阅读说明：本技术 一种2-氨基-3-氰基-4h-吡喃类化合物的机械球磨辅助合成方法 (Mechanical ball-milling auxiliary synthesis method of 2-amino-3-cyano-4H-pyran compounds ) 是由 姜灵 鲁青青 储消和 于 2021-06-18 设计创作，主要内容包括：本发明涉及化学合成技术领域,为解决现有现有技术下用化学法合成2-氨基-3-氰基-4H-吡喃类化合物污染大,所用催化剂制备繁琐的问题,公开了一种2-氨基-3-氰基-4H-吡喃类化合物的机械球磨辅助合成方法,包括以下步骤：(a)将底物1、底物2及丙二腈作为原料,加入蛋白质催化剂及助磨剂后进行机械球磨；(b)球磨结束后将反应物刮出,加入溶剂,过滤后经浓缩、柱层析制得2-氨基-3-氰基-4H-吡喃类化合物。机械球磨技术有利于反应物分子相互接触,实现无溶剂反应,蛋白类催化剂易得对环境友好。本发明有效地实现了对2-氨基-3-氰基-4H-吡喃类化合物的绿色合成,制备条件温和,操作简便,反应速率快。(The invention relates to the technical field of chemical synthesis, and discloses a mechanical ball-milling auxiliary synthesis method of a 2-amino-3-cyano-4H-pyran compound, which aims to solve the problems of high pollution and complicated preparation of a used catalyst in the prior art of synthesizing the 2-amino-3-cyano-4H-pyran compound by a chemical method, and comprises the following steps: (a) taking a substrate 1, a substrate 2 and malononitrile as raw materials, adding a protein catalyst and a grinding aid, and then carrying out mechanical ball milling; (b) and after the ball milling is finished, scraping out the reactant, adding a solvent, filtering, concentrating, and carrying out column chromatography to obtain the 2-amino-3-cyano-4H-pyran compound. The mechanical ball milling technology is beneficial to the mutual contact of reactant molecules, the solvent-free reaction is realized, and the protein catalyst is easy to obtain and is environment-friendly. The invention effectively realizes the green synthesis of the 2-amino-3-cyano-4H-pyran compound, and has mild preparation conditions, simple and convenient operation and high reaction rate.)

1. A mechanical ball milling auxiliary synthesis method of 2-amino-3-cyano-4H-pyran compounds is characterized by comprising the following steps:

(a) taking a substrate 1, a substrate 2 and malononitrile as raw materials, adding a protein catalyst and a grinding aid, and then carrying out mechanical ball milling;

(b) and after the ball milling is finished, scraping out the reactant, adding a solvent, filtering, concentrating, and carrying out column chromatography to obtain the 2-amino-3-cyano-4H-pyran compound.

2. The method as claimed in claim 1, wherein the substrate 1 in step a is an aromatic aldehyde including but not limited to benzaldehyde, 2-nitrobenzaldehyde, 3-nitrobenzaldehyde, 4-nitrobenzaldehyde, 2-fluorobenzaldehyde, 3-fluorobenzaldehyde, 4-fluorobenzaldehyde, 2-methylbenzaldehyde, 3-methylbenzaldehyde, 4-methylbenzaldehyde, 2-methoxybenzaldehyde, 3-methoxybenzaldehyde, 4-bromobenzaldehyde, 4-cyanobenzaldehyde, 2, 3-dichlorobenzaldehyde, 2-bromo-5-methoxybenzaldehyde, 2, 5-dimethoxybenzaldehyde, 2-amino-3-cyano-4H-pyrane, 2-bromo-5-methoxybenzaldehyde, 2-dimethoxybenzaldehyde, 2-methoxy-methoxybenzaldehyde, 2-methoxy-methyl-benzaldehyde, 2-methyl-ethyl-methyl-benzaldehyde, 2-methyl-ethyl-benzyl-ethyl-methyl-ethyl-benzyl-methyl-ethyl-benzyl-methyl-ethyl, At least one of furfural and 2-thiophenecarboxaldehyde.

3. The mechanical ball milling assisted synthesis method of 2-amino-3-cyano-4H-pyran compounds as claimed in claim 1, wherein the substrate 2 in the step a is dimedone or N, N-dimethyl m-hydroxyaniline.

4. The mechanical ball milling assisted synthesis method of 2-amino-3-cyano-4H-pyran compounds according to claim 1, wherein the protein in the step a is bovine serum albumin, protease or lipase.

5. The mechanical ball milling assisted synthesis method of the 2-amino-3-cyano-4H-pyran compounds as claimed in claim 1 or 4, wherein the feeding mass ratio of the protein to the substrate 1 in the step a is 1 (0.5-5).

6. The mechanical ball milling assisted synthesis method of the 2-amino-3-cyano-4H-pyran compound as claimed in claim 1, wherein in the step a, the grinding aid is any one of sodium sulfate, sodium chloride, potassium bromide, neutral alumina and silica gel, and the mass ratio of the grinding aid to the substrate 1 is (4-10): 1.

7. The mechanical ball milling assisted synthesis method of the 2-amino-3-cyano-4H-pyran compound as claimed in claim 1, wherein the ball milling frequency in the step a is 10-30 Hz, and the ball milling time is 10-60 minutes.

8. The mechanical ball milling assisted synthesis method of the 2-amino-3-cyano-4H-pyran compound as claimed in claim 7, wherein the ball milling frequency in the step a is 20-30 Hz, and the ball milling time is 30-60 minutes.

9. The mechanical ball milling assisted synthesis method of 2-amino-3-cyano-4H-pyran compounds according to claim 1, wherein the solvent in the step b is one or any mixture of methanol, ethanol and ethyl acetate.

10. The mechanical ball milling assisted synthesis method of the 2-amino-3-cyano-4H-pyran compound as claimed in claim 1, wherein the column chromatography eluent in the step b is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is (2-4): 1.

Technical Field

The invention relates to the technical field of chemical synthesis, in particular to a mechanical ball-milling auxiliary synthesis method of 2-amino-3-cyano-4H-pyran compounds.

Background

The 2-amino-3-cyano-4H-pyran compound has a plurality of important biological activities and pharmacological activities, such as functions of resisting tumors, bacteria, allergy, aging and the like. The compounds are generally prepared by a chemical method, but the chemical method has the defects of complicated preparation of used catalysts, difficult separation of products and the like, so that the practical application of synthesizing the 2-amino-3-cyano-4H-pyran compounds by the chemical method is restricted, and in the synthesis by the common chemical method, organic reagents are required to be used as solvents, so that great pressure is caused to the environment.

For example, a "supported imidazole ionic liquid catalyst and a method for synthesizing 2-amino-3-cyano-4H-pyrane compounds" disclosed in chinese patent literature, which is published under the publication number CN111229311A, the synthesis process comprises using malononitrile, aryl aldehyde and ethyl acetoacetate as raw materials, and carrying out condensation and michael addition reactions under the catalytic action of KIT-6 supported imidazole ionic liquid to synthesize 2-amino-3-cyano-4H-pyrane compounds. The synthesis process of the KIT-6 supported imidazole ionic liquid catalyst used in the method is complex, the synthesis process of the 2-amino-3-cyano-4H-pyran compound needs heating, and the reaction time is long.

Disclosure of Invention

The invention provides a mechanical ball-milling auxiliary synthesis method of 2-amino-3-cyano-4H-pyran compounds, aiming at overcoming the problems that in the prior art, the catalyst used in the chemical synthesis method is complicated to prepare, the synthesis process needs heating and the synthesis time is long, and the synthesis method has the advantages that the synthesis reaction is solvent-free, the reaction condition is mild, the synthesis efficiency and the yield are high, and the reaction uses protein as the catalyst, so that the method has the characteristics of less pollution, environmental friendliness and the like.

In order to achieve the purpose, the invention adopts the following technical scheme:

a mechanical ball milling auxiliary synthesis method of 2-amino-3-cyano-4H-pyran compounds comprises the following steps:

(a) taking a substrate 1, a substrate 2 and malononitrile as raw materials, adding a protein catalyst and a grinding aid, and then carrying out mechanical ball milling;

(b) and after the ball milling is finished, scraping out the reactant, adding a solvent, filtering, concentrating, and carrying out column chromatography to obtain the 2-amino-3-cyano-4H-pyran compound.

The mechanical ball milling technology is not only beneficial to increasing the contact frequency between substrate molecules and between the substrate molecules and catalyst molecules and improving the reaction efficiency, but also can avoid the use of organic solvents and is beneficial to realizing the solvent-free rapid synthesis of target compounds; meanwhile, the protein catalyst has the advantages of simple acquisition, environmental friendliness and the like. The mechanical ball milling technology is coupled with the protein catalysis technology and is used for synthesizing the 2-amino-3-cyano-4H-pyran compounds, so that the green and high-efficiency synthesis of the compounds can be realized. After the reaction is finished, the 2-amino-3-cyano-4H-pyran product with high purity can be obtained by column chromatography purification.

Preferably, the substrate 1 in step a is an aromatic aldehyde, including but not limited to at least one of benzaldehyde, 2-nitrobenzaldehyde, 3-nitrobenzaldehyde, 4-nitrobenzaldehyde, 2-fluorobenzaldehyde, 3-fluorobenzaldehyde, 4-fluorobenzaldehyde, 2-methylbenzaldehyde, 3-methylbenzaldehyde, 4-methylbenzaldehyde, 2-methoxybenzaldehyde, 3-methoxybenzaldehyde, 4-bromobenzaldehyde, 4-cyanobenzaldehyde, 2, 3-dichlorobenzaldehyde, 2-bromo-5-methoxybenzaldehyde, 2, 5-dimethoxybenzaldehyde, furfural and 2-thiophenecarboxaldehyde.

Preferably, the substrate 2 in the step a is dimedone or N, N-dimethyl m-hydroxyaniline.

Preferably, the protein in step a is bovine serum albumin, protease or lipase.

The protein is easy to obtain, the cost is low when the protein is used as a catalyst, and the protein is harmless to the environment, wherein the cost is the lowest when the bovine serum albumin is used as the catalyst; under general synthesis conditions, the catalytic effect of bovine serum albumin on synthesis of 2-amino-3-cyano-4H-pyran compounds is difficult to detect, the catalytic rate of protease and lipase on synthesis of 2-amino-3-cyano-4H-pyran compounds is slow, the bovine serum albumin, protease and lipase have good catalytic effect on synthesis reaction under the action of mechanical ball milling, and the bovine serum albumin, protease or lipase is easy to separate from products.

Preferably, the feeding mass ratio of the protein to the substrate 1 in the step a is 1 (0.5-5).

Preferably, in the step a, the grinding aid is any one of sodium sulfate, sodium chloride, potassium bromide, neutral alumina and silica gel, and the mass ratio of the grinding aid to the substrate 1 is (4-10): 1.

