CN110201714B - Synthesis method and catalyst of dihydropyrimidinone compound - Google Patents

Abstract

The invention discloses a method for synthesizing dihydropyrimidinone compounds and a catalyst, and mainly relates to the technical field of organic synthesis. The synthesis method comprises synthesizing dihydropyrimidinone compounds by taking ethyl acetoacetate, aromatic aldehyde and urea as raw materials, taking organic acid loaded by silica gel as a catalyst and ethanol as a solvent by a one-pot method. The invention has the beneficial effects that: the method for synthesizing dihydropyrimidinone compounds is mild in reaction conditions, simple to operate and environment-friendly.

Description

Synthesis method and catalyst of dihydropyrimidinone compounds

technical field

The invention relates to the technical field of organic synthesis, in particular to a method for synthesizing dihydropyrimidone compounds and a catalyst.

Background technique

Dihydropyrimidinones (DHPMs) are important pharmaceutical intermediates with biological and pharmacological activities such as antiviral, antitumor, antibacterial, and antihypertensive. In 1893, Biginelli first synthesized 3,4-dihydropyrimidinones by "one-pot method" using concentrated hydrochloric acid as catalyst and aromatic aldehyde, ethyl acetoacetate and urea as raw materials. Since then, a lot of research has been done on the selection of catalysts, the expansion of the range of reaction raw materials and the optimization of reaction conditions. The reaction has been improved and developed in terms of reaction conditions and product diversity. The catalysts that can be selected in the synthesis of such compounds mainly include: protic acids such as sulfuric acid, phosphoric acid, hydrochloric acid, p-toluenesulfonic acid, acetic acid, etc.; Lewis acids such as BF ₃ ·OEt ₂ /CuCl, Cu(OTf) ₂ , CuI, In( OTf) ₃ , La(OTf) ₃ , Yb(OTf) ₃ , Mn(OAc) ₃ · 2H ₂ O, LiClO ₄ , Ce(NO ₃ ) ₃ · 6H ₂ O, FeCl ₃ · 6H ₂ O, NiCl ₂ · 6H ₂ O, ZnCl ₂ , ZrCl ₄ , ZrOCl ₂ . 8H ₂ O, Sr(OTf) ₂ , Bi(OTf) ₃ , CaF ₂ , Y(NO ₃ ) ₃ . 6H ₂ O, SmI ₂ , etc.; catalysts used Generally, the price is relatively high, and it is easy to cause pollution to the environment. How to choose a simple and effective catalyst to synthesize dihydropyrimidinones has become a research hotspot and difficulty in this reaction.

SUMMARY OF THE INVENTION

The purpose of the present invention is to provide a method for synthesizing dihydropyrimidinones and a catalyst, which provide a method for synthesizing dihydropyrimidinones with mild reaction conditions, simple operation and environmental protection.

The present invention is achieved by the following technical solutions in order to achieve the above object:

The silica gel catalyst used for one-pot synthesis of dihydropyrimidinone compounds is characterized in that, it is prepared by the following steps:

S1. Activation of silica gel:

Concentrated sulfuric acid and concentrated nitric acid are evenly mixed according to the volume ratio of 5:1, add silica gel with a mass ratio of 1 to 1.5:8 to concentrated sulfuric acid, and react at 120 to 160 ° C for 24 to 48 hours. After cooling, filtration, deionized water After washing to neutrality, washing with methanol and dichloromethane respectively, and drying to obtain activated silica gel;

S2. Preparation of amino functionalized silica gel:

Add 3-aminopropyltriethoxysilane and the activated silica gel to anhydrous toluene. The reaction is carried out at °C for 24-48 hours, after cooling and filtration, washing with acetone and dichloromethane, and drying to obtain amino-functionalized silica gel;

S3. Preparation of silica gel supported organic acid catalyst:

Add acid anhydride and the amino-functionalized silica gel to dichloromethane, the ratio of the acid anhydride and amino-functionalized silica gel is 9-18 mmol/g, shake at room temperature for 24-48 hours, filter, and then use methanol, dichloromethane It was washed with methyl chloride and dried to obtain a silica gel supported organic acid catalyst.

