4-Alkyl-1,4-dihydropyridine compound and preparation method and application thereof

Abstract

The invention discloses a 4-alkyl-1,4-dihydropyridine compound and a preparation method thereof. The method comprises the following steps: using an N-substituted enaminone compound or an N-substituted enaminone compound and an anhydride compound as raw materials, and using an ether compound as a solvent. The method comprises the following steps: reacting in a nitrogen atmosphere at 60 to 120° C. in the presence of a catalyst, an auxiliary agent and an oxidant. After the reaction is complete, extracting the reaction product with ethyl acetate, collecting and combining organic phases, drying with anhydrous sodium sulfate, and then concentrating under reduced pressure. The concentrate is separated and purified by silica gel column chromatography to obtain the 4-alkyl-1,4-dihydropyridine compound. The method has the characteristics of mild reaction conditions, convenient operation, short synthesis route, novel synthesis method and the like, and high yield. Preliminary exploration of the inhibitory activity of PDE 4 confirms that the compound has application value in anti-inflammatory aspects.

Description

Technical Field

[0001] The invention belongs to the technical field of compound synthesis, and specifically relates to a 4-alkyl-1,4-dihydropyridine derivative and a synthesis method thereof and an application thereof as a PED4 inhibitor. Background Art

[0002] Phosphodiesterases (PDEs) have the function of degrading intracellular second messengers such as cyclic adenosine monophosphate (cAMP) or cyclic guanosine monophosphate (cGMP), thereby terminating the biochemical effects transduced by these second messengers. PDEs are a large multi-gene family, including 11 types and more than 30 types, with different substrate specificity, enzyme kinetic characteristics, regulatory characteristics and other functions. As a new therapeutic target, PDEs have attracted widespread attention from many scholars and have become a research hotspot. Among them, PDE4 is related to the hydrolysis of cAMP in a variety of inflammatory cells. Therefore, the use of selective PDE4 inhibitors can effectively inhibit immune and inflammatory cells, and has certain effects on cAMP-mediated airway smooth muscle relaxation, and has certain effects on respiratory diseases such as asthma. Therefore, the clinical research of selective PDE4 inhibitors has received special attention.

[0003] 1,4-Dihydropyridine compounds are an important class of six-membered nitrogen heterocyclic compounds, which have been widely used to treat cardiovascular diseases, toxic hepatitis, fatty liver and other diseases. The traditional synthesis method of 1,4-dihydropyridine compounds is mainly achieved by the Hantzsch reaction, which is a three-component condensation reaction of 1,3-dicarbonyl compounds, aldehydes and ammonia water or ammonium salts. However, this synthesis strategy has defects such as the use of concentrated ammonia water and insufficient structural diversity (Lu Lingling, Xu Hui, Zhou Pan, Yu Fuchao. Organic Chemistry, 2016, 36, 2858.). In recent years, some new methods for synthesizing 1,4-dihydropyridine have been developed. For example, in 2013, Wan et al. used TMSCl to catalyze the reaction. Through a "byproduct-intermediate-product" cycle strategy, the reaction was fully utilized to the maximum extent, the atom economy was enhanced, and the structurally symmetrical 1,4-DHPs were synthesized with high yields. However, the reaction is not applicable to aliphatic amine compounds, and the post-treatment is relatively complicated (Wan, J.-P.; Zhou, R.; Liu, Y.; Cai, M. RSC Adv. 2013, 3, 2477.); in 2014, Banafsheh Yazdanparast et al. reported that under solvent-free conditions, aldehydes, benzyl acetoacetate and a catalytic amount of iron (III) phosphate were used to efficiently prepare new 1,4-dihydropyridine compounds through the Hantzsch reaction with good yields. (FKBehbahani, B. Yazdanparast. Arab. J. Chem. 2019.12, 1353–1357.). However, among the many strategies for constructing 1,4-dihydropyridine compounds, whether it is the traditional Hantzsch reaction or the newly developed synthetic method, the 4-carbon of 1,4-dihydropyridine is achieved through chemically highly active carbonyl compounds, while methods achieved through other substrates are rarely reported.

[0004] On the other hand, ether compounds are widely present in nature and are often used as solvents in organic synthesis (such as tetrahydrofuran and dioxane). 3 )-H bond functionalization has been extensively studied, and the α-C(sp 3 )-H bond is more inert, and its α-C(sp 3 )-H bonds are stable and difficult to activate. Currently, most studies focus on ether α-C(sp 3 )-H bond functionalization. Considering that ether compounds are widely present in physiologically active drugs and natural products, and are cheap and easily available, it is of great significance to achieve efficient conversion of ethers by carbon-hydrogen bond functionalization. There are few studies on the construction of heterocyclic products by further introducing tandem cyclization reactions of ether CO bond severance. In-depth research on ether functionalization / cyclization reactions is of great significance to organic chemistry and drug synthesis, and also has very great industrial prospects.

[0005] In summary, 1,4-dihydropyridine compounds have been widely used in the pharmaceutical field, and the synthesis methods are very mature. However, the traditional Hantzsch reaction and some new synthesis methods still have problems such as cumbersome operation, pre-preparation of starting materials, and limited substrates. In particular, the 4-carbon construction strategy of 1,4-dihydropyridine is still limited to the use of carbonyl compounds. Summary of the invention

[0006] The present invention provides a class of 4-alkyl-1,4-dihydropyridine compounds, the structural formula of which is selected from the following formula:

[0007]

[0008] Formula I, wherein R 1 is selected from aryl, heterocyclic, alkyl; R 2 is selected from aryl, heterocycle, alkyl; n is selected from 1, 2;

[0009]

[0010] Formula II, wherein R 1 is selected from aryl, heterocyclic, alkyl; R 2 is selected from aryl, heterocyclic, alkyl; R 3 is selected from aryl and alkyl, and n is selected from 1 and 2.

[0011] Another object of the present invention is to provide a method for preparing the above-mentioned 4-alkyl-1,4-dihydropyridine compound, in which the ether compound is both a reaction solvent and a 4-carbon source of 1,4-dihydropyridine, by effectively cutting off OC(sp 3 ) key and C(sp 3 )-H bond, and efficiently synthesize 4-alkyl-1,4-dihydropyridine derivatives. The compound of formula I is prepared as follows:

[0012] Adding N-substituted enaminone compound 1 into a reactor, using ether compound 2 as solvent, reacting in nitrogen atmosphere at 60-120° C. in the presence of a catalyst, an auxiliary agent and an oxidant, monitoring the reaction progress by thin layer chromatography until the reaction is complete, extracting the reaction product with ethyl acetate 2-3 times, collecting and combining the organic phases, drying with anhydrous sodium sulfate, and then concentrating under reduced pressure, and separating and purifying the concentrate by silica gel column chromatography to obtain the target compound 4-alkyl-1,4-dihydropyridine compound 3;

[0013] Where R 1 is selected from aryl, heterocyclic, alkyl; R 2 is selected from aryl, heterocycle, and alkyl; n is selected from 1 and 2.

[0014] The compound of formula II is prepared as follows:

[0015] Add N-substituted enaminone compound 1 and acid anhydride compound 4 into a reactor, use ether compound 2 as solvent, react in nitrogen atmosphere at 60-120° C. in the presence of a catalyst, an auxiliary agent and an oxidant, monitor the reaction progress by thin layer chromatography until the reaction is complete, extract the reaction product with ethyl acetate 2-3 times, collect and combine the organic phases, dry them with anhydrous sodium sulfate, and then concentrate under reduced pressure. The concentrate is separated and purified by silica gel column chromatography to obtain the target compound 4-alkyl-1,4-dihydropyridine compound 5;

[0016]

[0017] Where R 1 is selected from aryl, heterocyclic, alkyl; R 2 is selected from aryl, heterocyclic, alkyl; R 3 is selected from aryl and alkyl; n is selected from 1 and 2.

[0018] The catalyst is ferrous chloride, ferric chloride, ferrous sulfate, palladium chloride, acetyl chloride, cobalt chloride, chromium chloride or nickel chloride hexahydrate, and the molar ratio of the N-substituted enaminoketone compound 1 to the catalyst is 1:0.1-5.

[0019] The oxidant is di-tert-butyl peroxide (DTBP), di-tert-butyl peroxide diisopropylbenzene, tert-butyl perbenzoate, tert-butyl hydroperoxide, hydrogen peroxide, dibenzoyl peroxide, cumene hydroperoxide, m-chloroperbenzoic acid or potassium persulfate, and the molar ratio of the N-substituted enaminone compound 1 to the oxidant is 1:0.5-4.

[0020] The auxiliary agent is tetrafluoroboric acid, perchloric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid or sulfuric acid, and the molar ratio of the N-substituted enaminone compound 1 to the auxiliary agent is 1:0.1-6.

[0021] The ether compound is tetrahydrofuran, tetrahydrothiophene, hydropyran or oxepane.

[0022] Another object of the present invention is to use the above 4-alkyl-1,4-dihydropyridine derivatives in the preparation of PDE4 inhibitors.