During mechanical ball milling, the raw materials and the catalyst can be heated due to heat generated by impact, the protein can be denatured at a higher temperature and lose catalytic activity, so that the synthesis rate is reduced, the yield of the product is reduced, and the grinding aid can absorb the heat generated by ball milling to protect the activity of the catalyst under the condition of high-frequency ball milling; when the grinding aid is used in too small amount, raw material adhesion and aggregation caused by static electricity cannot be eliminated, and when the grinding aid is used in too large amount, the raw material concentration is diluted, and the reaction rate is reduced.

Preferably, the ball milling frequency in the step a is 10-30 Hz, and the ball milling time is 10-60 minutes.

The ball milling frequency influences the contact probability of reaction raw materials so as to influence the reaction rate, and under the same reaction time, the higher the ball milling frequency is, the higher the yield is; when the ball milling frequency is too high, the temperature of the raw materials is increased too much, the protein denaturation loses the catalytic effect, and the reaction rate is reduced.

Preferably, the ball milling frequency in the step a is 20-30 Hz, and the ball milling time is 30-60 minutes.

When the ball milling frequency is 25-30 Hz, the yield of the target product is high.

Preferably, the solvent in the step b is one or a mixture of any several of methanol, ethanol and ethyl acetate in any proportion.

The solvent can dissolve the product, and is convenient for subsequent column chromatography purification.

Preferably, the column chromatography eluent in the step b is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is (2-4): 1.

Eluting the synthesized 2-amino-3-cyano-4H-pyran compound from the chromatographic column by using an eluant.

Therefore, the invention has the following beneficial effects: (1) the mechanical ball milling technology is beneficial to the close contact of substrate molecules, the catalytic effect of bovine serum albumin, protease and lipase is enhanced, the use of organic solvent can be avoided by the mechanical ball milling, and the green synthesis of the 2-amino-3-cyano-4H-pyran compounds is effectively realized; (2) the operation is simple and convenient, the reaction condition is mild, and the reaction time is short; (3) the preparation method has wide application range and can be used for synthesizing various 2-amino-3-cyano-4H-pyrane compounds.

Drawings

FIG. 1 is a schematic diagram of the synthetic reaction scheme of the present invention.

FIG. 2 is a nuclear magnetic hydrogen spectrum and a nuclear magnetic carbon spectrum of the product obtained in example 1.

FIG. 3 is a nuclear magnetic hydrogen spectrum and a nuclear magnetic carbon spectrum of the product obtained in example 21.

FIG. 4 is a nuclear magnetic hydrogen spectrum and a nuclear magnetic carbon spectrum of the product obtained in example 42.

FIG. 5 is a nuclear magnetic hydrogen spectrum and a nuclear magnetic carbon spectrum of the product obtained in example 43.

Detailed Description

The invention is further described with reference to the accompanying drawings and specific embodiments.

The synthetic reaction route of the invention is shown in figure 1, and a substrate 1 and malononitrile can be respectively synthesized into 2-amino-3-cyano-4H-pyran compounds with dimedone and N, N-dimethyl m-hydroxyaniline under the action of mechanical ball milling and protein.

Example 1

(a) Adding 3 stainless steel balls with the diameter of 10 mm into a 50 mL stainless steel ball milling tank, then sequentially adding 0.5 mmol benzaldehyde, 0.5 mmol malononitrile, 0.5 mmol dimedone, 50 mg bovine serum albumin and 300 mg sodium chloride, and carrying out ball milling for 30 minutes at 20 Hz;

(b) after the ball milling is finished, scraping out the reaction mixture, adding 30 mL of ethyl acetate for dissolving and filtering, taking the filtrate for rotary evaporation and concentration, and finally purifying by column chromatography, wherein the used eluent is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 4: 1;

(c) the eluent containing the product was rotary evaporated to give 2-amino-3-cyano-4-phenyl-7, 7-dimethyl-5-oxo-4H-5, 6,7, 8-tetrahydrobenzo [ b ] pyran as a white solid in 72.8% yield.

The nuclear magnetic hydrogen spectrum and nuclear magnetic carbon spectrum of the product are shown in figure 2, the characterization data is m, p, 222-223 ℃,¹H NMR (400 MHz, DMSO-d ₆) δ 7.29 (t, J = 7.4 Hz, 2H, ArH), 7.17 (dd, J = 20.2, 7.3 Hz, 3H, ArH), 7.01 (s, 2H, NH₂), 4.18 (s, 1H, CH), 2.49 (d, J = 12.1 Hz, 2H, CH₂), 2.26 (d, J = 16.1 Hz, 1H, CH₂), 2.11 (d, J = 16.1 Hz, 1H, CH₂), 1.05 (s, 3H, CH₃), 0.96 (s, 3H, CH₃).¹³C NMR (101 MHz, DMSO-d ₆) δ 196.12, 162.96, 158.94, 145.21, 128.80, 127.61, 127.03, 120.20, 113.19, 58.75, 50.44, 36.04, 27.27。

example 2

(a) Adding 3 stainless steel balls with the diameter of 10 mm into a 50 mL stainless steel ball milling tank, then sequentially adding 0.5 mmol benzaldehyde, 0.5 mmol malononitrile, 0.5 mmol dimedone, 50 mg bovine serum albumin and 300 mg sodium chloride, and carrying out ball milling for 40 minutes at 30 Hz;

(b) after the ball milling is finished, scraping out the reaction mixture, adding 30 mL of ethyl acetate for dissolving and filtering, taking the filtrate for rotary evaporation and concentration, and finally purifying by column chromatography, wherein the used eluent is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 4: 1;

(c) the eluent containing the product was rotary evaporated to give 2-amino-3-cyano-4-phenyl-7, 7-dimethyl-5-oxo-4H-5, 6,7, 8-tetrahydrobenzo [ b ] pyran as a white solid in 96.0% yield.

The characterization data for this product are the same as for the product of example 1.

Example 3

(a) Adding 3 stainless steel balls with the diameter of 10 mm into a 50 mL stainless steel ball milling tank, then sequentially adding 0.5 mmol benzaldehyde, 0.5 mmol malononitrile, 0.5 mmol dimedone and 50 mg bovine serum albumin, and carrying out ball milling at 30 Hz for 30 minutes;

(b) after the ball milling is finished, scraping out the reaction mixture, adding 30 mL of ethyl acetate for dissolving and filtering, taking the filtrate for rotary evaporation and concentration, and finally purifying by column chromatography, wherein the used eluent is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 4: 1;

(c) the eluent containing the product was rotary evaporated to give 2-amino-3-cyano-4-phenyl-7, 7-dimethyl-5-oxo-4H-5, 6,7, 8-tetrahydrobenzo [ b ] pyran as a white solid in 42.5% yield.

The characterization data for this product are the same as for the product of example 1.

Example 4

(a) Adding 3 stainless steel balls with the diameter of 10 mm into a 50 mL stainless steel ball milling tank, then sequentially adding 0.5 mmol benzaldehyde, 0.5 mmol malononitrile, 0.5 mmol dimedone, 50 mg bovine serum albumin and 300 mg sodium sulfate, and carrying out ball milling for 30 minutes at 30 Hz;

(b) after the ball milling is finished, scraping out the reaction mixture, adding 30 mL of ethyl acetate for dissolving and filtering, taking the filtrate for rotary evaporation and concentration, and finally purifying by column chromatography, wherein the used eluent is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 4: 1;

(c) the eluent containing the product was rotary evaporated to give 2-amino-3-cyano-4-phenyl-7, 7-dimethyl-5-oxo-4H-5, 6,7, 8-tetrahydrobenzo [ b ] pyran as a white solid in 62.5% yield.

The characterization data for this product are the same as for the product of example 1.

Example 5

(a) Adding 3 stainless steel balls with the diameter of 10 mm into a 50 mL stainless steel ball milling tank, then sequentially adding 0.5 mmol benzaldehyde, 0.5 mmol malononitrile, 0.5 mmol dimedone, 50 mg bovine serum albumin and 300 mg neutral alumina, and carrying out ball milling for 30 minutes at 30 Hz;

(b) after the ball milling is finished, scraping out the reaction mixture, adding 30 mL of ethyl acetate for dissolving and filtering, taking the filtrate for rotary evaporation and concentration, and finally purifying by column chromatography, wherein the used eluent is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 4: 1;

(c) the eluent containing the product was rotary evaporated to give 2-amino-3-cyano-4-phenyl-7, 7-dimethyl-5-oxo-4H-5, 6,7, 8-tetrahydrobenzo [ b ] pyran as a white solid in 73.8% yield.

The characterization data for this product are the same as for the product of example 1.

Example 6

(a) Adding 3 stainless steel balls with the diameter of 10 mm into a 50 mL stainless steel ball milling tank, then sequentially adding 0.5 mmol benzaldehyde, 0.5 mmol malononitrile, 0.5 mmol dimedone, 50 mg bovine serum albumin and 300 mg silica gel, and carrying out ball milling for 30 minutes at 30 Hz;

(b) after the ball milling is finished, scraping out the reaction mixture, adding 30 mL of ethyl acetate for dissolving and filtering, taking the filtrate for rotary evaporation and concentration, and finally purifying by column chromatography, wherein the used eluent is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 4: 1;

(c) the eluent containing the product was rotary evaporated to give 2-amino-3-cyano-4-phenyl-7, 7-dimethyl-5-oxo-4H-5, 6,7, 8-tetrahydrobenzo [ b ] pyran as a white solid in 87.0% yield.

The characterization data for this product are the same as for the product of example 1.

Example 7

(a) Adding 3 stainless steel balls with the diameter of 10 mm into a 50 mL stainless steel ball milling tank, then sequentially adding 0.5 mmol of 2-nitrobenzaldehyde, 0.5 mmol of malononitrile, 0.5 mmol of dimedone, 50 mg of bovine serum albumin and 300 mg of sodium chloride, and carrying out ball milling for 40 minutes at 30 Hz;

(b) after the ball milling is finished, scraping out the reaction mixture, adding 30 mL of ethyl acetate for dissolving and filtering, taking the filtrate for rotary evaporation and concentration, and finally purifying by column chromatography, wherein the used eluent is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 4: 1;

(c) the eluent containing the product was rotary evaporated to give 2-amino-3-cyano-4- (2-nitrophenyl) -7, 7-dimethyl-5-oxo-4H-5, 6,7, 8-tetrahydrobenzo [ b ] pyran as a yellow solid in 91.0% yield.

