阅读说明：本技术 一种连续流动合成4-吡啶酮及其衍生物的方法 (Method for synthesizing 4-pyridone and derivatives thereof by continuous flow ) 是由 黄超 刘腾 李伟强 于 2021-10-13 设计创作，主要内容包括：本发明公开了一种连续流动合成4-吡啶酮及其衍生物的方法,包括以下步骤：1)将反应原料以烷氧基甲叉-3-氧代羧酸酯、炔和胺类化合物分别溶于有机溶剂中得到物料a、物料b和物料c；2)将物料a和物料c经单元泵连续流动下混合得到物料d；3)物料d再与物料b在催化剂条件下进行流动反应得到反应液e；4)将反应液e经除去溶剂、层析分离、洗脱、干燥得到目标产物4-吡啶酮及其衍生物。本发明提供了一种通过简单易得的原料乙氧基甲叉丙二酸二乙酯、乙炔二羧酸二乙酯和胺类在流动条件下制得4-吡啶酮及其衍生物,为后续工业生产提供一种简单易行的方法。(The invention discloses a method for synthesizing 4-pyridone and derivatives thereof by continuous flow, which comprises the following steps: 1) respectively dissolving alkoxy methylene-3-oxocarboxylate, alkyne and amine compounds serving as reaction raw materials in an organic solvent to obtain a material a, a material b and a material c; 2) continuously flowing and mixing the material a and the material c through a unit pump to obtain a material d; 3) carrying out flow reaction on the material d and the material b under the condition of a catalyst to obtain a reaction liquid e; 4) and removing the solvent from the reaction liquid e, carrying out chromatographic separation, eluting and drying to obtain the target product 4-pyridone and the derivative thereof. The invention provides a simple and easily-obtained method for preparing 4-pyridone and derivatives thereof by using simple and easily-obtained raw materials of diethyl ethoxymethylene malonate, diethyl acetylenedicarboxylate and amines under a flowing condition, and provides a simple and easy method for subsequent industrial production.)

1. a method for continuously synthesizing 4-pyridone and derivatives thereof by flowing is characterized in that alkoxy methylene-3-oxocarboxylate, alkyne and amine compounds are used as reaction raw materials, and the 4-pyridone and the derivatives thereof are obtained by flowing reaction under the condition of a catalyst, wherein the synthetic route is as follows:

。

2. the continuous flow synthesis method of 4-pyridone and its derivatives according to claim 1, wherein the continuous flow synthesis method of 4-pyridone and its derivatives comprises the steps of:

1) respectively dissolving alkoxy methylene-3-oxocarboxylate, alkyne and amine compounds serving as reaction raw materials in an organic solvent to obtain a material a, a material b and a material c;

2) continuously flowing and mixing the material a and the material c through a unit pump to obtain a material d;

3) carrying out flow reaction on the material d and the material b under the condition of a catalyst to obtain a reaction liquid e;

4) and removing the solvent from the reaction liquid e, carrying out chromatographic separation, eluting and drying to obtain the target product 4-pyridone and the derivative thereof.

3. The continuous flow synthesis method of 4-pyridone and derivatives thereof according to claim 1 or 2, wherein the molar ratio of the alkoxy methylene-3-oxocarboxylate, alkyne and amine compounds is (0.9-1.3): (0.9-1.1): (0.9-1.1).

4. The continuous flow process for the synthesis of 4-pyridones and derivatives according to claim 3, wherein the alkoxymethylene-3-oxocarboxylate is diethyl ethoxymethylene malonate or dimethyl methoxymethylpentenoate.

5. The continuous flow synthesis of 4-pyridones and derivatives thereof according to claim 3, wherein the alkyne is acetylenedicarboxylic acid or dimethyl butynedioate.

6. The continuous flow process for the synthesis of 4-pyridones and derivatives thereof according to claim 3, wherein the amine compound is aniline, pyridylamine or alkylamine.

7. The continuous flow process for the synthesis of 4-pyridone and its derivatives according to claim 1 or 2, wherein the catalyst is a basic catalyst.

8. The continuous flow process for the synthesis of 4-pyridone and its derivatives according to claim 7, wherein the basic catalyst is triethylenediamine (DABCO).

9. The continuous flow process for the synthesis of 4-pyridone and its derivatives according to claim 2, wherein the organic solvent in step 1) is acetonitrile.

10. The continuous flow method for synthesizing 4-pyridone and its derivatives according to claim 2, wherein the elution in step 4) is performed with a petroleum ether-ethyl acetate mixture at a volume ratio of 3: 1.

Technical Field

The invention belongs to the technical field of chemistry, and particularly relates to a method for synthesizing 4-pyridone and derivatives thereof by continuous flow.

Background

4-pyridone is an important skeleton compound widely existing in drug molecules, and is not easy to oxidize or methylate, so that different biological characteristics are often shown, and biological activities such as fibrosis resistance, epilepsy resistance, anti-inflammation and the like can be used as core modules of various drugs, as shown in the following:

the pyridone compound has wide biological activity and application value in synthesizing medicine molecules. Over the past few decades, N-aryl/alkyl-2-pyridines have been synthesized with great progress, while N-aryl/alkyl-4-pyridines have been rarely synthesized. Several synthetic routes have been identified so far for N-aryl/alkyl-4-pyridones, including p-TSA catalyzed reaction of N-aryl acetoacetamide with diketene after self-condensation, sodium persulfate mediated acyl migration reaction, 3-aminocyclobutenone with [4+2] cycloaddition reaction of electron-deficient alkyne, ruthenium catalyzed reaction of C-H activated benzene with pyridine ring, etc. However, the methods reported so far often require the use of strong acids, strong oxidants, carcinogenic solvents (benzene), transition metal catalysis (Ru, Rh), and generally have poor selectivity and low yields, slow reaction and limited substrate universality. To address these limitations, it remains a formidable challenge to explore an efficient and versatile method for obtaining N-aryl/alkyl-4-pyridines.