[0023] Compared with the prior art, the present invention has the following advantages:

[0024] 1. The present invention uses widely existing, cheap and easily available ether compounds as the 4-carbon source for constructing the 1,4-dihydropyridine ring. It is the first time that non-carbonyl compounds are introduced into the construction of the 1,4-dihydropyridine ring, which is not only conducive to the development of new 1,4-dihydropyridine compounds, but also helps to provide new ideas for the development of new strategies for 1,4-dihydropyridine;

[0025] 2. The present invention provides two methods for preparing 4-alkyl-1,4-dihydropyridine derivatives, which are beneficial to the structural diversity synthesis of 4-alkyl-1,4-dihydropyridine derivatives;

[0026] 3. The 4-alkyl-1,4-dihydropyridine compounds of the present invention have PDE 4 inhibitory effects and have the potential to be developed into anti-inflammatory drugs;

[0027] The synthesis method of the invention has the characteristics of simplicity, high efficiency, simple operation, environmental friendliness, high yield, etc., and is conducive to industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 This is the single crystal structure diagram of compound 3a. DETAILED DESCRIPTION

[0029] The present invention is further described in detail below through examples, but the protection scope of the present invention is not limited to the above contents. Unless otherwise specified, the reagents in the examples are conventional commercially available reagents or reagents prepared by conventional methods; the product structures in the following examples are confirmed by nuclear magnetic resonance, high-resolution mass spectrometry and single crystal diffraction tests of representative products;

[0030] Embodiment 1:

[0031] In a nitrogen atmosphere at 80°C, N-substituted enaminones 1a (0.5 mmol), di-tert-butyl peroxide (DTBP, 0.5 mmol), ferrous chloride (0.4 mmol), and HBF4 (0.5 mmol) were added to a thick-walled reaction tube, and 3 mL of tetrahydrofuran (THF) 2a was added. The mixture was reacted under magnetic stirring, and the reaction was monitored by TLC until the N-substituted enaminones were completely reacted. The reaction mixture was cooled to room temperature, saturated sodium bicarbonate solution was added, and ethyl acetate was extracted three times. The upper organic solvent was collected and combined, and anhydrous sodium sulfate was added to dry the organic layer. The dried organic layer was concentrated, and the concentrate was finally separated by silica gel column chromatography. The solvent used for column chromatography separation was a mixed solvent of petroleum ether and ethyl acetate (volume ratio of 5:1) to obtain the target compound 4-alkyl-1,4-dihydropyridine compound 3a. The reaction formula is as follows:

[0032]

[0033] The morphology, melting point, NMR, and high-resolution mass spectrometry data of the product 3a obtained in Example 1 are as follows:

[0034] V 石油醚 / V 乙酸乙酯 =5:1,R f =0.2, yellow solid: 85 mg, yield: 81%, melting point = 160–162 °C; 1H NMR (600MHz, CDCl3): δ=7.67–7.65(m,4H,ArH),7.53–7.50(m,2H,ArH),7.46–7.44(m,4H,ArH),7.38–7.36(m,2H,ArH),7.25(s,2H,C=CH ),7.08–7.07(m,2H,ArH),4.66(t,J=5.3Hz,1H,C–CH),3.72(t,J=6.4Hz,2H,OCH2),1.76–1.72(m,2H,C–CH2),1.68–1.63(m,2H,C–CH2); 13 C NMR (150MHz, CDCl3): δ=194.9,194.9,143.3,141.4,141.4,139.3,139.3,131.8,131.8,130.5,130.5,129.0,129. 0,129.0,129.0,128.9,128.9,128.9,128.9,127.1,121.5,121.5,119.2,119.2,61.5,32.3,30.2,28.8; HRMS(TOF ES+):m / z calcd forC 28 H 25 NO3[(M+H) + ],424.1907,found,424.1906. The single crystal structure of compound 3a is shown in Figure 1 .

[0035] Example 2: The preparation process of this example is the same as that of Example 1, except that the N-substituted enaminoketone compound 1a is 3-(phenylamino)-1-(4-methoxyphenyl)-2-propen-1-one;

[0036] The structure, morphology, melting point, NMR and high-resolution mass spectrometry data of 3b prepared in this example are as follows:

[0037]

[0038] V 石油醚 / V 乙酸乙酯 =5:1,R f =0.15, yellow solid: 92.9 mg, yield: 77%, melting point = 137–139 °C; 1HNMR (600MHz, DMSO–d6): δ=7.71–7.69(m,4H,ArH),7.41–7.40(m,2H,ArH),7.34–7.33(m,2H,ArH),7.27–7.26(m,3H,ArH+C=CH),7.05–7.03(m,4H ArH),4.42–4.39(m,2H,C–CH2),3.82(s,6H,OCH3),3.35–3.34(m,1H,C–CH),1.51–1.46(m,4H,C–CH2); 13 C NMR (150MHz, DMSO–d6): δ=193.9,193.9,162.3,162.3,143.4,140.0,140.0,131.6,131.6,131.2,131.2,131.2,131.2,13 0.5,130.5,130.5,130.5,126.8,121.3,121.3,119.2,119.2,114.3,114.3,61.5,55.8,55.8,32.6,31.0,28.9; HRMS(TOF ES+):m / z calcd for C 30 H 29 NO5[(M+H) + ],484.2118,found,484.2120.

[0039] Example 3: The preparation process of this example is the same as that of Example 1, except that the N-substituted enaminoketone compound 1a is 3-(phenylamino)-1-(4-ethylphenyl)-2-propen-1-one;

[0040] The structure, morphology, melting point, NMR and high-resolution mass spectrometry data of the obtained product 3c are as follows:

[0041]

[0042] V 石油醚 / V 乙酸乙酯 =5:1,R f =0.1, yellow solid: 99 mg, yield: 83%, melting point = 169–171 °C; 1H NMR (600MHz, DMSO–d6): δ = 7.62 (d, J = 7.8Hz, 4H, ArH), 7.41 (t, J = 7.8Hz, 2H, ArH), 7.34–7.31 (m, 6H, ArH), 7.28–7.26 (m, 1H, ArH), 7.25 (s, 2H, C = CH),4.42(q,J=4.9Hz,2H,C–CH2),3.37–3.35(m,1H,C–CH),2.66(q,J=7.6Hz,4H,ArCH2),1.53–1.45(m,4H,C–CH2),1.19(t,J=7.7Hz,6H,CH3); 13 C NMR (150MHz, DMSO–d6): δ=194.6,194.6,148.0,148.0,143.3,140.8,140.8,136.7,136.7,130.5,130.5,129.2,129.2,129.2,1 29.2,128.4,128.4,128.4,128.4,127.0,121.6,121.6,119.1,119.1,61.5,32.5,30.5,28.9,28.5,28.5,15.7,15.7; HRMS (TOF ES+):m / zcalcd for C 32 H 33 NO3[(M+H) + ],480.2533,found,480.2534.

[0043] Example 4: The preparation process of this example is the same as that of Example 1, except that the N-substituted enaminoketone compound 1a is 3-(phenylamino)-1-(4-fluorophenyl)-2-propen-1-one;

[0044] The structure, morphology, melting point, NMR and high-resolution mass spectrometry data of the obtained product 3d are as follows:

[0045]

[0046] V 石油醚 / V 乙酸乙酯 =5:1,R f =0.1, yellow solid: 85 mg, yield: 74%, melting point = 177–179 °C; 1H NMR (600MHz, DMSO–d6): δ=7.78–7.75(m,4H,ArH),7.41(t,J=7.9Hz,2H,ArH),7.36–7.31(m,7H,ArH ),7.27(s,2H,C=CH),4.41–4.39(m,2H,C–CH2),3.37–3.35(m,1H,C–CH),1.53–1.45(m,4H,C–CH2); 13 C NMR (150MHz, DMSO–d6): δ = 193.6, 193.6, 164.3 (J C–F =248.9Hz),164.3(J C–F =248.9Hz),143.2,141.3,135.8(J C–F =2.9Hz),135.8(J C–F =2.9Hz),131.6(J C–F =8.9Hz),131.6(J C–F =8.9Hz),131.6(J C–F =8.9Hz),131.6(J C–F =8.9Hz),130.4,130.4,130.4,130.4,127.0,121.5,121.5,119.0,116.0(J C–F =21.7Hz),116.0(J C–F =21.7Hz),116.0(J C–F =21.7Hz),116.0(J C–F =21.7Hz),61.4,32.4,30.4,28.8; HRMS(TOF ES+):m / zcalcd for C 28 H 23 F2NO3[(M+Na) + ],482.1538,found,482.1536.

[0047] Example 5: The preparation process of this example is the same as that of Example 1, except that the N-substituted enaminoketone compound 1a is 3-(phenylamino)-1-(4-chlorophenyl)-2-propen-1-one;

[0048] The structure, morphology, melting point, NMR and high-resolution mass spectrometry data of the obtained product 3e are as follows:

[0049]

[0050] V 石油醚 / V 乙酸乙酯 =5:1,Rf =0.1, yellow solid: 96.9 mg, yield: 79%, melting point = 194–196 °C; 1 HNMR (600MHz, DMSO–d6): δ = 7.61 (d, J = 8.3Hz, 4H, ArH), 7.43–7.37 (m, 6H, ArH), 7.30 (d, J = 7.5Hz, 1H, ArH), 7.20 (s, 2H, C = CH), 7.08 ( d,J=7.9Hz,2H,ArH),4.61(t,J=5.4Hz,1H,C–CH),3.70(t,J=6.4Hz,2H,C–CH2),1.73–1.69(m,2H,C–CH2),1.65–1.60(m,2H,C–CH2); 13 CNMR (150MHz, DMSO–d6): δ = 194.4, 194.4, 142.4, 140.3, 140.3, 137.1, 137.1, 137.0, 137.0, 129.8, 129.8, 129.5, 12 9.5,129.5,129.5,128.4,128.4,128.4,128.4,126.7,120.6,120.6,119.7,119.7,62.1,32.1,29.4,28.1; HRMS(TOF ES+):m / z calcd for C 28 H 23 Cl2NO3[(M+H) + ],492.1128,found,492.1130.