Further, the silica gel catalyst for one-pot synthesis of dihydropyrimidone compounds according to claim 1, is characterized in that, comprises the following steps:

S1. Activation of silica gel:

Concentrated sulfuric acid and concentrated nitric acid were mixed uniformly according to the volume ratio of 5:1, and silica gel with a mass ratio of 1 to 1.5:8 was added to the concentrated sulfuric acid, reacted at 140 ° C for 24 hours, cooled, filtered, and washed with deionized water until neutral. , washed with methanol and dichloromethane respectively, and dried to obtain activated silica gel;

S2. Preparation of amino functionalized silica gel:

Add 3-aminopropyltriethoxysilane and the activated silica gel to anhydrous toluene. The ratio of the 3-aminopropyltriethoxysilane to the silica gel is 3 mmol/g, and the reaction is carried out at 120°C under nitrogen protection. After 24 hours, after cooling, filtering, washing with acetone and dichloromethane, and drying to obtain amino-functionalized silica gel;

S3. Preparation of silica gel supported organic acid catalyst:

Add acid anhydride and the amino-functional silica gel to dichloromethane, the ratio of the acid anhydride and amino-functional silica gel is 9 mmol/g, shake at room temperature for 24 hours, filter, and then wash with methanol and dichloromethane, Dry to obtain a silica gel supported organic acid catalyst.

Further, the silica gel used in the step S1 is 100-200 mesh silica gel, and the acid anhydride in the step S3 is one of succinic anhydride or glutaric anhydride.

Further, in specific applications, it is used as a catalyst for one-pot synthesis of dihydropyrimidinone compounds.

Further, in specific application, ethyl acetoacetate, aromatic aldehyde and urea are used as raw materials, and ethanol is used as solvent.

As another aspect of the present invention, the synthesis method of dihydropyrimidinone compounds is synthesized by using ethyl acetoacetate, aromatic aldehyde and urea as raw materials, using silica gel-supported organic acid as catalyst, ethanol as solvent, one-pot method synthesis, the organic acid supported by the silica gel is the catalyst according to any one of claims 1-5.

Further, the amount of the organic acid catalyst supported by the silica gel is 6-10 mol% of the aromatic aldehyde, calculated as the carboxyl group -CO ₂ H contained therein.

Further, the molar ratio of the ethyl acetoacetate, aromatic aldehyde and urea is: 1:1:1.2-1.5.

Further, the aromatic aldehydes include benzaldehyde, p-methylbenzaldehyde, p-methoxybenzaldehyde, p-fluorobenzaldehyde, p-nitrobenzaldehyde, p-trifluoromethylbenzaldehyde, p-chlorobenzaldehyde, m-bromine Any one or more of benzaldehyde and o-bromobenzaldehyde.

Further, the method includes:

Add ethyl acetoacetate, aromatic aldehyde, urea, silica gel supported organic acid catalyst and ethanol solvent to the reactor, heat under reflux for 4 to 5 hours, crystallize by cooling with ice water, filter to obtain a crude product, and then recrystallize with ethanol , that is, get;

The organic acid catalyst supported by silica gel recovered in the recrystallization process is directly used in the synthesis reaction of the next cycle.

Compared with the prior art, the beneficial effects of the present invention are:

Compared with the existing literature, the use of silica gel-supported organic acid catalysts not only improves the yield of dihydropyrimidinones, but also avoids the use of catalysts such as inorganic strong acids and precious metals, shortens product purification time, and simplifies The post-processing operation is reduced, the environmental pollution is reduced, the cost is saved, and the large-scale production is facilitated. The organic acid catalyst supported by silica gel can be recycled and reused, which saves the cost.

