A 1,4-dihydropyridine derivative, its preparation method and application

Abstract

The application belongs to the technical field of organic synthesis, and particularly relates to a preparation method of 1,4-dihydropyridine derivatives, which comprises the following steps: preparing ethylene tar into petroleum coke, and performing acidification treatment on the petroleum coke to obtain a petroleum coke catalyst; mixing ethyl acetoacetate, an aldehyde compound and an acetate to obtain a mixture; and adding the petroleum coke catalyst into the mixture to perform a catalytic reaction, so that the 1,4-dihydropyridine derivatives are obtained. The preparation method adopts the inexpensive and nontoxic petroleum coke as the catalyst, and a series of dihydropyridine compounds are obtained through the catalytic reaction under the conditions of no solvent and room temperature or low temperature. The preparation method is simple in process and low in cost, and the use of the solvent and the environmental pollution are avoided.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a 1,4-dihydropyridine derivative and its preparation method and application. Background Technology

[0002] 1,4-Dihydropyridine compounds are an important class of nitrogen-containing heterocyclic compounds with good physiological activity and wide applications in biology, medicine, and organocatalysis. Most importantly, they are used as calcium channel blockers. Their pharmacological mechanism involves selectively acting on calcium channels, blocking the influx of extracellular calcium ions into cells, thus reducing intracellular calcium ion concentration. These compounds also possess broad cardiovascular pharmacological effects. In agriculture, 1,4-dihydropyridine compounds are important green and environmentally friendly additives, widely used in livestock farming both domestically and internationally. Studies have shown that they can not only improve the immunity of livestock and poultry but also reduce fatty liver disease, among other benefits. Due to their rapid metabolism and minimal residue in animals, 1,4-dihydropyridines have broad commercial prospects in agriculture. The significant applications of 1,4-dihydropyridine compounds in various fields have attracted widespread 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.), naming it the Hantzsch ester. He later published the synthetic method named after him—the Hantzsch reaction—which has since been recognized as a classic synthetic method for monohydropyridine compounds. In the past decade, scientists both domestically and internationally have made significant improvements to the Hantzsch condensation reaction in order to find more efficient and convenient synthetic methods and develop more effective clinical drugs, resulting in the synthesis of many dihydropyridine compounds and substantial progress in synthetic methods.

[0004] Strategies and methods for synthesizing these compounds include microwave synthesis [A Shaabani, A H Rezayan, A Aahmati, et al. Ultrasound-accelerated synthesis of 1,4-dihydropyridines in an Ionic liquid[J]. Monatsh Chem., 2006, 137(1):77-85.], ultrasonic synthesis [J Legeay, JJ VEyndeb, J PBazureau. Ionic liquid phase technology supported the three components synthesis of hantzsch 1,4-dihydropyridines and biginelli 3,4-dihydropyrimidin-2(1H)-ones under microwave dielectric heating[J]. Tetrahedron, 2005, 61(10):12386-12397.], and phase transfer catalyst synthesis [TFatemeh, RZahra, JABbbsAli. 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 traditional stepwise reaction synthesis methods, the preparation process of 1,4-dihydropyridine by simultaneous reaction of multiple components is of greater research value. Among them, the Hantzsch reaction of aromatic aldehydes, ethyl acetoacetate, and ammonium acetate is the most common. Various catalysts for this reaction system have been reported, such as protic acid catalysts such as perchloric acid, phenylboronic acid, alumina sulfuric acid, and silica sulfonic acid, and Lewis acid catalysts such as aluminum trichloride [SD Sharma, PHazarika, D Konwar. A simple, green and one-pot four-component synthesis of 1,4-dihydropyridines and their aromatization[J]. Catal Commun, 2008, 9(5): 709-714.], and ionic liquid catalysts such as N,N,N′,N′-tetramethylguanidine trifluoroacetate (TMGT) and 1-ethyl-3-methylimidazolium acetate [EMIM]OA [SDeshayes, MLiage, ALoupy, et al. Microwave activation in phase transfer catalysis[J]. Tetrahedron, 1999, 55(6): 10851-10870.]

