阅读说明：本技术 一种4,4-二甲基-4,5-二氢哒嗪-3-酮的合成方法 (Synthesis method of 4, 4-dimethyl-4, 5-dihydropyridazin-3-one ) 是由 雷健 王慧 杨国艳 谢晓兰 孙丽丹 于 2021-10-29 设计创作，主要内容包括：本发明属于有机合成技术领域,具体涉及一种从炔烃出发合成4,4-二甲基-4,5-二氢哒嗪-3-酮的方法,其包括以下步骤：将溴化亚铜、偶氮二甲酸二叔丁酯用溶剂溶解,并加入炔烃混合均匀,然后加入偶氮二异丁酸二甲酯,在密闭条件下升温至80±10～(o)C搅拌6-9小时,反应结束后经简单后处理得到粗品。所得粗产品加入溶剂和盐酸/乙酸乙酯溶液,升温至70±10～(o)C搅拌反应1-8小时,反应结束经后处理即得。本发明方法具有不使用对环境有害的水合肼、不使用对水敏感的有机金属试剂、反应条件温和、原料廉价易得、步骤简单、底物适用性广等特点,适用于合成各种4,4-二甲基-4,5-二氢哒嗪-3-酮化合物。(The invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing 4, 4-dimethyl-4, 5-dihydropyridazin-3-one from alkyne, which comprises the following steps: dissolving cuprous bromide and di-tert-butyl azodicarboxylate in solvent, adding alkyne, mixing, adding dimethyl azodiisobutyrate, heating to 80 +/-10 deg.C under sealed condition o C, stirring for 6-9 hours, and obtaining a crude product through simple post-treatment after the reaction is finished. Adding solvent and hydrochloric acid/ethyl acetate solution into the obtained crude product, and heating to 70 +/-10 DEG o C, stirring and reacting for 1-8 hours, and carrying out post-treatment after the reaction is finished. The method has the characteristics of no use of hydrazine hydrate which is harmful to the environment, no use of organic metal reagent which is sensitive to water, mild reaction conditions, cheap and easily obtained raw materials, simple steps, wide substrate applicability and the like, and is suitable for synthesizing various 4, 4-dimethyl-4, 5-dihydropyridazin-3-one compounds.)

1. A method for synthesizing 4, 4-dimethyl-4, 5-dihydropyridazin-3-one is characterized by comprising the following steps: the method comprises the following steps:

(1) dissolving cuprous bromide and di-tert-butyl azodicarboxylate by using a solvent, adding alkyne, uniformly mixing, then adding dimethyl azodiisobutyrate, reacting under a closed condition, and obtaining an intermediate through simple post-treatment after the reaction is finished;

(2) and adding a solvent and a hydrochloric acid/ethyl acetate solution into the obtained intermediate for reaction, and carrying out post-treatment after the reaction is finished to obtain the 4, 4-dimethyl-4, 5-dihydropyridazin-3-one.

2. The method for synthesizing 4, 4-dimethyl-4, 5-dihydropyridazin-3-one according to claim 1, characterized in that: the alkyne is any one of phenylacetylene compounds with various substituents on aromatic rings, ethynylpyridine or ethynylthiophene.

3. The method for synthesizing 4, 4-dimethyl-4, 5-dihydropyridazin-3-one according to claim 2, characterized in that: the alkyne is any one of phenylacetylene, p-methoxyphenylacetylene, m-methoxyphenylacetylene, p-ethylphenylacetylene, p-chlorobenzeneacetylene, 4-fluorophenylacetylene, 4-ethynylphenylacetonitrile, 3, 5-dimethoxyphenylacetylene, 3-ethynylpyridine and 3-ethynylthiophene compounds.

4. The method for synthesizing 4, 4-dimethyl-4, 5-dihydropyridazin-3-one according to claim 1, characterized in that: the reaction condition of the step (1) is specifically that the temperature is increased to 80 +/-10^oC, stirring for 7-8 hours.

