1, 4-dihydropyridine derivative as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of a 1, 4-dihydropyridine derivative, which comprises the following steps: preparing petroleum coke from ethylene tar, and acidizing the petroleum coke to obtain a petroleum coke catalyst; mixing ethyl acetoacetate, an aldehyde compound and acetate to obtain a mixture; and adding a petroleum coke catalyst into the mixture for catalytic reaction to obtain the 1, 4-dihydropyridine derivative. According to the preparation method, cheap and nontoxic petroleum coke is adopted as a catalyst, and a series of dihydropyridine compounds are obtained through a catalytic reaction at room temperature or low temperature without a solvent. The preparation method has the advantages of simple process and low cost, and avoids the use of a solvent and the pollution to the environment.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and specifically relates to a 1,4-dihydropyridine derivative and a preparation method and application thereof. Background Art

[0002] 1,4-Dihydropyridine compounds are an important class of nitrogen-containing heterocyclic compounds with good physiological activity. They are widely used in biology, medicine, and organic catalysis. The most important of these is as calcium channel blockers. Their pharmacological mechanism is to selectively act on calcium channels, blocking the influx of extracellular calcium ions into cells, and reducing the intracellular calcium ion concentration. They are a class of drugs with a wide range of cardiovascular pharmacological effects. 1,4-Dihydropyridine compounds are an important green environmentally friendly additive in agriculture and have been widely used in animal husbandry at home and abroad. Studies have shown that it can not only improve the immunity of livestock and poultry, but also reduce fatty liver in livestock and poultry and other functions. 1,4-Dihydropyridine has broad commercial prospects in agriculture due to its fast metabolism and almost no residue in animals. It is precisely because 1,4-Dihydropyridine compounds have very important application pathways in various aspects that they have received extensive attention from scientists.

[0003] In 1882, chemist Arthur Hantzsch first synthesized 1,4-dihydropyridine (1,4-DHP) (A Hantzsch, et al Ann. Chem., 1882, 215 (5): 1-5.) and named it Hantzsch ester. He later published a synthesis method named after him, the Hantzsch reaction, which was later recognized as a classic synthesis method for dihydropyridine compounds. In the past 10 years, scientists at home and abroad have made a lot of improvements to the Hantzsch condensation reaction in order to find more efficient and convenient synthesis methods and develop more effective clinical drugs. Many dihydropyridine compounds have been synthesized and great progress has been made in synthesis methods.

[0004] The strategies and methods for synthesizing this type of compounds include microwave method [A Shaabani, A HRezayan, A Rahmati, et al. Ultrasound-accelerated synthesis of 1,4-dihydropyridines in an Ionic liquid [J]. Monatsh Chem., 2006, 137 (1): 77-85.], ultrasonic method [J Legeay, JJ VEyndeb, J PBazureau. Ionic liquid phase technology supported the three components synthesis of hantzsch 1,4-dihydropyridines and biginelli3,4-dihydropyrimidin-2(1H)-ones under microwave dielectric heating [J]. Tetrahedron, 2005, 61 (10): 12386-12397.], phase transfer catalyst method [T Fatemeh, R Zahra, J Abbs Ali. Synthesis of 3,4-dihydropyrimidin-2(1H)-ones and1,4-dihydropyridines using ammonium carbonatein water[J].Tetrahedron Lett,2010,51(3):1187-1189.], Browns acid method[R SVarma.Solvent-free organic syntheses using supported reagents and microwaveirradiation[J].Green Chem.,1999,1(1):43-55.], etc.