[0051] Example 6: The preparation process of this example is the same as that of Example 1, except that the N-substituted enaminoketone compound 1a is 3-(phenylamino)-1-(2-bromophenyl)-2-propen-1-one;

[0052] The structure, morphology, melting point, NMR and high-resolution mass spectrometry data of the obtained product 3f are as follows:

[0053]

[0054] V 石油醚 / V 乙酸乙酯 =5:1,R f =0.2, yellow solid: 107 mg, yield: 74%, melting point = 95–97 °C; 1H NMR (600MHz, CDCl3): δ=7.61–7.60(m,2H,ArH),7.39–7.34(m,4H,ArH),7.32–7.29(m,4H,ArH),7.25(d,J=7.5Hz,1H,ArH),7.01–6.99(m,2 H,ArH),6.96(s,2H,C=CH),4.62(t,J=4.6Hz,1H,C–CH),3.76(t,J=6.4Hz,2H,C–CH2),1.85–1.81(m,2H,C–CH2),1.79–1.75(m,2H,C–CH2); 13 C NMR (150MHz, CDCl3): δ=193.6,193.6,142.8,142.8,142.7,140.6,140.6,133.3,133.3,130.8,130.8,130.2,130. 2,128.8,128.8,127.4,127.4,127.3,121.3,121.3,120.4,120.4,119.5,119.5,62.8,31.4,28.7,28.3; HRMS(TOF ES+):m / z calcd forC 28 H 24 Br2NO3[(M+H) + ],580.0177,found,580.0117.

[0055] Example 7: The preparation process of this example is the same as that of Example 1, except that the N-substituted enaminoketone compound 1a is 3-(phenylamino)-1-(4-nitrophenyl)-2-propen-1-one;

[0056] The structure, morphology, melting point, NMR and high-resolution mass spectrometry data of the obtained product 3g are as follows:

[0057]

[0058] V 石油醚 / V 乙酸乙酯 =4:1,R f =0.15, yellow solid: 105 mg, yield: 82%, melting point = 163–165 °C; 1HNMR (600MHz, DMSO–d6): δ = 7.67 (d, J = 7.2Hz, 4H, ArH), 7.56 (t, J = 7.4Hz, 2H, ArH), 7.50 (q, J = 7.3Hz, 4H, ArH), 7.41–7.37 (m, 2H ,ArH),7.30–7.29(m,1H,ArH),7.24(s,2H,C=CH),4.46–4.41(m,2H,C–CH2),3.38–3.36(m,1H,C–CH),1.55–1.49(m,4H,C–CH2); 13 C NMR (150MHz, DMSO–d6): δ=194.9,194.9,143.3,141.4,141.4,139.3,139.3,131.8,131.8,130.5,130.5,129.0,129 .0,129.0,129.0,129.0,129.0,129.0,129.0,127.1,121.5,121.5,119.2,119.2,61.5,33.3,30.2,28.8; HRMS(TOF ES+):m / z calcd for C 28 H 23 N3O7[(M+H) + ],514.1609,found,514.1606.

[0059] Example 8: The preparation process of this example is the same as that of Example 1, except that the N-substituted enaminoketone compound 1a is 3-(phenylamino)-1-(4-methylsulfonylphenyl)-2-propen-1-one;

[0060] The structure, morphology, melting point, NMR and high-resolution mass spectrometry data of the obtained product 3h are as follows:

[0061]

[0062] V 石油醚 / V 乙酸乙酯 =8:1,R f =0.1, yellow solid: 123.1 mg, yield: 85%, melting point = 181–183 °C; 1HNMR (600MHz, DMSO–d6): δ = 8.04 (d, J = 8.0Hz, 4H, ArH), 7.92 (d, J = 8.0Hz, 4H, ArH), 7.43–7.38 (m, 4H, ArH), 7.32 (s, 2H, C = CH), 7. 29(t,J=7.2Hz,1H,ArH),4.43(t,J=5.1Hz,2H,C–CH2),3.28(s,6H,S–CH3),1.58–1.54(m,2H,C–CH2),1.52–1.46(m,2H,C–CH2); 13 C NMR (150MHz, DMSO–d6): δ=193.6,193.6,143.7,143.7,143.1,143.1,142.6,130.4,130.4,130.4,130.4,129.7,129.7,12 9.7,129.7,127.7,127.7,127.7,127.7,127.4,122.0,122.0,119.0,119.0,61.4,43.8,43.8,32.3,30.0,28.7; HRMS (TOF ES+):m / z calcd forC 30 H 29 NO7S2[(M+H) + ],580.1458,found,580.1459.

[0063] Example 9: The preparation process of this example is the same as that of Example 1, except that the N-substituted enaminoketone compound 1a is 3-(phenylamino)-1-(4-biphenyl)-2-propen-1-one;

[0064] The structure, morphology, melting point, NMR and high-resolution mass spectrometry data of the obtained product 3i are as follows:

[0065]

[0066] V 石油醚 / V 乙酸乙酯 =8:1,R f =0.1, yellow solid: 81.9 mg, yield: 57%, melting point = 231–233 °C; 1HNMR (600MHz, CDCl3): δ = 7.77–7.76 (m, 4H, ArH), 7.68 (d, J = 8.0Hz, 4H, ArH), 7.64–7.6 2(m,4H,ArH),7.48(t,J=7.6Hz,4H,ArH),7.39(q,J=8.6,8.2Hz,4H,ArH),7.33(s,2H, C=CH),7.25(d,J=7.7Hz,1H,ArH),7.13(d,J=8.3Hz,2H,ArH),4.71(t,J=5.3Hz,1H,C– CH),3.75(t,J=6.4Hz,2H,C–CH2),1.80–1.76(m,2H,C–CH2),1.72–1.67(m,2H,C–CH2); 13 C NMR (150MHz, CDCl3): δ=194.5,194.5,143.8,143.8,142.7,140.3,140.3,139. 7,139.7,137.5,137.5,129.8,129.8,128.9,128.9,128.9,128.9,128.6,128. 6,128.6,128.6,127.7,127.7,126.9,126.9,126.9,126.9,126.8,126.8,126. 8,126.8,126.5,120.7,120.7,120.0,120.0,62.2,32.3,29.6,28.3; HRMS(TOF ES+):m / z calcd for C 40 H 33 NO3[(M+H) + ],576.2533,found,576.2534.

[0067] Example 10: The preparation process of this example is the same as that of Example 1, except that the N-substituted enaminoketone compound 1a is 3-(phenylamino)-1-(2-naphthyl)-2-propen-1-one;

[0068] The structure, morphology, melting point, NMR and high-resolution mass spectrometry data of the obtained product 3j are as follows:

[0069]

[0070] V 石油醚 / V 乙酸乙酯 =5:1,R f =0.15, yellow solid: 118 mg, yield: 90%, melting point = 193–195 °C; 1HNMR (600MHz, DMSO–d6): δ = 8.36 (s, 2H, ArH), 8.16 (d, J = 8.0Hz, 2H, ArH), 8.06 (d, J = 8.5H z,2H,ArH),8.02(d,J=8.0Hz,2H,ArH),7.80(d,J=8.4Hz,2H,ArH),7.66–7.61(m,4H,ArH ),7.43(s,2H,C=CH),7.36–7.35(m,4H,ArH),7.23–7.21(m,1H,ArH),4.58(d,J=5.7Hz,1 H,C–CH),4.51–4.49(m,1H,C–CH2),1.69–1.66(m,2H,C–CH2),1.64–1.59(m,2H,C–CH2); 13 C NMR (150MHz, DMSO–d6): δ=194.9,194.9,143.2,141.6,141.6,136.6,136.6,134.6,134.6,132.6,132.6,130.4,130.4,129.6,129.6,129.3,129 .3,128.7,128.7,128.3,128.3,128.1,128.1,127.3,127.3,127.0,125 .8,125.8,121.4,121.4,119.5,119.5,61.6,32.7,30.4,29.0; HRMS(TOF ES+):m / zcalcd for C 36 H 30 NO3[(M+H) + ],524.2220,found,524.2219.