5. The method for synthesizing 4, 4-dimethyl-4, 5-dihydropyridazin-3-one according to claim 1, characterized in that: the solvent used in the step (1) is acetonitrile or N, N-dimethylformamide.

6. The method for synthesizing 4, 4-dimethyl-4, 5-dihydropyridazin-3-one according to claim 1, characterized in that: the molar ratio of the di-tert-butyl azodicarboxylate, dimethyl azodiisobutyrate and alkyne in the step (1) is 1:1:1-1:1: 5.

7. The method for synthesizing 4, 4-dimethyl-4, 5-dihydropyridazin-3-one according to claim 1, characterized in that: the molar ratio of the cuprous bromide to the di-tert-butyl azodicarboxylate in the step (1) is 10-30: 100.

8. The method for synthesizing 4, 4-dimethyl-4, 5-dihydropyridazin-3-one according to claim 1, characterized in that: the reaction in the step (2) is specifically carried out by heating to 70 +/-10 DEG C^oC, stirring and reacting for 1-8 hours; the solvent is one of ethyl acetate, methanol, 1, 4-dioxane and isopropanol.

9. The method for synthesizing 4, 4-dimethyl-4, 5-dihydropyridazin-3-one according to claim 1, characterized in that: the molar ratio of the hydrochloric acid/ethyl acetate to the di-tert-butyl azodicarboxylate is 1.5-3: 1.

10. The method for synthesizing 4, 4-dimethyl-4, 5-dihydropyridazin-3-one according to claim 1, characterized in that: the hydrochloric acid/ethyl acetate is specifically prepared by dissolving 1mol-4mol of hydrogen chloride in 1L of ethyl acetate.

Technical Field

The invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing 4, 4-dimethyl-4, 5-dihydropyridazin-3-one by using di-tert-butyl azodicarboxylate, dimethyl azodiisobutyrate and alkyne compounds as raw materials.

Background

Nitrogen-containing heterocyclic compounds generally have unique low toxicity, biological activity, and are often used as building blocks for pharmaceutical and pesticidal molecules. Of the small molecule drugs approved by the U.S. Food and Drug Administration (FDA), approximately 59% contain an azacyclic backbone. (Vitaku, E.; Smith, D.T.; Njardarson, Jon T.J.Med.chem.2014,54,10257.) introduction of heterocyclic structures into drug molecules can improve bioavailability, water solubility and lipid solubility, molecular polarity, etc. of the drug. Among them, the compound having the hexabasic pyridazinone structure as the mother nucleus structure has wide applications in medicines, including blood pressure lowering, platelet aggregation inhibiting, blood pressure lowering, cardiotonic activity and the like. ((a) Curran, w.v.; Ross, a.j.med.chem.1974,17,273.(b) Thyes, m.; Lehmann, h.d.; Gries, j.; Koenig, h.; Kretzschmar, r.; Kunze, j.; lebkcher, r.; len, d.j.med.chem.1983,26,800.) in recent years, several novel pyridazinone compounds have been synthesized and exhibit novel pharmacological activities. For example, some molecules with 4, 4-dimethyl-4, 5-dihydropyridazin-3-one are considered to be potential histamine H₃A receptor inverse agonist. ((a) Wang, Y.; Przyuski, K.; Roemmole, R.C.; et al.org.Process Res.Dev.2013,17,846.(b) Hudkins, R.L.; Zulli, A.L.; Dandu, R.r.; et al.Bioorg.Med.Chem.Lett.2012,22,1504.) therefore, the rapid, efficient, mild construction of a 4, 4-dimethyl-4, 5-dihydropyridazin-3-one scaffold is of great importance for the batch synthesis of biologically active compounds.