Disclosure of Invention

The invention aims to provide a method for synthesizing 4-pyridone and derivatives thereof by continuous flow.

The invention aims to realize that the method for synthesizing the 4-pyridone and the derivatives thereof by continuous flow takes alkoxy methylene-3-oxocarboxylate, alkyne and amine compounds as reaction raw materials, and the 4-pyridone and the derivatives thereof are obtained by the flow reaction under the condition of a catalyst, and the synthetic route is as follows:

。

in recent years, continuous flow chemistry has received wide attention from synthesizers and process producers, and compared with a conventional batch reactor, a continuous flow microreactor has the advantages of high specific surface area, high heat transfer efficiency, high mass transfer efficiency, capability of being accurately controlled and the like, and is easy for industrial production amplification. Meanwhile, the method is rapidly developed in organic synthesis and becomes an effective method for replacing the traditional operation.

Based on the reasons, the invention provides a simple and easily obtained method for preparing 4-pyridone and derivatives thereof by using simple and easily obtained raw materials of diethyl ethoxymethylene malonate, diethyl acetylenedicarboxylate and amines under a flowing condition, and provides a simple and easy method for subsequent industrial production.

According to the invention, amines and diethyl ethoxymethylene malonate or dimethyl methoxymethylpentenoate react in a reaction coil under flowing, do not enter a collecting device after the reaction, then react with alkyne ester and a catalyst DABCO in another reaction coil, finally, effluent reaction liquid is collected on line by a product collector, and the product 4-pyridone and derivatives thereof are obtained after post-treatment.

The beneficial effects are mainly embodied as follows:

1) the raw materials are simple and easily available, can be bought in the market and are low in price;

2) the separation operation is not needed in the middle, and the reaction is efficient and labor-saving;

3) the green reaction process, the byproduct is only ethanol, and the atom economy is high;

4) the yield is high, the method can be used for mass production on a flow synthesizer, and a simple and feasible method is provided for the process production of the 4-pyridone and the derivatives thereof.

Drawings

FIG. 1 is a nuclear magnetic spectrum of a compound 4a in example 1 of the present invention;

FIG. 2 shows the NMR spectra of the compound 4c in example 1 of the present invention;

FIG. 3 is a nuclear magnetic spectrum of a 4o compound in example 1 of the present invention;

FIG. 4 is a nuclear magnetic spectrum of a 4j compound in example 1 of the present invention;

FIG. 5 shows the NMR spectra of 4l of the compound in example 1 of the present invention;

FIG. 6 shows the NMR spectra of 5i compound in example 2 of the present invention.

Detailed Description

The present invention is further illustrated by the following examples, which are not intended to be limiting in any way, and any modifications or alterations based on the teachings of the present invention are intended to fall within the scope of the present invention.

The method for continuously synthesizing 4-pyridone and derivatives thereof takes alkoxy methylene-3-oxocarboxylate, alkyne and amine compounds as reaction raw materials, and the 4-pyridone and the derivatives thereof are obtained by the flow reaction under the condition of a catalyst, and the synthetic route is as follows:

。

the method for synthesizing the 4-pyridone and the derivatives thereof by continuous flow comprises the following steps:

1) respectively dissolving alkoxy methylene-3-oxocarboxylate, alkyne and amine compounds serving as reaction raw materials in an organic solvent to obtain a material a, a material b and a material c;

2) continuously flowing and mixing the material a and the material c through a unit pump to obtain a material d;

3) carrying out flow reaction on the material d and the material b under the condition of a catalyst to obtain a reaction liquid e;

4) and removing the solvent from the reaction liquid e, carrying out chromatographic separation, eluting and drying to obtain the target product 4-pyridone and the derivative thereof.

The molar ratio of the alkoxy methylene-3-oxo carboxylate to the alkyne and amine compounds is (0.9-1.3): (0.9-1.1): (0.9-1.1).

The alkoxy methylene-3-oxocarboxylate is ethoxy methylene diethyl malonate or methoxy methyl pentenoic acid dimethyl ester.

The alkyne is acetylene dicarboxylic acid or dimethyl butynedioate.

The amine compound is aniline, pyridylamine or alkylamine.

The catalyst is an alkaline catalyst.

The obtained basic catalyst is triethylene Diamine (DABCO).

1) The organic solvent in the step (a) is acetonitrile.

4) The elution in the step is carried out by using petroleum ether-ethyl acetate mixed liquor with the volume ratio of 3: 1.

The invention provides a method for continuously synthesizing 4-pyridone and derivatives thereof by flowing, wherein a monomer is one of diethyl ethoxymethylene malonate or dimethyl methoxymethylpentenoate, an alkyne ester is one of diethyl acetylenedicarboxylate or dimethyl butynedioate, an amine is one of common various substituted arylamine, benzylamine or aliphatic amine, a catalyst is organic base DABCO, and reactants in a flow pipeline are heated under the heating condition to prepare the required 4-pyridone. The device used for synthesis comprises a unit pump, a transparent pipeline coil, a heating device and a collecting device. The method comprises the following specific steps:

acetonitrile is used as a reaction solvent, aniline, ethoxy methylene diethyl malonate and acetylene dicarboxylic diethyl ester are used as raw materials, and DABCO is used as a catalyst. Dissolving raw materials of aniline and diethyl ethoxymethylene malonate by using solvents respectively, then placing the raw materials into A, B test tubes respectively, dissolving and mixing diethyl acetylenedicarboxylate and catalyst DABCO by using solvents, and then placing the mixture into a C test tube. Continuously introducing aniline and diethyl ethoxymethylene malonate in a test tube A, B into a reaction coil 1 to react under the driving of a peristaltic pump, and controlling the temperature to be 25-80 DEG C^oC (preferably 50) ^oC) The reaction time of the reaction liquid flowing continuously in the reaction channel 1 is 10-50 min (preferably 25 min), the reaction time is accurately controlled to enable the reaction product of aniline and diethyl ethoxymethylenemalonate to flow out of the reaction channel 1, then the diethyl acetylenedicarboxylate and the catalyst DABCO in the test tube C are pumped in, the reaction product of aniline and diethyl ethoxymethylenemalonate and the reaction product of diethyl acetylenedicarboxylate and the catalyst DABCO in the test tube C are enabled to react in the reaction coil 2, and the temperature is controlled to be 25-80 DEG C ^oC(preferably 55) ^oC) And the reaction time of the reaction liquid continuously flowing in the reaction channel 2 is 10-50 min (preferably 30 min), the effluent reaction liquid is collected on line by a product collector, and the product 4-pyridone product is obtained after post-treatment.