[0005] Compared with the traditional step-by-step reaction synthesis method, the preparation process of 1,4-dihydropyridine generated by multi-component synchronous reaction has higher research value. Among them, the Hantzsch reaction of aromatic aldehydes, ethyl acetoacetate and ammonium acetate is the most common, and various catalysts for this reaction system have also been reported, such as protonic acid catalysts such as perchloric acid, phenylboric acid, alumina sulfuric acid and silica sulfonic acid and Lewis acid catalysts such as aluminum chloride [SD Sharma, PHazarika, DKonwar. A simple, green and one-pot four-component synthesis of 1,4-dihydropyridines and their aromatization [J]. Catal Commun, 2008, 9 (5): 709-714.], N, N, N', N'-tetramethylguanidine trifluoroacetate (TMGT), 1-ethyl-3-methylimidazolium acetate [EMIM]OA and other ionic liquid catalysts [SD Deshayes, M Liagere, A Loupy, et al. Microwave activation in phase transfer catalysis [J]. Tetrahedron, 1999, 55 (6): 10 851-10 870.]

[0006] In recent years, the research focus of 1,4-dihydropyridine compounds has been mainly on: (1) Research on the synthesis method of 1,4-dihydropyridine compounds; (2) Synthesis of pyridine derivatives by aromatization; (3) Reduction of imines using it as a model of coenzyme; (4) Use of 1,4-DHP type drugs to treat cardiovascular and cerebrovascular diseases, and conduct bactericidal and pharmacological activity research. The synthesis of 1,4-dihydropyridine is usually synthesized by the Hantzsch method reported in the literature, that is, aromatic aldehyde, ethyl acetoacetate, and concentrated ammonia water are refluxed in ethanol for more than ten hours to obtain it. This method has the disadvantages of long reflux time, low yield, and the inconvenience of operation caused by the irritation of concentrated ammonia water to the human body. Sumino [ Sumino S, Uno M, Fukuyama T, et al. Photoredox-catalyzed hydrodifluoroalkylation of alkenes using difluorohaloalkyl compounds and a Hantzsch Ester [J]. The Journal of Organic Chemistry, 2017, 82 (10): 5469-5474. et al. used ammonium bicarbonate instead of concentrated ammonia to synthesize a series of 4-aryl-1, 4-dihydropyridine compounds, the reaction time was shortened to 1.5h, and the yield was improved.[ Li Z, Yang JD, Cheng J P. Thermodynamic and kinetic studies of hydride transfer from Hantzsch ester under the promotion of organic bases [J]. Organic Chemistry Frontiers, 2021, 8 (5): 876-882. et al. first prepared methyl acetoacetate into amino methyl crotonate, and then mixed it with aromatic aldehyde and methyl acetoacetate in equal moles to synthesize 2,6-dimethyl-4-aryl-3,5-dimethoxycarbonyl-1,4-dihydropyridine compounds using microwave radiation technology, but methyl acetoacetate must first be prepared into amino crotonate, and then 1,4-dihydropyridine compounds are synthesized. However, most of the above-mentioned synthesis methods have the disadvantages of harsh reaction conditions, high cost, high catalyst toxicity, and environmental pollution. Therefore, it is of great practical significance to explore and optimize green and efficient synthesis methods. Summary of the invention

[0007] In order to overcome the shortcomings of the prior art, the present invention aims to provide a method for preparing 1,4-dihydropyridine derivatives, which uses cheap and non-toxic petroleum coke as a catalyst, and catalytically reacts in the absence of solvents at room temperature or low temperature to obtain a series of dihydropyridine compounds. The preparation method is simple in process, low in cost, and avoids the use of solvents and pollution to the environment.

[0008] In order to achieve the above object, the technical solution of the present invention is:

[0009] In a first aspect, the present invention provides a 1,4-dihydropyridine derivative having a structure as shown in Formula I,

[0010]

[0011] Wherein, R is selected from one of an alkyl group, a carboxyl group, an alkoxy acyl group, an alkyl acyl group, an aryl group and a substituted aryl group.

