonstrated that emission isothiazologuanine analogs are excellent substrates for human GDA, facilitating real-time monitoring of deamination and its inhibition. Paul Ludford confirmed this. th C, tz C is the active fluorescent substrate of CDA. Summary of the Invention

[0006] To address the aforementioned problems in existing technologies, this invention provides a method for synthesizing furadiazole[3,4-d]fluorescein and thiadiazole[3,4-d]fluorescein. This invention uses 4-amino-2,6-dihydroxy-5-nitrosopyrimidine as a starting material, and synthesizes furadiazole[3,4-d]fluorescein and thiadiazole[3,4-d]fluorescein through a reaction. This invention directly generates the target products, avoiding glycosylation, hydrolysis, and other reactions. It features relatively simple and controllable reaction conditions, no byproduct formation, and high yield. After obtaining the products, cell activity is measured to determine the inhibitory effect.

[0007] The technical solution adopted in this invention is as follows: The first objective of this invention is to provide a method for synthesizing furadiazole[3,4-d]fluorescent uridine and thiadiazole[3,4-d]fluorescent uridine, using 4-amino-2,6-dihydroxy-5-nitrosopyrimidine as the starting material, and the synthetic route is as follows: ; Where X is O or S.

[0008] In one embodiment of the present invention, the synthesis method includes the following steps: S1, using 4-amino-2,6-dihydroxy-5-nitrosopyrimidine as the starting material, the compound shown in formula (1) was prepared; S2, the compound shown in formula (1) is reacted with 1-acetoxy-2,3,5-tribenzoyloxy-1-β-D-furanose and trimethylsilyltrifluoromethanesulfonic acid to prepare the compound shown in formula (2); S3, the compound shown in formula (2) under alcohol / NH3 conditions, forms the compound shown in formula (3), namely furadiazole [3,4-d]fluorescent uridine and thiadiazole [3,4-d]fluorescent uridine.

[0009] In one embodiment of the present invention, in step S1, when X is 0, the specific method is as follows:

[0010] Weigh 4-amino-2,6-dihydroxy-5-nitrosopyrimidine and lithium hydride, pass N2 through, add DMF, stir, then add iodophenyl diacetate, react at room temperature, and separate and purify to obtain compound 1.

[0011] In one embodiment of the present invention, the catalyst is LiH and iodophenyl diacetate; the molar ratio of 4-amino-2,6-dihydroxy-5-nitrosopyrimidine to LiH is 1:2.8-3.1; the molar ratio of 4-amino-2,6-dihydroxy-5-nitrosopyrimidine to iodophenyl diacetate is 1:1.1-1.3; the amount of DMF relative to 4-amino-2,6-dihydroxy-5-nitrosopyrimidine is 3-4 mL / mmol; and the reaction conditions are: reaction at 25-30℃ for 3-4 h.

[0012] In one embodiment of the present invention, in step S1, when X is S, the specific method is as follows:

[0013] Weigh 4-amino-2,6-dihydroxy-5-nitrosopyrimidine, pass N2 through it, add aqueous acetic acid solution, and add sodium thiosulfate in batches while stirring at 80°C until the purple color disappears. Continue stirring until the reaction is complete, and cool to crystallize to obtain compound 4.

[0014] In one embodiment of the present invention, 4-amino-2,6-dihydroxy-5-nitrosopyrimidine is reacted with sodium thiosulfate at a ratio of 1:1.9-2; the amount of acetic acid aqueous solution relative to 4-amino-2,6-dihydroxy-5-nitrosopyrimidine is 7.8-9.0 mL / mmol; and the reaction conditions are 80-90°C for 1-2 h.

[0015] In one embodiment of the present invention, in step S2, the compound shown in formula (1) is completely dissolved in an anhydrous acetonitrile-filled nip flask with N2, and then N,O-bistrimethylsilylacetamide solution diluted with acetonitrile is added to it. After the reactants are dissolved, 1-acetoxy-2,3,5-tribenzoyloxy-1-β-D-furanose is slowly added, the mixture is heated and stirred, and then trimethylsilyl trifluoromethanesulfonate diluted with ultra-dry acetonitrile is added to continue the reaction. After the reaction is completed, the compound shown in formula (2) is separated and purified.

[0016] In one embodiment of the present invention, the molar ratio of the compound shown in formula (1) to anhydrous acetonitrile is 1:1.01-1.7; the molar ratios of N,O-bistrimethylsilaneacetamide, trimethylsilyl trifluoromethanesulfonate to the compound shown in formula (1) are 1:2.5-3 and 1:1-1.2, respectively; the molar ratio of 1-acetoxy-2,3,5-tribenzoyloxy-1-β-D-ribofuranoside to the compound shown in formula (1) is 1:1.3-1.5; and the reaction conditions are 60-65℃ for 5-6 h.