After the aniline, the diethyl ethoxymethylene malonate and the diethyl acetylenedicarboxylate are respectively dissolved by acetonitrile, the concentration of the obtained solution is recommended to be 1.0 mol/L.

The DABCO is triethylene diamine and is an organic base catalyst, and the used amount of the DABCO is 2-15% of the amount of a reaction substrate, and is particularly preferably 10%.

The post-treatment method specifically comprises the following steps: and (3) distilling the reaction solution under reduced pressure to remove the solvent, carrying out silica gel column chromatography separation, and filling the column by a 200-mesh and 300-mesh silica gel dry method, wherein an elution reagent is petroleum ether: ethyl acetate volume ratio 3:1, tracking the elution process by TLC, collecting the eluent containing the target compound, evaporating the solvent and drying to obtain the product 4-pyridone and the derivative thereof.

The reaction principle is as follows:

。

the invention is further illustrated by the following specific examples:

example 1

The preparation method comprises the following steps:

acetonitrile is used as a system solvent, aniline, ethoxy methylene diethyl malonate and acetylene dicarboxylic diethyl ester are used as raw materials, and DABCO is used as a catalyst. The raw materials of aniline, diethyl ethoxymethylene malonate and diethyl acetylenedicarboxylate are respectively diluted to 1.0mol/L by acetonitrile and then respectively placed in A, B test tubes and C test tubes, and DABCO is placed in the C test tube according to the equivalent of 10%. Under the drive of a peristaltic pump, aniline and diethyl ethoxymethylene malonate in a test tube A, B are continuously fed into a reaction coil 1 for reaction, and the temperature is controlled to be 50 DEG^oC, the reaction time of the reaction liquid flowing in the reaction channel 1 is 25min, and the reaction time is accurately controlled to ensure that the reaction product of the aniline and the diethyl ethoxymethylene malonate flows outDirectly feeding the reaction channel 1 into the next reaction coil without entering a collecting device, pumping the diethyl acetylenedicarboxylate and the catalyst DABCO in the test tube C into the reaction channel, reacting the reaction product of aniline and diethyl ethoxymethylene malonate with the diethyl acetylenedicarboxylate and the catalyst DABCO in the test tube C in the reaction coil 2, and controlling the temperature to be 55 DEG C^oAnd C, continuously flowing the reaction liquid in the reaction channel 2 for 30min, collecting the outflow reaction liquid on line through a product collector, and performing post-treatment to obtain a product 4-pyridone product.

In the examples, the yield of 4-pyridone compounds prepared by changing electron donating amino amine compounds and ester groups is as follows:

the above compound data are as follows:

Triethyl 4-oxo-1-phenyl-1,4-dihydropyridine-2,3,5-tricarboxylate (4a)：Yellow oil; yield 90%; ¹H NMR (400 MHz, CDCl₃) δ 7.50–7.42 (m, 3H, Ph-H), 7.24 (dd, J = 4.7, 1.7 Hz, 2H, Ph-H), 6.80 (s, 1H, CH), 4.36 (q, J = 7.2 Hz, 2H, OCH₂), 4.25 (q, J = 7.1 Hz, 2H, OCH₂), 3.92 (q, J = 7.2 Hz, 2H, OCH₂), 1.36 (t, J = 7.2 Hz, 3H, CH₃), 1.28 (t, J = 7.2 Hz, 3H), 0.93 (t, J = 7.2 Hz, 3H, CH₃); ¹³C NMR (100 MHz, CDCl₃) δ 165.4, 163.4, 161.0, 145.7, 143.8, 136.6, 130.1, 129.5, 128.5, 121.4, 107.2, 62.9, 62.5, 62.3, 14.2, 14.0, 13.5; HRMS (ESI-TOF⁺) m/z: calcd for C₂₀H₂₂NO₇ ⁺ [(M + H)⁺], 388.1391; found, 388.1387.

Triethyl 4-oxo-1-(o-tolyl)-1,4-dihydropyridine-2,3,5-tricarboxylate (4b)：Pale yellow oil; yield 89%; ¹H NMR (400 MHz, CDCl₃) δ 7.33–7.28 (m, 1H, Ph-H), 7.25 (d, J = 6.5 Hz, 1H, Ph-H), 7.24–7.18 (m, 1H, Ph-H), 7.11–6.99 (m, 1H, Ph-H), 6.76 (s, 1H, CH), 4.32 (q, J = 7.2 Hz, 2H, OCH₂), 4.20 (dd, J = 7.1, 2.3 Hz, 2H, OCH₂), 3.88–3.83 (m, 2H, OCH₂), 2.11 (s, 3H, CH₃), 1.32 (t, J= 7.2 Hz, 3H, CH₃), 1.22 (t, J = 7.2 Hz, 3H, CH₃), 0.88 (t, J = 7.2 Hz, 3H, CH₃); ¹³C NMR (100 MHz, CDCl₃) δ 165.6, 163.3, 160.9, 160.3, 145.9, 144.1, 137.0, 135.8, 131.2, 130.4, 128.5, 127.0, 121.1, 106.9, 62.8, 62.6, 62.3, 17.7, 14.2, 14.0, 13.4; HRMS (ESI-TOF⁺) m/z: calcd for C₂₁H₂₄NO₇ ⁺ [(M + H)⁺], 402.1547; found, 402.1544.