[0012] In some other embodiments, the substituted aryl group is selected from aryl groups substituted by one of halogen, alkyl, carboxyl, alkoxy acyl, alkyl acyl, nitrogen, alkyl substituted nitrogen, oxy and nitro;

[0013] The halogen is selected from F, Cl, Br and I;

[0014] The alkyl group is selected from -CH3 and -(CH2) n -CH3, n is any integer from 1 to 5;

[0015] The alkoxy acyl group is selected from -COOCH3 and -COO(CH2) n -CH3, n is any integer from 1 to 5;

[0016] The alkyl acyl group is selected from -COCH3 and -CO(CH2) n -CH3, n is any integer from 1 to 5;

[0017] The alkyl substituted nitrogen group is selected from -NH-CH3, -N-(CH3)2, -NH(CH2) n -CH3, n is any integer from 1 to 5;

[0018] Preferably, R is selected from one of -Ph-F, -Ph-NO2, -Ph-OH, -CH3, -Ph-N(CH3)2, -COOH, Ph-CH2-CH2- and Ph-O-, and the substitution position is para to the aromatic group.

[0019] In a second aspect, the present invention provides a method for preparing a 1,4-dihydropyridine derivative, comprising the following steps:

[0020] Ethylene tar is prepared into petroleum coke, and the petroleum coke is subjected to acidification treatment to obtain a petroleum coke catalyst; ethyl acetoacetate, R-CHO, and acetate are mixed to obtain a mixture; and the petroleum coke catalyst is added to the mixture to carry out a catalytic reaction to obtain a 1,4-dihydropyridine derivative;

[0021] The substituent R in the R-CHO is as defined in the first aspect.

[0022] In some other embodiments, the preparation conditions of petroleum coke are: reaction temperature of 300-500° C., reaction pressure of 3-6 MPa, and reaction time of 2-7 h.

[0023] In some other embodiments, the acid used in the acidification treatment of petroleum coke is one or more of sulfuric acid, hydrochloric acid, nitric acid and phosphoric acid, the mass ratio of the acid to petroleum coke is (5-50):1, and the time is 10-24h.

[0024] In some other embodiments, the molar ratio of ethyl acetoacetate, aldehyde compound, and acetate is 1:(1-2):(1-5);

[0025] The molar ratio of the petroleum coke catalyst to the mixture is 1:(10-100).

[0026] In some other embodiments, the R-CHO is selected from one of acetaldehyde, phenylacetaldehyde, p-hydroxybenzaldehyde, p-aminobenzaldehyde, p-sulfonylbenzaldehyde, anisaldehyde, p-hydroxyphenylacetaldehyde, p-aminophenylacetaldehyde, p-sulfonylphenylacetaldehyde, propionaldehyde, p-hydroxyphenylpropionaldehyde, p-aminophenylpropionaldehyde, p-sulfonylphenylpropionaldehyde, p-fluorobenzaldehyde, p-chlorobenzaldehyde, p-bromobenzaldehyde, p-fluorophenylacetaldehyde, p-dimethylaminobenzaldehyde, glyoxylic acid, p-chlorophenylacetaldehyde and p-bromophenylacetaldehyde.

[0027] In some other embodiments, the acetate is selected from one of sodium acetate, potassium acetate, ammonium acetate, calcium acetate, acetic acid, cesium acetate, silver acetate, cobalt acetate, platinum acetate and chromium acetate.

[0028] In some other embodiments, the catalytic reaction temperature is 20-40° C. and the time is 12-24 hours.

[0029] In a third aspect, the present invention provides use of the 1,4-dihydropyridine derivatives described in the first aspect in feed additives.

[0030] Beneficial effects of the present invention:

[0031] The invention adopts non-toxic and cheap petroleum coke as a catalyst. The preparation process of the catalyst is simple and efficient. The catalyst can catalyze the synthesis of 1,4-dihydropyridine derivatives in the absence of solvent and at room temperature or below 40°C. The catalytic preparation method is simple and inexpensive, and avoids the use of solvents and pollution to the environment. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] The accompanying drawings in the specification, which constitute a part of the present invention, are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute improper limitations on the present invention.