[0006] In recent years, the research focus of 1,4-dihydropyridine compounds has mainly been on: (1) the study of synthetic methods of 1,4-dihydropyridine compounds; (2) the synthesis of pyridine derivatives through aromatization; (3) the reduction of imines using 1,4-DHP-type drugs as a model for coenzymes; and (4) the use of 1,4-DHP-type drugs to treat cardiovascular and cerebrovascular diseases, and the study of their bactericidal and pharmacological activities. The biosynthesis of 1,4-dihydropyridine is usually carried out using the Hantzsch method reported in the literature, which involves refluxing aromatic aldehydes, ethyl acetoacetate, and concentrated ammonia in ethanol for more than ten hours. This method suffers from long reflux times, low yields, and operational inconvenience due to the irritating effect of concentrated ammonia on the human body. [ Sumino S, Uno M, Fukuyama T, et al. Photoredox-catalyzed hydrodifluoroalkylation of alkenes using difluorohaloalkyl compounds and aHantzsch Ester[J]. The Journal of Organic Chemistry, 2017, 82(10): 5469-5474. Li et al. synthesized a series of 4-aryl-1,4-dihydropyridine compounds by replacing concentrated ammonia with ammonium bicarbonate, shortening the reaction time to 1.5 h and improving the yield.[ 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. They first converted methyl acetoacetate to aminocrotonate, and then mixed it with aromatic aldehydes and methyl acetoacetate in equimolar amounts before synthesizing 2,6-dimethyl-4-aryl-3,5-dimethoxycarbonyl-1,4-dihydropyridine compounds using microwave irradiation. However, this requires first converting methyl acetoacetate to aminocrotonate before synthesizing 1,4-dihydropyridine compounds. However, most of the above synthetic methods suffer from drawbacks such as harsh reaction conditions, high cost, high catalyst toxicity, and environmental pollution. Therefore, exploring and optimizing green and efficient synthetic methods is of significant practical importance. Summary of the Invention

[0007] To overcome the shortcomings of existing technologies, the present invention aims to provide a method for preparing 1,4-dihydropyridine derivatives. This method utilizes inexpensive and non-toxic petroleum coke as a catalyst, and a series of dihydropyridine compounds are obtained through a solvent-free reaction at room temperature or low temperature. This preparation method is simple, inexpensive, and avoids the use of solvents and environmental pollution.

[0008] To achieve the above objectives, the technical solution of the present invention is as follows:

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

[0010]

[0011] R is selected from one of alkyl, carboxyl, alkoxyacyl, alkylacyl, aryl, and substituted aryl groups.

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

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

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

[0015] The alkoxyacyl group is selected from -COOCH3 and -COO(CH2). n - One of CH3, where n is any integer from 1 to 5;

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

[0017] The alkyl-substituted nitrogen group is selected from -NH-CH3, -N-(CH3)2, and -NH(CH2). n - One of CH3, where 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-aryl.

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

[0020] Ethylene tar was prepared into petroleum coke, and the petroleum coke was acidified to obtain a petroleum coke catalyst. Ethyl acetoacetate, R-CHO and acetate were mixed to obtain a mixture. The petroleum coke catalyst was 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 for petroleum coke are: a reaction temperature of 300-500°C, a reaction pressure of 3-6 MPa, and a reaction time of 2-7 h.

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

[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 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-aminobenzaldehyde, p-sulfonylbenzaldehyde, propionaldehyde, p-hydroxyphenylpropionaldehyde, p-aminophenylpropionaldehyde, p-sulfonylbenzaldehyde, 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 sodium acetate, potassium acetate, ammonium acetate, calcium acetate, acetic acid, cesium acetate, silver acetate, cobalt acetate, molybdenum acetate, and chromium acetate.

[0028] In some other embodiments, the catalytic reaction is carried out at a temperature of 20-40°C for a time of 12-24 hours.

