A preparation method of coumarin 6

Abstract

The present invention relates to a preparation method of coumarin 6, which is characterized by comprising the following steps: adding 2-aminothiophenol, 4-(diethylamino) salicylaldehyde, ethyl cyanoacetate, zinc trifluoromethanesulfonate, and DBU into an organic solvent, reacting at 80°C, and post-processing to obtain a crude coumarin 6 product; and subjecting the crude product to reflux beating, suction filtration, washing, and vacuum drying to obtain high-purity coumarin 6, with an HPLC purity of 98.1% and a yield of more than 90.3%.

Description

Technical Field

[0001] The present invention relates to a process for synthesizing coumarin 6, and belongs to the technical field of organic synthesis. Background Art

[0002] Coumarins are a class of compounds that contain six-membered oxygen-containing heterocycles (1,2-benzopyrone). Due to their excellent biological activities, such as antitumor, anticoagulant, antibacterial, and anti-inflammatory properties, as well as their exceptional optical activity, they have been widely used in a variety of fields, including pharmaceutical synthesis and optoelectronic materials. Therefore, achieving a simple, efficient, and green synthesis of coumarins is of great research value. Traditional methods rely on strong bases or acids to catalyze the condensation reaction of phenolic compounds with reactive carbonyl compounds; or on transition metals such as silver, copper, zinc, palladium, rhodium, and platinum to form C-C and C-O bonds, thereby constructing the coumarin skeleton. However, the high equipment and process requirements of strong acids and bases, coupled with the high price of precious metals, and the multi-step reaction process, requiring the separation and purification of intermediates through extraction, concentration, column chromatography, or reduced-pressure distillation, significantly limit their industrialization. Summary of the Invention

[0003] The problem to be solved by the present invention is to develop a process for synthesizing coumarin 6 with low raw material price, short reaction time, high product conversion rate, simple operation, no harsh reaction requirements, easy industrialization, and economical and efficient performance.

[0004] A multi-component reaction is the process of efficiently synthesizing new compounds containing at least two or more major structural fragments by combining three or more compounds in a "one-pot" fashion. This type of reaction requires no additional reagents or catalysts. Compared to traditional multi-step linear reactions, multi-component "one-pot" methods typically use readily available starting materials, effectively reducing the number of reaction steps, lowering the difficulty, and significantly reducing the amount of solvent used. It also eliminates the need for functional group protection and deprotection processes involved in the reaction, making automated production easy.

[0005] The present invention solves the above technical problems through the following technical solutions:

[0006] The present invention provides a preparation method of coumarin 6, comprising the following steps: adding 2-aminothiophenol, 4-(diethylamino) salicylaldehyde, ethyl cyanoacetate, zinc trifluoromethanesulfonate and DBU into an organic solvent, and reacting at 80° C. to obtain coumarin 6.

[0007]

[0008] Preferably, the organic solvent is one or more of ethanol, dichloromethane and acetonitrile.

[0009] Preferably, the weight ratio of the organic solvent to 4-(diethylamino)salicylaldehyde is 10.4 L / kg.

[0010] Preferably, the molar ratio of 2-aminothiophenol, 4-(diethylamino) salicylaldehyde, ethyl cyanoacetate, zinc trifluoromethanesulfonate, and DBU is: 1:1:(2.2-2.5):(0.055-0.088):(0.210-0.0.263).

[0011] Preferably, the adding temperature is room temperature, and the reaction time is 3.5-4 hours.

[0012] Preferably, after the reaction is completed, the method further comprises the following post-processing steps: washing with water, washing with an organic solvent 1, filtering to obtain a crude product, beating, filtering, washing with an organic solvent 2, and drying.

[0013] Further preferably, the organic solvent 1 is a mixed solvent of acetonitrile and dichloromethane, the weight and volume ratio of the crude product and organic solvent 1 is 1.06g: (2.5-5) ml, the beating time is 1-2 hours, the organic solvent 2 is dichloromethane, the drying temperature is 40 degrees, the time is 4 hours, and the conditions are vacuum drying.