Triethyl 4-oxo-1-(m-tolyl)-1,4-dihydropyridine-2,3,5-tricarboxylate (4c)：Drak yellow oil; yield 90%; ¹H NMR (400 MHz, CDCl₃) δ 7.34 (t, J = 7.8 Hz, 1H, Ph-H), 7.25 (d, J = 5.9 Hz, 1H, Ph-H), 7.09–6.98 (m, 2H, Ph-H), 6.81 (d, J = 11.9 Hz, 1H, CH), 4.36 (q, J = 7.2 Hz, 2H, OCH₂), 4.25 (q, J = 7.1 Hz, 2H, OCH₂), 3.97–3.92 (m, 2H, OCH₂), 2.37 (s, 3H, CH₃), 1.36 (t, J = 7.2 Hz, 3H, CH₃), 1.28 (d, J = 7.1 Hz, 3H, CH₃), 0.94 (t, J = 7.2 Hz, 3H, CH₃); ¹³C NMR (100 MHz, CDCl₃) δ 164.3, 162.2, 159.8, 144.6, 142.6, 138.4, 135.3, 129.6, 128.1, 127.8, 124.3, 120.2, 106.0, 61.6, 61.3, 61.1, 20.2, 13.0, 12.8, 12.3; HRMS (ESI-TOF⁺) m/z: calcd for C₂₁H₂₅NO₇ ⁺ [(M + H)⁺], 402.1547; found, 402.1549.

Triethyl 4-oxo-1-(p-tolyl)-1,4-dihydropyridine-2,3,5-tricarboxylate (4d)：Pale yellow oil; yield 93%; ¹H NMR (400 MHz, CDCl₃) δ 7.27 (s, 1H, Ph-H), 7.25 (s, 1H, Ph-H), 7.12 (d, J = 8.3 Hz, 2H, Ph-H), 6.82 (s, 1H, CH), 4.36 (q, J = 7.1 Hz, 2H, OCH₂), 4.25 (q, J = 7.1 Hz, 2H, OCH₂), 3.96 (q, J = 7.2 Hz, 2H, OCH₂), 2.40 (d, J = 10.0 Hz, 3H, CH₃), 1.36 (t, J = 7.2 Hz, 3H, CH₃), 1.28 (t, J = 7.2 Hz, 3H, CH₃), 0.98 (t, J = 7.2 Hz, 3H, CH₃); ¹³C NMR (100 MHz, CDCl₃) δ 165.5, 163.5, 161.1, 145.9, 143.8, 140.3, 133.9, 130.1, 128.2, 121.3, 107.1, 62.8, 62.5, 62.3, 21.4, 14.2, 14.0, 13.5; HRMS (ESI-TOF⁺) m/z: calcd for C₂₁H₂₄NO₇ ⁺ [(M + H)⁺], 402.1547; found, 402.1544.

Triethyl 1-(2-methoxyphenyl)-4-oxo-1,4-dihydropyridine-2,3,5- tricarboxylate (4e)：Pale yellow oil; yield 89%; ¹H NMR (400 MHz, CDCl₃) δ7.44–7.38 (m, 1H, Ph-H), 7.16–7.14 (m, 1H, Ph-H), 7.02–6.97 (m, 2H, Ph-H), 6.78 (d, J = 1.6 Hz, 1H, CH), 4.38–4.33 (m, 2H, OCH₂), 4.23 (d, J = 7.2 Hz, 2H, OCH₂), 3.94–3.91 (m, 2H, OCH₂), 3.79 (d, J = 1.6 Hz, 3H, OCH₃), 1.38–1.34 (m, 3H, CH₃), 1.26 (dd, J = 7.2, 5.7 Hz, 3H, CH₃), 0.96–0.92 (m, 3H, CH₃); ¹³C NMR (100 MHz, CDCl₃) δ 165.7, 163.4, 161.0, 160.5, 155.4, 146.5, 143.9, 131.8, 129.7, 125.5, 121.1, 120.7, 112.3, 106.8, 62.6, 62.5, 62.2, 56.1, 14.2, 14.0, 13.6; HRMS (ESI-TOF⁺) m/z: calcd for C₂₁H₂₄NO₈ ⁺ [(M + H)⁺], 418.1496; found, 418.1494.

Triethyl 1-(3-methoxyphenyl)-4-oxo-1,4-dihydropyridine-2,3,5- tricarboxylate (4f)：Pale yellow oil; yield 92%; ¹H NMR (400 MHz, CDCl₃) δ 7.36 (t, J = 8.1 Hz, 1H, Ph-H), 7.03–6.94 (m, 1H, Ph-H), 6.87–6.78 (m, 2H, Ph-H), 6.77 (t, J = 2.2 Hz, 1H, CH), 4.36 (q, J = 7.2 Hz, 2H, OCH₂), 4.25 (q, J = 7.1 Hz, 2H, OCH₂), 4.00–3.94 (m, 2H, OCH₂), 3.78 (s, 3H, OCH₃), 1.36 (t, J = 7.2 Hz, 3H, CH₃), 1.27 (t, J = 7.1 Hz, 3H, CH₃), 0.97 (t, J = 7.2 Hz, 3H, CH₃); ¹³C NMR (100 MHz, CDCl₃) δ 165.4, 163.4, 161.0, 160.8, 160.3, 145.6, 143.7, 137.4, 130.2, 121.5, 120.6, 116.2, 114.0, 107.3, 62.9, 62.5, 62.3, 55.7, 14.2, 14.0, 13.5; HRMS (ESI-TOF⁺) m/z: calcd for C₂₁H₂₄NO₈ ⁺ [(M + H)⁺], 418.1496; found, 418.1498.