The characterization data of the product is m.p.210-212 ℃,¹H NMR (500 MHz, DMSO-d ₆) δ 8.08 – 7.91 (m, 2H, ArH), 7.66 – 7.55 (m, 2H, ArH), 7.15 (s, 2H, NH₂), 4.38 (s, 1H, CH), 2.52 (d, J = 1.8 Hz, 2H, CH₂), 2.24 (d, J = 16.1 Hz, 1H, CH₂), 2.08 (d, J = 16.1 Hz, 1H, CH₂), 1.01 (s, 3H, CH₃), 0.93 (s, 3H, CH₃). ¹³C NMR (126 MHz, DMSO-d ₆) δ 196.21, 163.62, 159.09, 148.23, 147.47, 134.65, 130.49, 122.12, 119.82, 112.24, 57.65, 50.34, 35.87, 32.31, 28.80, 27.22。

example 8

(a) Adding 3 stainless steel balls with the diameter of 10 mm into a 50 mL stainless steel ball milling tank, then sequentially adding 0.5 mmol of 3-nitrobenzaldehyde, 0.5 mmol of malononitrile, 0.5 mmol of dimedone, 50 mg of bovine serum albumin and 300 mg of sodium chloride, and carrying out ball milling for 40 minutes at 30 Hz;

(b) after the ball milling is finished, scraping out the reaction mixture, adding 30 mL of ethyl acetate for dissolving and filtering, taking the filtrate for rotary evaporation and concentration, and finally purifying by column chromatography, wherein the used eluent is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 4: 1;

(c) the eluent containing the product was rotary evaporated to give 2-amino-3-cyano-4- (3-nitrophenyl) -7, 7-dimethyl-5-oxo-4H-5, 6,7, 8-tetrahydrobenzo [ b ] pyran as a white solid in 93.7% yield.

The characterization data of the product is m.p. 213-215 ℃,¹H NMR (500 MHz, DMSO-d ₆) δ 8.14 – 8.05 (m, 1H, ArH), 7.98 (s, 1H, ArH), 7.72 – 7.56 (m, 2H, ArH), 7.19 (s, 2H, NH₂), 4.43 (s, 1H, CH), 2.56 (s, 2H, CH₂), 2.28 (d, J = 16.1 Hz, 1H, CH₂), 2.12 (d, J = 16.1 Hz, 1H, CH₂), 1.05 (s, 3H, CH₃), 0.96 (s, 3H, CH₃).¹³C NMR (126 MHz, DMSO-d ₆) δ 196.21, 163.62, 159.09, 148.23, 147.47, 134.65, 130.49, 122.25, 119.82, 112.24, 57.66, 50.34, 35.88, 32.31, 28.80, 27.22。

example 9

(a) Adding 3 stainless steel balls with the diameter of 10 mm into a 50 mL stainless steel ball milling tank, then sequentially adding 0.5 mmol 4-nitrobenzaldehyde, 0.5 mmol malononitrile, 0.5 mmol dimedone, 50 mg bovine serum albumin and 300 mg sodium chloride, and carrying out ball milling for 40 minutes at 30 Hz;

(b) after the ball milling is finished, scraping out the reaction mixture, adding 30 mL of ethyl acetate for dissolving and filtering, taking the filtrate for rotary evaporation and concentration, and finally purifying by column chromatography, wherein the used eluent is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 2: 1;

(c) the eluent containing the product was rotary evaporated to give 2-amino-3-cyano-4- (4-nitrophenyl) -7, 7-dimethyl-5-oxo-4H-5, 6,7, 8-tetrahydrobenzo [ b ] pyran as a light yellow solid in 95.0% yield.

The characterization data of the product is m.p.184-185 ℃,¹H NMR (500 MHz, DMSO-d ₆) δ 8.18 (d, J = 8.7 Hz, 2H, ArH), 7.46 (s, 2H, ArH), 7.19 (s, 2H, NH₂), 4.37 (s, 1H, CH), 2.55 (d, J = 3.1 Hz, 2H, CH₂), 2.27 (d, J = 16.1 Hz, 1H, CH₂), 2.12 (d, J = 16.1 Hz, 1H, CH₂), 1.05 (s, 3H, CH₃), 0.97 (s, 3H, CH₃). ¹³C NMR (126 MHz, DMSO-d ₆) δ 196.14, 163.56, 159.04, 152.74, 146.73, 129.08, 124.13, 119.77, 112.20, 60.22, 57.45, 50.33, 36.12, 32.30, 28.73, 27.41, 21.23, 14.55。

example 10

(a) Adding 3 stainless steel balls with the diameter of 10 mm into a 50 mL stainless steel ball milling tank, then sequentially adding 0.5 mmol of 2-methylbenzaldehyde, 0.5 mmol of malononitrile, 0.5 mmol of dimedone, 50 mg of bovine serum albumin and 300 mg of sodium chloride, and carrying out ball milling at 30 Hz for 40 minutes;

(b) after the ball milling is finished, scraping out the reaction mixture, adding 30 mL of ethyl acetate for dissolving and filtering, taking the filtrate for rotary evaporation and concentration, and finally purifying by column chromatography, wherein the used eluent is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 4: 1;

(c) the eluent containing the product was rotary evaporated to give 2-amino-3-cyano-4- (2-methylphenyl) -7, 7-dimethyl-5-oxo-4H-5, 6,7, 8-tetrahydrobenzo [ b ] pyran as a white solid in 91.5% yield.

The characterization data of the product is m.p.208-210 ℃,¹H NMR (500 MHz, DMSO-d ₆) δ 7.12 (dd, J = 14.5, 7.1 Hz, 2H, ArH), 7.05 (td, J = 7.4, 1.3 Hz, 1H, ArH), 6.96 (s, 2H, NH₂), 6.94 (s, 1H, ArH), 4.47 (s, 1H, CH), 2.53 (d, J = 7.5 Hz, 2H, CH₂), 2.47 (s, 3H, CH₃), 2.25 (d, J = 16.1 Hz, 1H, CH), 2.08 (d, J = 16.1 Hz, 1H, CH), 1.05 (s, 3H, CH₃), 0.97 (s, 3H, CH₃).¹³C NMR (101 MHz, DMSO-d ₆) δ 196.25, 162.98, 158.74, 144.05, 135.22, 130.36, 127.74, 126.86, 126.66, 120.24, 113.92, 58.67, 50.40, 32.35, 31.37, 28.90, 27.25, 19.56。

example 11

(a) Adding 3 stainless steel balls with the diameter of 10 mm into a 50 mL stainless steel ball milling tank, then sequentially adding 0.5 mmol of 3-methylbenzaldehyde, 0.5 mmol of malononitrile, 0.5 mmol of dimedone, 50 mg of bovine serum albumin and 300 mg of sodium chloride, and carrying out ball milling at 30 Hz for 40 minutes;

(b) after the ball milling is finished, scraping out the reaction mixture, adding 30 mL of ethyl acetate for dissolving and filtering, taking the filtrate for rotary evaporation and concentration, and finally purifying by column chromatography, wherein the used eluent is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 2: 1;

(c) the eluent containing the product was rotary evaporated to give 2-amino-3-cyano-4- (3-methylphenyl) -7, 7-dimethyl-5-oxo-4H-5, 6,7, 8-tetrahydrobenzo [ b ] pyran as a white solid in 92.2% yield.

The characterization data of the product is m.p.207-208 ℃,¹H NMR (500 MHz, DMSO-d ₆) δ 7.17 (t, J = 7.5 Hz, 1H, ArH), 7.00 (d, J = 7.0 Hz, 3H, ArH), 6.96 – 6.90 (m, 2H, NH₂), 4.12 (s, 1H, CH), 2.52 (s, 2H, CH₂), 2.27 (s, 3H, CH₃), 2.24 (s, 1H, CH₂), 2.11 (d, J = 16.1 Hz, 1H, CH₂), 1.05 (s, 3H, CH₃), 0.97 (s, 3H, CH₃).¹³C NMR (101 MHz, DMSO-d ₆) δ 196.11, 162.90, 158.90, 145.19, 137.76, 128.71, 128.17, 127.72, 124.76, 120.22, 113.22, 58.84, 50.45, 35.95, 32.31, 28.89, 27.21, 21.56。

example 12

(a) Adding 3 stainless steel balls with the diameter of 10 mm into a 50 mL stainless steel ball milling tank, then sequentially adding 0.5 mmol 4-methylbenzaldehyde, 0.5 mmol malononitrile, 0.5 mmol dimedone, 50 mg bovine serum albumin and 300 mg sodium chloride, and carrying out ball milling at 30 Hz for 40 minutes;

(b) after the ball milling is finished, scraping out the reaction mixture, adding 30 mL of ethyl acetate for dissolving and filtering, taking the filtrate for rotary evaporation and concentration, and finally purifying by column chromatography, wherein the used eluent is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 4: 1;

(c) the eluent containing the product was rotary evaporated to give 2-amino-3-cyano-4- (4-methylphenyl) -7, 7-dimethyl-5-oxo-4H-5, 6,7, 8-tetrahydrobenzo [ b ] pyran as a white solid in 92.0% yield.

The characterization data of the product is m.p. 218-220 ℃,¹H NMR (400 MHz, DMSO-d ₆) δ 7.09 (d, J = 7.9 Hz, 2H, ArH), 7.02 (d, J = 8.0 Hz, 2H, ArH), 6.98 (s, 2H, NH₂), 4.12 (s, 1H, CH), 2.53 – 2.50 (m, 2H, CH₂), 2.25 (s, 3H, CH₃), 2.23 (s, 1H, CH), 2.09 (d, J = 16.1 Hz, 1H, CH₂), 1.04 (s, 3H, CH₃), 0.95 (s, 3H, CH₃).¹³C NMR (101 MHz, DMSO-d ₆) δ 196.09, 162.74, 158.88, 142.29, 136.07, 129.34, 127.54, 120.23, 113.32, 58.87, 50.45, 35.64, 32.27, 28.89, 27.22, 21.07。

example 13

(a) Adding 3 stainless steel balls with the diameter of 10 mm into a 50 mL stainless steel ball milling tank, then sequentially adding 0.5 mmol of 2-fluorobenzaldehyde, 0.5 mmol of malononitrile, 0.5 mmol of dimedone, 50 mg of bovine serum albumin and 300 mg of sodium chloride, and carrying out ball milling for 40 minutes at 30 Hz;

(b) after the ball milling is finished, scraping out the reaction mixture, adding 30 mL of ethyl acetate for dissolving and filtering, taking the filtrate for rotary evaporation and concentration, and finally purifying by column chromatography, wherein the used eluent is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 2: 1;

(c) after rotary evaporation of the eluent containing the product, the desired product 2-amino-3-cyano-4- (2-fluorophenyl) -7, 7-dimethyl-5-oxo-4H-5, 6,7, 8-tetrahydrobenzo [ b ] pyran was obtained as a yellow solid in 92.0% yield.