[0029] Thirdly, the present invention provides the application of the 1,4-dihydropyridine derivative described in the first aspect in feed additives.

[0030] The beneficial effects of this invention are:

[0031] This invention uses non-toxic and inexpensive petroleum coke as a catalyst. The preparation process of this catalyst is simple and efficient, and it can catalyze the synthesis of 1,4-dihydropyridine derivatives without solvents at room temperature or below 40°C. Moreover, the catalytic preparation method is simple, inexpensive, and avoids the use of solvents and environmental pollution. Attached Figure Description

[0032] The accompanying drawings, which form part of this invention, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an improper limitation of the invention.

[0033] Figure 1 The image shows the infrared spectrum of the petroleum coke prepared in Example 1 of this invention.

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

[0035] Figure 3 The above is the 1H NMR spectrum of compound 1 prepared in Example 1 of this invention;

[0036] Figure 4 The hydrogen NMR spectrum of compound 2 prepared in Example 2 of this invention is shown below.

[0037] Figure 5 The above is the 1H NMR spectrum of compound 3 prepared in Example 3 of this invention;

[0038] Figure 6The hydrogen NMR spectrum of compound 4 prepared in Example 4 of this invention is shown below.

[0039] Figure 7 The above is the 1H NMR spectrum of compound 5 prepared in Example 5 of this invention;

[0040] Figure 8 The above is the 1H NMR spectrum of compound 6 prepared in Example 6 of this invention;

[0041] Figure 9 The hydrogen NMR spectrum of compound 7 prepared in Example 7 of this invention is shown below. Detailed Implementation

[0042] 1. Preparation of compounds

[0043] Example 1

[0044] Preparation of Compound 1

[0045] 100 ml of ethylene tar was reacted at 400 °C and 4 MPa for 6 h, and then cooled to obtain 20 g of petroleum coke product. The petroleum coke product was soaked in a 250 ml beaker with 40 ml of 36% hydrochloric acid and stirred at room temperature for 24 h. Then, 100 ml of water was added, and the mixture was filtered under reduced pressure. The resulting 20 g solid was dried and used as the petroleum coke catalyst. 262 ml of ethyl acetoacetate, 137 g of anisaldehyde, and 81 g of ammonium acetate were added to a 500 ml three-necked flask, followed by 20 g of the petroleum coke catalyst. The mixture was stirred at room temperature for 24 h, and after the reaction was complete, a large amount of solid was obtained. The solid was filtered, and the resulting solid product was redissolved in 50 ml of anhydrous ethanol. Filtration was performed to separate the solid, yielding a black petroleum coke catalyst. The remaining filtrate was allowed to crystallize, yielding 301 g of a yellow solid compound, a 1,4-dihydropyridine derivative with a substituent of -Ph-OCH3, labeled as compound 1, with the structure shown in the formula. The yield was 83.5%.

[0046]

[0047] Figure 1 Infrared images of petroleum coke before and after acidification treatment are shown, where PC represents petroleum coke without acidification treatment, and PC-S represents petroleum coke after sulfuric acid treatment. Figure 1 It can be clearly seen that after acidification, petroleum coke exhibits absorption characteristic peaks for S=O bonds and CS bonds, indicating that the acid modification of petroleum coke was successful.

[0048] Figure 2 The scanning electron microscope (SEM) image of the prepared petroleum coke catalyst is shown below. Figure 2As can be seen, (a) is a scanning electron microscope image of petroleum coke before acid treatment. It can be seen from the image that before acid treatment, the petroleum coke has a regular morphological arrangement and is a typical petroleum coke product. (b) is a scanning electron microscope image of petroleum coke after concentrated sulfuric acid treatment. It can be seen from the image that after acid treatment with concentrated sulfuric acid, the surface of the petroleum coke has an irregular blocky structure and a large number of wrinkles and cracks. Due to the strong oxidizing and corrosive properties of concentrated sulfuric acid, it can effectively etch the petroleum coke, causing its morphology to change significantly, thus giving it a special catalytic effect.