[0071] Example 11: The preparation process of this example is the same as that of Example 1, except that the N-substituted enaminoketone compound 1a is 3-(phenylamino)-1-(benzo[d]dioxole)-2-propen-1-one;

[0072] The structure, morphology, melting point, NMR and high-resolution mass spectrometry data of the obtained product 3k are as follows:

[0073]

[0074] V 石油醚 / V 乙酸乙酯 =5:1,R f =0.2, yellow solid: 105 mg, yield: 82%, melting point = 150–152 °C; 1HNMR (600MHz, DMSO–d6): δ = 7.44 (t, J = 7.7Hz, 2H, ArH), 7.37 (d, J = 7.9Hz, 2H, ArH), 7.31–7.28 (m, 5H, ArH), 7.23 (s, 2H, C = CH), 7.02 (d, J = 8.0Hz,2H,ArH),6.13(s,2H,OCH2),6.12(s,2H,OCH2),4.40–4.39(m,1H,C–CH),3.36(d,J=5.8Hz,2H,C–CH2),1.51–1.44(m,4H,C–CH2); 13 C NMR (150MHz, DMSO–d6): δ=193.4,193.4,150.6,150.6,148.0,148.0,143.3,140.3,140.3,133.4,133.4,130.4,130.4,126 .9,124.6,124.6,121.4,121.4,119.0,119.0,108.9,108.9,108.4,108.4,102.2,102.2,61.5,32.6,30.9,28.9; HRMS (TOF ES+):m / z calcd for C 30 H 26 NO7[(M+H) + ],512.1704,found,512.1704.

[0075] Example 12: The preparation process of this example is the same as that of Example 1, except that the N-substituted enaminoketone compound 1a is 3-(phenylamino)-1-phenylvinyl-2-propen-1-one;

[0076] The structure, morphology, melting point, NMR and high-resolution mass spectrometry data of the obtained product 3l are as follows:

[0077]

[0078] V 石油醚 / V 乙酸乙酯 =5:1,R f =0.1, yellow solid: 82 mg, yield: 69%, melting point = 127–129 °C; 1H NMR (600MHz, CDCl3): δ = 7.75 (s, 1H, C = CH), 7.72 (s, 1H, C = CH), 7.67 (s, 2H, C = CH),7.60–7.59(m,4H,ArH),7.54–7.51(m,4H,ArH),7.40–7.35(m,9H,ArH+C= CH),7.27(s,1H,C=CH),7.24(s,1H,C=CH),4.58(t,J=5.1Hz,1H,C–CH),3.70 (t,J=6.5Hz,2H,C–CH2),1.65–1.61(m,2H,C–CH2),1.59–1.54(m,2H,C–CH2); 13 C NMR (150MHz, CDCl3): δ=187.7,187.7,143.4,142.6,142.6,137.6,137.6,135.1,135.1,130.2,130.2,130.2,130.2,128.9,128. 9,128.9,128.9,128.3,128.3,128.3,128.3,127.3,121.8,121.8,121.5,121.5,120.8,120.8,62.8,33.1,29.2,28.1; HRMS (TOF ES+):m / z calcd for C 32 H 30 NO3[(M+H) + ],476.2220,found,476.2218.

[0079] Example 13: The preparation process of this example is the same as that of Example 1, except that the N-substituted enaminoketone compound 1a is 3-(phenylamino)-1-(2-furyl)-2-propen-1-one;

[0080] The structure, morphology, melting point, NMR and high-resolution mass spectrometry data of the obtained product 3m are as follows:

[0081]

[0082] V 石油醚 / V 乙酸乙酯 =5:1,R f =0.1, yellow solid: 81.6 mg, yield: 81%, melting point = 171–173 °C; 1HNMR (600MHz, CDCl3): δ = 8.05 (s, 2H, C = CH), 7.58 (s, 2H, C = CH), 7.52–7.49 (m, 2H, ArH), 7.37–7.36 (m, 1H, ArH), 7.27 (s, 2H, C = CH), 7.21 (d, J = 3.5Hz ,2H,C=CH),6.55–6.54(m,2H,ArH),4.60(t,J=5.2Hz,1H,C–CH),3.67(t,J=6.4Hz,2H,C–CH2),1.66–1.63(m,2H,C–CH2),1.60–1.56(m,2H,C–CH2); 13 C NMR (150MHz, CDCl3): δ=179.8,179.8,153.3,153.3,145.3,145.3,143.5,139.5,139.5,130.2,130. 2,126.9,121.3,121.3,119.2,119.2,117.5,117.5,112.0,112.0,62.6,32.7,29.3,28.3; HRMS(TOF ES+):m / z calcd forC 24 H 21 NO5[(M+H) + ],404.1492,found,404.1493.

[0083] Example 14: The preparation process of this example is the same as that of Example 1, except that the N-substituted enaminoketone compound 1a is 3-(phenylamino)-1-cyclopropyl-2-propen-1-one;

[0084] The structure, morphology, melting point, NMR and high-resolution mass spectrometry data of the obtained product 3n are as follows:

[0085]

[0086] V 石油醚 / V 乙酸乙酯 =10:1,R f =0.15, yellow solid: 50 mg, yield: 57%, melting point = 136–138 °C; 1HNMR (600MHz, CDCl3): δ = 7.66 (s, 2H, C = CH), 7.48 (t, J = 7.9Hz, 2H, ArH), 7.35–7.32 (m, 3H, ArH), 4.33 (d, J = 4.3Hz, 1H, C–CH), 3.67–3.65 (m, 2H, C–CH2),2.04(d,J=19.6Hz,2H,C–CH),1.50–1.49(m,4H,C–CH2),1.14–1.11(m,2H,C–CH2),1.08–1.06(m,2H,C–CH2),0.90–0.84(m,4H,C–CH2); 13 C NMR (150MHz, CDCl3): δ=198.0,198.0,143.5,137.0,137.0,130.1,130.1,126.8,126.8,1 21.4,121.4,120.8,62.7,33.2,28.9,28.0,15.9,15.9,10.7,10.7,10.6,10.6; HRMS(TOF ES+):m / z calcd for C 22 H 25 NO3[(M+H) + ],352.1907,found,352.1909.

[0087] Example 15: The preparation process of this example is the same as that of Example 1, except that the N-substituted enaminoketone compound 1a is 3-(4-methoxyphenylamino)-1-phenyl-2-propen-1-one;

[0088] The structure, morphology, melting point, NMR and high-resolution mass spectrometry data of the obtained product 3o are as follows:

[0089]

[0090] V 石油醚 / V 乙酸乙酯 =5:1,R f =0.1, yellow solid: 93 mg, yield: 82%, melting point = 190–192 °C; 1H NMR (600MHz, CDCl3): δ = 7.64 (d, J = 7.5Hz, 4H, ArH), 7.50 (t, J = 7.4Hz, 2H, ArH) ,7.44(d,J=7.5Hz,4H,ArH),7.14(s,2H,C=CH),7.02(d,J=8.8Hz,2H,ArH),6.8 7(d,J=8.9Hz,1H,ArH),4.65(t,J=5.2Hz,1H,C–CH),3.78(s,3H,ArOCH3),3.7 2(t,J=6.4Hz,2H,C–CH2),1.75–1.71(m,2H,C–CH2),1.68–1.65(m,2H,C–CH2); 13 C NMR (150MHz, CDCl3): δ=195.2,195.2,158.5,141.6,141.6,139.2,139.2,136.4,131.2,131.2,128.6,128.6,128.6, 128.6,128.5,128.5,128.5,128.5,123.1,123.1,119.7,119.7,115.1,115.1,62.6,55.6,32.7,29.5,28.6; HRMS(TOF ES+):m / z calcd for C 29 H 28 NO4[(M+H) + ],454.2013,found,454.2013.

[0091] Example 16: The preparation process of this example is the same as that of Example 1, except that the N-substituted enaminoketone compound 1a is 3-(4-chlorophenylamino)-1-phenyl-2-propene-1-one;

[0092] The structure, morphology, melting point, NMR and high-resolution mass spectrometry data of the obtained product 3p are as follows:

[0093]

[0094] V 石油醚 / V 乙酸乙酯 =5:1,R f =0.15, yellow solid: 85 mg, yield: 79%, melting point = 207–209 °C; 1HNMR (600MHz, CDCl3): δ=7.66–7.65(m,4H,ArH),7.54–7.51(m,2H,ArH),7.46(t,J=7.5Hz,4H,ArH),7.34–7.32(m,2H,ArH),7.18(s,2H,C=CH ),7.02(d,J=8.8Hz,2H,ArH),4.65(t,J=5.3Hz,1H,C–CH),3.71(t,J=6.4Hz,2H,C–CH2),1.75–1.71(m,2H,C–CH2),1.67–1.63(m,2H,C–CH2); 13 C NMR (150MHz, CDCl3): δ=195.2,195.2,141.5,140.3,140.3,139.0,139.0,132.4,131.4131.4,130.2,130.2,128. 6,128.6,128.6,128.6,128.5,128.5,128.5,128.5,122.3,122.3,120.6,120.6,62.5,32.6,29.8,28.6; HRMS (TOF ES+):m / z calcd forC 28 H 25 ClNO3[(M+H) + ],458.1517,found,458.1518.