The method for synthesizing the 4, 4-dimethyl-4, 5-dihydropyridazin-3-one compound can be summarized as synthesizing 2, 2-dimethyl-4-carbonyl-1-butyrate structure and condensing with poisonous hydrazine hydrate. The synthesis of 2, 2-dimethyl-4-carbonyl-1-butyric acid ester requires addition and esterification of 2, 2-dimethyl succinic anhydride by using water-sensitive aryl Grignard reagent (Hudkins, R.L.; Aimone, L.D.; Dandu, R.r.; et al. Bioorg. Med. Chem.Lett.2012,22,194.), or (a) Li, D.J. Org. Chem.2021,86,1,609 (b) Hu, B.; Chen, H.; Liu, Y.; et al. mumn.2014, 50,13547.(c) Fang, X.; Wang, P. -F.; Yi, W.; Oral. J. 84,15677.) with 2-bromoisobutyrate in the presence of an olefin, enamine, enol, silyl ether, etc. Due to the limitations of the existing synthesis method of 4, 4-dimethyl-4, 5-dihydropyridazin-3-one, a mild, economic, green and efficient synthesis method needs to be discovered.

Disclosure of Invention

The invention aims to provide a method for modularizing and synthesizing 4, 4-dimethyl-4, 5-dihydropyridazin-3-one by alkyne, di-tert-butyl azodicarboxylate and dimethyl azodiisobutyrate compound, which has the advantages of no need of using toxic hydrazine hydrate, no use of water-sensitive organic metal reagent, easily available raw materials, wide substrate application range and the like.

In order to achieve the purpose, the following specific scheme is adopted:

a method for synthesizing 4, 4-dimethyl-4, 5-dihydropyridazin-3-one comprises the following steps:

(1) dissolving cuprous bromide and di-tert-butyl azodicarboxylate by using a solvent, adding alkyne, uniformly mixing, then adding dimethyl azodiisobutyrate, heating to 80 +/-10 ℃ under a closed condition, stirring for 7-8 hours, and simply performing post-treatment after the reaction to obtain an intermediate.

(2) Adding a solvent and a hydrochloric acid/ethyl acetate solution into the obtained intermediate, heating to 70 +/-10 ℃, stirring to react for 1-8 hours, and carrying out post-treatment after the reaction is finished.

The specific reaction equation is as follows:

in the formula, the compound 1 is alkyne, and may be phenylacetylene compounds, ethynylpyridine, ethynylthiophene and the like with various substituents on the aromatic ring, and specific examples thereof are phenylacetylene, p-methoxyphenylacetylene, m-methoxyphenylacetylene, p-ethylphenylacetylene, p-chlorophenylacetylene, p-fluorophenylacetylene, 4-cyanomethylphenylacetylene, 3, 5-dimethoxyphenylacetylene, 3-ethynylpyridine or 3-ethynylthiophene compounds.

In the formula, the compound 2 is di-tert-butyl azodicarboxylate.

In the formula, the compound 3 is dimethyl azodiisobutyrate.

The solvent used in step (1) of the above reaction may be acetonitrile (MeCN) or N, N-Dimethylformamide (DMF), and preferably 2 to 3ml of a solvent is added to 0.2mmol of di-tert-butyl azodicarboxylate.

The solvent used in the step (2) is one of ethyl acetate (EtOAc), methanol (MeOH), 1, 4-dioxane (1, 4-dioxane) or isopropanol (iPrOH).

Specifically, the molar ratio of the di-tert-butyl azodicarboxylate, dimethyl azodiisobutyrate and alkyne is 1:1:1-1:1: 5.

Specifically, the molar ratio of the cuprous bromide to the di-tert-butyl azodicarboxylate is 10-30: 100.

Specifically, the molar ratio of the hydrochloric acid/ethyl acetate to the di-tert-butyl azodicarboxylate is 1.5-3: 1.

Specifically, the hydrochloric acid/ethyl acetate is prepared by dissolving 1mol to 4mol of hydrogen chloride in 1L of ethyl acetate.

The invention has the following remarkable advantages:

1) the invention provides a synthesis method of 4, 4-dimethyl-4, 5-dihydropyridazin-3-one with mild conditions, and provides a simple and universal synthesis method for further expanding application of the synthesis method in medicines.