[0049] Figure 3 The 1H 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] 200 ml of ethylene tar was reacted at 500 °C and 3 MPa for 5 h, and then cooled to obtain 49 g of petroleum coke product. The petroleum coke product was soaked in a 250 ml beaker with 60 ml of concentrated sulfuric acid and stirred at room temperature for 24 h. Then, 100 ml of water was added, and the mixture was filtered under reduced pressure. The resulting 49.5 g solid was dried and used as the petroleum coke catalyst. 92 ml of ethyl acetoacetate, 43 g of p-fluorobenzaldehyde, and 31 g of ammonium acetate were added to a 500 ml three-necked flask, followed by 10 g of the petroleum coke catalyst. The mixture was stirred at room temperature for 24 h to obtain the product. The product was filtered, and the solid was redissolved in 50 ml of anhydrous ethanol. Filtration yielded a black petroleum coke catalyst. The filtrate was allowed to crystallize, yielding 78 g of a yellow solid compound, a 1,4-dihydropyridine derivative with a -Ph-F substituent, labeled as compound 2, with the structure shown below, at a yield of 63.9%.

[0053]

[0054] Figure 4 Here is the 1H 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] 400 ml of ethylene tar was reacted at 300 °C and 5 MPa for 6 h, and then cooled to obtain 82 g of petroleum coke product. The petroleum coke product was soaked in a 250 ml beaker with 200 ml of concentrated sulfuric acid and stirred at room temperature for 24 h. Then, 200 ml of water was added, and the mixture was filtered under reduced pressure. The resulting 89.5 g solid was dried and used as the petroleum coke catalyst. 200 ml of ethyl acetoacetate, 94 g of p-hydroxybenzaldehyde, and 71 g of ammonium acetate were added to a 500 ml three-necked flask, along with 30 g of the acidified petroleum coke catalyst. The mixture was stirred at room temperature for 24 h to obtain the product. The product was filtered, and the solid was redissolved in 100 ml of anhydrous ethanol. Filtration yielded a black petroleum coke catalyst. The filtrate was allowed to crystallize, yielding 250 g of a yellow solid compound, a 1,4-dihydropyridine derivative with a -Ph-OH substituent, labeled as compound 3, with the structure shown below, in a yield of 95%.

[0058]

[0059] Figure 5 The 1H NMR spectrum of compound 3 is shown below: 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] Unlike Example 1, 262 ml of ethyl acetoacetate, 74.5 g of glyoxylic acid, and 81 g of ammonium acetate were directly added, along with 20 g of petroleum coke catalyst. The rest of the reaction process was exactly the same as in Example 1, and compound 6 was prepared with the structure shown in the formula. The yield was 91.5%.

[0063]

[0064] Figure 6 Here is the 1H 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] Unlike Example 1, 262 ml of ethyl acetoacetate, 137 g of phenylacetaldehyde, and 81 g of ammonium acetate were directly added, and 20 g of petroleum coke catalyst was added to carry out the reaction. The other reaction processes were exactly the same as in Example 1, and compound 5 was prepared with the structure shown in the formula: the yield was 85.6%.

[0068]

[0069] Figure 7 Here is the 1H 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] Unlike Example 1, 262 ml of ethyl acetoacetate, 137 g of acetaldehyde, and 81 g of ammonium acetate were directly added, and 20 g of petroleum coke catalyst was added to carry out the reaction. The other reaction processes were exactly the same as in Example 1, and compound 6 was prepared with the structure shown in the formula: the yield was 92.5%.

[0073]

[0074] Figure 8 The 1H 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] Unlike Example 1, 262 ml of ethyl acetoacetate, 137 g of p-dimethylaminobenzaldehyde and 81 g of ammonium acetate were directly added, and 20 g of petroleum coke catalyst was added to carry out the reaction. The other reaction processes were exactly the same as in Example 1, and compound 7 was prepared with the structure shown in the formula: the yield was 87%.