[0095] Example 17: The preparation process of this example is the same as that of Example 1, except that the N-substituted enaminoketone compound 1a is 3-(4-bromophenylamino)-1-phenyl-2-propen-1-one;

[0096] The structure, morphology, melting point, NMR and high-resolution mass spectrometry data of the obtained product 3q are as follows:

[0097]

[0098] V 石油醚 / V 乙酸乙酯 =5:1,R f =0.1, yellow solid: 98 mg, yield: 79%, melting point = 213–215 °C; 1H NMR (600MHz, CDCl3): δ=7.66–7.64(m,4H,ArH),7.54–7.51(m,2H,ArH),7.48–7.44(m,6H,ArH),7.18(s,2H,C=CH),6.95(d,J=8 .7Hz,2H,ArH),4.64(t,J=5.3Hz,1H,C–CH),3.70(t,J=6.4Hz,2H,C–CH2),1.74–1.71(m,2H,C–CH2),1.66–1.61(m,2H,C–CH2); 13 C NMR (150MHz, CDCl3): δ=195.2,195.2,142.0,140.2,140.2,139.0,139.0,133.2,133.2,131.5,131.5,128.6,128. 6,128.6,128.6,128.5,128.5,128.5,128.5,122.5,122.5,120.7,120.7,120.1,62.5,32.6,29.8,28.6; HRMS (TOF ES+):m / z calcd for C 28 H 25 BrNO3[(M+H) + ],502.1012,found,502.1011.

[0099] Example 18: The preparation process of this example is the same as that of Example 1, except that the N-substituted enaminoketone compound 1a is 3-(4-hydroxyphenylamino)-1-phenyl-2-propene-1-one;

[0100] The structure, morphology, melting point, NMR and high-resolution mass spectrometry data of the obtained product 3r are as follows:

[0101]

[0102] V 石油醚 / V 乙酸乙酯 =5:1,R f =0.2, yellow solid: 98 mg, yield: 85%, melting point = 163–165 °C; 1H NMR (600MHz, DMSO–d6): δ = 9.78 (s, 1H, ArOH), 7.66–7.64 (m, 4H, ArH), 7.57 (t, J = 7.3Hz, 2H, ArH), 7.51 (t, J = 7.5Hz, 4H, ArH), 7.14 (d, J = 8. 4Hz,2H,ArH),7.09(s,2H,C=CH),6.77(d,J=8.6Hz,2H,ArH),4.47–4.43(m,2H,C–CH2),3.41–3.39(m,1H,C–CH),1.54–1.49(m,4H,C–CH2); 13 C NMR (150MHz, DMSO–d6): δ=194.5,194.5,156.9,142.4,142.4,139.4,139.4,135.3,131.7,131.7,129.0,129.0,129 .0,129.0,128.8,128.8,128.8,128.8,123.8,123.8,118.4,118.4,116.7,116.7,61.5,32.4,29.9,28.9; HRMS(TOF ES+):m / z calcd forC 28 H 26 NO4[(M+H) + ],440.1856,found,440.1853.

[0103] Example 19: The preparation process of this example is the same as that of Example 1, except that the N-substituted enaminoketone compound 1a is 3-cyclohexyl-1-phenyl-2-propen-1-one;

[0104] The structure, morphology, melting point, NMR and high-resolution mass spectrometry data of the obtained product 3s are as follows:

[0105]

[0106] V 石油醚 / V 乙酸乙酯 =5:1,R f =0.15, yellow solid: 56 mg, yield: 52%, melting point = 171–173 °C; 1HNMR (600MHz, CDCl3): δ=7.60–7.59(m,4H,ArH),7.52(t,J=7.3Hz,2H,ArH),7 .45(t,J=7.5Hz,4H,ArH),7.27(s,2H,C=CH),4.58(t,J=5.0Hz,1H,C–CH),3.6 9(t,J=6.1Hz,2H,C–CH2),3.08–3.05(m,1H,N–CH),1.86–1.85(m,2H,C–CH2), 1.82–1.80(m,2H,C–CH2),1.65–1.56(m,6H,C–CH2),1.29–1.23(m,4H,C–CH2); 13 C NMR (150MHz, CDCl3): δ=195.0,195.0,141.2,141.2,139.6,139.6,130.9,130.9,128.6,128.6,128.6,128.6,1 28.4,128.4,128.4,128.4,118.4,118.4,63.7,62.6,32.6,32.4,32.4,29.7,28.4,25.4,25.4,24.8; HRMS(TOF ES+):m / z calcd for C 28 H 32 NO3[(M+H) + ],430.2377,found,430.2378.

[0107] Example 20: The preparation process of this example is the same as that of Example 1, except that tetrahydrofuran (THF) 2a is replaced by oxahedrine;

[0108] The structure, morphology, melting point, NMR and high-resolution mass spectrometry data of the obtained product 3t are as follows:

[0109]

[0110] V 石油醚 / V 乙酸乙酯 =4:1,R f =0.1, yellow solid: 63 mg, yield: 57%, melting point = 182–184 °C; 1H NMR (600MHz, CDCl3): δ=7.67–7.65(m,4H,ArH),7.52–7.50(m,2H,ArH),7.46– 7.44(m,4H,ArH),7.38–7.35(m,2H,ArH),7.24–7.23(m,3H,ArH+C=CH),7.08– 7.07(m,2H,ArH),4.66(t,J=5.3Hz,1H,C–CH),3.61(t,J=6.5Hz,2H,C–CH2),1 .70–1.67(m,2H,C–CH2),1.62–1.58(m,2H,C–CH2),1.48–1.43(m,2H,C–CH2); 13 C NMR (150MHz, CDCl3): δ=195.3,195.3,143.1,140.8,140.8,139.2,139.2,131.3,131.3,130.1,130.1,128.6,128.6, 128.6,128.6,128.5,128.5,128.5,128.5,126.8,121.0,121.0,120.4,120.4,62.7,35.8,32.6,30.5,21.4; HRMS(TOF ES+):m / z calcd for C 29 H 28 NO3[(M+H) + ],438.2064,found,438.2064.

[0111] Embodiment 21:

[0112] In a nitrogen atmosphere at 80°C, N-substituted enaminone compound 1a (0.4 mmol), di-tert-butyl diisopropylbenzene peroxide (DCP, 1.2 mmol), ferrous chloride (0.4 mmol), acetic anhydride 4a (2.4 mmol), and 3 mL of tetrahydrofuran (THF) 2a were added to a thick-walled reaction tube, and the mixture was reacted under magnetic stirring. The reaction was monitored by TLC. After the N-substituted enaminone 1a was completely reacted, the reaction mixture was cooled to room temperature, a saturated sodium bicarbonate solution was added, and the organic solvent ethyl acetate was used for extraction three times. The upper organic solvent was collected and combined, and dried over anhydrous sodium sulfate. The dried organic layer was concentrated, and the concentrate was separated by silica gel column chromatography. The solvent used for column chromatography separation was a mixed solvent of petroleum ether and ethyl acetate (volume ratio of 5:1) to obtain the target compound 4-alkyl-1,4-dihydropyridine compound 5a, which has the following general formula:

[0113]

[0114] The morphology, melting point, NMR, and high-resolution mass spectrometry data of the product 5a obtained in Example 21 are as follows:

[0115] V 石油醚 / V 乙酸乙酯 =5:1,R f =0.5, yellow solid: 68 mg, yield: 71%, melting point = 115–117 °C; 1 H NMR (600MHz, DMSO-d6) δ = 7.69 (d, J = 7.6Hz, 4H, ArH), 7.59–7.57 (m, 2H, ArH), 7.53–7.50(m,4H,ArH),7.43–7.40(m,2H,ArH),7.33–7.32(m,2H,ArH),7.29– 7.28(m,3H,ArH+C=CH),4.46(t,J=5.2Hz,1H,C-CH),4.00(t,J=6.5Hz,2H,C-C H2),1.94(s,3H,C-CH3),1.69–1.62(m,2H,C-CH2),1.58–1.55(m,2H,C-CH2); 13 C NMR (150MHz, DMSO-d6)δ=194.8,194.8,170.9,143.2,141.7,141.7,139.2,139.2,131.8,131.8,130.5,130.5,129.0,129 .0,129.0,129.0,128.9,128.9,128.9,128.9,127.2,121.6,121.6,118.7,118.7,64.5,31.9,29.9,24.5,21.2; HRMS(TOF ES + ):m / zcalcd for C 30 H 27 NO4[(M+H) + ],466.2013,found,466.2017.

[0116] Example 22: The preparation process of this example is the same as that of Example 21, except that the N-substituted enaminoketone compound 1a is 3-(phenylamino)-1-(4-methoxyphenyl)-2-propen-1-one;

[0117] The structure, morphology, melting point, NMR and high-resolution mass spectrometry data of the obtained product 5b are as follows:

[0118]

[0119] V 石油醚 / V 乙酸乙酯 =5:1,Rf =0.5, yellow solid: 76 mg, yield: 72%, melting point = 137–139 °C; 1 H NMR (600MHz, DMSO-d6)δ=7.70(d,J=8.3Hz,4H,ArH),7.43–7.40(m,2H,ArH),7.36–7.35(m,2H,ArH),7.27–7.26(m,3H,ArH+C=CH),7.04(d,J=8.2Hz,5H,Ar H),4.42(t,J=5.4Hz,1H,C-CH),3.96(t,J=6.5Hz,2H,C-CH2),3.82(s,6H,Ar OCH3),1.91(s,3H,C-CH3),1.63–1.60(m,2H,C-CH2),1.54–1.50(m,2H,CH2); 13 C NMR (150MHz, DMSO-d6)δ=193.8,193.8,170.9,162.4,162.4,143.3,140.4,140.4,131.5,131.5,131.2,131.2,131.2,131.2,130.4 ,130.4,126.9,121.4,121.4,118.6,118.6,114.3,114.3,114.3,114.3,64.44,55.85,55.85,32.10,30.64,24.61,21.16; HRMS (TOF ES + ):m / z calcd for C 32 H 31 NO6[(M+H) + ],526.2224,found,526.2238.