Description of drawings

Accompanying drawing 1 is the preparation of silica gel supported organic acid catalyst.

Figure 2 shows the synthesis of dihydropyrimidinones using silica-supported organic acids as catalysts.

Figure 3 is the recycling of the organic acid catalyst supported by silica gel.

Detailed ways

The present invention will be further described below in conjunction with specific embodiments. It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention. In addition, it should be understood that after reading the teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the present application.

1) the silica gel catalyst of one-pot synthesis of dihydropyrimidinone compounds, the concrete preparation method is as follows:

1) Activation of silica gel: Mix uniformly according to the volume ratio of concentrated sulfuric acid and concentrated nitric acid to 5:1, then add an appropriate amount of silica gel (100-200 mesh), wherein the mass ratio of silica gel to concentrated sulfuric acid is 1-1.5:8 , reacted at 140 ℃ for 24 h, cooled, filtered, washed with deionized water until neutral, then washed with methanol and dichloromethane respectively, and dried to obtain activated silica gel.

2) Preparation of amino-functionalized silica gel: in anhydrous toluene, add 3-aminopropyl triethoxysilane (APTS) and the above-mentioned activated silica gel, wherein the ratio of 3-aminopropyl triethoxysilane to silica gel is 3 mmol/g, react at 120 °C for 24 hours under nitrogen protection, after cooling, filtering, washing with acetone and dichloromethane, and drying to obtain amino-functionalized silica gel (APS).

3) Preparation of silica gel supported organic acid catalyst (as shown in Figure 1): add an appropriate amount of acid anhydride and the above amino-functionalized silica gel (APS) in dichloromethane, wherein the ratio of acid anhydride and amino-functionalized silica gel (APS) is 9 mmol/g, shaken at room temperature for 24 hours, then filtered, washed with methanol and dichloromethane, and dried to obtain a silica gel supported organic acid catalyst. (According to the acid-base titration reaction, the content of the organic acid supported on the silica gel was 0.8 mmol/g).

The acid anhydride is one of succinic anhydride or glutaric anhydride.

Please refer to Figure 1 for details.

2) Synthesis of Dihydropyrimidinones

Add raw material ethyl acetoacetate, aromatic aldehyde and urea, silica gel supported organic acid catalyst and ethanol solvent into the reaction vessel, heat under reflux for 4 to 5 hours, crystallize by cooling with ice water, filter to obtain crude product, then rehydrate with ethanol Crystallization to obtain dihydropyrimidinone compounds.

The molar ratio of ethyl acetoacetate, aromatic aldehyde and urea is: 1:1:1.2-1.5, preferably 1:1:1.2.

The raw aromatic aldehydes are benzaldehyde, p-methylbenzaldehyde, p-methoxybenzaldehyde, p-fluorobenzaldehyde, p-nitrobenzaldehyde, p-trifluoromethylbenzaldehyde, p-chlorobenzaldehyde, m-bromobenzaldehyde, ortho- Bromobenzaldehyde (the corresponding yields of dihydropyrimidinones are shown in Table 1).

The specific reflection is shown in Figure 2.

Table 1 Silica gel-supported organic acids are used as catalysts to synthesize dihydropyrimidinones

3) Recycling and use of silica gel supported organic acid catalyst

In the present invention, after the reaction, the target product is obtained by recrystallization with ethanol, and the silica gel-supported organic acid catalyst obtained by filtration and recovery can be reused. Table 2 is that the mol ratio of ethyl acetoacetate, benzaldehyde and urea is: 1:1:1.2, and the organic acid catalyst consumption of silica gel support is under the condition of 10mol% (in contained carboxyl group-CO ₂ H), The recovery and utilization of the catalyst after heating and refluxing for 5 hours. It can be seen from Table 2 that the organic acid catalyst supported by silica gel still has good catalytic activity after being recycled and reused.