The characterization data of the product is m.p.237- ­ 239 ℃,¹H NMR (500 MHz, DMSO-d ₆) δ 7.28 – 7.09 (m, 4H, ArH), 7.06 (s, 2H, NH₂), 4.45 (s, 1H, CH), 2.60 – 2.50 (m, 2H, CH₂), 2.27 (d, J = 16.1 Hz, 1H, CH₂), 2.09 (d, J = 16.1 Hz, 1H, CH₂), 1.05 (s, 3H, CH₃), 0.97 (s, 3H, CH₃). ¹³C NMR (101 MHz, DMSO-d ₆) δ 196.05, 163.58, 161.62, 159.21, 131.72, 130.12, 129.08, 124.88, 119.98, 115.99, 115.77, 111.82, 57.14, 50.35, 32.27, 30.29, 28.96, 27.06。

example 14

(a) Adding 3 stainless steel balls with the diameter of 10 mm into a 50 mL stainless steel ball milling tank, then sequentially adding 0.5 mmol of 3-fluorobenzaldehyde, 0.5 mmol of malononitrile, 0.5 mmol of dimedone, 50 mg of bovine serum albumin and 300 mg of sodium chloride, and carrying out ball milling for 40 minutes at 30 Hz;

(b) after the ball milling is finished, scraping out the reaction mixture, adding 30 mL of ethyl acetate for dissolving and filtering, taking the filtrate for rotary evaporation and concentration, and finally purifying by column chromatography, wherein the used eluent is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 4: 1;

(c) the eluent containing the product was rotary evaporated to give 2-amino-3-cyano-4- (3-fluorophenyl) -7, 7-dimethyl-5-oxo-4H-5, 6,7, 8-tetrahydrobenzo [ b ] pyran as a yellow solid in 92.6% yield.

The characterization data of the product is m.p.211-212 ℃,¹H NMR (500 MHz, DMSO-d ₆) δ 7.21 – 7.15 (m, 2H, ArH), 7.15 – 7.08 (m, 2H, ArH), 7.05 (s, 2H, NH₂), 4.20 (s, 1H, CH), 2.51 (s, 2H, CH₂), 2.25 (d, J = 16.1 Hz, 1H, CH₂), 2.11 (d, J = 16.1 Hz, 1H, CH₂), 1.04 (s, 3H, CH₃), 0.95 (s, 3H, CH₃).¹³C NMR (101 MHz, DMSO-d ₆) δ 196.16, 163.81, 163.28, 161.39, 158.99, 148.18, 148.12, 130.79, 130.70, 123.71, 123.69, 120.00, 114.44, 114.23, 113.97, 113.77, 112.62, 58.14, 50.40, 35.78, 32.29, 28.72, 27.39。

example 15

(a) Adding 3 stainless steel balls with the diameter of 10 mm into a 50 mL stainless steel ball milling tank, then sequentially adding 0.5 mmol 4-fluorobenzaldehyde, 0.5 mmol malononitrile, 0.5 mmol dimedone, 50 mg bovine serum albumin and 300 mg sodium chloride, and carrying out ball milling for 40 minutes at 30 Hz;

(b) after the ball milling is finished, scraping out the reaction mixture, adding 30 mL of ethyl acetate for dissolving and filtering, taking the filtrate for rotary evaporation and concentration, and finally purifying by column chromatography, wherein the used eluent is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 4: 1;

(c) the eluent containing the product was rotary evaporated to give 2-amino-3-cyano-4- (4-fluorophenyl) -7, 7-dimethyl-5-oxo-4H-5, 6,7, 8-tetrahydrobenzo [ b ] pyran as a yellow solid in 97.8% yield.

The characterization data of the product is m.p. 189-,¹H NMR (500 MHz, DMSO-d ₆) δ 7.35 (td, J = 8.0, 6.2 Hz, 1H, ArH), 7.09 (s, 2H, ArH), 7.04 (dd, J = 8.6, 2.3 Hz, 1H, ArH), 7.02 – 6.91 (m, 2H, NH₂), 4.23 (s, 1H, CH), 2.53 (d, J = 2.8 Hz, 2H, CH₂), 2.26 (d, J = 16.0 Hz, 1H, CH₂), 2.14 (d, J = 16.0 Hz, 1H, CH₂), 1.04 (s, 3H, CH₃), 0.97 (s, 3H, CH₃).¹³C NMR (101 MHz, DMSO-d ₆) δ 196.14, 162.94, 162.55, 160.14, 158.93, 141.39, 129.55, 129.46, 120.10, 115.59, 115.38, 113.05, 58.52, 50.42, 35.37, 32.27, 28.80, 27.31。

example 16

(a) Adding 3 stainless steel balls with the diameter of 10 mm into a 50 mL stainless steel ball milling tank, then sequentially adding 0.5 mmol of 2-methoxybenzaldehyde, 0.5 mmol of malononitrile, 0.5 mmol of dimedone, 50 mg of bovine serum albumin and 300 mg of sodium chloride, and carrying out ball milling for 40 minutes at 30 Hz;

(b) after the ball milling is finished, scraping out the reaction mixture, adding 30 mL of ethyl acetate for dissolving and filtering, taking the filtrate for rotary evaporation and concentration, and finally purifying by column chromatography, wherein the used eluent is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 4: 1;

(c) the eluent containing the product was rotary evaporated to give 2-amino-3-cyano-4- (2-methoxyphenyl) -7, 7-dimethyl-5-oxo-4H-5, 6,7, 8-tetrahydrobenzo [ b ] pyran as a yellow solid in 90.7% yield.

The characterization data of the product is m.p.200-202 ℃,¹H NMR (400 MHz, DMSO-d ₆) δ 7.15 – 6.81 (m, 4H, ArH), 6.79 (s, 2H, NH₂), 4.44 (s, 1H, CH), 3.71 (s, 3H, OCH₃), 2.49 (s, 1H, CH), 2.41 (d, J = 17.6 Hz, 1H, CH), 2.21 (d, J = 16.1 Hz, 1H, CH), 2.03 (d, J = 16.1 Hz, 1H, CH), 1.01 (s, 3H, CH₃), 0.93 (s, 3H, CH₃).¹³C NMR (101 MHz, DMSO-d ₆) δ 196.04, 163.56, 159.45, 157.27, 132.61, 129.01, 128.26, 120.78, 120.32, 112.33, 111.91, 57.79, 56.06, 50.50, 32.25, 30.79, 29.09, 27.00。

example 17

(a) Adding 3 stainless steel balls with the diameter of 10 mm into a 50 mL stainless steel ball milling tank, then sequentially adding 0.5 mmol of 3-methoxybenzaldehyde, 0.5 mmol of malononitrile, 0.5 mmol of dimedone, 50 mg of bovine serum albumin and 300 mg of sodium chloride, and carrying out ball milling for 40 minutes at 30 Hz;

(b) after the ball milling is finished, scraping out the reaction mixture, adding 30 mL of ethyl acetate for dissolving and filtering, taking the filtrate for rotary evaporation and concentration, and finally purifying by column chromatography, wherein the used eluent is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 2: 1;

(c) the eluent containing the product was rotary evaporated to give 2-amino-3-cyano-4- (3-methoxyphenyl) -7, 7-dimethyl-5-oxo-4H-5, 6,7, 8-tetrahydrobenzo [ b ] pyran as a white solid in 91.0% yield.

The characterization data of the product is m.p. 193- & 195 ℃,¹H NMR (400 MHz, DMSO-d ₆) δ 7.21 (t, J = 7.9 Hz, 1H, ArH), 7.01 (s, 2H, NH₂), 6.77 (dd, J = 8.1, 2.3 Hz, 1H, ArH), 6.74 – 6.63 (m, 2H, ArH), 4.15 (s, 1H, CH), 3.72 (s, 3H, OCH₃), 2.52 (s, 2H, CH₂), 2.24 (s, 1H, CH₂), 2.12 (d, J = 16.1 Hz, 1H, CH₂), 1.04 (s, 3H, CH₃), 0.98 (s, 3H, CH₃).¹³C NMR (101 MHz, DMSO-d ₆) δ 196.10, 163.04, 159.66, 158.95, 146.78, 129.90, 120.16, 119.79, 113.70, 113.05, 111.91, 60.23, 58.67, 55.38, 50.44, 35.93, 32.27, 28.91, 27.23。

example 18

(a) Adding 3 stainless steel balls with the diameter of 10 mm into a 50 mL stainless steel ball milling tank, then sequentially adding 0.5 mmol 4-methoxybenzaldehyde, 0.5 mmol malononitrile, 0.5 mmol dimedone, 50 mg bovine serum albumin and 300 mg sodium chloride, and carrying out ball milling at 30 Hz for 40 minutes;

(b) after the ball milling is finished, scraping out the reaction mixture, adding 30 mL of ethyl acetate for dissolving and filtering, taking the filtrate for rotary evaporation and concentration, and finally purifying by column chromatography, wherein the used eluent is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 2: 1;

(c) the eluent containing the product was rotary evaporated to give 2-amino-3-cyano-4- (4-methoxyphenyl) -7, 7-dimethyl-5-oxo-4H-5, 6,7, 8-tetrahydrobenzo [ b ] pyran as a white solid in 92.0% yield.

The characterization data of the product is m.p.202-204 ℃,¹H NMR (400 MHz, DMSO-d ₆) δ 7.05 (d, J = 8.6 Hz, 2H, ArH), 6.97 (s, 2H, NH₂), 6.84 (d, J = 8.6 Hz, 2H, ArH), 4.12 (s, 1H, CH), 3.72 (s, 3H, OCH₃ ), 2.51 (s, 2H, CH₂), 2.25 (d, J = 16.1 Hz, 1H, CH₂), 2.09 (d, J = 16.1 Hz, 1H, CH₂), 1.04 (s, 3H, CH₃), 0.95 (s, 3H, CH₃).¹³C NMR (101 MHz, DMSO-d ₆) δ 196.12, 162.59, 158.86, 158.36, 137.31, 128.68, 120.28, 114.13, 113.44, 58.99, 55.45, 50.47, 35.22, 32.26, 28.89, 27.23。

example 19

(a) Adding 3 stainless steel balls with the diameter of 10 mm into a 50 mL stainless steel ball milling tank, then sequentially adding 0.5 mmol 4-cyanobenzaldehyde, 0.5 mmol malononitrile, 0.5 mmol dimedone, 50 mg bovine serum albumin and 300 mg sodium chloride, and carrying out ball milling at 30 Hz for 40 minutes;

(b) after the ball milling is finished, scraping out the reaction mixture, adding 30 mL of ethyl acetate for dissolving and filtering, taking the filtrate for rotary evaporation and concentration, and finally purifying by column chromatography, wherein the used eluent is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 2: 1;

(c) the eluent containing the product was rotary evaporated to give 2-amino-3-cyano-4- (4-cyanophenyl) -7, 7-dimethyl-5-oxo-4H-5, 6,7, 8-tetrahydrobenzo [ b ] pyran as a white solid in 90.8% yield.