[0033] Figure 1 is an infrared image of the petroleum coke prepared in Example 1 of the present invention;

[0034] Figure 2 is a scanning electron microscope image of the petroleum coke catalyst prepared in Example 1 of the present invention;

[0035] Figure 3 is the hydrogen nuclear magnetic resonance spectrum of compound 1 prepared in Example 1 of the present invention;

[0036] Figure 4 is the hydrogen nuclear magnetic resonance spectrum of compound 2 prepared in Example 2 of the present invention;

[0037] Figure 5 is the hydrogen nuclear magnetic resonance spectrum of compound 3 prepared in Example 3 of the present invention;

[0038] Figure 6is the hydrogen nuclear magnetic resonance spectrum of compound 4 prepared in Example 4 of the present invention;

[0039] Figure 7 is the hydrogen nuclear magnetic resonance spectrum of compound 5 prepared in Example 5 of the present invention;

[0040] Figure 8 is the hydrogen nuclear magnetic resonance spectrum of compound 6 prepared in Example 6 of the present invention;

[0041] Fig. 9 This is the hydrogen nuclear magnetic resonance spectrum of compound 7 prepared in Example 7 of the present invention. DETAILED DESCRIPTION

[0042] 1. Preparation of Compounds

[0043] Example 1

[0044] Preparation of compound 1

[0045] 100ml of ethylene tar was reacted at 400℃ and 4 MPa for 6h, and then cooled to obtain 20g of petroleum coke product. 40ml of 36% concentrated hydrochloric acid was used to soak the petroleum coke product in a 250ml beaker, and after stirring at room temperature for 24h, 100ml of water was added, and the 20g solid obtained was dried for standby use, namely, petroleum coke catalyst. 262ml of ethyl acetoacetate, 137g of anisaldehyde, 81g of ammonium acetate were added to a 500ml three-necked flask, and 20g of petroleum coke catalyst was added thereto, and the reaction was stirred at room temperature for 24h. After the reaction was completed, a large amount of solid was obtained. The solid was filtered, and the obtained solid product was redissolved in 50ml of anhydrous ethanol, and the black petroleum coke catalyst was obtained by filtration and separation. The remaining filtrate was allowed to stand for crystallization to obtain 301g of yellow solid compound, namely, a 1,4-dihydropyridine derivative with a substituent of -Ph-OCH3, marked as compound 1, and the structure was shown in the formula: The yield was 83.5%.

[0046]

[0047] Figure 1 The infrared images of petroleum coke before and after acidification treatment, where PC is petroleum coke without acidification treatment and PC-S is petroleum coke after sulfuric acid treatment. Figure 1 It can be clearly seen that after acidification, the petroleum coke shows absorption characteristic peaks of S=O bond and CS bond, indicating that the acid has successfully modified the petroleum coke.

[0048] Figure 2 The SEM image of the prepared petroleum coke catalyst is Figure 2It can be seen that (a) is a scanning electron microscope image of petroleum coke without acid treatment. From the figure, it can be seen that before the petroleum coke is treated with acid, its morphology and appearance show a regular arrangement, which is a typical petroleum coke product. (b) is a scanning electron microscope image of petroleum coke treated with concentrated sulfuric acid. From the figure, it can be seen that after the concentrated sulfuric acid acid treatment, an irregular block structure appears on the surface of the petroleum coke, and a large number of wrinkles and cracks appear on the surface. Due to the strong oxidizing and corrosive properties of concentrated sulfuric acid, the petroleum coke can be well etched, causing a significant change in its morphology, thereby having a specific catalytic effect.

[0049] Figure 3 This is the H NMR spectrum of compound 1: 1 H NMR (400MHz, DMSO-d6) δ (ppm): 8.74 (s, 1H), 7.04 (d, J-8.2Hz, 2H), 6.76 (d, J-8.2Hz, 2H), 4.79 (s, 1Hs), 3.98 (p, J=6.8Hz, 4H), 3.72 (s, 1H), 3.67 (s, 3H), 2.24 (s, 6H), 1.13 (t, J=7.1Hz, 7H).