[0014] Compared with the prior art, the present invention has the following beneficial effects:

[0015] 1. The raw materials required for the synthesis used in the present invention, 2-aminothiophenol, 4-(diethylamino) salicylaldehyde, ethyl cyanoacetate zinc trifluoromethanesulfonate and DBU, ethanol, dichloromethane and acetonitrile, are all cheap and readily available industrial products. The synthesis process has the advantages of mild reaction conditions, simple operation, easy reaction control, few side reactions, high reaction conversion rate, simple purification of the target product, etc., and the entire process is suitable for industrial production.

[0016] 2. The present invention uses a three-component, one-step synthesis method to obtain the target product, coumarin 6. 2-aminothiophenol, 4-(diethylamino)salicylaldehyde, and ethyl cyanoacetate are the main raw materials. By controlling the reaction temperature and the material ratio, the occurrence of side reactions is reduced and the conversion rate is improved. Through simple purification methods such as filtration, washing, and drying, high-purity coumarin 6 is obtained, with an HPLC purity of 98.1% and a yield of over 90.3%. DETAILED DESCRIPTION

[0017] In order to make the present invention more clearly understood, preferred embodiments are described in detail as follows:

[0018] Example 1 A method for synthesizing coumarin 6, comprising the following steps:

[0019] (1) Prepare a 2 L three-necked flask, add 1 L of ethanol at room temperature, and add 2-aminothiophenol (62.6 g, 0.5 mol), 4-(diethylamino) salicylaldehyde (96.6 g, 0.5 mol), and ethyl cyanoacetate (101.9 g, 0.9 mol) under stirring, respectively, and stir for 5 minutes. Then, add zinc trifluoromethanesulfonate (10 g, 27.5 mmol) and DBU (16 g, 0.105 mol), and stir for another 5 minutes.

[0020] (2) Heat in a water bath at 80°C, reflux and monitor the reaction progress. The reaction is complete in 4 hours.

[0021] (3) Cool to room temperature, prepare a Buchner funnel or other filtration equipment, and filter the reaction liquid from reaction (2). Wash the orange-yellow filter cake obtained by filtration twice with 250 ml of pure water; after drying, wash it twice with 125 ml of ethanol. The obtained wet solid is spread out and dried in a forced air drying oven at 40°C for 2 hours to obtain 168.3 g of dry crude product.

[0022] (4) Prepare a 1 L single-necked flask, add 360 ml of dichloromethane and 110 ml of acetonitrile at room temperature and stir. Then add 168.3 g of the crude product obtained in (3) all at once. After stirring and dispersing, reflux for 1 hour. Remove the heat source, cool naturally to room temperature, filter, drain, wash once with 50 ml of dichloromethane, and drain again. Scoop out the orange-yellow filter cake, spread it in a glass Petri dish, and vacuum dry it at 50°C for 4 hours to obtain 165.3 g of the compound.

[0023] The NMR data, HPLC, elemental analysis, and melting point of the compound obtained above were tested as follows:

[0024] 1H-NMR (400MHz, CDCl3): δ=1.25(t,6H),3.46(q,4H),6.56(s,1H),6.67(d,1H),7.36(t,1H),7.48(m,2H),7.99(d,1H),8.01(d,1H),8.90(s,1H)

[0025] HPLC 98.1%

[0026] Anal Calcd for C 20 H 18 N2O2S

[0027] C, 68.55; H, 5.72; N, 7.99; H, 5.18; S, 9.15. Found: C, 68.63; H, 5.68; N, 7.98; S, 9.23;

[0028] Melting point: 206.7℃, total yield: 90.3%.