[0017] In one embodiment of the present invention, in step S3, the compound shown in formula (2) and methanol are added to the pressure-resistant tube and stirred at room temperature. At this time, the reactants are insoluble in methanol. Then, NH3 is slowly passed into the reaction solution while stirring until a saturated alcohol-ammonia solution is formed. The ammonia gas is stopped, the cap of the pressure-resistant tube is tightened, and the pressure-resistant tube is placed in a heated reaction. After the reaction is completed, the compound shown in formula (3) is separated and purified.

[0018] In one embodiment of the present invention, the molar ratio of the compound shown in formula (2) to methanol is 1:2-7; the reaction conditions are 60-70℃ for 20-24h.

[0019] In one embodiment of the present invention, the synthesis route is as follows:

[0020] The synthetic method for furadiazole[3,4-d]fluorescein and thiadiazole[3,4-d]fluorescein includes the following steps: (1) Synthesis of compound 1 Weigh 4-amino-2,6-dihydroxy-5-nitrosopyrimidine and lithium hydride, pass N2 through, add DMF, stir, then add iodophenyl diacetate, react at room temperature, and separate and purify to obtain compound 1.

[0021] (2) Synthesis of compound 2 Compound 1 was completely dissolved in an anhydrous acetonitrile-filled nip flask with N2. Then, N,O-bistrimethylsilylacetamide solution diluted with acetonitrile was added. After the reactants dissolved, 1-acetoxy-2,3,5-tribenzoyloxy-1-β-D-furanose was slowly added. After heating and stirring for 0.5 h, trimethylsilyl trifluoromethanesulfonate diluted with ultra-dry acetonitrile was added. The reaction was carried out overnight at 70 °C. Compound 2 was obtained by separation and purification.

[0022] (3) Synthesis of furadiazole[3,4-d]fluorescein Compound 2 and methanol were added to the pressure-resistant tube and stirred at room temperature. At this time, the reactants were insoluble in methanol. Then, NH3 was slowly passed into the reaction solution while stirring until a saturated alcohol-ammonia solution was formed. The ammonia gas was stopped, the cap of the pressure-resistant tube was tightened, and the pressure-resistant tube was placed at 70 °C for reaction. The reaction lasted for 24 h. Furaniazole [3,4-d]fluorescent uridine was obtained by separation and purification.

[0023] (4) Synthesis of compound 4 Weigh 4-amino-2,6-dihydroxy-5-nitrosopyrimidine, pass N2 through it, add aqueous acetic acid solution, and add sodium thiosulfate in batches while stirring at 80°C until the purple color disappears. Continue stirring for one hour, then cool and crystallize to obtain compound 4.

[0024] (5) Synthesis of compound 5 Compound 4 was completely dissolved in an anhydrous acetonitrile-filled nip flask with N2. Then, N,O-bistrimethylsilylacetamide solution diluted with acetonitrile was added. After the reactants dissolved, 1-acetoxy-2,3,5-tribenzoyloxy-1-β-D-furanose was slowly added. The mixture was heated and stirred for 0.5 h. Then, trimethylsilyl trifluoromethanesulfonate diluted with ultra-dry acetonitrile was added. The mixture was reacted overnight at 70 °C. Compound 5 was obtained by separation and purification.

[0025] (6) Synthesis of thiadiazole [3,4-d]fluorescent uridine Compound 5 and methanol were added to the pressure-resistant tube and stirred at room temperature. At this time, the reactants were insoluble in methanol. Then, NH3 was slowly passed into the reaction solution while stirring until a saturated alcohol-ammonia solution was formed. The ammonia gas was stopped, the cap of the pressure-resistant tube was tightened, and the pressure-resistant tube was placed at 70°C for reaction. The reaction lasted for 24 h. Thiadiazole [3,4-d]fluorescent uridine was obtained by separation and purification.