2) The raw materials used in the reaction are easy to obtain, the reagent price is low, the operation is simple and convenient, and toxic hydrazine hydrate and organic metal reagents sensitive to water are not needed.

3) The compound synthesized by the invention can be used as a medicine or organic synthesis intermediate, and further generates a functionalization reaction, so that the pyridazinone compound with more medical value is synthesized.

Drawings

FIG. 1 is a nuclear magnetic hydrogen spectrum of the product of example 1;

FIG. 2 is a nuclear magnetic carbon spectrum of the product of example 1;

FIG. 3 is a nuclear magnetic hydrogen spectrum of the product of example 2;

FIG. 4 is a nuclear magnetic carbon spectrum of the product of example 2;

FIG. 5 is a nuclear magnetic hydrogen spectrum of the product of example 9;

FIG. 6 is a nuclear magnetic carbon spectrum of the product of example 9.

Detailed Description

The technical solution of the present invention is further described in detail with reference to the following examples, but the scope of the present invention is not limited thereto.

Example 1:

first, a stirrer was placed in a 15mL sealed tube, and di-tert-butyl azodicarboxylate (46.4mg,0.2mmol) and cuprous bromide (5.7mg,0.04mmol) were added. The reaction tube was purged three times under argon atmosphere. Anhydrous acetonitrile (2.0mL) and p-methoxyphenylacetylene (79.2mg,0.6mmol), dimethyl azodiisobutyrate (46.4mg,0.2mmol) were added. The reaction was stirred at the indicated temperature (80 ℃) for 8 hours and then cooled to room temperature. Filter through celite and wash with ethyl acetate (20 mL). After concentration by rotary evaporation, the crude product is separated roughly on silica gel column chromatography (V)_{Petroleum ether}/V_{Ethyl acetate}3:1) to give the corresponding vinyl hydrazine intermediate as an oil. Subsequently, ethyl acetate (0.4mL) and a 2M hydrochloric acid/ethyl acetate solution (0.6mL) were added thereto, and the reaction was stirred at 70 ℃ for 7 hours. After the reaction was completed, the system was cooled to room temperature, 3mL of saturated sodium bicarbonate was added to the reaction mixture, extraction was performed with ethyl acetate (5 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the crude product was subjected to silica gel column chromatography (V)_{Petroleum ether}/V_{Ethyl acetate}Isolated as a white solid 16.7mg, 36% yield. The reaction is shown in the following formula:

spectrogram analysis data

¹H NMR(400MHz,DMSO-d₆)δ10.79(s,1H),7.72(d,J＝8.8Hz,2H),6.98(d,J＝8.8Hz,2H),3.79(s,3H),2.79(s,2H),1.07(s,6H)；¹³C NMR(100MHz,DMSO-d₆)δ172.6,160.2,149.3,128.8,127.2,113.9,55.3,35.7,33.1,23.4；C₁₃H₁₇N₂O₂[M+H]⁺233.1285,found 233.1282.

Example 2:

first, a stirrer was placed in a 15mL sealed tube, and di-tert-butyl azodicarboxylate (46.4mg,0.2mmol) and cuprous bromide (5.7mg,0.04mmol) were added. The reaction tube was purged three times under argon atmosphere. Anhydrous acetonitrile (2.0mL) and phenylacetylene (61.3mg,0.6mmol), dimethyl azodiisobutyrate (46.4mg,0.2mmol) were added. The reaction was stirred at the indicated temperature (80 ℃) for 8 hours and then cooled to room temperature. Filter through celite and wash with ethyl acetate (20 mL). After concentration by rotary evaporation, the crude product is isolated by column chromatography on silica gel (V)_{Petroleum ether}/V_{Ethyl acetate}3:1) to give the corresponding vinyl hydrazine intermediate as an oil. Subsequently, ethyl acetate (0.4mL) and a 2M hydrochloric acid/ethyl acetate solution (0.6mL) were added thereto, and the reaction was stirred at 70 ℃ for 7 hours. After the reaction was completed, the system was cooled to room temperature, 3mL of saturated sodium bicarbonate was added to the reaction mixture, extraction was performed with ethyl acetate (5 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the crude product was subjected to silica gel column chromatography (V)_{Petroleum ether}/V_{Ethyl acetate}Isolated as a white solid 13.8mg with 34% yield as 3: 1). The reaction is shown in the following formula:

spectrogram analysis data

¹H NMR(400MHz,DMSO-d₆)δ10.91(s,1H),7.82-7.71(m,2H),7.49-7.36(m,3H),2.82(s,2H),1.08(s,6H)；¹³C NMR(100MHz,DMSO-d₆)δ173.1,149.9,136.8,129.8,129.1,126.1,36.2,33.6,23.9.

Example 3:

first, a stirrer was placed in a 15mL sealed tube, and di-tert-butyl azodicarboxylate (46.4mg,0.2mmol) and cuprous bromide (5.7mg,0.04mmol) were added. The reaction tube was purged three times under argon atmosphere. Anhydrous acetonitrile (2.0mL) and m-methoxyphenylacetylene (79.2mg,0.6mmol), dimethyl azodiisobutyrate (46.4mg,0.2mmol) were added. The reaction was stirred at the indicated temperature (80 ℃) for 8 hours and then cooled to room temperature. Filter through celite and wash with ethyl acetate (20 mL). After concentration by rotary evaporation, the crude product is isolated by column chromatography on silica gel (V)_{Petroleum ether}/V_{Ethyl acetate}3:1) to give the corresponding vinyl hydrazine intermediate as an oil. Subsequently, ethyl acetate (0.4mL) and a 2M hydrochloric acid/ethyl acetate solution (0.6mL) were added thereto, and the reaction was stirred at 70 ℃ for 7 hours. After the reaction was completed, the system was cooled to room temperature, 3mL of saturated sodium bicarbonate was added to the reaction mixture, extraction was performed with ethyl acetate (5 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the crude product was subjected to silica gel column chromatography (V)_{Petroleum ether}/V_{Ethyl acetate}Isolated as a white solid 11.9mg, 26% yield. The reaction is shown in the following formula:

spectrogram analysis data

¹H NMR(400MHz,DMSO-d₆)δ10.90(s,1H),7.39-7.28(m,3H),7.02-6.90(m,1H),3.80(s,3H),2.83(s,2H),1.08(s,6H)；¹³C NMR(100MHz,DMSO-d₆)δ173.2,159.2,149.8,138.3,130.1,118.7,115.1,111.0,55.6,36.3,33.6,23.9.

Example 4:

first, a stirrer was placed in a 15mL sealed tube, and di-tert-butyl azodicarboxylate (46.4mg,0.2mmol) and cuprous bromide (5.7mg,0.04mmol) were added. The reaction tube was purged three times under argon atmosphere. Anhydrous acetonitrile (2.0mL) and p-ethylphenylacetylene (78.1mg,0.6mmol), dimethyl azodiisobutyrate (46.4mg,0.2mmol) were added. The reaction is carried out at a specified temperature (80℃)) After stirring for 8 hours, the mixture was cooled to room temperature. Filter through celite and wash with ethyl acetate (20 mL). After concentration by rotary evaporation, the crude product is isolated by column chromatography on silica gel (V)_{Petroleum ether}/V_{Ethyl acetate}3:1) to give the corresponding vinyl hydrazine intermediate as an oil. Subsequently, ethyl acetate (0.4mL) and a 2M hydrochloric acid/ethyl acetate solution (0.6mL) were added thereto, and the reaction was stirred at 70 ℃ for 7 hours. After the reaction was completed, the system was cooled to room temperature, 3mL of saturated sodium bicarbonate was added to the reaction mixture, extraction was performed with ethyl acetate (5 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the crude product was subjected to silica gel column chromatography (V)_{Petroleum ether}/V_{Ethyl acetate}Isolated as a white solid 17.9mg, 39% yield. The reaction is shown in the following formula:

spectrogram analysis data

¹H NMR(400MHz,DMSO-d₆)δ10.84(s,1H),7.68(d,J＝8.4Hz,2H),7.27(d,J＝8.4Hz,2H),4.09(s,2H),2.81(s,2H),2.63(q,J＝7.6Hz,2H),1.19(t,J＝7.6Hz,3H),1.08(s,6H)；¹³C NMR(100MHz,DMSO-d₆)δ173.1,150.0,145.7,134.4,128.4,126.1,36.3,33.6,28.4,23.9,15.9.