[0078]

[0079] Figure 9 The 1H 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] Unlike Example 1, no petroleum coke catalyst was added, but the rest of the reaction process was exactly the same as in Example 1, and compound 1 was prepared with a yield of 46.2%.

[0082] Comparative Example 2

[0083] Unlike Example 1, the reaction temperature was set to 80°C, but the rest of the reaction process was exactly the same as in Example 1, and compound 1 was prepared with a yield of 79.5%.

[0084] Comparative Example 3

[0085] Unlike Example 1, the reaction temperature was set to 25°C and the reaction was carried out under ultrasonic radiation conditions (25 kHz, 250 W). The other reaction processes were exactly the same as in Example 1, and compound 1 was prepared with a yield of 70%.

[0086] In Comparative Example 1, without the addition of petroleum coke catalyst, the reaction rate at room temperature is extremely low. This is primarily because the reaction is endothermic, and it is difficult to react at room temperature without external energy supply. In Comparative Example 2, the reaction yield is relatively high because the reaction is endothermic; as the temperature increases, the reaction rate accelerates, 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, thus increasing the reaction rate.

[0087] 2. Examples of the application of compounds

[0088] Dihydropyridine is a novel, multifunctional additive that possesses some of the properties of the natural antioxidant Vitamin E, inhibiting the peroxidation of lipid compounds. Simultaneously, it can alter the levels of certain hormones in serum, promoting growth, development, reproductive performance, and enhancing immune function in livestock and poultry. Furthermore, it is completely metabolized with virtually no residue. In addition, dihydropyridine can significantly enhance small intestinal motility and slow the retrograde movement of chyme in the small intestine, facilitating digestion and absorption, thereby improving feed utilization.

[0089] In this embodiment, by adding different doses of dihydropyridine derivatives to the diet, the effects of these derivatives on the growth and development of Hysex laying hens were investigated and the optimal addition amount was screened. This not only provides a theoretical basis for basic research in poultry production, but also provides guidance and reference for feed formulation of laying hens.

[0090] Five hundred healthy 14-week-old Hydex laying hens of similar weight were selected and divided into a control group and an experimental group (containing eight compounds: the seven compounds synthesized in this invention and the known compound 2,6-dimethyl-3,5-diethyl ester 1,4-dihydropyridine). The control group (20 Hydex laying hens randomly selected as the control group) received a diet without the addition of 1,4-dihydropyridine derivatives. The experimental groups (480 Hydex laying hens randomly divided into eight large groups of 60 hens each, and each large group further divided into three smaller groups of 20 hens each) received supplemental feedings of each compound at 100 mg / kg, 150 mg / kg, and 200 mg / kg, respectively, in their growing diets. The composition and nutrient levels of the growing diets are shown in Table 1 below. The hens were fed twice daily (at 8:00 AM and 4:00 PM) for 30 days.

[0091] Table 1. Nutritional composition and nutritional levels of pullets

[0092]

[0093] Fasting weights were measured 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 weight of pullets. In the Hysex layer hen diet, the initial weight was approximately 630g. The seven compounds prepared above were added to the Hysex layer hen diet at doses of 100mg / kg, 150mg / kg, and 200mg / kg, respectively, and the changes in weight of each group were observed. The Hysex layer hen diet without the addition of dihydropyridine derivatives served as the control group, and the weight of pullets after 30 days was 1275.4g. The Hysex layer hen diets with the addition of 100mg / kg, 150mg / kg, and 200mg / kg of 2,6-dimethyl-3,5-diethyl ester 1,4-dihydropyridine, respectively, resulted in weights of 1285.4g, 1300g, and 1292.5g after 30 days, respectively.

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

[0095] Table 2. Effects of different doses of dihydropyridine added to the diet on the weight gain of pullets after 30 days.

[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 indicate that after adding different doses of dihydropyridine to the diet for 30 days, the body weight of Hydex laying hens in each supplementation group differed significantly from that in the control group. Adding dihydropyridine to the diet can significantly improve the growth rate of Hydex laying hens, with the optimal supplementation level being 150 mg / kg.