[0050] Example 2

[0051] Preparation of compound 2

[0052] 200ml of ethylene tar was reacted at 500℃ and 3 MPa for 5h, and then cooled to obtain 49g of petroleum coke product. 60ml of concentrated sulfuric acid was used to soak the petroleum coke product in a 250ml beaker, and after stirring at room temperature for 24h, 100ml of water was added, and the obtained 49.5g of solid was dried for standby use, namely, petroleum coke catalyst. 92ml of ethyl acetoacetate, 43g of p-fluorobenzaldehyde, 31g of ammonium acetate were added to a 500ml three-necked flask, and 10g of petroleum coke catalyst was added thereto, and the reaction was stirred at room temperature for 24h to obtain the product. Filter and redissolve the solid product in 50ml of anhydrous ethanol, filter and separate to obtain a black petroleum coke catalyst, and the filtrate was allowed to stand for crystallization to obtain 78g of a yellow solid compound, namely, a 1,4-dihydropyridine derivative with a substituent of -Ph-F, marked as compound 2, with a structure shown in the following formula, and a yield of 63.9%.

[0053]

[0054] Figure 4 This is the H NMR spectrum of compound 2: 1H NMR (400MHz, DMSO-d6) δ (ppm): 8.82 (s, 1H), 7.19-7.11 (m, 2H), 7.09 (s, 1Hs), 7.06-6.97 (m, 2Hs), 4.84 (s, 1H), 3.98 (p, J=11.1Hz, 5H), 2.25 (s, 6H), 1.13 (dt, J=7.2, 3.6Hz, 6H).

[0055] Example 3

[0056] Preparation of compound 3

[0057] 400ml of ethylene tar was reacted at 300℃ and 5 MPa for 6h, and then cooled to obtain 82g of petroleum coke product. 200ml of concentrated sulfuric acid was used to soak the petroleum coke product in a 250ml beaker, and after stirring at room temperature for 24h, 200ml of water was added, and the obtained solid was dried for standby use, namely, petroleum coke catalyst. 200ml of ethyl acetoacetate, 94g of p-hydroxybenzaldehyde, 71g of ammonium acetate were added to a 500ml three-necked flask, and 30g of acidified petroleum coke catalyst was added thereto, and the reaction was stirred at room temperature for 24h to obtain the product. Filter and redissolve the solid product in 100ml of anhydrous ethanol, filter and separate to obtain a black petroleum coke catalyst, and the filtrate was allowed to stand for crystallization to obtain 250g of a yellow solid compound, namely, a 1,4-dihydropyridine derivative with a substituent of -Ph-OH, marked as compound 3, with a structure shown in the following formula, and a yield of 95%.

[0058]

[0059] Figure 5 This is the H NMR spectrum of compound 3: 1 HNMR (400MHz, DMSO-d6) δ (ppm): 9.30 (s, 1H), 8.54 (d, J = 4.5Hz, 1H), 7.02-6.96 (m, 1H), 6.95-6.89 (m, 1H), 6.69-6.63 (m, 1H) ), 6.60-6.54(m,1H), 5.38(dt, J=4.4Hz, 1H), 4.14-3.89(m,4H), 2.28(s,2H), 2.23(s,2H), 2.17(s,2H), 1.23-1.02(m,7H).

[0060] Example 4

[0061] Preparation of compound 4

[0062] The difference from Example 1 is that 262 ml of ethyl acetoacetate, 74.5 g of glyoxylic acid and 81 g of ammonium acetate are directly added, and 20 g of petroleum coke catalyst is added thereto for reaction. The other reaction processes are exactly the same as those in Example 1, and compound 6 is prepared, and the structure is shown in the formula: The yield is 91.5%.

[0063]

[0064] Figure 6 This is the H NMR spectrum of compound 4: 1 H NMR (400MHz, Chloroform-d) δ7.19-7.11 (m, 1H), 6.70-6.62 (m, 1Hs), 4.09 (p, J=7.0Hz, 2H), 2.74 (s, 1H), 2.33 (s, 2H), 1.24 (d, J=12.6Hz, 15H), 1.00 (t, J=7.1Hz, 1H) and 0.92-0.83 (m, 1H).