[0026] This invention discloses a novel method for preparing nucleoside derivatives. These products exhibit excellent fluorescence properties and can be used as fluorescent probes to reduce fluorescence quenching. They have wide applications in biochemistry and medicine. Beneficial effects: This invention presents a synthetic route for obtaining furadiazole[3,4-d]fluorescent uridine and thiadiazole[3,4-d]fluorescent uridine from 4-amino-2,6-dihydroxy-5-nitrosopyrimidine via a reaction. This method directly generates the target products, effectively avoiding common side reactions such as glycosylation and hydrolysis in traditional routes. It not only simplifies the reaction process but also significantly improves the overall controllability and purity of the synthesis. Experiments have demonstrated that this synthetic route possesses comprehensive advantages, including simple and mild reaction conditions, no byproduct formation, and high product yield. These products can be used as fluorescent probes and have significant application prospects in various fields such as biology and medicine, including DNA fluorescent probes and RNA-based process research. Attached Figure Description

[0027] Figure 1 This is a synthesis route diagram for the method of the present invention. Detailed Implementation The following are specific embodiments of the present invention.

[0028] Example 1: Synthesis of Compound 1 Under nitrogen protection, 4-amino-2,6-dihydroxy-5-nitrosopyrimidine (156 mg, 1.0 mmol) and lithium hydride (26.2 mg, 3.1 mmol) were added to 3 mL of DMF and stirred for 0.5 h. Then, iodophenyl diacetate (419 mg, 1.3 mmol) was added, and the mixture was reacted at room temperature for 2 h. The color of the mixture gradually faded from purple. After the reaction was complete, it was diluted with 50 mL of water, the pH was adjusted to neutral with dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. After filtration and concentration, the crude product was purified by column chromatography to give 322 mg of white solid compound 1, with a yield of 52%. 1 H NMR (400 MHz, DMSO- d 6) d 12.33 (s, 1H), 11.78 (s, 1H). Example 2: Synthesis of Compound 2 Under nitrogen protection, compound 1 (100 mg, 0.65 mmol) was added to ultra-dry acetonitrile and stirred at 55 °C to obtain a turbid solution. Then, N,O-bistrimethylsilylacetamide (0.5 mL, 1.95 mmol), diluted with acetonitrile, was added dropwise. The reactants gradually dissolved and became clear with each drop. Once the reaction solution was completely transparent, 1-acetoxy-2,3,5-tribenzoyloxy-1- β-D-ribofuranoside (328 mg, 1.95 mmol). The mixture was then heated to 65 °C and stirred for 30 min. Using a long-needle syringe inserted below the surface of the reaction solution, 0.13 mL of trimethylsilyl trifluoromethanesulfonate diluted with ultra-dry acetonitrile (0.715 mmol) was added. The reaction was carried out at 70 °C for 8 hours (TLC monitoring). After the reaction was complete, the acetonitrile was removed by concentration. The residue was dissolved in dichloromethane, quenched with saturated sodium bicarbonate solution, and the organic phase was dried overnight with anhydrous MgSO4. After filtration and concentration, the crude product was purified by column chromatography to give 200 mg of a white sugar-like solid compound 2, with a yield of 51.4%. 1 H NMR (400 MHz, DMSO) d 12.35 (s, 1H), 8.09-8.02 (m, 2H), 7.97-7.91 (m,2H), 7.86-7.80 (m, 2H), 7.70-7.59 (m, 3H), 7.51 (dt, J = 13.0, 7.8 Hz, 4H),7.42-7.35 (m, 2H), 6.62 (d, J = 4.1 Hz, 1H), 6.17 (dd, J = 6.4, 4.1 Hz, 1H), 6.09 (t, J = 6.6 Hz, 1H), 4.74 (ddd, J = 6.8, 4.7, 3.3 Hz, 1H), 4.64 (dd, J =12.3, 3.3 Hz, 1H), 4.62 (dd, J = 12.3, 4.8 Hz, 1H). Example 3: Synthesis of furadiazole[3,4-d]fluorescent uridine Compound 2 (150 mg, 0.25 mmol) and 10 mL of methanol were added to a 50 mL pressure-resistant tube and stirred at room temperature. At this point, the reactants were insoluble in methanol. Then, NH3 was slowly passed into the reaction solution while stirring for 2 h. With the addition of sufficient NH3, the reactants slowly dissolved, the reaction solution became clear and the liquid level rose, forming a saturated alcohol-ammonia solution. The ammonia gas was stopped, the pressure-resistant tube was tightened, and the tube was placed at 70 °C for 24 h. The reaction was then stopped, and TLC showed that the reactants disappeared. The solution was concentrated and purified by column chromatography to obtain 62.7 mg of furadiazole [3,4-d]fluorescein, with a yield of 25.2%. 