Example 5:

first, a stirrer was placed in a 15mL sealed tube, and di-tert-butyl azodicarboxylate (46.4mg,0.2mmol) and cuprous bromide (5.7mg,0.04mmol) were added. The reaction tube was purged three times under argon atmosphere. Anhydrous acetonitrile (2.0mL) and p-chlorophenylacetylene (82.0mg,0.6mmol), dimethyl azodiisobutyrate (46.4mg,0.2mmol) were added. The reaction was stirred at the indicated temperature (80 ℃) for 8 hours and then cooled to room temperature. Filter through celite and wash with ethyl acetate (20 mL). After concentration by rotary evaporation, the crude product is isolated by column chromatography on silica gel (V)_{Petroleum ether}/V_{Ethyl acetate}3:1) to give the corresponding vinyl hydrazine intermediate as an oil. Subsequently, ethyl acetate (0.4mL) and a 2M hydrochloric acid/ethyl acetate solution (0.6mL) were added thereto, and the temperature was raised to 70 deg.CThe reaction was stirred for 7 hours. After the reaction was completed, the system was cooled to room temperature, 3mL of saturated sodium bicarbonate was added to the reaction mixture, extraction was performed with ethyl acetate (5 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the crude product was subjected to silica gel column chromatography (V)_{Petroleum ether}/V_{Ethyl acetate}Isolated as a white solid 13.1mg, 28% yield 3: 1). The reaction is shown in the following formula:

spectrogram analysis data

¹H NMR(400MHz,DMSO-d₆)δ10.97(s,1H),7.78(d,J＝8.4Hz,2H),7.50(d,J＝8.4Hz,2H),2.84(s,2H),1.08(s,6H)；¹³C NMR(100MHz,DMSO-d₆)δ173.0,148.9,135.7,134.4,129.0,127.9,36.1,33.5,23.9.

Example 6:

first, a stirrer was placed in a 15mL sealed tube, and di-tert-butyl azodicarboxylate (46.4mg,0.2mmol) and cuprous bromide (5.7mg,0.04mmol) were added. The reaction tube was purged three times under argon atmosphere. Anhydrous acetonitrile (2.0mL) and 4-ethynylphenylacetonitrile (CAS:351002-90-9) (84.7mg,0.6mmol), dimethyl azodiisobutyrate (46.4mg,0.2mmol) were added. The reaction was stirred at the indicated temperature (80 ℃) for 8 hours and then cooled to room temperature. Filter through celite and wash with ethyl acetate (20 mL). After concentration by rotary evaporation, the crude product is isolated by column chromatography on silica gel (V)_{Petroleum ether}/V_{Ethyl acetate}3:1) to give the corresponding vinyl hydrazine intermediate as an oil. Subsequently, ethyl acetate (0.4mL) and a 2M hydrochloric acid/ethyl acetate solution (0.6mL) were added thereto, and the reaction was stirred at 70 ℃ for 7 hours. After the reaction was completed, the system was cooled to room temperature, 3mL of saturated sodium bicarbonate was added to the reaction mixture, extraction was performed with ethyl acetate (5 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the crude product was subjected to silica gel column chromatography (V)_{Petroleum ether}/V_{Ethyl acetate}Isolated as a white solid 7.1mg, 17% yield 3: 1). The reaction is shown in the following formula:

spectrogram analysis data

¹H NMR(400MHz,DMSO-d₆)δ10.92(s,1H),7.79(d,J＝8.4Hz,2H),7.41(d,J＝8.4Hz,2H),4.09(s,2H),2.84(s,2H),1.08(s,6H)；¹³C NMR(100MHz,DMSO-d₆)δ173.1,149.4,136.2,132.8,128.8,126.7,119.5,36.2,33.6,23.9,22.6.