[0098] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A process for the preparation of a 1,4-dihydropyridine derivative, characterized in that, The method comprises the following steps: The ethylene tar is prepared into petroleum coke, and the petroleum coke is acidized to obtain a petroleum coke catalyst; the ethyl acetoacetate, the R-CHO and the ammonium acetate are mixed to obtain a mixture; the petroleum coke catalyst is added into the mixture to perform a catalytic reaction, and thus the 1,4-dihydropyridine derivative is obtained; The 1,4-dihydropyridine derivative has a structure of formula I, Formula I wherein R is selected from one of an alkyl group, a carboxyl group, an alkoxyacyl group, an alkylacyl group, an aryl group and a substituted aryl group.

2. The method according to claim 1, wherein the substituted aryl group is selected from an aryl group substituted by one of a halogen, an alkyl group, a carboxyl group, an alkoxyacyl group, an alkylacyl group, a nitrogen group, an alkyl-substituted nitrogen group, an oxygen group and a nitro group; the halogen is selected from F, Cl, Br and I; and R is selected from one of -Ph-F, -Ph-NO2, -Ph-OH, -CH3, -Ph-N(CH3)2, -COOH, Ph-CH2-CH2- and Ph-O-. The preparation conditions of the petroleum coke are as follows: the reaction temperature is 300-500 DEG C, the reaction pressure is 3-6 MPa, and the reaction time is 2-7 h. The acid used in the acidizing treatment of the petroleum coke is one or more of sulfuric acid, hydrochloric acid, nitric acid and phosphoric acid, and the mass ratio of the acid to the petroleum coke is (5-50):1, and the time is 10-24 h. said alkyl is selected from the group consisting of -CH3and -(CH2) n -CH3, n is any integer from 1 to 5; said alkoxyacyl is selected from the group consisting of -COOCH3and -COO(CH2) n -CH3, n is any integer from 1 to 5; said alkyl acyl is selected from the group consisting of -COCH3and -CO(CH2) n -CH3, n is any integer from 1 to 5; said alkyl substituted nitrogen group is selected from the group consisting of -NH-CH3, -N-(CH3)2, -NH(CH2) n -CH3, n is any integer from 1 to 5.

3. The method of claim 1 for the preparation of 1,4-dihydropyridine derivatives, characterized by, The molar ratio of the ethyl acetoacetate, the aldehyde compound and the ammonium acetate is 1:(1-2):(1-5).

4. The method of claim 1 for the preparation of 1,4-dihydropyridine derivatives, characterized by, The molar ratio of the petroleum coke catalyst to the mixture is 1:(10-100).

5. The method for preparing the 1,4-dihydropyridine derivative according to claim 1, characterized in that, The R-CHO is selected from one of acetaldehyde, phenylacetaldehyde, p-hydroxybenzaldehyde, p-aminobenzaldehyde, p-sulfonic acid benzaldehyde, anisaldehyde, p-hydroxyphenylacetaldehyde, p-aminophenylacetaldehyde, p-sulfonic acid phenylacetaldehyde, propyl aldehyde, p-hydroxyphenylpropyl aldehyde, p-aminophenylpropyl aldehyde, p-sulfonic acid phenylpropyl aldehyde, p-fluorobenzaldehyde, p-chlorobenzaldehyde, p-bromobenzaldehyde, p-fluorophenylacetaldehyde, p-dimethylaminobenzaldehyde, glyoxylic acid, p-chlorophenylacetaldehyde and p-bromophenylacetaldehyde.

6. The method for preparing the 1,4-dihydropyridine derivative according to claim 1, characterized in that, The temperature of the catalytic reaction is 20-40 DEG C, and the time is 12-24 h. ​ 7. The method for preparing the 1,4-dihydropyridine derivative according to claim 1, characterized in that, ​ 8. The method of claim 1 for the preparation of 1,4-dihydropyridine derivatives, characterized by, ​

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