[0120] Example 23: The preparation process of this example is the same as that of Example 21, except that the N-substituted enaminoketone compound 1a is 3-(phenylamino)-1-(4-ethylphenyl)-2-propen-1-one;

[0121] The structure, morphology, melting point, NMR and high-resolution mass spectrometry data of the obtained product 5c are as follows:

[0122]

[0123] V 石油醚 / V 乙酸乙酯 =5:1,R f =0.5, yellow solid: 63 mg, yield: 60%, melting point = 134–136 °C; 1H NMR (600MHz, DMSO-d6) δ = 7.63 (d, J = 7.8Hz, 4H, ArH), 7.43–7.41 (m, 2H, ArH), 7.3 5(d,J=7.8Hz,6H,ArH),7.29-7.27(m,3H,C=CH+ArH),4.44(t,J=5.9Hz,1H,C-CH ),3.98(t,J=6.4Hz,2H,C-CH2),2.69–2.65(m,4H,C-CH2),1.93(s,3H,C-CH3),1 .67–1.60(m,2H,C-CH2),1.57–1.52(m,2H,C-CH2),1.20(t,J=7.6Hz,6H,C-CH3); 13 C NMR (150MHz, DMSO-d6)δ=194.6,194.6,170.9,148.0,148.0,143.3,141.2,141.2,136.7,136.7,130.5,130.5,130.5,130.5,129.2,12 9.2,129.2,129.2,128.4,128.4,128.4,128.4,127.1,121.7,121.7,118.6,118.6,64.5,32.0,30.2,28.5,24.6,21.2,15.7; HRMS (TOF ES + ):m / z calcdfor C 34 H 35 NO4[(M+H) + ],520.2614,found,520.2625.

[0124] Example 24: The preparation process of this example is the same as that of Example 21, except that the N-substituted enaminoketone compound 1a is 3-(phenylamino)-1-(4-fluorophenyl)-2-propen-1-one;

[0125] The structure, morphology, melting point, NMR and high-resolution mass spectrometry data of the obtained product 5d are as follows:

[0126]

[0127] V 石油醚 / V 乙酸乙酯 =5:1,R f =0.5, yellow solid: 65 mg, yield: 65%, melting point = 127-129 ° C; 1H NMR (600MHz, DMSO-d6)δ=7.78–7.76(m,4H,ArH),7.41–7.28(m,11H,ArH+C=CH),4.43–4.41(m,1H,C- CH),3.98–3.96(m,2H,C-CH2),1.92(s,3H,C-CH3),1.63–1.61(m,2H,CH2),1.55–1.53(m,2H,C-CH2); 13 C NMR(150MHz,DMSO-d6)δ=193.6,193.6,170.9,164.3(J C-F =249.5Hz),164.3(J C-F =249.5Hz),143.2,141.7,141.7,135.7,131.7(J C-F =9.0Hz),131.7(J C-F =9.0Hz),131.7(J C-F =9.0Hz),131.7(J C-F =9.0Hz),130.40,130.40,130.40,130.40,127.1,121.6,121.6,118.5,118.5,116.0(J C-F =21.6Hz),116.0(J C-F =21.6Hz),116.0(J C-F =21.6Hz),116.0(J C-F =21.6Hz),64.4,31.9,30.0,24.5,21.2; HRMS(TOF ES + ):m / z calcdfor C 30 H 25 Cl2NO4[(M+H) + ],502.1824,found,502.1831.

[0128] Example 25: The preparation process of this example is the same as that of Example 21, except that the N-substituted enaminoketone compound 1a is 3-(phenylamino)-1-(4-chlorophenyl)-2-propen-1-one;

[0129] The structure, morphology, melting point, NMR and high-resolution mass spectrometry data of the obtained product 5e are as follows:

[0130]

[0131] V 石油醚 / V 乙酸乙酯 =5:1,R f=0.5, yellow solid: 59 mg, yield: 56%, melting point = 153–155 °C; 1 H NMR (600MHz, DMSO-d6) δ = 7.73 (d, J = 7.9Hz, 4H, ArH), 7.58–7.57 (m, 4H, ArH), 7.43–7.39 (m, 2H, ArH), 7.33 (s, 2H, C = CH), 7.31–7.30 (m, 1H,ArH),4.43–4.42(m,1H,C-CH),4.00–3.98(m,2H,C-CH2),1.94(s,3H,C-CH3),1.69–1.61(m,2H,C-CH2),1.61–1.50(m,2H,C-CH2); 13 CNMR(150MHz,DMSO-d6)δ=193.6,193.6,170.9,143.1,142.0,142.0,137.9,137.9,136.6,130.6,130.9,130.9,130.9,13 0.9,130.4,130.4,129.1,129.1,129.1,129.1,127.2,121.7,121.7,118.5,118.5,64.4,31.8,29.9,24.5,21.2; HRMS(TOF ES + ):m / z calculation forC 30 H 25 Cl2NO4[(M+H) + ],534.1233,found,534.1238.

[0132] Example 26: The preparation process of this example is the same as that of Example 21, except that the N-substituted enaminoketone compound 1a is 3-(phenylamino)-1-(2-naphthyl)-2-propen-1-one;

[0133] The structure, morphology, melting point, NMR and high-resolution mass spectrometry data of the obtained product 5e are as follows:

[0134]

[0135] V 石油醚 / V 乙酸乙酯 =3:1,R f =0.5, yellow solid: 66 mg, yield: 58%, melting point = 175–177 °C; 1H NMR (600MHz, DMSO-d6) δ = 8.34 (s, 2H, ArH), 8.14–8.13 (m, 2H, ArH), 8.05–7.99 (m, 4H, ArH),7.78(d,J=8.5Hz,2H,ArH),7.65–7.55(m,4H,ArH),7.43(s,2H,ArH),7.36–7.34 (m,4H,ArH+C=CH),7.22–7.20(m,1H,ArH),4.57–4.55(m,1H,C–CH),4.05(t,J=6.6Hz, 2H,C-CH2),1.92(s,3H,C-CH3),1.79–1.72(m,2H,C-CH2),1.68–1.64(m,2H,C-CH2).; 13 C NMR(150MHz,DMSO-d6)δ=194.8,194.8,171.0,143.2,141.9,136.6,136.6,1 34.6,134.6,132.6,132.6,130.4,130.4,130.4,129.6,129.6,129.3,129.3, 128.7,128.7,128.3,128.3,128.1,128.1,127.4,127.4,127.0,125.8,125. 8,121.5,121.5,121.5,119.0,119.0,64.6,32.2,30.1,24.7,21.2; HRMS(TOF ES + ):m / z calcd for C 38 H 31 NO4[(M+H) + ],566.2326,found,566.2333.

[0136] Example 27: The preparation process of this example is the same as that of Example 21, except that the N-substituted enaminoketone compound 1a is 3-(phenylamino)-1-(2-furyl)-2-propen-1-one;

[0137] The structure, morphology, melting point, NMR and high-resolution mass spectrometry data of the obtained product 5f are as follows:

[0138]

[0139] V 石油醚 / V 乙酸乙酯 =4:1,R f =0.5, yellow solid: 53 mg, yield: 59%, melting point = 130–132 °C; 1H NMR (600MHz, DMSO-d6) δ = 7.99 (d, J = 8.9 Hz, 4H, C = CH), 7.59–7.57 (m, 2H, C = CH), 7.54–7.51 (m, 2H, ArH), 7.38–7.35 (m, 3H, ArH + C = CH), 6.76–6. 67(m,2H,C=CH),4.36–7.34(m,1H,C–CH),3.93–3.91(m,2H,C-CH2),1.90(s,3H,C-CH3),1.56-1.50(m,2H,C-CH2),1.49–1.44(m,2H,C-CH2); 13 C NMR (150MHz, DMSO-d6)δ=179.9,179.9,170.8,152.3,152.3,147.4,147.4,143.4,139.9,139.9,130.5,130 .5,127.1,121.6,121.6,118.5,118.5,117.8,117.8,112.6,112.6,64.4,32.0,29.9,24.4,21.1; HRMS(TOF ES + ):m / z calcd for C 26 H 23 NO6[(M+H) + ],446.1598,found,446.1604.