[0065] Example 5

[0066] Preparation of compound 5

[0067] The difference from Example 1 is that 262 ml of ethyl acetoacetate, 137 g of phenylacetaldehyde and 81 g of ammonium acetate are directly added, and 20 g of petroleum coke catalyst is added thereto for reaction. The other reaction processes are exactly the same as those in Example 1, and compound 5 is prepared, and the structure is shown in the formula: The yield is 85.6%.

[0068]

[0069] Figure 7 This is the H NMR spectrum of compound 5: 1 H NMR (400MHz, Chloroform-d) δ7.32-7.19 (m, 4H), 7.23-7.08 (m, 5H), 5.56 (s, 2H), 4.42 (dq, J=15 .6, 7.1Hz, 1H), 4.28-4.10 (m, 7H), 4.06 (t, J=5.7Hz, 2H) 7.1Hz, 10H), 1.25 (s, 1H), 0.86 (s, 1Hs).

[0070] Example 6

[0071] Preparation of compound 6

[0072] The difference from Example 1 is that 262 ml of ethyl acetoacetate, 137 g of acetaldehyde and 81 g of ammonium acetate are directly added, and 20 g of petroleum coke catalyst is added thereto for reaction. The other reaction processes are exactly the same as those in Example 1, and compound 6 is prepared, and the structure is shown in the formula: The yield is 92.5%.

[0073]

[0074] Figure 8 This is the H NMR spectrum of compound 6: 1 H NMR (400MHz, Chloroform-d) δ5.69 (s, 1H), 4.42 (q, J=7.1Hz, 1H), 4.28-4.10 (m, 5H), 3.83 (q, J=6.5Hz, 1H ), 2.54 (s, 2H), 2.27 (d, J = 5.4Hz, 8H), 1.40 (t, J = 7.2Hz, 2H), 1.30 (t, J = 7.1Hz, 8H), 0.97 (t, J = 6.5Hz, 4H).

[0075] Example 7

[0076] Preparation of compound 7

[0077] The difference from Example 1 is that 262 ml of ethyl acetoacetate, 137 g of p-dimethylaminobenzaldehyde and 81 g of ammonium acetate are directly added, and 20 g of petroleum coke catalyst is added thereto for reaction. The other reaction processes are exactly the same as those in Example 1, and compound 7 is prepared, and the structure is shown in the formula: The yield is 87%.

[0078]

[0079] Fig. 9 This is the H NMR spectrum of compound 7: 1 H NMR (400MHz, Chloroform-d) δ7.19-7.11 (m, 1H), 6.67-6.58 (m, 1H), 5.70 (s, 0H), 4.89 (s, 1H), 4.09 (qd, J = 7.1, 2.7Hz, 2H), 2.88 (s, 3H), 2.31 (s, 3H), 1.24 (t, J = 7.1Hz, 3H).

[0080] Comparative Example 1

[0081] The difference from Example 1 is that no petroleum coke catalyst is added. The other reaction processes are exactly the same as those of Example 1, and Compound 1 is prepared with a yield of 46.2%.

[0082] Comparative Example 2

[0083] The difference from Example 1 is that the reaction temperature is set to 80° C. The other reaction processes are exactly the same as Example 1, and Compound 1 is prepared with a yield of 79.5%.

[0084] Comparative Example 3

[0085] The difference from Example 1 is that the reaction temperature is set to 25°C, under ultrasonic irradiation conditions (25kHz, 250W), and the other reaction processes are exactly the same as Example 1, to prepare Compound 1 with a yield of 70%.

[0086] In Comparative Example 1, no petroleum coke catalyst is added, and the reaction rate of the reaction at room temperature is extremely low. The essential reason is that the reaction is an endothermic reaction, and it is difficult to react at room temperature without external energy supply. The reaction yield in Comparative Example 2 is relatively high because the reaction is an endothermic reaction. As the temperature increases, the reaction rate increases and the yield increases; in Comparative Example 3, the reaction yield is relatively high under ultrasonic external conditions because ultrasound accelerates the molecular motion between the reactants, which speeds up the reaction rate.