The specific reflection is shown in Figure 3.

Table 2 Recycling of organic acid catalyst supported by silica gel

The above is a further explanation to the specific embodiment, and the following examples illustrate:

Example 1: Silica gel catalyst

For one-pot synthesis of dihydropyrimidinone compounds, the specific preparation method is as follows:

1) Activation of silica gel: After adding 150 mL of concentrated sulfuric acid and 30 mL of concentrated nitric acid to a round-bottomed flask and mixing evenly, add 25.0 g of silica gel (180 mesh), react at 140 ° C for 24 hours, cool to room temperature, filter, deionize Washed with water until neutral, then washed with methanol and dichloromethane, respectively, and dried to obtain activated silica gel.

2) Preparation of amino-functionalized silica gel: 6.0 g of the above activated silica gel and 18.0 mmol of 3-aminopropyltriethoxysilane (APTS) were added to 40 mL of anhydrous toluene, and the reaction was carried out at 120° C. for 24 hours under nitrogen protection. After cooling, filtering, washing with acetone and dichloromethane, and drying, 6.4 g of amino-functionalized silica gel (APS) was obtained.

3) Preparation of silica gel supported organic acid catalyst: 2.0 g of the above amino-functionalized silica gel (APS) and 18.0 mmol of glutaric anhydride were added to 20 ml of dichloromethane, shaken at room temperature for 24 hours, then filtered, and then used Wash with methanol and dichloromethane, and dry to obtain 2.15 g of silica gel supported organic acid catalyst (II).

Example 2: Synthesis of dihydropyrimidinones using the catalyst described in Example 1

In a 50ml round-bottomed flask, were sequentially added raw material ethyl acetoacetate (1.0mmol), p-methoxybenzaldehyde (1.0mmol) and urea (1.2mmol), 1.0g of the above-mentioned silica gel-supported organic acid catalyst (containing a carboxyl group) -CO ₂ H 0.08 mmol) and 10 ml of ethanol solvent, heated under reflux for 5 hours, crystallized by cooling with ice water, filtered to obtain a crude product, and then recrystallized with ethanol to obtain the target product with a yield of 94%.

Example 3: Silica gel catalyst

For one-pot synthesis of dihydropyrimidinone compounds, the specific preparation method is as follows:.

1), the preparation of the organic acid supported by silica gel:

1) Activation of silica gel: add 75 mL of concentrated sulfuric acid and 15 mL of concentrated nitric acid to a round-bottomed flask and mix evenly, then add 12.0 g of silica gel (100 mesh), react at 140°C for 24 hours, cool to room temperature, filter, deionize Washed with water until neutral, then washed with methanol and dichloromethane, respectively, and dried to obtain activated silica gel.

2) Preparation of amino-functionalized silica gel: 4.0 g of the above activated silica gel and 12.0 mmol of 3-aminopropyltriethoxysilane (APTS) were added to 25 mL of anhydrous toluene, and the reaction was carried out at 120° C. for 24 hours under nitrogen protection. After cooling, filtering, washing with acetone and dichloromethane, and drying, 4.3 g of amino-functionalized silica gel (APS) were obtained.

3) Preparation of silica gel supported organic acid catalyst: 2.0 g of the above amino-functionalized silica gel (APS) and 18.0 mmol of succinic anhydride were added to 12 ml of dichloromethane, shaken at room temperature for 24 hours, then filtered, and then used Wash with methanol and dichloromethane, and dry to obtain 2.16 g of silica gel supported organic acid catalyst (III).

Example 4: Synthesis of dihydropyrimidinones using the catalyst described in Example 3

In a 50ml round-bottomed flask, the raw materials, ethyl acetoacetate (1.0mmol), p-chlorobenzaldehyde (1.0mmol) and urea (1.2mmol), were successively added, and the above-mentioned silica gel supported organic acid catalyst 0.75g (containing a carboxyl group-CO2H0 06 mmol) and 10 ml of ethanol solvent, heated under reflux for 4 hours, crystallized by cooling with ice water, filtered to obtain a crude product, and then recrystallized with ethanol to obtain the target product with a yield of 92%.