The characterization data of the product is m.p.225- & 228 ℃,¹H NMR (400 MHz, DMSO-d ₆) δ 7.78 (d, J = 8.2 Hz, 2H, ArH), 7.36 (d, J = 8.2 Hz, 2H, ArH), 7.16 (s, 2H, NH₂), 4.30 (s, 1H, CH), 2.53 (s, 2H, CH₂), 2.26 (d, J = 16.0 Hz, 1H, CH₂), 2.12 (d, J = 16.0 Hz, 1H, CH₂), 1.04 (s, 3H, CH₃), 0.96 (s, 3H, CH₃).¹³C NMR (101 MHz, DMSO-d ₆) δ 196.16, 163.55, 159.02, 150.71, 132.88, 128.81, 119.85, 119.25, 112.20, 109.90, 57.56, 50.33, 36.28, 32.30, 28.71, 27.42。

example 20

(a) Adding 3 stainless steel balls with the diameter of 10 mm into a 50 mL stainless steel ball milling tank, then sequentially adding 0.5 mmol of 4-bromobenzaldehyde, 0.5 mmol of malononitrile, 0.5 mmol of dimedone, 50 mg of bovine serum albumin and 300 mg of sodium chloride, and carrying out ball milling at 30 Hz for 40 minutes;

(b) after the ball milling is finished, scraping out the reaction mixture, adding 30 mL of ethyl acetate for dissolving and filtering, taking the filtrate for rotary evaporation and concentration, and finally purifying by column chromatography, wherein the used eluent is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 2: 1;

(c) the eluent containing the product was rotary evaporated to give 2-amino-3-cyano-4- (4-bromophenyl) -7, 7-dimethyl-5-oxo-4H-5, 6,7, 8-tetrahydrobenzo [ b ] pyran as a white solid in 91.4% yield.

The characterization data of the product is m.p.225- & 228 ℃,¹H NMR (400 MHz, DMSO-d ₆) δ 7.45 (d, J = 8.3 Hz, 2H, ArH), 7.07 (d, J = 8.4 Hz, 2H, ArH), 7.04 (s, 2H, NH₂), 4.14 (s, 1H, CH), 2.47 (s, 2H, CH₂), 2.21 (d, J = 16.1 Hz, 1H, CH), 2.07 (d, J = 16.0 Hz, 1H, CH), 1.00 (s, 3H, CH₃), 0.91 (s, 3H, CH₃).¹³C NMR (101 MHz, DMSO-d ₆) δ 196.15, 163.09, 158.92, 144.65, 131.67, 129.98, 120.07, 120.03, 112.70, 58.11, 50.39, 35.65, 32.28, 28.78, 27.32。

example 21

(a) Adding 3 stainless steel balls with the diameter of 10 mm into a 50 mL stainless steel ball milling tank, then sequentially adding 0.5 mmol of 2, 3-dichlorobenzaldehyde, 0.5 mmol of malononitrile, 0.5 mmol of dimedone, 50 mg of bovine serum albumin and 300 mg of sodium chloride, and carrying out ball milling at 30 Hz for 40 minutes;

(b) after the ball milling is finished, scraping out the reaction mixture, adding 30 mL of ethyl acetate for dissolving and filtering, taking the filtrate for rotary evaporation and concentration, and finally purifying by column chromatography, wherein the used eluent is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 2: 1;

(c) the eluent containing the product was rotary evaporated to give 2-amino-3-cyano-4- (2, 3-dichlorophenyl) -7, 7-dimethyl-5-oxo-4H-5, 6,7, 8-tetrahydrobenzo [ b ] pyran as a yellow solid in 90.0% yield.

The nuclear magnetic hydrogen spectrum and nuclear magnetic carbon spectrum of the product are shown in figure 3, the characterization data is m, p, 231-233 ℃,¹H NMR (400 MHz, DMSO-d ₆) δ 7.49 (dd, J = 7.9, 1.4 Hz, 1H, ArH), 7.31 (t, J = 7.9 Hz, 1H, ArH), 7.21 – 7.14 (m, 1H, ArH), 7.13 (s, 2H, NH₂), 4.78 (s, 1H, CH), 2.53 (d, J = 4.0 Hz, 2H, CH₂), 2.25 (d, J = 16.0 Hz, 1H, CH₂), 2.09 (d, J= 16.0 Hz, 1H, CH₂), 1.05 (s, 3H, CH₃), 0.98 (s, 3H, CH₃).¹³C NMR (101 MHz, DMSO-d ₆) δ 196.12, 163.79, 159.16, 132.25, 130.65, 129.25, 128.74, 119.58, 112.10, 56.79, 50.34, 32.27, 28.78, 27.44。

example 22

(a) Adding 3 stainless steel balls with the diameter of 10 mm into a 50 mL stainless steel ball milling tank, then sequentially adding 0.5 mmol of 2, 5-dimethoxybenzaldehyde, 0.5 mmol of malononitrile, 0.5 mmol of dimedone, 50 mg of bovine serum albumin and 300 mg of sodium chloride, and carrying out ball milling at 30 Hz for 40 minutes;

(b) after the ball milling is finished, scraping out the reaction mixture, adding 30 mL of ethyl acetate for dissolving and filtering, taking the filtrate for rotary evaporation and concentration, and finally purifying by column chromatography, wherein the used eluent is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 2: 1;

(c) the eluent containing the product was rotary evaporated to give 2-amino-3-cyano-4- (2, 5-dimethoxyphenyl) -7, 7-dimethyl-5-oxo-4H-5, 6,7, 8-tetrahydrobenzo [ b ] pyran as a light yellow solid in 86.6% yield.

The characterization data of the product is m.p.211-213 ℃,¹H NMR (400 MHz, DMSO-d ₆) δ 6.91 – 6.83 (m, 3H, ArH), 6.76 – 6.48 (m, 2H, NH₂), 4.44 (s, 1H, CH), 3.70 (s, 3H, OCH₃), 3.65 (s, 3H, OCH₃), 2.55 (d, J = 17.7 Hz, 1H, CH₂), 2.45 (d, J = 17.6 Hz, 1H, CH₂), 2.26 (d, J = 16.1 Hz, 1H, CH₂), 2.07 (d, J = 16.1 Hz, 1H, CH₂), 1.04 (s, 3H, CH₃), 0.98 (s, 3H, CH₃). ¹³C NMR (101 MHz, DMSO-d ₆) δ 196.03, 163.63, 159.40, 153.53, 151.48, 133.93, 120.25, 115.27, 113.08, 112.22, 111.97, 57.70, 56.72, 55.64, 50.46, 32.25, 30.74, 29.13, 26.93。

example 23

(a) Adding 3 stainless steel balls with the diameter of 10 mm into a 50 mL stainless steel ball milling tank, then sequentially adding 0.5 mmol of 2-bromo-5-methoxybenzaldehyde, 0.5 mmol of malononitrile, 0.5 mmol of dimedone, 50 mg of bovine serum albumin and 300 mg of sodium chloride, and carrying out ball milling for 40 minutes at 30 Hz;

(b) after the ball milling is finished, scraping out the reaction mixture, adding 30 mL of ethyl acetate for dissolving and filtering, taking the filtrate for rotary evaporation and concentration, and finally purifying by column chromatography, wherein the used eluent is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 4: 1;

(c) the eluent containing the product was rotary evaporated to give 2-amino-3-cyano-4- (2-bromo-5-methoxyphenyl) -7, 7-dimethyl-5-oxo-4H-5, 6,7, 8-tetrahydrobenzo [ b ] pyran as a light yellow solid in 87.0% yield.

The characterization data of the product is m.p.211-213 ℃,¹H NMR (400 MHz, DMSO-d ₆) δ 7.50 (d, J = 8.8 Hz, 1H, ArH), 7.10 (s, 2H, ArH), 6.85 – 6.61 (m, 2H, NH₂), 4.70 (s, 1H, CH), 3.76 (s, 3H, OCH₃), 2.59 (s, 2H, CH₂), 2.31 (d, J = 16.0 Hz, 1H, CH₂), 2.16 (d, J = 16.0 Hz, 1H, CH₂), 1.11 (s, 3H, CH₃), 1.06 (s, 3H, CH₃).¹³C NMR (101 MHz, DMSO-d ₆) δ 195.96, 163.58, 159.38, 159.03, 133.79, 119.54, 114.25, 113.63, 112.42, 57.43, 55.74, 50.39, 32.25, 28.88, 27.34。

example 24

(a) Adding 3 stainless steel balls with the diameter of 10 mm into a 50 mL stainless steel ball milling tank, then sequentially adding 0.5 mmol furfural, 0.5 mmol malononitrile, 0.5 mmol dimedone, 50 mg bovine serum albumin and 300 mg sodium chloride, and carrying out ball milling for 40 minutes at 30 Hz;

(b) after the ball milling is finished, scraping out the reaction mixture, adding 30 mL of ethyl acetate for dissolving and filtering, taking the filtrate for rotary evaporation and concentration, and finally purifying by column chromatography, wherein the used eluent is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 4: 1;

(c) the eluent containing the product was rotary evaporated to give 2-amino-3-cyano-4- (2-furyl) -7, 7-dimethyl-5-oxo-4H-5, 6,7, 8-tetrahydrobenzo [ b ] pyran as a yellow solid in 83.0% yield.

The characterization data of the product is m.p.226-228 ℃,¹H NMR (400 MHz, DMSO-d ₆ ) δ 7.54 (s, 1H, ArH), 7.15 (s, 2H, NH₂), 6.39 (s, 1H, ArH), 6.12 (s, 1H, ArH), 4.39 (s, 1H, CH), 2.57 (s, 2H, CH₂), 2.35 (d, J = 16.1 Hz, 1H, CH₂), 2.23 (d, J = 16.1 Hz, 1H, CH₂), 1.11 (s, 3H, CH₃), 1.05 (s, 3H, CH₃).¹³C NMR (101 MHz, DMSO-d ₆) δ 195.89, 163.73, 159.76, 156.17, 142.22, 120.03, 110.91, 110.81, 105.52, 55.82, 50.35, 32.29, 29.45, 28.90, 27.02。

example 25

(a) Adding 3 stainless steel balls with the diameter of 10 mm into a 50 mL stainless steel ball milling tank, then sequentially adding 0.5 mmol of 2-thiophenecarboxaldehyde, 0.5 mmol of malononitrile, 0.5 mmol of dimedone, 50 mg of bovine serum albumin and 300 mg of sodium chloride, and carrying out ball milling for 40 minutes at 30 Hz;

(b) after the ball milling is finished, scraping out the reaction mixture, adding 30 mL of ethyl acetate for dissolving and filtering, taking the filtrate for rotary evaporation and concentration, and finally purifying by column chromatography, wherein the used eluent is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 4: 1;

(c) the eluent containing the product was rotary evaporated to give 2-amino-3-cyano-4- (2-thienyl) -7, 7-dimethyl-5-oxo-4H-5, 6,7, 8-tetrahydrobenzo [ b ] pyran as a white solid in 80.3% yield.