[0087] 2. Application examples of compounds

[0088] Dihydropyridine is a new multifunctional additive with some effects of natural antioxidant Ve, which can inhibit the peroxidation process of lipid compounds. At the same time, it can also change the levels of certain hormones in serum, promote the growth and development of livestock and poultry, reproductive performance and enhance immune function, and its metabolism is complete and almost no residue. In addition, dihydropyridine can significantly enhance the activity of the small intestine and slow down the backward movement of small intestinal chyme, which is beneficial to small intestinal digestion and absorption, thereby improving feed utilization.

[0089] In this example, different doses of dihydropyridine derivatives were added to the diet to explore their effects on the growth and development of Hessex laying hens and screen out the optimal amount of addition, which not only provides a certain theoretical basis for basic research on poultry production, but also provides guidance and reference for the feed formulation of laying hens.

[0090] 500 healthy, 14-week-old Hexex laying hens with similar body weight were selected and divided into a blank group and an experimental group (7 compounds synthesized by the present invention and the known compound 2,6-dimethyl-3,5-diethyl ester 1,4-dihydropyridine, a total of 8 compounds). The blank group (20 Hexex laying hens were randomly selected as the blank group) did not add 1,4-dihydropyridine derivatives to the nutritional diet of the growing chickens; each compound in the experimental group (480 Hexex laying hens were randomly divided into 8 large groups, each with 60, each large group was further divided into 3 small groups, each with 20) was added to the nutritional diet of the growing chickens at 100 mg / kg, 150 mg / kg, and 200 mg / kg. The composition and nutritional level of the nutritional diet for growing chickens are shown in Table 1 below. The diet was fed twice a day (8:00 am and 4:00 pm), and the experimental period was 30 days.

[0091] Table 1 Nutrient composition and nutritional level of growing chickens

[0092]

[0093] The chickens were weighed on an empty stomach in the morning at the beginning and middle of the experiment. Table 2 shows the effect of adding different doses of dihydropyridine derivatives to the diet on the body weight of growing chickens. In the diet of Hesex laying hens, the initial body weight was close to about 630g. The above 7 compounds were added to the diet of Hesex laying hens at 100mg / kg, 150mg / kg and 200mg / kg, respectively, and the changes in body weight of each group were observed. The control group was the Hesex laying hens without adding dihydropyridine derivatives to the diet, and the body weight of the growing chickens after 30 days was 1275.4g; the Hesex laying hens were added with 100mg / kg, 150mg / kg and 200mg / kg of 2.6-dimethyl-3,5-diethyl ester 1,4-dihydropyridine, respectively, and the body weight of the growing chickens after 30 days was 1285.4g, 1300g and 1292.5g, respectively.

[0094] As can be seen from Table 2, after adding different doses of dihydropyridine derivatives to the diet for 30 days, the body weight of Hesex laying hens in each supplementation group was significantly different from that in the control group, and there was no significant difference between the 100 mg / kg and 200 mg / kg supplementation groups. When 150 mg / kg of dihydropyridine was added, the body weight of the growing chickens increased significantly, but with the increase in the addition level, the body weight gain showed a downward trend.

[0095] Table 2 Effects of adding different doses of dihydropyridine to the diet on the growth of chickens after 30 days of growth

[0096] Serial number 100mg / kg 150mg / kg 200mg / kg Compound 1 1296.5 1355 1300.7 Compound 2 1308.4 1361.6 1299.6 Compound 3 1310.3 1366 1300.0 Compound 4 1332.9 1382.2 1333.4 Compound 5 1328.1 1380.7 1329.1 Compound 6 1320.1 1379 1318.8 Compound 7 1309.6 1361 1300.0

[0097] The results of this study showed that after adding different doses of dihydropyridine to the diet for 30 days, the weight of Hesex laying hens in each group was significantly different from that in the control group. Adding dihydropyridine to the diet can significantly increase the growth rate of Hesex laying hens, and the optimal amount of dihydropyridine added to the diet is 150 mg / kg.