[0029] Example 2 A method for synthesizing coumarin 6, comprising the following steps:

[0030] (1) Prepare a 2 L three-necked flask, add 1.1 L of ethanol at room temperature, and add 2-aminothiophenol (62.6 g, 0.5 mol), 4-(diethylamino) salicylaldehyde (96.6 g, 0.5 mol), and ethyl cyanoacetate (141.4.4 g, 1.25 mol) under stirring, respectively, and stir for 5 minutes. Then, add zinc trifluoromethanesulfonate (16 g, 44 mmol) and DBU (20 g, 0.131 mol), and stir for another 5 minutes.

[0031] (2) Heat in a water bath at 80°C, reflux and monitor the reaction progress. The reaction is complete in 3.5 hours.

[0032] (3) Cool to room temperature, prepare a Buchner funnel or other filtration equipment, and filter the reaction liquid from reaction (2). Wash the orange-yellow filter cake obtained by filtration twice with 250 ml of pure water; after drying, wash it twice with 125 ml of ethanol. The obtained wet solid is spread out and dried in a forced air drying oven at 40°C for 2 hours to obtain 155.8 g of dry crude product.

[0033] (4) Prepare a 1 L single-necked flask, add 360 ml of dichloromethane and 110 ml of acetonitrile at room temperature and stir. Then add 155.8 g of the crude product obtained in (3) all at once. After stirring and dispersing, reflux for 2 hours. Remove the heat source, cool naturally to room temperature, filter, drain, wash once with 60 ml of dichloromethane, and drain again. Scoop out the bright yellow filter cake, spread it in a glass Petri dish, and dry it in a vacuum at 50°C for 4 hours to obtain 142.5 g of the compound. The NMR data, HPLC, elemental analysis, and melting point of the compound obtained above were determined as follows: 1H-NMR (400 MHz, CDCl 3 ): δ=1.25 (t, 6H), 3.46 (q, 4H), 6.56 (s, 1H), 6.67 (d, 1H), 7.36 (t, 1H), 7.48 (m, 2H), 7.99 (d, 1H), 8.01 (d, 1H), 8.90 (s, 1H)

[0034] HPLC 98.7%

[0035] Anal Calcd for C 20 H 18 N2O2S

[0036] C, 68.55; H, 5.72; N, 7.99; H, 5.18; S, 9.15. Found: C, 68.63; H, 5.59;

[0037] Melting point: 207°C, total yield: 82.8%.

Claims

1. A method for preparing coumarin 6, characterized in that: The method comprises the following steps: adding 2-aminothiophenol, 4-(diethylamino) salicylaldehyde, ethyl cyanoacetate, zinc trifluoromethanesulfonate and DBU into an organic solvent, and reacting at 80 DEG C to obtain coumarin 6.

2. The preparation method according to claim 1, wherein The organic solvent is one or more of ethanol, dichloromethane and acetonitrile.

3. The preparation method according to claim 1, wherein The volume-to-weight ratio of the organic solvent to 4-(diethylamino) salicylaldehyde is 10.4 L / kg.

4. The preparation method according to claim 1, wherein The molar ratio of 2-aminothiophenol, 4-(diethylamino) salicylaldehyde, ethyl cyanoacetate, zinc trifluoromethanesulfonate and DBU is 1:1:(2.2-2.5):(0.055-0.088):(0.210-0.263).

5. The preparation method according to claim 1, wherein The addition temperature is room temperature, and the reaction time is 3.5-4 hours.

6. The preparation method according to claim 1, wherein After the reaction is completed, the method further comprises the following post-processing steps: washing with water, washing with an organic solvent 1, filtering to obtain a crude product, beating, filtering, washing with an organic solvent 2, and drying.

7. The preparation method according to claim 6, wherein The organic solvent 1 is a mixed solvent of acetonitrile and dichloromethane, the weight and volume ratio of the crude product to the organic solvent 1 is 1.06g: (2.5-5) ml, the beating time is 1-2 hours, the organic solvent 2 is dichloromethane, the drying temperature is 40 degrees, the time is 4 hours, and the condition is vacuum drying.

Images