The characterization data of the product is m.p. 227-230 ℃,¹H NMR (400 MHz, DMSO-d ₆) δ 7.27 (d, J = 4.9 Hz, 1H, ArH), 7.09 (s, 2H, NH₂), 6.86 (dd, J = 4.9, 3.6 Hz, 1H, ArH), 6.81 (d, J = 3.1 Hz, 1H, ArH), 4.48 (s, 1H, CH), 2.50 (d, J = 17.7 Hz, 1H, CH₂), 2.38 (d, J = 17.7 Hz, 1H, CH₂), 2.26 (d, J = 16.2 Hz, 1H, CH₂), 2.10 (d, J = 16.2 Hz, 1H, CH₂), 1.00 (s, 3H, CH₃), 0.93 (s, 3H, CH₃).¹³C NMR (101 MHz, DMSO-d ₆) δ 196.00, 162.96, 159.35, 149.74, 127.27, 124.89, 124.46, 120.08, 113.36, 58.48, 50.32, 32.23, 30.87, 29.10, 26.92。

example 26

(a) Adding 3 stainless steel balls with the diameter of 10 mm into a 50 mL stainless steel ball milling tank, then sequentially adding 0.5 mmol benzaldehyde, 0.5 mmol malononitrile, 0.5 mmol N, N-dimethyl m-hydroxyaniline, 80 mg bovine serum albumin and 300 mg sodium chloride, and carrying out ball milling for 40 minutes at 30 Hz;

(b) after the ball milling is finished, scraping out the reaction mixture, adding 30 mL of ethyl acetate for dissolving and filtering, taking the filtrate for rotary evaporation and concentration, and finally purifying by column chromatography, wherein the used eluent is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 4: 1;

(c) the eluent containing the product was rotary evaporated to give 2-amino-3-cyano-4-phenyl-7- (dimethylamino) -4H-benzopyran as a yellow solid in 82.1% yield.

The characterization data of the product is m, p, 201.0-203.0 ℃,¹H NMR (400 MHz, DMSO-d ₆) δ 7.30 (t, J = 7.5 Hz, 2H, ArH), 7.18 (dd, J = 16.3, 7.3 Hz, 3H, ArH), 6.83 (s, 2H, NH₂), 6.79 (d, J = 8.6 Hz, 1H, ArH), 6.45 (dd, J = 8.6, 2.4 Hz, 1H, ArH), 6.24 (d, J = 2.4 Hz, 1H, ArH), 4.60 (s, 1H, CH), 2.86 (s, 6H, CH₃).¹³C NMR (101 MHz, DMSO-d ₆) δ 160.85, 150.65, 149.42, 147.09, 129.91, 128.98, 127.82, 126.99, 121.31, 110.94, 109.85, 98.96, 56.79。

example 27

(a) Adding 3 stainless steel balls with the diameter of 10 mm into a 50 mL stainless steel ball milling tank, then sequentially adding 0.5 mmol of 3-nitrobenzaldehyde, 0.5 mmol of malononitrile, 0.5 mmol of N, N-dimethyl m-hydroxyaniline, 80 mg of bovine serum albumin and 300 mg of sodium chloride, and carrying out ball milling for 40 minutes at 30 Hz;

(b) after the ball milling is finished, scraping out the reaction mixture, adding 30 mL of ethyl acetate for dissolving and filtering, taking the filtrate for rotary evaporation and concentration, and finally purifying by column chromatography, wherein the used eluent is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 2: 1;

(c) the eluate containing the product was rotary evaporated to give 2-amino-3-cyano-4- (3-nitrophenyl) -7- (dimethylamino) -4H-benzopyran as an orange solid in 86.0% yield.

The characterization data of the product is m.p. 196.0-198.0 ℃,¹H NMR (400 MHz, DMSO-d ₆) δ 8.13 – 8.07 (m, 1H, ArH), 8.02 (s, 1H, ArH), 7.69 – 7.59 (m, 2H, ArH), 7.00 (s, 2H, NH₂), 6.83 (d, J = 8.7 Hz, 1H, ArH), 6.47 (dd, J = 8.7, 2.5 Hz, 1H, ArH), 6.26 (d, J = 2.5 Hz, 1H, ArH), 4.89 (s, 1H, CH), 2.87 (s, 6H, CH₃).¹³C NMR (101 MHz, DMSO-d ₆) δ 161.09, 150.90, 149.47, 149.37, 148.38, 134.76, 130.76, 129.93, 122.23, 122.17, 120.99, 109.99, 109.61, 98.98, 55.89。

example 28

(a) Adding 3 stainless steel balls with the diameter of 10 mm into a 50 mL stainless steel ball milling tank, then sequentially adding 0.5 mmol of 4-nitrobenzaldehyde, 0.5 mmol of malononitrile, 0.5 mmol of N, N-dimethyl m-hydroxyaniline, 80 mg of bovine serum albumin and 300 mg of sodium chloride, and carrying out ball milling for 40 minutes at 30 Hz;

(b) after the ball milling is finished, scraping out the reaction mixture, adding 30 mL of ethyl acetate for dissolving and filtering, taking the filtrate for rotary evaporation and concentration, and finally purifying by column chromatography, wherein the used eluent is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 2: 1;

(c) the eluent containing the product was rotary evaporated to give 2-amino-3-cyano-4- (4-nitrophenyl) -7- (dimethylamino) -4H-benzopyran as a yellow solid in 88.4% yield.

The characterization data of the product is m, p, 186.0-188.0 ℃,¹H NMR (400 MHz, DMSO-d ₆) δ 8.19 (d, J = 8.6 Hz, 2H, ArH), 7.45 (d, J = 8.7 Hz, 2H, ArH), 7.01 (s, 2H, NH₂), 6.79 (d, J = 8.7 Hz, 1H, ArH), 6.53 – 6.43 (m, 1H, ArH), 6.26 (d, J = 2.4 Hz, 1H, ArH), 4.84 (s, 1H, CH), 2.87 (s, 6H, CH₃).¹³C NMR (101 MHz, DMSO-d ₆) δ 161.03, 154.56, 150.93, 149.45, 146.68, 129.92, 129.12, 124.43, 120.97, 109.96, 109.38, 99.00, 55.65。

example 29

(a) Adding 3 stainless steel balls with the diameter of 10 mm into a 50 mL stainless steel ball milling tank, then sequentially adding 0.5 mmol of 2-fluorobenzaldehyde, 0.5 mmol of malononitrile, 0.5 mmol of N, N-dimethyl m-hydroxyaniline, 80 mg of bovine serum albumin and 300 mg of sodium chloride, and carrying out ball milling for 40 minutes at 30 Hz;

(b) after the ball milling is finished, scraping out the reaction mixture, adding 30 mL of ethyl acetate for dissolving and filtering, taking the filtrate for rotary evaporation and concentration, and finally purifying by column chromatography, wherein the used eluent is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 4: 1;

(c) the eluent containing the product was rotary evaporated to give 2-amino-3-cyano-4- (2-fluorophenyl) -7- (dimethylamino) -4H-benzopyran as a purple solid in 82.6% yield.

The characterization data of the product are m, p, 207.0-209.0 ℃,¹H NMR (400 MHz, DMSO-d ₆) δ 7.26 (ddd, J = 9.3, 4.8, 2.8 Hz, 1H, ArH), 7.21 – 7.09 (m, 3H, ArH), 6.88 (s, 2H, NH₂), 6.78 (d, J = 8.6 Hz, 1H, ArH), 6.46 (dd, J = 8.6, 2.6 Hz, 1H, ArH), 6.24 (d, J = 2.5 Hz, 1H, ArH), 4.88 (s, 1H, CH), 2.86 (s, 6H, CH₃).¹³C NMR (101 MHz, DMSO-d ₆) δ 160.47, 160.17, 158.04, 149.72, 148.59, 132.32, 129.17, 128.38, 128.11, 124.07, 120.00, 115.13, 108.77, 108.58, 97.90, 54.06, 33.53。

example 30

(a) Adding 3 stainless steel balls with the diameter of 10 mm into a 50 mL stainless steel ball milling tank, then sequentially adding 0.5 mmol of 3-fluorobenzaldehyde, 0.5 mmol of malononitrile, 0.5 mmol of N, N-dimethyl m-hydroxyaniline, 80 mg of bovine serum albumin and 300 mg of sodium chloride, and carrying out ball milling for 40 minutes at 30 Hz;

(b) after the ball milling is finished, scraping out the reaction mixture, adding 30 mL of ethyl acetate for dissolving and filtering, taking the filtrate for rotary evaporation and concentration, and finally purifying by column chromatography, wherein the used eluent is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 4: 1;

(c) the eluent containing the product was rotary evaporated to give 2-amino-3-cyano-4- (3-fluorophenyl) -7- (dimethylamino) -4H-benzopyran as an orange solid in 82.0% yield.

The characterization data of the product is m, p, 144.0-146.0 ℃,¹H NMR (400 MHz, DMSO-d ₆) δ 7.24 – 7.08 (m, 4H, ArH), 6.87 (s, 2H, NH₂), 6.77 (d, J = 8.7 Hz, 1H, ArH), 6.46 (dd, J = 8.7, 2.5 Hz, 1H, ArH), 6.24 (d, J = 2.4 Hz, 1H, ArH), 4.64 (s, 1H, CH), 2.86 (s, 6H, CH₃).¹³C NMR (101 MHz, DMSO-d ₆) δ 163.91, 161.48, 160.98, 150.77, 150.07, 149.40, 131.04, 129.85, 123.89, 121.16, 114.54, 113.94, 110.20, 109.88, 98.96, 56.20。

example 31

(a) Adding 3 stainless steel balls with the diameter of 10 mm into a 50 mL stainless steel ball milling tank, then sequentially adding 0.5 mmol of 4-fluorobenzaldehyde, 0.5 mmol of malononitrile, 0.5 mmol of N, N-dimethyl m-hydroxyaniline, 80 mg of bovine serum albumin and 300 mg of sodium chloride, and carrying out ball milling for 40 minutes at 30 Hz;

(b) after the ball milling is finished, scraping out the reaction mixture, adding 30 mL of ethyl acetate for dissolving and filtering, taking the filtrate for rotary evaporation and concentration, and finally purifying by column chromatography, wherein the used eluent is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 4: 1;

(c) the eluent containing the product was rotary evaporated to give 2-amino-3-cyano-4- (4-fluorophenyl) -7- (dimethylamino) -4H-benzopyran as a yellow solid in 86.0% yield.

The product has the characterization data of m, p, 141.0-142.0 ℃,¹H NMR (400 MHz, DMSO-d ₆) δ 7.20 (dd, J = 8.6, 5.7 Hz, 2H, ArH), 7.12 (t, J = 8.8 Hz, 2H, ArH), 6.87 (s, 2H, NH₂), 6.77 (d, J = 8.7 Hz, 1H, ArH), 6.46 (dd, J = 8.7, 2.5 Hz, 1H, ArH), 6.24 (d, J = 2.4 Hz, 1H, ArH), 4.64 (s, 1H, CH), 2.86 (s, 6H, CH₃).¹³C NMR (101 MHz, DMSO-d ₆) δ 162.57, 160.80, 160.16, 150.69, 149.38, 143.30, 143.27, 129.90, 129.71, 129.63, 121.23, 115.79, 115.58, 110.69, 109.88, 98.95, 56.71。

example 32

(a) Adding 3 stainless steel balls with the diameter of 10 mm into a 50 mL stainless steel ball milling tank, then sequentially adding 0.5 mmol of 2-methylbenzaldehyde, 0.5 mmol of malononitrile, 0.5 mmol of N, N-dimethyl m-hydroxyaniline, 80 mg of bovine serum albumin and 300 mg of sodium chloride, and carrying out ball milling for 40 minutes at 30 Hz;

(b) after the ball milling is finished, scraping out the reaction mixture, adding 30 mL of ethyl acetate for dissolving and filtering, taking the filtrate for rotary evaporation and concentration, and finally purifying by column chromatography, wherein the used eluent is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 4: 1;

(c) the eluent containing the product was rotary evaporated to give 2-amino-3-cyano-4- (2-methylphenyl) -7- (dimethylamino) -4H-benzopyran as a yellow solid in 80.1% yield.