Triethyl 1-(2-(tert-butyl)phenyl)-4-oxo-1,4-dihydropyridine-2,3,5- tricarboxylate (4g)：Pale yellow oil; yield 88%; ¹H NMR (400 MHz, CDCl₃) δ 7.59 (dd, J = 8.2, 1.3 Hz, 1H, Ph-H), 7.44–7.35 (m, 1H, Ph-H), 7.24–7.18 (m, 1H, Ph-H), 6.92 (dd, J = 7.9, 1.4 Hz, 1H, Ph-H), 6.78 (s, 1H, CH), 4.37 (q, J = 7.2 Hz, 2H, OCH₂), 4.28–4.22 (m, 2H, OCH₂), 3.98–3.92 (m, 2H, OCH₂), 1.37 (t, J = 7.2 Hz, 3H, CH₃), 1.30 (d, J = 2.1 Hz, 9H, CH₃), 1.28 (d, J = 7.2 Hz, 3H, CH₃), 0.95 (t, J = 7.2 Hz, 3H, CH₃); ¹³C NMR (100 MHz, CDCl₃) δ 165.6, 163.5, 162.1, 161.1, 147.7, 146.4, 144.2, 133.4, 130.7, 130.6, 130.2, 126.8, 121.0, 106.9, 62.9, 62.6, 62.3, 37.1, 31.7, 14.2, 14.0, 13.5; HRMS (ESI-TOF⁺) m/z: calcd for C₂₄H₃₀NO₇ ⁺ [(M + H)⁺], 444.2017; found, 444.2019.

Triethyl 1-(3,4-dimethylphenyl)-4-oxo-1,4-dihydropyridine-2,3,5- tricarboxylate (4h)：Drak yellow solid; yield 95%; ¹H NMR (400 MHz, CDCl₃) δ7.21 (d, J = 8.0 Hz, 1H, Ph-H), 7.04–6.93 (m, 2H, Ph-H), 6.81 (s, 1H, CH), 4.35 (q, J = 7.2 Hz, 2H, OCH₂), 4.25 (q, J = 7.1 Hz, 2H, OCH₂), 3.96 (dd, J = 7.2, 5.2 Hz, 2H, OCH₂), 2.26 (d, J = 5.3 Hz, 6H, CH₃), 1.36 (t, J = 7.2 Hz, 3H, CH₃), 1.27 (t, J = 7.2 Hz, 3H, CH₃), 0.96 (t, J = 7.2 Hz, 3H, CH₃); ¹³C NMR (100 MHz, CDCl₃) δ 165.5, 163.4, 161.1, 161.1, 145.9, 143.7, 138.9, 138.0, 134.0, 130.5, 129.2, 125.5, 121.3, 106.9, 62.7, 62.5, 62.2, 19.9, 19.7, 14.1, 14.0, 13.5; HRMS (ESI-TOF⁺) m/z: calcd for C₂₁H₂₇NO₇ ⁺ [(M + H)⁺], 416.1704; found, 416.1700.

Triethyl 1-(naphthalen-1-yl)-4-oxo-1,4-dihydropyridine-2,3,5- tricarboxylate (4i)：Pale yellow oil; yield 95%; ¹H NMR (400 MHz, CDCl₃) δ 7.97 (d, J = 8.2 Hz, 1H, Ph-H), 7.93–7.87 (m, 1H, Ph-H), 7.55–7.55 (m, 4H, Ph-H), 7.39 (dd, J = 7.3, 1.0 Hz, 1H, Ph-H), 6.91 (s, 1H, CH), 4.41 (q, J = 7.2 Hz, 2H, OCH₂), 4.26 (dd, J = 7.1, 2.5 Hz, 2H, OCH₂), 3.67 (dd, J = 7.2, 4.4 Hz, 2H, OCH₂), 1.40 (t, J = 7.2 Hz, 3H, CH₃), 1.28 (d, J = 7.1 Hz, 3H, CH₃), 0.46 (t, J = 7.2 Hz, 3H, CH₃); ¹³C NMR (100 MHz, CDCl₃) δ 165.6, 163.4, 160.9, 160.9, 146.5, 144.2, 134.2, 133.4, 130.9, 130.0, 128.5, 127.9, 127.1, 127.0, 125.2, 122.7, 121.3, 107.3, 62.7, 62.6, 62.4, 14.2, 14.0, 13.0; HRMS (ESI-TOF⁺) m/z: calcd for C₂₄H₂₄NO₇ ⁺ [(M + H)⁺], 438.1547; found, 438.1543.

Triethyl 4-oxo-1-(quinolin-3-yl)-1,4-dihydropyridine-2,3,5- tricarboxylate (4j)：Yellow solid; yield 92%; ¹H NMR (400 MHz, CDCl₃) δ 8.77 (d, J = 2.4 Hz, 1H, Ph-H), 8.16 (d, J = 8.5 Hz, 1H, Ph-H), 8.09 (d, J = 2.4 Hz, 1H, Ph-H), 7.88–7.75 (m, 2H, Ph-H), 7.62 (dd, J = 8.0, 7.1 Hz, 1H, Ph-H), 6.89 (d, J = 0.5 Hz, 1H, CH), 4.38 (q, J = 7.1 Hz, 2H, OCH₂), 4.27 (q, J = 7.1 Hz, 2H, OCH₂), 3.92–3.82 (m, 2H, OCH₂), 1.38 (t, J = 7.2 Hz, 3H, CH₃), 1.28 (t, J = 7.1 Hz, 3H, CH₃), 0.80 (t, J = 7.2 Hz, 3H, CH₃); ¹³C NMR (100 MHz, CDCl₃) δ 164.0, 162.0, 159.8, 159.6, 148.1, 146.8, 144.2, 142.9, 134.2, 130.1, 129.1, 128.5, 127.2, 126.8, 126.1, 120.4, 106.9, 62.0, 61.5, 61.3, 13.0, 12.8, 12.2; HRMS (ESI-TOF⁺) m/z: calcd for C₂₃H₂₃N₂O₇ ⁺ [(M + H)⁺], 439.1500; found, 439.1503.