1 H NMR (400 MHz, DMSO) d12.04 (s, 1H), 6.14 (d, J = 4.5 Hz, 1H), 5.20 (d, J = 57.7 Hz, 2H), 4.68 (t, J = 11.8 Hz, 2H), 3.80 (dd, J = 10.3, 5.8 Hz,1H), 3.66 (d, J = 11.4 Hz, 1H), 3.55-3.45 (m, 2H). 13 C NMR (101 MHz, DMSO) d 155.24 (s), 154.99 (s), 150.36 (s), 140.31 (s), 90.69 (s), 85.11 (s), 70.63(s), 70.46 (s), 62.47 (s). Example 4: Synthesis of Compound 4 Under nitrogen protection, 400 mg (2.56 mmol) of 4-amino-2,6-dihydroxy-5-nitrosopyrimidine was weighed and added to a 20% aqueous acetic acid solution. Sodium thiosulfate (1.28 g, 5.122 mmol) was added in batches while stirring at 80 °C until the purple color disappeared. After stirring for one hour, the mixture was cooled and crystallized to give compound 4 in 60% yield. 1 H NMR (400 MHz, DMSO- d 6) d 11.93 (s, 2H). Example 5: Synthesis of Compound 5 Under nitrogen protection, compound 4 (110 mg, 0.65 mmol) was added to ultra-dry acetonitrile and stirred at 55 °C to obtain a turbid solution. Then, N,O-bistrimethylsilylacetamide (0.5 mL, 1.95 mmol), diluted with acetonitrile, was added dropwise. The reactants gradually dissolved and became clear with each drop. Once the reaction solution was completely transparent, 1-acetoxy-2,3,5-tribenzoyloxy-1- β -D-ribofuranoside (328 mg, 1.95 mmol). The mixture was then heated to 65 °C and stirred for 30 min. Using a long-needle syringe inserted below the surface of the reaction solution, 0.13 mL of trimethylsilyl trifluoromethanesulfonate diluted with ultra-dry acetonitrile (0.715 mmol) was added. The reaction was carried out at 70 °C for 8 hours (TLC monitoring). After the reaction was complete, the acetonitrile was removed by concentration. The residue was dissolved in dichloromethane, quenched with saturated sodium bicarbonate solution, and the organic phase was dried overnight with anhydrous MgSO4. After filtration and concentration, the crude product was purified by column chromatography to give 200 mg of a white sugar-like solid compound 5, with a yield of 48.5%. 1H NMR (400 MHz, DMSO) d 12.21 (s, 1H), 8.01 (d, J = 7.5 Hz, 2H), 7.93(d, J = 7.5 Hz, 2H), 7.82 (d, J = 7.5 Hz, 2H), 7.67 (t, J = 6.7 Hz, 2H), 7.61(t, J = 7.4 Hz, 1H), 7.50 (dt, J = 15.3, 7.7 Hz, 4H), 7.37 (t, J = 7.8 Hz,2H), 6.70 (d, J = 3.0 Hz, 1H), 6.31-6.20 (m, 2H), 4.83-4.71 (m, 2H), 4.59(dd, J = 12.3, 4.9 Hz, 1H). Example 6: Synthesis of thiadiazole [3,4-d]fluorescent uridine Compound 5 (151 mg, 0.25 mmol) and 10 mL of methanol were added to a 50 mL pressure-resistant tube and stirred at room temperature. At this point, the reactants were insoluble in methanol. Then, NH3 was slowly passed into the reaction solution while stirring for 2 h. With the addition of sufficient NH3, the reactants slowly dissolved, the reaction solution became clear and the liquid level rose, forming a saturated alcohol-ammonia solution. The ammonia gas was stopped, the pressure-resistant tube was tightened, and the tube was placed at 70°C for 24 h. The reaction was then stopped, and TLC showed that the reactants disappeared. The solution was concentrated and purified by column chromatography to obtain 62.7 mg of thiadiazole [3,4-d]fluorescein, with a yield of 23.8%. 1 H NMR (400 MHz, DMSO) d 12.05 (s, 1H), 6.13 (d, J = 4.5 Hz, 1H), 5.17 (d, J = 9.4 Hz, 1H), 4.68 (dd, J = 5.9, 4.5 Hz, 1H), 4.19 (t, J = 5.8 Hz,1H), 3.79 (td, J = 6.0, 4.3 Hz, 1H), 3.67 (dd, J = 11.7, 4.3 Hz, 1H), 3.49 (dd, J = 11.7, 6.3 Hz, 1H), 3.17 (s, 2H). 13 C NMR (101 MHz, DMSO) d155.24 (s),154.99 (s), 150.35 (s), 140.30 (s), 90.69 (s), 85.11 (s), 70.63 (s), 70.46(s), 62.47 (s).