The characterization data of the product is m, p, 177.0-179.0 ℃,¹H NMR (400 MHz, DMSO-d ₆) δ 7.16 – 7.05 (m, 3H, ArH), 6.97 (dd, J = 7.0, 2.4 Hz, 1H, ArH), 6.77 (s, 2H, NH₂), 6.63 (d, J = 8.6 Hz, 1H, ArH), 6.43 (dd, J = 8.6, 2.6 Hz, 1H, ArH), 6.24 (d, J = 2.5 Hz, 1H, ArH), 4.89 (s, 1H, CH), 2.86 (s, 6H, CH₃), 2.31 (s, 3H, CH₃).¹³C NMR (101 MHz, DMSO-d ₆) δ 160.56, 150.62, 149.67, 144.70, 135.28, 131.09, 129.67, 126.87, 126.78, 121.21, 110.66, 109.84, 98.81, 56.56, 37.19, 19.51。

example 33

(a) Adding 3 stainless steel balls with the diameter of 10 mm into a 50 mL stainless steel ball milling tank, then sequentially adding 0.5 mmol of 3-methylbenzaldehyde, 0.5 mmol of malononitrile, 0.5 mmol of N, N-dimethyl m-hydroxyaniline, 80 mg of bovine serum albumin and 300 mg of sodium chloride, and carrying out ball milling for 40 minutes at 30 Hz;

(b) after the ball milling is finished, scraping out the reaction mixture, adding 30 mL of ethyl acetate for dissolving and filtering, taking the filtrate for rotary evaporation and concentration, and finally purifying by column chromatography, wherein the used eluent is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 4: 1;

(c) the eluent containing the product was rotary evaporated to give 2-amino-3-cyano-4- (3-methylphenyl) -7- (dimethylamino) -4H-benzopyran as a yellow solid in 89.0% yield.

The product has the characterization data of m, p, 174.0-176.0 ℃,¹H NMR (400 MHz, DMSO-d ₆) δ 7.18 (t, J = 7.8 Hz, 1H, ArH), 7.01 (d, J = 7.6 Hz, 1H, ArH), 6.96 (dd, J = 4.6, 2.2 Hz, 2H, ArH), 6.80 (d, J = 6.9 Hz, 2H, NH₂), 6.77 (s, 1H, ArH), 6.45 (dd, J = 8.7, 2.6 Hz, 1H, ArH), 6.23 (d, J = 2.5 Hz, 1H, ArH), 4.55 (s, 1H, CH), 2.86 (s, 6H, CH₃), 2.26 (s, 3H, CH₃). ¹³C NMR (101 MHz, DMSO-d ₆) δ 160.82, 150.61, 149.39, 147.07, 138.02, 129.91, 128.86, 128.31, 127.71, 125.05, 121.32, 111.00, 109.83, 98.97, 56.89, 21.57。

example 34

(a) Adding 3 stainless steel balls with the diameter of 10 mm into a 50 mL stainless steel ball milling tank, then sequentially adding 0.5 mmol 4-methylbenzaldehyde, 0.5 mmol malononitrile, 0.5 mmol N, N-dimethyl m-hydroxyaniline, 80 mg bovine serum albumin and 300 mg sodium chloride, and carrying out ball milling for 40 minutes at 30 Hz;

(b) after the ball milling is finished, scraping out the reaction mixture, adding 30 mL of ethyl acetate for dissolving and filtering, taking the filtrate for rotary evaporation and concentration, and finally purifying by column chromatography, wherein the used eluent is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 4: 1;

(c) the eluent containing the product was rotary evaporated to give 2-amino-3-cyano-4- (4-methylphenyl) -7- (dimethylamino) -4H-benzopyran as a light yellow solid in 90.2% yield.

The product has the characterization data of m, p, 164.0-166.0 ℃,¹H NMR (400 MHz, DMSO-d ₆) δ 7.10 (d, J = 7.9 Hz, 2H, ArH), 7.04 (d, J = 7.9 Hz, 2H, ArH), 6.78 (d, J = 6.2 Hz, 2H, NH₂), 6.75 (s, 1H, ArH), 6.44 (dd, J = 8.7, 2.6 Hz, 1H, ArH), 6.22 (d, J= 2.5 Hz, 1H, ArH), 4.55 (s, 1H, CH), 2.86 (s, 6H, CH₃), 2.25 (s, 3H, CH₃).¹³C NMR (101 MHz, DMSO-d ₆) δ 159.66, 149.52, 148.30, 143.06, 134.95, 128.84, 128.44, 126.68, 120.24, 110.03, 108.74, 97.87, 55.88, 19.99。

example 35

(a) Adding 3 stainless steel balls with the diameter of 10 mm into a 50 mL stainless steel ball milling tank, then sequentially adding 0.5 mmol of 2-methoxybenzaldehyde, 0.5 mmol of malononitrile, 0.5 mmol of N, N-dimethyl m-hydroxyaniline, 80 mg of bovine serum albumin and 300 mg of sodium chloride, and carrying out ball milling for 40 minutes at 30 Hz;

(b) after the ball milling is finished, scraping out the reaction mixture, adding 60 mL of ethyl acetate for dissolving and filtering, taking the filtrate for rotary evaporation and concentration, and finally purifying by column chromatography, wherein the used eluent is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 4: 1;

(c) the eluent containing the product was rotary evaporated to give 2-amino-3-cyano-4- (2-methoxyphenyl) -7- (dimethylamino) -4H-benzopyran as a yellow solid in 84.0% yield.

The characterization data of the product is m.p. 196.0-198.0 ℃,¹H NMR (400 MHz, DMSO-d ₆) δ 7.21 – 7.15 (m, 1H, ArH), 7.00 (s, 1H, ArH), 6.97 (dd, J = 8.3, 2.3 Hz, 1H, ArH), 6.91 – 6.81 (m, 2H, ArH), 6.76 (s, 2H, NH₂), 6.42 (dd, J = 8.7, 2.5 Hz, 1H, ArH), 6.22 (d, J = 2.5 Hz, 1H, ArH), 4.99 (s, 1H, CH), 3.80 (s, 3H, OCH₃), 2.84 (s, 6H, CH₃).¹³C NMR (101 MHz, DMSO-d ₆) δ 161.55, 156.71, 150.55, 149.72, 134.78, 129.24, 128.95, 128.21, 121.18, 111.90, 111.33, 109.75, 99.00, 56.10, 55.83, 33.62。

example 36

(a) Adding 3 stainless steel balls with the diameter of 10 mm into a 50 mL stainless steel ball milling tank, then sequentially adding 0.5 mmol of 3-methoxybenzaldehyde, 0.5 mmol of malononitrile, 0.5 mmol of N, N-dimethyl m-hydroxyaniline, 80 mg of bovine serum albumin and 300 mg of sodium chloride, and carrying out ball milling for 40 minutes at 30 Hz;

(b) after the ball milling is finished, scraping out the reaction mixture, adding 60 mL of ethyl acetate for dissolving and filtering, taking the filtrate for rotary evaporation and concentration, and finally purifying by column chromatography, wherein the used eluent is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 4: 1;

(c) the eluent containing the product was rotary evaporated to give 2-amino-3-cyano-4- (3-methoxyphenyl) -7- (dimethylamino) -4H-benzopyran as a yellow solid in 87.0% yield.

The product has the characterization data of m, p, 164.0-166.0 ℃,¹H NMR (400 MHz, DMSO-d ₆) δ 7.21 (t, J = 7.9 Hz, 1H, ArH), 6.87 – 6.80 (m, 3H, ArH), 6.80 – 6.75 (m, 1H, ArH), 6.72 (dd, J = 7.3, 1.4 Hz, 2H, NH₂), 6.45 (dd, J = 8.7, 2.6 Hz, 1H, ArH), 6.23 (d, J = 2.5 Hz, 1H, ArH), 4.57 (s, 1H, CH), 3.72 (s, 3H, OCH₃), 2.86 (s, 6H, CH₃).¹³C NMR (101 MHz, DMSO-d ₆) δ 160.91, 159.76, 150.66, 149.39, 148.69, 130.11, 129.85, 121.30, 120.05, 113.95, 111.81, 110.81, 109.82, 98.96, 56.65, 55.42。

example 37

(a) Adding 3 stainless steel balls with the diameter of 10 mm into a 50 mL stainless steel ball milling tank, then sequentially adding 0.5 mmol 4-methoxybenzaldehyde, 0.5 mmol malononitrile, 0.5 mmol N, N-dimethyl m-hydroxyaniline, 80 mg bovine serum albumin and 300 mg sodium chloride, and carrying out ball milling for 40 minutes at 30 Hz;

(b) after the ball milling is finished, scraping out the reaction mixture, adding 60 mL of ethyl acetate for dissolving and filtering, taking the filtrate for rotary evaporation and concentration, and finally purifying by column chromatography, wherein the used eluent is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 2: 1;

(c) the eluent containing the product was rotary evaporated to give 2-amino-3-cyano-4- (4-methoxyphenyl) -7- (dimethylamino) -4H-benzopyran as a yellow solid in 89.4% yield.

The product has the characterization data of m, p, 180.0-182.0 ℃,¹H NMR (400 MHz, DMSO-d ₆) δ 7.07 (d, J = 8.6 Hz, 2H, ArH), 6.85 (d, J = 8.6 Hz, 2H, ArH), 6.77 (d, J = 1.9 Hz, 2H, NH₂), 6.74 (s, 1H, ArH), 6.48 – 6.42 (m, 1H, ArH), 6.22 (d, J = 2.4 Hz, 1H, ArH), 4.54 (s, 1H, CH), 3.71 (s, 3H, OCH₃), 2.85 (s, 6H, CH₃).¹³C NMR (101 MHz, DMSO-d ₆) δ 159.57, 157.27, 149.50, 148.26, 138.12, 128.85, 127.78, 120.25, 113.24, 110.20, 108.76, 97.86, 56.06, 54.40。

example 38

(a) Adding 3 stainless steel balls with the diameter of 10 mm into a 50 mL stainless steel ball milling tank, then sequentially adding 0.5 mmol of 4-bromobenzaldehyde, 0.5 mmol of malononitrile, 0.5 mmol of N, N-dimethyl m-hydroxyaniline, 80 mg of bovine serum albumin and 300 mg of sodium chloride, and carrying out ball milling for 40 minutes at 30 Hz;

(b) after the ball milling is finished, scraping out the reaction mixture, adding 60 mL of ethyl acetate for dissolving and filtering, taking the filtrate for rotary evaporation and concentration, and finally purifying by column chromatography, wherein the used eluent is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 4: 1;

(c) the eluent containing the product was rotary evaporated to give 2-amino-3-cyano-4- (4-bromophenyl) -7- (dimethylamino) -4H-benzopyran as a yellow solid in 89.1% yield.