Triethyl 1-isopropyl-4-oxo-1,4-dihydropyridine-2,3,5-tricarboxylate (4k)：Pale yellow oil; yield 83%; ¹H NMR (400 MHz, CDCl₃) δ 6.62 (s, 1H, CH), 4.46–4.40 (m, 2H, OCH₂), 4.35–4.29 (m, 2H, OCH₂), 4.26–4.21 (m, 2H, OCH₂), 4.19–4.10 (m, 1H, CH), 1.61 (s, 3H, CH₃), 1.60 (s, 3H, CH₃), 1.41–1.38 (m, 3H, CH₃), 1.35–1.32 (m, 3H, CH₃), 1.30–1.26 (m, 3H, CH₃); ¹³C NMR (100 MHz, CDCl₃) δ 164.5, 162.6, 161.3, 160.1, 144.7, 141.3, 120.8, 105.7, 62.2, 61.2, 61.0, 55.9, 18.3, 13.0, 12.9 12.7; HRMS (ESI-TOF⁺) m/z: calcd for C₁₇H₂₄NO₇ ⁺ [(M + H)⁺],354.1547; found, 354.1543.

Triethyl 1-cyclopropyl-4-oxo-1,4-dihydropyridine-2,3,5-tricarboxylate (4l)：Pale yellow oil; yield 85%; ¹H NMR (400 MHz, CDCl₃) δ 6.76 (s, 1H, CH), 4.40 (q, J = 7.2 Hz, 2H, OCH₂), 4.30 (q, J = 7.1 Hz, 1H, OCH₂), 4.24 (q, J = 7.2 Hz, 1H, OCH₂), 3.18–2.99 (m, 1H, CH), 1.39 (t, J = 7.2 Hz, 3H, CH₃), 1.32 (t, J = 6.7 Hz, 3H, CH₃), 1.28 (d, J = 7.2 Hz, 3H, CH₃), 1.13 (d, J = 7.0 Hz, 2H, CH₂), 0.91–0.84 (m, 1H, CH₂); ¹³C NMR (100 MHz, CDCl₃) δ 165.0, 164.1, 162.0, 161.4, 145.6, 141.6, 122.1, 109.4, 63.2, 62.5, 62.3, 31.2, 14.2, 14.0, 14.0, 9.0; HRMS (ESI-TOF⁺) m/z: calcd for C₁₇H₂₂NO₇ ⁺ [(M + H)⁺], 352.1391; found, 352.1394.

Triethyl 1-cyclohexyl-4-oxo-1,4-dihydropyridine-2,3,5-tricarboxylate (4m)：Pale yellow oil; yield 90%; ¹H NMR (400 MHz, CDCl₃) δ 6.60 (s, 1H, CH), 4.44 (q, J = 7.2 Hz, 2H, OCH₂), 4.31 (q, J = 7.2 Hz, 2H, OCH₂), 4.23 (q, J = 7.2 Hz, 2H, OCH₂), 3.63 (s, 1H, CH), 2.62 (d, J = 11.5 Hz, 2H, CH₂), 1.86 (d, J = 12.0 Hz, 2H, CH₂), 1.72 (d, J = 10.8 Hz, 2H, CH₂), 1.62 (d, J = 8.7 Hz, 2H, CH₂), 1.41 (t, J = 7.2 Hz, 3H, CH₃), 1.33 (t, J = 7.2 Hz, 3H, CH₃), 1.28 (d, J = 7.2 Hz, 3H, CH₃), 1.25–1.09 (m, 4H, CH₂).¹³C NMR (100 MHz, CDCl₃) δ 164.6, 162.5, 161.4, 160.2, 145.1, 141.3, 120.8, 62.1, 61.1, 61.0, 27.3, 25.3, 23.8, 13.0, 12.9; HRMS (ESI-TOF⁺) m/z: calcd for C₂₀H₂₇NO₇ ⁺ [(M + H)⁺], 393.1788; found, 393.1790.

2,3-Diethyl 5-methyl 4-oxo-1-phenyl-1,4-dihydropyridine-2,3,5- tricarboxylate (4n)：Pale yellow oil; yield 87%; ¹H NMR (400 MHz, CDCl₃) δ7.50–7.44 (m, 3H, Ph-H), 7.28–7.22 (m, 2H, Ph-H), 6.82 (s, 1H, CH), 4.25 (q, J = 7.2 Hz, 2H, OCH₂), 3.97–3.91 (m, 2H, OCH₂), 3.91 (d, J = 2.8 Hz, 3H, OCH₃), 1.28 (t, J = 7.2 Hz, 3H, CH₃), 0.94 (t, J = 7.2 Hz, 3H, CH₃); ¹³C NMR (100 MHz, CDCl₃) δ 164.8, 162.1, 159.8, 159.7, 144.7, 142.4, 135.3, 128.9, 128.3, 127.4, 120.2, 105.8, 61.7, 61.2, 52.1, 12.8, 12.3; HRMS (ESI-TOF⁺) m/ z: calcd for C₁₉H₂₀NO₇ ⁺ [(M + H)⁺], 374.1234; found, 374.1231.

5-Ethyl 2,3-dimethyl 4-oxo-1-phenyl-1,4-dihydropyridine-2,3,5- tricarboxylate (4o)：Pale yellow oil; yield 91%; ¹H NMR (400 MHz, CDCl₃) δ7.49–7.39 (m, 3H, Ph-H), 7.24–7.16 (m, 2H, Ph-H), 6.86–6.74 (m, 1H, CH), 4.33 (q, J = 7.1 Hz, 2H, OCH₂), 3.75 (s, 3H, OCH₃), 3.44 (s, 3H, OCH₃), 1.32 (t, J= 7.2 Hz, 3H, CH₃); ¹³C NMR (100 MHz, CDCl₃) δ 165.2, 163.7, 161.3, 160.6, 145.5, 143.5, 136.3, 129.9, 129.4, 128.1, 121.4, 106.8, 62.5, 53.1, 52.8, 14.0; HRMS (ESI-TOF⁺) m/z: calcd for C₁₈H₁₈NO₇ ⁺ [(M + H)⁺], 360.1078; found, 360.1075.