Example 7:

first, a stirrer was placed in a 15mL sealed tube, and di-tert-butyl azodicarboxylate (46.4mg,0.2mmol) and cuprous bromide (5.7mg,0.04mmol) were added. The reaction tube was purged three times under argon atmosphere. Anhydrous acetonitrile (2.0mL) and 4-fluoroacetylene (72.1mg,0.6mmol), dimethyl azodiisobutyrate (46.4mg,0.2mmol) were added. The reaction was stirred at the indicated temperature (80 ℃) for 8 hours and then cooled to room temperature. Filter through celite and wash with ethyl acetate (20 mL). After concentration by rotary evaporation, the crude product is isolated by column chromatography on silica gel (V)_{Petroleum ether}/V_{Ethyl acetate}3:1) to give the corresponding vinyl hydrazine intermediate as an oil. Subsequently, ethyl acetate (0.4mL) and a 2M hydrochloric acid/ethyl acetate solution (0.6mL) were added thereto, and the reaction was stirred at 70 ℃ for 7 hours. After the reaction was completed, the system was cooled to room temperature, 3mL of saturated sodium bicarbonate was added to the reaction mixture, extraction was performed with ethyl acetate (5 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the crude product was subjected to silica gel column chromatography (V)_{Petroleum ether}/V_{Ethyl acetate}Isolated as a white solid 9.2mg, 21% yield 3: 1). The reaction is shown in the following formula:

spectrogram analysis data

¹H NMR(400MHz,DMSO-d₆)δ10.90(s,1H),7.85-7.78(m,2H),7.31-7.23(m,2H),2.84(s,2H),1.08(s,6H)；¹³C NMR(100MHz,DMSO-d₆)δ173.0,163.2(d,J＝245.2Hz),149.0,133.4(d,J＝3.1Hz),128.4(d,J＝8.4Hz),115.9(d,J＝21.5Hz),36.3,33.5,23.9.

Example 8:

first, a stirrer was placed in a 15mL sealed tube, and di-tert-butyl azodicarboxylate (46.4mg,0.2mmol) and cuprous bromide (5.7mg,0.04mmol) were added. The reaction tube was purged three times under argon atmosphere. Anhydrous acetonitrile (2.0mL) and 3, 5-dimethoxyphenylacetylene (97.3mg,0.6mmol), dimethyl azodiisobutyrate (46.4mg,0.2mmol) were added. The reaction was stirred at the indicated temperature (80 ℃) for 8 hours and then cooled to room temperature. Filter through celite and wash with ethyl acetate (20 mL). After concentration by rotary evaporation, the crude product is isolated by column chromatography on silica gel (V)_{Petroleum ether}/V_{Ethyl acetate}3:1) to give the corresponding vinyl hydrazine intermediate as an oil. Subsequently, ethyl acetate (0.4mL) and a 2M hydrochloric acid/ethyl acetate solution (0.6mL) were added thereto, and the reaction was stirred at 70 ℃ for 7 hours. After the reaction was completed, the system was cooled to room temperature, 3mL of saturated sodium bicarbonate was added to the reaction mixture, extraction was performed with ethyl acetate (5 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the crude product was subjected to silica gel column chromatography (V)_{Petroleum ether}/V_{Ethyl acetate}Isolated as a white solid 7.0mg, 13% yield 3: 1). The reaction is shown in the following formula:

spectrogram analysis data

¹H NMR(400MHz,DMSO-d₆)δ10.88(s,1H),6.89(d,J＝2.4Hz,2H),6.55(dd,J＝2.4,2.4Hz,1H),3.78(s,6H),2.81(s,2H),1.08(s,6H)；¹³C NMR(100MHz,DMSO-d₆)δ173.2,161.0,149.7,138.9,104.1,101.8,55.8,36.2,33.6,23.8.