The characterization data of the product are m, p, 211.0-213.0 ℃,¹H NMR (400 MHz, DMSO-d ₆) δ 7.50 (d, J = 8.3 Hz, 2H, ArH), 7.13 (d, J = 8.4 Hz, 2H, ArH), 6.88 (s, 2H, NH₂), 6.77 (d, J = 8.7 Hz, 1H, ArH), 6.46 (dd, J = 8.7, 2.5 Hz, 1H, ArH), 6.23 (d, J = 2.5 Hz, 1H, ArH), 4.63 (s, 1H, CH), 2.86 (s, 6H, CH₃).¹³C NMR (101 MHz, DMSO-d ₆) δ 159.76, 149.67, 148.31, 145.40, 131.11, 130.80, 129.03, 128.81, 120。

example 39

(a) Adding 3 stainless steel balls with the diameter of 10 mm into a 50 mL stainless steel ball milling tank, then sequentially adding 0.5 mmol 4-cyanobenzaldehyde, 0.5 mmol malononitrile, 0.5 mmol N, N-dimethyl m-hydroxyaniline, 80 mg bovine serum albumin and 300 mg sodium chloride, and carrying out ball milling for 40 minutes at 30 Hz;

(b) after the ball milling is finished, scraping out the reaction mixture, adding 60 mL of ethyl acetate for dissolving and filtering, taking the filtrate for rotary evaporation and concentration, and finally purifying by column chromatography, wherein the used eluent is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 2: 1;

(c) the eluent containing the product was rotary evaporated to give 2-amino-3-cyano-4- (4-cyanophenyl) -7- (dimethylamino) -4H-benzopyran as an orange solid in 87.2% yield.

The product has the characterization data of m, p, 175.0-177.0 ℃,¹H NMR (400 MHz, DMSO-d ₆) δ 7.78 (d, J = 8.2 Hz, 2H, ArH), 7.36 (d, J = 8.2 Hz, 2H, ArH), 6.97 (s, 2H, NH₂), 6.78 (d, J = 8.7 Hz, 1H, ArH), 6.46 (dd, J = 8.7, 2.5 Hz, 1H, ArH), 6.25 (d, J = 2.5 Hz, 1H, ArH), 4.76 (s, 1H, CH), 2.87 (s, 6H, CH₃).¹³C NMR (101 MHz, DMSO-d ₆) δ 161.05, 152.52, 150.89, 149.48, 133.11, 129.87, 128.88, 121.00, 119.27, 109.94, 109.87, 109.57, 98.99, 55.77。

example 40

(a) Adding 3 stainless steel balls with the diameter of 10 mm into a 50 mL stainless steel ball milling tank, then sequentially adding 0.5 mmol of 2, 3-dichlorobenzaldehyde, 0.5 mmol of malononitrile, 0.5 mmol of N, N-dimethyl m-hydroxyaniline, 80 mg of bovine serum albumin and 300 mg of sodium chloride, and carrying out ball milling for 40 minutes at 30 Hz;

(b) after the ball milling is finished, scraping out the reaction mixture, adding 60 mL of ethyl acetate for dissolving and filtering, taking the filtrate for rotary evaporation and concentration, and finally purifying by column chromatography, wherein the used eluent is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 4: 1;

(c) the eluent containing the product was rotary evaporated to give 2-amino-3-cyano-4- (2, 3-dichlorophenyl) -7- (dimethylamino) -4H-benzopyran as a white solid in 87.0% yield.

The product has the characterization data of m, p, 210.0-211.0 ℃,¹H NMR (400 MHz, DMSO-d ₆) δ 7.52 (dd, J = 7.9, 1.2 Hz, 1H, ArH), 7.33 (t, J = 7.9 Hz, 1H, ArH), 7.17 (d, J = 7.6 Hz, 1H, ArH), 6.96 (s, 2H, NH₂), 6.72 (d, J = 8.7 Hz, 1H, ArH), 6.45 (dd, J = 8.7, 2.5 Hz, 1H, ArH), 6.24 (d, J = 2.5 Hz, 1H, ArH), 5.21 (s, 1H, CH), 2.87 (s, 6H, CH₃).¹³C NMR (101 MHz, DMSO-d ₆) δ 160.11, 149.86, 148.52, 145.09, 131.48, 129.31, 128.88, 128.40, 128.07, 127.96, 119.73, 108.82, 107.94, 97.82, 53.95。

EXAMPLE 41

(a) Adding 3 stainless steel balls with the diameter of 10 mm into a 50 mL stainless steel ball milling tank, then sequentially adding 0.5 mmol of 2-bromo-5-methoxybenzaldehyde, 0.5 mmol of malononitrile, 0.5 mmol of N, N-dimethyl m-hydroxyaniline, 80 mg of bovine serum albumin and 300 mg of sodium chloride, and carrying out ball milling for 40 minutes at 30 Hz;

(b) after the ball milling is finished, scraping out the reaction mixture, adding 60 mL of ethyl acetate for dissolving and filtering, taking the filtrate for rotary evaporation and concentration, and finally purifying by column chromatography, wherein the used eluent is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 4: 1;

(c) the eluent containing the product was rotary evaporated to give 2-amino-3-cyano-4- (2-bromo-5-methoxyphenyl) -7- (dimethylamino) -4H-benzopyran as a yellow solid in 92.7% yield.

The characterization data of the product is m.p. 203.0-205.0 ℃,¹H NMR (400 MHz, DMSO-d ₆) δ 7.50 (d, J = 8.8 Hz, 1H, ArH), 6.90 (s, 2H, NH₂), 6.84 – 6.72 (m, 2H, ArH), 6.65 (s, 1H, ArH), 6.45 (dd, J = 8.7, 2.5 Hz, 1H, ArH), 6.23 (d, J = 2.5 Hz, 1H, ArH), 5.06 (s, 1H, CH), 3.69 (s, 3H, OCH₃), 2.86 (s, 6H, CH₃).¹³C NMR (101 MHz, DMSO-d ₆) δ 160.08, 158.38, 149.76, 148.34, 133.03, 127.98, 119.76, 116.21, 113.36, 112.09, 108.77, 108.48, 97.84, 54.72, 54.42。

example 42

(a) Adding 3 stainless steel balls with the diameter of 10 mm into a 50 mL stainless steel ball milling tank, then sequentially adding 0.5 mmol furfural, 0.5 mmol malononitrile, 0.5 mmol N, N-dimethyl m-hydroxyaniline, 80 mg bovine serum albumin and 300 mg sodium chloride, and carrying out ball milling for 40 minutes at 30 Hz;

(b) after the ball milling is finished, scraping out the reaction mixture, adding 60 mL of ethyl acetate for dissolving and filtering, taking the filtrate for rotary evaporation and concentration, and finally purifying by column chromatography, wherein the used eluent is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 4: 1;

(c) the eluent containing the product was rotary evaporated to give 2-amino-3-cyano-4- (2-furyl) -7- (dimethylamino) -4H-benzopyran as a red solid in 82.6% yield.

The nuclear magnetic hydrogen spectrum and nuclear magnetic carbon spectrum of the product are shown in figure 4, the characterization data is m, p, 178.0-180.0 ℃,¹H NMR (400 MHz, DMSO-d ₆) δ 7.53 – 7.48 (m, 1H, ArH), 6.94 (d, J = 8.7 Hz, 1H, ArH), 6.90 (s, 2H, NH₂), 6.50 (dd, J = 8.6, 2.5 Hz, 1H, ArH), 6.34 (dd, J = 3.0, 1.9 Hz, 1H, ArH), 6.22 (d, J = 2.4 Hz, 1H, ArH), 6.13 (d, J = 3.1 Hz, 1H, ArH), 4.74 (s, 1H, CH), 2.87 (s, 6H, CH₃).¹³C NMR (101 MHz, DMSO-d ₆) δ 160.46, 156.61, 149.88, 148.63, 141.67, 128.47, 120.00, 109.64, 108.59, 107.10, 104.73, 98.03, 52.59, 33.00。

example 43

(a) Adding 3 stainless steel balls with the diameter of 10 mm into a 50 mL stainless steel ball milling tank, then sequentially adding 0.5 mmol of 2-thiophenecarboxaldehyde, 0.5 mmol of malononitrile, 0.5 mmol of N, N-dimethyl m-hydroxyaniline, 80 mg of bovine serum albumin and 300 mg of sodium chloride, and carrying out ball milling for 40 minutes at 30 Hz;

(b) after the ball milling is finished, scraping out the reaction mixture, adding 60 mL of ethyl acetate for dissolving and filtering, taking the filtrate for rotary evaporation and concentration, and finally purifying by column chromatography, wherein the used eluent is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 4: 1;

(c) the eluate containing the product was rotary evaporated to give 2-amino-3-cyano-4- (2-thienyl) -7- (dimethylamino) -4H-benzopyran as a purple solid in 81.3% yield.

The nuclear magnetic hydrogen spectrum and nuclear magnetic carbon spectrum of the product are shown in figure 5, the characterization data is m, p, 176.0-178.0 ℃,¹H NMR (400 MHz, DMSO-d ₆) δ 7.36 – 7.30 (m, 1H, ArH), 7.00 – 6.96 (m, 1H, ArH), 6.94 (s, 1H, ArH), 6.92 (d, J = 3.7 Hz, 2H, NH₂), 6.91 (s, 1H, ArH), 6.49 (dd, J = 8.7, 2.5 Hz, 1H, ArH), 6.21 (d, J = 2.5 Hz, 1H, ArH), 4.96 (s, 1H, CH), 2.86 (s, 6H, CH₃).¹³C NMR (101 MHz, DMSO-d ₆) δ 159.82, 151.26, 149.76, 148.03, 128.77, 126.05, 124.29, 123.25, 120.07, 109.54, 108.69, 97.82, 55.94, 34.57。

in the preparation method, when no grinding aid is added in the reaction system, the yield of the product is low, and when sodium chloride, sodium sulfate, neutral alumina or silica gel is added in the reaction system as the grinding aid, the yield of the product is remarkably improved, wherein the yield is the highest when the sodium chloride is selected as the grinding aid; when sodium chloride is used as a grinding aid, the yield of the product is over 80 percent at 30 Hz, which shows that the preparation method is generally used for synthesizing various 2-amino-3-cyano-4H-pyrane compounds.