Trimethyl 4-oxo-1-phenyl-1,4-dihydropyridine-2,3,5-tricarboxylate (4p)：Pale yellow oil; yield 96%; ¹H NMR (400 MHz, CDCl₃) δ 7.52–7.45 (m, 3H, Ph-H),7.25–7.23 (m, 2H, Ph-H), 6.83 (s, 1H, CH), 3.91 (s, 3H, CH₃), 3.80 (s, 3H, CH₃), 3.48 (s, 3H, CH₃).¹³C NMR (100 MHz, CDCl₃) δ 164.7, 162.6, 160.3, 159.6, 144.6, 142.2, 135.3, 129.0, 128.4, 127.1, 120.5, 105.7, 52.2, 52.1, 51.9; HRMS (ESI-TOF⁺) m/z: calcd for C₁₇H₁₅NO₇ ⁺ [(M + H)⁺], 345.0849; found, 345.0846.

example 2

The preparation method comprises the following steps:

acetonitrile is used as a system solvent, aniline, ethoxy methylene diethyl malonate and acetylene dicarboxylic diethyl ester are used as raw materials, and DABCO is used as a catalyst. The raw materials of aniline, diethyl ethoxymethylene malonate and diethyl acetylenedicarboxylate are respectively diluted to 1.0mol/L by acetonitrile and then respectively placed in A, B test tubes and C test tubes, and DABCO is placed in the C test tube according to the equivalent of 10%. The aniline and ethoxy methylene malonic acid diethyl ester in a test tube A, B are continuously fed into a reaction coil 1 to react under the driving of a peristaltic pump, the temperature is controlled to be 50 ℃, the reaction time of the reaction liquid continuously flowing in the reaction channel 1 is 25min, the reaction time is accurately controlled, so that the reaction product of the aniline and the ethoxy methylene malonic acid diethyl ester directly enters a next reaction coil without entering a collecting device after flowing out of the reaction channel 1, acetylene dicarboxylic acid diethyl ester and a catalyst DABCO in a test tube C are pumped in, so that the reaction product of the aniline and the ethoxy methylene malonic acid diethyl ester and the acetylene dicarboxylic acid diethyl ester and the catalyst DABCO in the test tube C are subjected to reaction in the reaction coil 2, the temperature is controlled to be 55 ℃, the reaction time of the reaction liquid continuously flowing in the reaction channel 2 is 30min, the effluent reaction liquid is collected on line through a product collector and is subjected to post-treatment, the product 4-pyridone is obtained.

In the examples, the yield of 4-pyridone compounds prepared by changing electron-withdrawing group amine compounds is as follows:

the above compound data are as follows:

Triethyl 1-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-2,3,5- tricarboxylate (5a)：Yellow oil; yield 83%; ¹H NMR (400 MHz, CDCl₃) δ 7.26–7.19 (m, 2H, Ph-H), 7.14 (t, J = 8.5 Hz, 2H, Ph-H), 6.79 (d, J = 2.5 Hz, 1H, CH), 4.34 (q, J = 7.1 Hz, 2H, OCH₂), 4.24 (q, J = 7.1 Hz, 2H, OCH₂), 3.96 (q, J = 7.2 Hz, 2H, OCH₂), 1.34 (t, J = 7.2 Hz, 3H, CH₃), 1.26 (t, J = 7.2 Hz, 3H, CH₃), 0.98 (t, J = 7.2 Hz, 3H, CH₃); ¹³C NMR (100 MHz, CDCl₃) δ 165.2, 164.4, 163.2, 161.9, 160.8, 145.6, 143.8, 132.3, 130.5, 121.3, 116.6, 116.4, 107.3, 62.9, 62.5, 62.3, 14.1, 13.9, 13.5; ¹⁹F NMR (311 MHz, CDCl₃) δ -110.1 (s, 1F); HRMS (ESI-TOF⁺) m/z: calcd for C₂₀H₂₁FNO₇ ⁺ [(M + H)⁺], 406.1297; found, 406.1295.

Triethyl 1-(4-chlorophenyl)-4-oxo-1,4-dihydropyridine-2,3,5- tricarboxylate (5b)：Pale yellow oil; yield 85%; ¹H NMR (400 MHz, CDCl₃) δ 7.45 (d, J = 8.5 Hz, 2H, Ph-H), 7.20 (d, J = 8.5 Hz, 2H, Ph-H), 6.83 (s, 1H, CH), 4.36 (q, J = 7.1 Hz, 2H, OCH₂), 4.26 (q, J = 7.2 Hz, 2H, OCH₂), 3.99 (q, J = 7.1 Hz, 2H, OCH₂), 1.36 (t, J = 7.2 Hz, 3H, CH₃), 1.29 (d, J = 7.1 Hz, 3H, CH₃), 1.01 (t, J = 7.1 Hz, 3H, CH₃); ¹³C NMR (100 MHz, CDCl₃) δ 164.1, 162.1, 159.7, 159.6, 144.2, 142.7, 135.1, 133.8, 128.8, 128.6, 120.3, 106.4, 61.9, 61.4, 61.2, 13.0, 12.8, 12.4; HRMS (ESI-TOF⁺) m/z: calcd for C₂₀H₂₁ClNO₇ ⁺ [(M + H)⁺], 422.1001; found, 422.1005.