[0098] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A 1,4-dihydropyridine derivative, characterized in that: Having the structure of formula I, Wherein, R is selected from one of an alkyl group, a carboxyl group, an alkoxy acyl group, an alkyl acyl group, an aryl group and a substituted aryl group.

2. The 1,4-dihydropyridine derivative according to claim 1, characterized in that The substituted aryl group is selected from an aryl group substituted by one of halogen, alkyl, carboxyl, alkoxy acyl, alkyl acyl, nitrogen, alkyl substituted nitrogen, oxy and nitro; The halogen is selected from F, Cl, Br and I; The alkyl group is selected from -CH3 and -(CH2) n -CH3, n is any integer from 1 to 5; The alkoxy acyl group is selected from -COOCH3 and -COO(CH2) n -CH3, n is any integer from 1 to 5; The alkyl acyl group is selected from -COCH3 and -CO(CH2) n -CH3, n is any integer from 1 to 5; The alkyl substituted nitrogen group is selected from -NH-CH3, -N-(CH3)2, -NH(CH2) n -CH3, n is any integer from 1 to 5; Preferably, R is selected from one of -Ph-F, -Ph-NO2, -Ph-OH, -CH3, -Ph-N(CH3)2, -COOH, Ph-CH2-CH2- and Ph-O-, and the substitution position is para to the aromatic group.

3. A method for preparing a 1,4-dihydropyridine derivative, characterized in that: The following steps are involved: Ethylene tar is prepared into petroleum coke, and the petroleum coke is subjected to acidification treatment to obtain a petroleum coke catalyst; ethyl acetoacetate, R-CHO, and acetate are mixed to obtain a mixture; and the petroleum coke catalyst is added to the mixture to carry out a catalytic reaction to obtain a 1,4-dihydropyridine derivative; The substituent R in the R-CHO is as defined in claim 1 or 2.

4. The method for preparing 1,4-dihydropyridine derivatives according to claim 3, characterized in that: The preparation conditions of petroleum coke are: reaction temperature of 300-500°C, reaction pressure of 3-6MPa, and reaction time of 2-7h.

5. The method for preparing 1,4-dihydropyridine derivatives according to claim 3, characterized in that: The acid used in the acidification treatment of petroleum coke is one or more of sulfuric acid, hydrochloric acid, nitric acid and phosphoric acid, the mass ratio of the acid to petroleum coke is (5-50):1, and the time is 10-24h.

6. The method for preparing 1,4-dihydropyridine derivatives according to claim 3, characterized in that: The molar ratio of ethyl acetoacetate, aldehyde compound and acetate is 1:(1-2):(1-5); The molar ratio of the petroleum coke catalyst to the mixture is 1:(10-100).

7. The method for preparing 1,4-dihydropyridine derivatives according to claim 6, characterized in that: The R-CHO is selected from one of acetaldehyde, phenylacetaldehyde, p-hydroxybenzaldehyde, p-aminobenzaldehyde, p-sulfonylbenzaldehyde, anisaldehyde, p-hydroxyphenylacetaldehyde, p-aminophenylacetaldehyde, p-sulfonylphenylacetaldehyde, propionaldehyde, p-hydroxyphenylpropionaldehyde, p-aminophenylpropionaldehyde, p-sulfonylphenylpropionaldehyde, p-fluorobenzaldehyde, p-chlorobenzaldehyde, p-bromobenzaldehyde, p-fluorophenylacetaldehyde, p-dimethylaminobenzaldehyde, glyoxylic acid, p-chlorophenylacetaldehyde and p-bromophenylacetaldehyde.

8. The method for preparing 1,4-dihydropyridine derivatives according to claim 6, characterized in that: The acetate is selected from one of sodium acetate, potassium acetate, ammonium acetate, calcium acetate, acetic acid, cesium acetate, silver acetate, cobalt acetate, platinum acetate and chromium acetate.

9. The method for preparing 1,4-dihydropyridine derivatives according to claim 3, characterized in that: The temperature of the catalytic reaction is 20-40°C and the time is 12-24h.

10. Use of the 1,4-dihydropyridine derivative according to claim 1 or 2 in feed additives.

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