Claims (4)

1. The silica gel catalyst for synthesizing dihydropyrimidinone compounds by a one-pot method is characterized by being prepared by the following steps:

(1) activation of silica gel: adding 150mL of concentrated sulfuric acid and 30mL of concentrated nitric acid into a round-bottom flask, uniformly mixing, adding 25.0g of 180-mesh silica gel, reacting at 140 ℃ for 24h, cooling to room temperature, filtering, washing with deionized water to be neutral, then washing with methanol and dichloromethane respectively, and drying to obtain activated silica gel;

(2) preparation of amino-functionalized silica gel: adding 6.0g of activated silica gel and 18.0mmol of 3-aminopropyltriethoxysilane into 40mL of anhydrous toluene, reacting for 24 hours at 120 ℃ under the protection of nitrogen, cooling, filtering, washing with acetone and dichloromethane, and drying to obtain amino-functionalized silica gel;

(3) Preparation of silica gel supported organic acid catalyst: adding 2.0g of amino-functionalized silica gel and 18.0mmol of glutaric anhydride into 20ml of dichloromethane, shaking for 24 hours at room temperature, then filtering, washing with methanol and dichloromethane, and drying to obtain a silica gel-loaded organic acid catalyst;

2. the silica gel catalyst for synthesizing dihydropyrimidinone compounds by a one-pot method is characterized by being prepared by the following steps:

(1) activation of silica gel: adding 75mL of concentrated sulfuric acid and 15mL of concentrated nitric acid into a round-bottom flask, uniformly mixing, adding 12.0g of 100-mesh silica gel, reacting at 140 ℃ for 24h, cooling to room temperature, filtering, washing with deionized water to be neutral, then washing with methanol and dichloromethane respectively, and drying to obtain activated silica gel;

(2) preparation of amino-functionalized silica gel: adding 4.0g of activated silica gel and 12.0mmol of 3-aminopropyltriethoxysilane into 25mL of anhydrous toluene, reacting for 24 hours at 120 ℃ under the protection of nitrogen, cooling, filtering, washing with acetone and dichloromethane, and drying to obtain amino-functionalized silica gel;

(3) preparation of silica gel supported organic acid catalyst: 2.0g of amino-functionalized silica gel and 18.0mmol of succinic anhydride were added to 12ml of dichloromethane, shaken at room temperature for 24 hours, then filtered, washed with methanol and dichloromethane, and dried to obtain a silica gel-supported organic acid catalyst.

3. The synthesis method of the dihydropyrimidinone compound is synthesized by taking ethyl acetoacetate, aromatic aldehyde and urea as raw materials, and is characterized in that: adding raw materials of ethyl acetoacetate 1.0mmol, p-methoxybenzaldehyde 1.0mmol and urea 1.2mmol, the silica gel supported organic acid catalyst 1.0g and 10ml of ethanol solvent into a round-bottom flask in sequence, heating and refluxing for 5 hours, cooling and crystallizing with ice water, filtering to obtain a crude product, and then recrystallizing with ethanol to obtain the target product.

4. The synthesis method of the dihydropyrimidinone compound is synthesized by taking ethyl acetoacetate, aromatic aldehyde and urea as raw materials, and is characterized in that: adding raw materials of ethyl acetoacetate 1.0mmol, p-chlorobenzaldehyde 1.0mmol and urea 1.2mmol, a silica gel supported organic acid catalyst 0.75g of claim 2 and 10ml of ethanol solvent into a round-bottom flask in sequence, heating and refluxing for 4 hours, cooling with ice water for crystallization, filtering to obtain a crude product, and then recrystallizing with ethanol to obtain the target product.

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