[0140] Example 28: The preparation process of this example is the same as that of Example 21, except that the N-substituted enaminoketone compound 1a is 3-(3,4,5-trimethoxyphenylamino)-1-(4-nitrophenyl)-2-propen-1-one;

[0141] The structure, morphology, melting point, NMR and high-resolution mass spectrometry data of 5g of the obtained product are as follows:

[0142]

[0143] V 石油醚 / V 乙酸乙酯 =4:1,R f =0.5, yellow solid: 50 mg, yield: 48%, melting point = 135–137 °C; 1H NMR (600MHz, DMSO-d6)δ=7.71–7.69(s,4H,ArH),7.56–7.49(m,6H,ArH),7.22(s,2H,C=CH),6.68–7.66(m,2H,ArH),4.43–4.45(m,1H,C–CH), 3.40–3.38(s,2H,C-CH2),3.72(s,6H,ArOCH3),3.58(s,3H,ArOCH3),1.92(s,3H,C-CH3),1.66–1.64(m,2H,C-CH2),1.57–1.55(m,2H,C-CH2); 13 C NMR (150MHz, DMSO-d6) δ = 194.8, 194.8, 170.9, 153.9, 153.9, 153.9, 142.4, 142.4, 139.6, 139.2, 136.7, 131.9, 131.9, 129.0, 129. 0,129.0,129.0,128.9,128.9,128.9,128.9,118.1,118.1,100.5,100.5,64.5,60.5,56.7,56.7,32.0,30.0,24.6,21.2; HRMS (TOF ES + ):m / zcalcd for C 31 H 30 NO5[(M+H) + ],556.2330,found,556.2333

[0144] Example 29: The preparation process of this example is the same as that of Example 21, except that the N-substituted enaminone compound 1a is 3-(4-methylphenylamino)-1-(4-nitrophenyl)-2-propen-1-one;

[0145] The structure, morphology, melting point, NMR and high-resolution mass spectrometry data of the obtained product 5h are as follows:

[0146]

[0147] V 石油醚 / V 乙酸乙酯 =5:1,R f =0.5, yellow solid: 63 mg, yield: 66%, melting point = 127–129 °C; 1H NMR (600MHz, DMSO-d6)δ=7.66–7.65(m,4H,ArH),7.57–7.55(m,2H,ArH),7.51–7.49(m,4H,ArH),7.20–7.18(m,6H,ArH+C=CH),4.44– 4.42(m,1H,C–CH),4.00–4.38(m,2H,C-CH2),2.24(s,3H,ArCH3),1.92(s,3H,C-CH3),1.65–1.63(m,2H,CH2),1.56–1.54(m,2H,CH2); 13 CNMR(150MHz,DMSO-d6)δ=194.8,194.8,170.9,142.0,142.0,140.9,139.2,139.2,136.8,131.8,131.8,130.8,130.8,130.0 ,130.0,130.0,130.0,128.8,128.8,128.8,128.8,121.7,121.7,118.4,118.4,64.5,31.9,29.8,24.5,21.2,20.8; HRMS(TOF ES + ):m / z calcdfor C 31 H 29 NO4[(M+H) + ],480.2169,found,480.2186.

[0148] Example 30: The preparation process of this example is the same as that of Example 21, except that the N-substituted enaminone compound 1a is 3-(4-N,N-dimethylphenylamino)-1-(4-nitrophenyl)-2-propen-1-one;

[0149] The structure, morphology, melting point, NMR and high-resolution mass spectrometry data of the obtained product 5i are as follows:

[0150]

[0151] V 石油醚 / V 乙酸乙酯 =5:1,R f =0.5, Yellow liquid: 47mg, Yield: 46%, 1H NMR(600MHz,DMSO-d6)δ=7.65–7.61(m,4H,ArH),7.54(d,J=7.6Hz,2H,ArH),7.50–7.47(m,4H,ArH),7.12–7.09(m,4H,ArH+C=CH),6.67(d,J=8.5Hz,2H, ArH),4.44–4.43(m,1H,C–CH),4.00(t,J=6.5Hz,2H,CH2),2.84(s,6H,N-CH 3),1.94(s,3H,C-CH3),1.66–1.64(m,2H,C-CH2),1.57–1.53(m,2H,C-CH2); 13 C NMR (150MHz, DMSO-d6)δ=194.7,194.7,170.9,149.8,142.9,142.9,139.4,139.4,132.7,131.6,131.6,128.5,128.5,128.5,12 8.5,128.9,128.9,128.9,128.9,123.2,123.2,117.8,117.8,113.3,113.3,64.5,40.6,40.6,31.9,29.6,24.5,21.2; HRMS (TOF ES + ):m / z calcd for C 31 H 29 NO5[(M+H) + ],496.2118,found,496.2122.

[0152] Example 31: The preparation process of this example is the same as that of Example 21, except that the N-substituted enaminone compound 1a is 3-(4-chlorophenylamino)-1-(4-nitrophenyl)-2-propen-1-one;

[0153] The structure, morphology, melting point, NMR and high-resolution mass spectrometry data of the obtained product 5j are as follows:

[0154]

[0155] V 石油醚 / V 乙酸乙酯 =5:1,R f =0.5, yellow solid: 64 mg, yield: 64%, melting point = 135–137 °C; 1H NMR (600MHz, DMSO-d6) δ = 7.69 (d, J = 7.5Hz, 4H, ArH), 7.59–7.56 (m, 2H, ArH), 7.51–7.49 (m, 4H, ArH), 7.44–7.44 (m, 2H, ArH), 7.37–7.36 (m, 2H, ArH) ),7.25(s,2H,C=CH),4.55–4.30(m,1H,C–CH),3.99–3.97(m,2H,C-CH2),1.92(s,3H,C-CH3),1.68–1.60(m,2H,C-CH2),1.57–1.53(m,2H,C-CH2); 13 C NMR (150MHz, DMSO-d6)δ=194.8,194.8,170.9,142.1,141.4,141.4,139.1,139.1,131.9,131.9,131.3,130.2,130.2,129 .0,129.0,129.0,129.0,128.9,128.9,128.9,128.9,123.5,123.5,118.8,118.8,64.4,31.9,29.9,24.5,21.2; HRMS(TOF ES + ):m / z calcd for C 30 H 26 ClNO4[(M+H) + ],500.1623,found,500.1630.

[0156] Example 32: The preparation process of this example is the same as that of Example 21, except that the N-substituted enaminone compound 1a is 3-(4-bromophenylamino)-1-(4-nitrophenyl)-2-propen-1-one;

[0157] The structure, morphology, melting point, NMR and high-resolution mass spectrometry data of the obtained product 5k are as follows:

[0158]

[0159] V 石油醚 / V 乙酸乙酯 =5:1,R f =0.5, yellow solid: 50 mg, yield: 46%, melting point = 133–135 °C; 1H NMR (600MHz, DMSO-d6) δ = 7.69 (d, J = 7.4Hz, 4H, ArH), 7.60–7.57 (m, 4H, ArH), 7.52–7.50 (m, 4H, ArH), 7.32 (d, J = 8.4Hz, 2H, ArH), 7.26 (s ,2H,C=CH),4.45–4.43(m,1H,C–CH),4.00–3.97(m,2H,C-CH2),1.93(s,3H,C-CH3),1.72–1.59(m,2H,C-CH2),1.56–1.54(m,2H,C-CH2); 13 C NMR (150MHz, DMSO-d6)δ=194.8,194.8,170.9,142.5,141.3,141.3,139.1,139.1,133.2,133.2,131.9,131.9,129.0,129 .0,129.0,129.0,128.9,128.9,128.9,128.9,123.8,123.8,119.5,118.9,118.9,64.4,31.8,29.9,24.5,21.2; HRMS(TOF ES + ):m / zcalcd for C 30 H 26 BrNO4[(M+H) + ],544.1118,found,544.1112.

[0160] Example 33: The preparation process of this example is the same as that of Example 21, except that the N-substituted enaminoketone compound 1a is 3-(4-methoxybenzylamino)-1-(4-nitrophenyl)-2-propen-1-one;

[0161] The structure, morphology, melting point, NMR and high-resolution mass spectrometry data of the obtained product 51 are as follows:

[0162]

[0163] V 石油醚 / V 乙酸乙酯 =6:1,R f =0.5, yellow solid: 45 mg, yield: 44%, melting point = 114–116 °C; 1H NMR (600MHz, DMSO-d6)δ=7.56–7.55(m,2H,ArH),7.48–7.47(m,8H,ArH),7.17( d,J=8.1Hz,2H,ArH),7.12(s,2H,C=CH),6.95(d,J=8.1Hz,2H,ArH),4.64(s,2H ,C-CH2),4.31(t,J=5.2Hz,1H,C–CH),3.90(t,J=6.5Hz,2H,C-CH2),3.75(s,3H ,ArOCH3),1.93(s,3H,C-CH3),1.49–1.42(m,2H,CH2),1.40–1.37(m,2H,CH2); 13 C NMR (150MHz, DMSO-d6)δ=194.3,194.3,170.8,159.4,144.3,144.3,139.6,139.6,131.5,131.5,129.5,129.5,129.3,128.8,12 8.8,128.8,128.8,128.7,128.7,128.7,128.7,116.6,116.6,114.6,114.6,64.5,56.5,55.6,31.8,29.4,24.4,21.1; HRMS (TOF ES + ):m / z calcd for C 32 H 31 NO5[(M+H) + ],510.2275,found,510.2281.