Example 9:

first, a stirrer was placed in a 15mL sealed tube, and di-tert-butyl azodicarboxylate (46.4mg,0.2mmol) and cuprous bromide (5.7mg,0.04mmol) were added. Reaction tube is pumped and ventilated under argon atmosphereNext, the process is carried out. Anhydrous acetonitrile (2.0mL) and 3-ethynylpyridine (61.9mg,0.6mmol), dimethyl azodiisobutyrate (46.4mg,0.2mmol) were added. The reaction was stirred at the indicated temperature (80 ℃) for 8 hours and then cooled to room temperature. Filter through celite and wash with ethyl acetate (20 mL). After concentration by rotary evaporation, the crude product is isolated by column chromatography on silica gel (V)_{Petroleum ether}/V_{Ethyl acetate}3:1) to give the corresponding vinyl hydrazine intermediate as an oil. Subsequently, ethyl acetate (0.4mL) and a 2M hydrochloric acid/ethyl acetate solution (0.6mL) were added thereto, and the reaction was stirred at 70 ℃ for 7 hours. After the reaction was completed, the system was cooled to room temperature, 3mL of saturated sodium bicarbonate was added to the reaction mixture, extraction was performed with ethyl acetate (5 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the crude product was subjected to silica gel column chromatography (V)_{Petroleum ether}/V_{Ethyl acetate}Isolated as a white solid 22.3mg, 55% yield 3: 1). The reaction is shown in the following formula:

spectrogram analysis data

¹H NMR(400MHz,DMSO-d₆)δ11.03(s,1H),8.95(br s,1H),8.60(br s,1H),8.12(ddd,J＝8.4,1.6,1.6Hz,1H),7.47(dd,J＝8.4,4.8Hz,1H),2.89(s,2H),1.10(s,6H)；¹³C NMR(100MHz,DMSO-d₆)δ173.1,150.5,148.0,147.3,133.4,132.4,124.1,35.9,33.5,23.9.

Example 10:

first, a stirrer was placed in a 15mL sealed tube, and di-tert-butyl azodicarboxylate (46.4mg,0.2mmol) and cuprous bromide (5.7mg,0.04mmol) were added. The reaction tube was purged three times under argon atmosphere. Anhydrous acetonitrile (2.0mL) and 3-ethynylthiophene (64.8mg,0.6mmol), dimethyl azodiisobutyrate (46.4mg,0.2mmol) were added. The reaction was stirred at the indicated temperature (80 ℃) for 8 hours and then cooled to room temperature. Filter through celite and wash with ethyl acetate (20 mL). After concentration by rotary evaporation, the crude product is isolated by column chromatography on silica gel (V)_{Petroleum ether}/V_{Ethyl acetate}3:1) to obtain the correspondingAn oily vinyl hydrazine intermediate. Subsequently, ethyl acetate (0.4mL) and a 2M hydrochloric acid/ethyl acetate solution (0.6mL) were added thereto, and the reaction was stirred at 70 ℃ for 7 hours. After the reaction was completed, the system was cooled to room temperature, 3mL of saturated sodium bicarbonate was added to the reaction mixture, extraction was performed with ethyl acetate (5 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the crude product was subjected to silica gel column chromatography (V)_{Petroleum ether}/V_{Ethyl acetate}Isolated as a white solid 16.0mg, 39% yield. The reaction is shown in the following formula:

spectrogram analysis data

¹H NMR(400MHz,DMSO-d₆)δ10.76(s,1H),7.91(dd,J＝2.8,1.2Hz,1H),7.60(dd,J＝5.2,2.8Hz,1H),7.46(dd,J＝5.2,1.2Hz,1H),2.81(s,2H),1.07(s,6H)；¹³C NMR(100MHz,DMSO-d₆)δ173.1,147.0,139.9,127.8,125.8,125.4,37.0,33.6,23.9.