Claims

1. A method for synthesizing furadiazole[3,4-d]fluorescent uridine and thiadiazole[3,4-d]fluorescent uridine, characterized in that, Using 4-amino-2,6-dihydroxy-5-nitrosopyrimidine as the starting material, the synthetic route is as follows: ； Where X is O or S.

2. The synthesis method according to claim 1, characterized in that, Includes the following steps: S1, using 4-amino-2,6-dihydroxy-5-nitrosopyrimidine as the starting material, the compound shown in formula (1) was prepared; S2, the compound shown in formula (1) is reacted with 1-acetoxy-2,3,5-tribenzoyloxy-1-β-D-furanose and trimethylsilyltrifluoromethanesulfonic acid to prepare the compound shown in formula (2); S3, the compound shown in formula (2) under alcohol / NH3 conditions, forms the compound shown in formula (3), namely furadiazole [3,4-d]fluorescent uridine and thiadiazole [3,4-d]fluorescent uridine.

3. The synthesis method according to claim 2, characterized in that, In step S1, when X is 0, the specific method is as follows: Weigh 4-amino-2,6-dihydroxy-5-nitrosopyrimidine and lithium hydride, pass N2 through, add DMF, stir, then add iodophenyl diacetate, react at room temperature, and separate and purify to obtain compound 1.

4. The synthesis method according to claim 3, characterized in that, The catalysts were LiH and iodophenyl diacetate. The molar ratio of 4-amino-2,6-dihydroxy-5-nitrosopyrimidine to LiH was 1:2.8-3.1; the molar ratio of 4-amino-2,6-dihydroxy-5-nitrosopyrimidine to iodophenyl diacetate was 1:1.1-1.3; the amount of DMF relative to 4-amino-2,6-dihydroxy-5-nitrosopyrimidine was 3-4 mL / mmol; and the reaction conditions were: reaction at 25-30℃ for 3-4 h.

5. The synthesis method according to claim 2, characterized in that, In step S1, when X is S, the specific method is as follows: Weigh 4-amino-2,6-dihydroxy-5-nitrosopyrimidine, pass N2 through it, add aqueous acetic acid solution, and add sodium thiosulfate in batches while stirring at 80°C until the purple color disappears. Continue stirring until the reaction is complete, and cool to crystallize to obtain compound 4.

6. The synthesis method according to claim 5, characterized in that, 4-Amino-2,6-dihydroxy-5-nitrosopyrimidine was reacted with sodium thiosulfate at a ratio of 1:1.9-2; the amount of acetic acid aqueous solution relative to 4-amino-2,6-dihydroxy-5-nitrosopyrimidine was 7.8-9.0 mL / mmol; the reaction conditions were 80-90℃ for 1-2 h.

7. The synthesis method according to claim 2, characterized in that, In step S2, the compound shown in formula (1) is completely dissolved in an anhydrous acetonitrile-filled nip flask with N2. Then, N,O-bistrimethylsilylacetamide solution diluted with acetonitrile is added to the flask. After the reactants are dissolved, 1-acetoxy-2,3,5-tribenzoyloxy-1-β-D-furanose is slowly added. The mixture is heated and stirred. Then, trimethylsilyl trifluoromethanesulfonate diluted with ultra-dry acetonitrile is added and the reaction continues. After the reaction is completed, the compound shown in formula (2) is separated and purified.

8. The synthesis method according to claim 7, characterized in that, The molar ratio of the compound shown in formula (1) to anhydrous acetonitrile is 1:1.01-1.7; the molar ratios of N,O-bistrimethylsilaneacetamide, trimethylsilyl trifluoromethanesulfonate and the compound shown in formula (1) are 1:2.5-3 and 1:1-1.2, respectively; the molar ratio of 1-acetoxy-2,3,5-tribenzoyloxy-1-β-D-ribofuranoside to the compound shown in formula (1) is 1:1.3-1.5; the reaction conditions are 60-65℃ for 5-6 h.

9. The synthesis method according to claim 2, characterized in that, In step S3, the compound shown in formula (2) and methanol are added to the pressure-resistant tube and stirred at room temperature. At this time, the reactants are insoluble in methanol. Then, NH3 is slowly passed into the reaction solution while stirring until a saturated alcohol-ammonia solution is formed. Stop the ammonia gas, tighten the cap of the pressure-resistant tube, and place the pressure-resistant tube in the heating reaction. After the reaction is completed, separate and purify to obtain the compound shown in formula (3).

10. The synthesis method according to claim 9, characterized in that, The molar ratio of the compound shown in formula (2) to methanol is 1:2-7; the reaction conditions are 60-70℃ for 20-24h.

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