[0164] Example 34: The preparation process of this example is the same as that of Example 21, except that acetic anhydride is replaced by chloroacetic anhydride;

[0165] The structure, morphology, melting point, NMR and high-resolution mass spectrometry data of the obtained product 5m are as follows:

[0166]

[0167] V 石油醚 / V 乙酸乙酯 =5:1,R f =0.5, yellow solid: 51 mg, yield: 51%, melting point = 119–121 °C; 1H NMR (600MHz, DMSO-d6)δ=7.69–7.67(m,4H,ArH),7.61–7.54(m,2H,ArH),7.52–7.49(m,4H,ArH),7.42–7.36(m,3H,ArH),7.33–7.29(m,2H,ArH),7. 25(s,2H,C=CH),4.46–4.42(m,1H,C–CH),4.33–4.29(m,2H,C-CH2),4.14 –4.09(m,2H,C-CH2),1.69–1.64(m,2H,C-CH2),1.59–1.55(m,2H,C-CH2); 13 C NMR (150MHz, DMSO-d6)δ=194.8,194.8,167.9,143.2,141.8,141.8,139.2,139.2,131.8,131.8,130.5,130.5,129.0,129 .0,129.0,129.0,128.9,128.9,128.9,128.9,127.2,121.6,121.6,118.7,118.7,66.2,41.6,31.9,29.8,24.4; HRMS(TOF ES + ):m / z calcd for C 30 H 26 ClNO4[(M+H) + ],500.1623,found,500.1626.

[0168] Example 35: The preparation process of this example is the same as that of Example 21, except that acetic anhydride is replaced by propionic anhydride;

[0169] The structure, morphology, melting point, NMR and high-resolution mass spectrometry data of the obtained product 5n are as follows:

[0170]

[0171] V 石油醚 / V 乙酸乙酯 =5:1,R f =0.5, yellow solid: 58 mg, yield: 61%, melting point = 130–132 °C; 1H NMR (600MHz, DMSO-d6) δ = 7.68 (d, J = 7.5Hz, 4H, ArH), 7.58–7.56 (m, 2H, ArH), 7.52–7.49 ( m,4H,ArH),7.40(t,J=7.7Hz,2H,ArH),7.31(d,J=7.9Hz,2H,ArH),7.28–7.26(m,2H,ArH+ C=CH),4.45(t,J=5.1Hz,1H,C–CH),4.01(t,J=6.4Hz,2H,C-CH2),2.21(q,J=7.5Hz,2H,C -CH2),1.67–1.63(m,2H,C-CH2),1.58–1.54(m,2H,C-CH2),0.94(t,J=7.5Hz,3H,C-CH3); 13 C NMR (150MHz, DMSO-d6)δ=194.8,194.8,174.1,143.2,141.7,141.7,139.2,139.2,131.8,131.8,130.5,130.5,129.0,129.0,12 9.0,129.0,129.0,128.9,128.9,128.9,128.9,127.2,121.6,121.6,118.7,118.7,64.3,31.7,29.9,27.3,24.6,9.5; HRMS (TOF ES + ):m / z calcd for C 31 H 29 NO4[(M+H) + ],480.2169,found,480.2173.

[0172] Example 36: The preparation process of this example is the same as that of Example 21, except that acetic anhydride is replaced by isobutyric anhydride;

[0173] The structure, morphology, melting point, NMR and high-resolution mass spectrometry data of the obtained product 5o are as follows:

[0174]

[0175] V 石油醚 / V 乙酸乙酯 =5:1,R f =0.5, yellow solid: 59 mg, yield: 60%, melting point = 148–150 °C; 1H NMR (600MHz, DMSO-d6) δ = 7.67 (d, J = 7.4Hz, 4H, ArH), 7.58–7.56 (m, 2H, ArH), 7.51–7. 49(m,4H,ArH),7.42–7.39(m,2H,ArH),7.31–7.30(m,2H,ArH),7.28–7.25(m,3H,ArH +C=CH),4.45(t,J=5.2Hz,1H,C-CH),4.02(t,J=6.2Hz,2H,C-CH2),2.43–2.42(m,1H, C-CH),1.67–1.63(m,2H,C-CH2),1.60–1.50(m,2H,C-CH2),0.98(d,J=7.0Hz,C-CH3); 13 C NMR (150MHz, DMSO-d6)δ=194.8,194.8,176.6,143.2,141.8,141.8,139.2,139.2,131.8,131.8,130.5,130.5,129.0,129.0,12 9.0,129.0,128.9,128.9,128.9,128.9,127.2,121.6,121.6,118.6,118.6,64.2,33.6,31.6,29.9,24.5,19.2,19.2; HRMS (TOF ES + ):m / z calculation forC 30 H 26 ClNO4[(M+H) + ],494.2326,found,494.2332.

[0176] PDE4 inhibitory effects of the above-mentioned example compounds

[0177] The PDE4 inhibitory activity of the compounds of the present invention was detected according to the method in “Prenylated Coumarins: Natural Phosphodiesterase-4 Inhibitors from Toddalia asiatica. J. Nat. Prod. 2014, 77, 955-962”. The results are shown in Table 1.

[0178] The results of the inhibitory activity of two representative 1,4-dihydropyridine compounds 3o and 5a on phosphodiesterase 4 are as follows: the inhibition rates at a concentration of 10 μM are 61.12% and 69.76%, respectively. The 4-alkyl-1,4-dihydropyridine compounds of the present invention show inhibitory activity on PDE4; the inhibition rates at a concentration of 1.0 μM are 8.51% and 16.21%, respectively, which are lower than the inhibition rate of the positive control drug Rolipram (59.21%);

[0179] Table 1

[0180]

[0181]

[0182] The above shows and describes the basic principles, main features and advantages of the present invention. It should be understood by those skilled in the art that the present invention is not limited to the above embodiments, and the above embodiments and descriptions are only for explaining the principles of the present invention. Without departing from the spirit and scope of the present invention, the present invention may have various changes and improvements, which fall within the scope of the present invention to be protected. The scope of protection of the present invention is defined by the attached claims and their equivalents.

Claims

1. A method for preparing a 4-alkyl-1,4-dihydropyridine compound, characterized in that: Add in the reactor N -substituted enaminone compound 1, using ether compound 2 as solvent, in the presence of catalyst, auxiliary agent and oxidant, reacting in nitrogen atmosphere at 60-120°C, monitoring the reaction progress by thin layer chromatography until the reaction is complete, extracting the reaction product with ethyl acetate 2-3 times, collecting and combining the organic phases, drying with anhydrous sodium sulfate, and then concentrating under reduced pressure, and separating and purifying the concentrate by silica gel column chromatography to obtain 4-alkyl-1,4-dihydropyridine compound 3; ， Where R 1 is selected from aryl, heterocyclic, alkyl; R 2 is selected from aryl, heterocycle, alkyl; n is selected from 1, 2; The catalyst is ferrous chloride, ferric chloride, ferrous sulfate, palladium chloride, cuprous chloride, cobalt chloride, chromium chloride or nickel chloride hexahydrate. N -The molar ratio of the substituted enaminone compound 1 to the catalyst is 1:0.1-5; the oxidant is di-tert-butyl peroxide, di-tert-butyl peroxide diisopropylbenzene, tert-butyl perbenzoate, tert-butyl hydroperoxide, hydrogen peroxide, dibenzoyl peroxide, cumene hydroperoxide, m-chloroperbenzoic acid or potassium persulfate, N - The molar ratio of the substituted enaminone compound 1 to the oxidant is 1:0.5-4; the auxiliary agent is tetrafluoroboric acid, perchloric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid or sulfuric acid, N The molar ratio of the substituted enaminone compound 1 to the auxiliary agent is 1:0.1-6; the ether compound is tetrahydrofuran, tetrahydrothiophene, hydrogenated pyran or oxepane.

2. A method for preparing a 4-alkyl-1,4-dihydropyridine compound, characterized in that: Add in the reactor N -Substituted enaminone compound 1 and anhydride compound 4 are reacted in the presence of ether compound 2 as solvent in a nitrogen atmosphere at 60-120°C in the presence of a catalyst, an auxiliary agent and an oxidant, and the reaction progress is monitored by thin layer chromatography until the reaction is complete, the reaction product is extracted 2-3 times with ethyl acetate, the organic phases are collected and combined, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure, and the concentrate is separated and purified by silica gel column chromatography to obtain 4-alkyl-1,4-dihydropyridine compound 5; ； Where R 1 is selected from aryl, heterocyclic, alkyl; R 2 is selected from aryl, heterocyclic, alkyl; R 3 is selected from aryl and alkyl; n is selected from 1 and 2; The catalyst is ferrous chloride, ferric chloride, ferrous sulfate, palladium chloride, cuprous chloride, cobalt chloride, chromium chloride or nickel chloride hexahydrate. N -The molar ratio of the substituted enaminone compound 1 to the catalyst is 1:0.1-5; the oxidant is di-tert-butyl peroxide, di-tert-butyl peroxide diisopropylbenzene, tert-butyl perbenzoate, tert-butyl hydroperoxide, hydrogen peroxide, dibenzoyl peroxide, cumene hydroperoxide, m-chloroperbenzoic acid or potassium persulfate, N - The molar ratio of the substituted enaminone compound 1 to the oxidant is 1:0.5-4; the auxiliary agent is tetrafluoroboric acid, perchloric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid or sulfuric acid, N The molar ratio of the substituted enaminone compound 1 to the auxiliary agent is 1:0.1-6; the ether compound is tetrahydrofuran, tetrahydrothiophene, hydrogenated pyran or oxepane.

3. Use of a 4-alkyl-1,4-dihydropyridine compound in the preparation of a PDE4 inhibitor; The structural formula of the 4-alkyl-1,4-dihydropyridine compound is as follows: 。

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