Triethyl 1-(4-bromophenyl)-4-oxo-1,4-dihydropyridine-2,3,5- tricarboxylate (5c)：Yellow oil; yield 84%;¹H NMR (400 MHz, CDCl₃) δ 7.61 (d, J= 8.7 Hz, 2H, Ph-H), 7.13 (d, J = 8.7 Hz, 2H, Ph-H), 6.83 (s, 1H, CH), 4.36 (q, J = 7.1 Hz, 2H, OCH₂), 4.26 (d, J = 7.2 Hz, 2H, OCH₂), 3.99 (q, J = 7.2 Hz, 2H, OCH₂), 1.37 (t, J = 7.2 Hz, 3H, CH₃), 1.28 (s, 3H, CH₃), 1.01 (t, J = 7.2 Hz, 3H, CH₃); ¹³C NMR (100 MHz, CDCl₃) δ 165.3, 163.4, 161.0, 160.8, 145.3, 144.0, 135.6, 132.9, 130.3, 124.5, 121.6, 107.8, 63.2, 62.7, 62.5, 14.3, 14.1, 13.7; HRMS (ESI-TOF⁺) m/z: calcd for C₂₀H₂₁BrNO₇ ⁺ [(M + H)⁺], 466.0496; found, 466.0493.

Triethyl 1-(4-iodophenyl)-4-oxo-1,4-dihydropyridine-2,3,5- tricarboxylate (5d)：Yellow oil; yield 87%; ¹H NMR (400 MHz, CDCl₃) δ 7.82 (d, J = 8.7 Hz, 2H, Ph-H), 7.00 (d, J = 8.7 Hz, 2H, Ph-H), 6.83 (s, 1H, CH), 4.37 (q, J = 7.2 Hz, 2H, OCH₂), 4.29–4.24 (m, 2H, OCH₂), 4.00 (q, J = 7.2 Hz, 2H), OCH₂, 1.37 (t, J = 7.2 Hz, 3H, CH₃), 1.29 (t, J = 7.2 Hz, 3H, CH₃), 1.01 (t, J= 7.2 Hz, 3H, CH₃); ¹³C NMR (100 MHz, CDCl₃) δ 165.3, 163.3, 160.9, 160.7, 145.2, 143.9, 138.8, 136.3, 130.4, 121.6, 107.7, 96.1, 63.2, 62.7, 62.4, 14.2, 14.0, 13.6; HRMS (ESI-TOF⁺) m/z: calcd for C₂₀H₂₁INO₇ ⁺ [(M + H)⁺], 514.0357; found, 514.0360.

Triethyl 4-oxo-1-(4-(trifluoromethyl)phenyl)-1,4-dihydropyridine-2,3, 5-tricarboxylate (5e)：Yellow oil; yield 82%; ¹H NMR (400 MHz, CDCl₃) δ 7.75 (d, J = 8.3 Hz, 2H, Ph-H), 7.40 (d, J = 8.2 Hz, 2H, Ph-H), 6.85 (s, 1H, CH), 4.37 (q, J = 7.2 Hz, 2H, OCH₂), 4.26 (q, J = 7.2 Hz, 2H, OCH₂), 3.96 (q, J = 7.2 Hz, 2H, OCH₂), 1.36 (t, J = 7.2 Hz, 3H, CH₃), 1.28 (t, J = 7.2 Hz, 3H, CH₃), 0.94 (t, J = 7.2 Hz, 3H, CH₃); ¹³C NMR (100 MHz, CDCl₃) δ 165.1, 163.3, 160.8, 160.5, 144.8, 143.9, 139.7, 129.3, 126.7, 126.6, 121.7, 108.1, 63.2, 62.7, 62.5, 14.1, 14.0, 13.4;¹⁹F NMR (311 MHz, CDCl₃) δ -62.9 (s, 3F); HRMS (ESI-TOF⁺) m/z: calcd for C₂₁H₂₁F₃NO₇ ⁺ [(M + H)⁺], 456.1265; found, 456.1267.

Triethyl 1-(4-nitrophenyl)-4-oxo-1,4-dihydropyridine-2,3,5- tricarboxylate (5f)：Yellow oil; yield 87%; ¹H NMR (400 MHz, CDCl₃) δ 8.35 (d, J = 8.6 Hz, 2H, Ph-H), 7.48 (d, J = 8.8 Hz, 2H, Ph-H), 6.88 (s, 1H, CH), 4.38 (q, J = 7.1 Hz, 2H, OCH₂), 4.28 (q, J = 7.1 Hz, 2H, OCH₂), 3.99 (q, J = 7.1 Hz, 2H, OCH₂), 1.38 (t, J = 7.1 Hz, 3H, CH₃), 1.30 (s, 3H, CH₃), 1.02 (t, J = 7.1 Hz, 3H, CH₃); ¹³C NMR (100 MHz, CDCl₃) δ 163.7, 162.0, 159.5, 159.2, 147.4, 143.0, 142.8, 140.8, 128.8, 123.6, 120.7, 107.4, 62.2, 61.6, 61.4, 13.0, 12.8, 12.4; HRMS (ESI-TOF⁺) m/z: calcd for C₂₀H₂₁N₂O₉ ⁺ [(M + H)⁺], 433.1242; found, 433.1240.

Triethyl 1-(2-chlorophenyl)-4-oxo-1,4-dihydropyridine-2,3,5- tricarboxylate (5g)：Yellow oil; yield 80%; ¹H NMR (400 MHz, CDCl₃) δ 7.53 (dd, J = 8.0, 1.4 Hz, 1H, Ph-H), 7.44–7.40 (m, 1H, Ph-H), 7.39–7.34 (m, 1H, Ph-H), 7.28 (dd, J = 7.8, 1.6 Hz, 1H, Ph-H), 6.84 (s, 1H, CH), 4.36 (q, J = 7.2 Hz, 2H, OCH₂), 4.28–4.22 (m, 2H, OCH₂), 3.98–3.92 (m, 2H, OCH₂), 1.36 (t, J = 7.2 Hz, 3H, CH₃), 1.27 (t, J = 7.2 Hz, 3H, CH₃), 0.96 (t, J = 7.2 Hz, 3H, CH₃); ¹³C NMR (100 MHz, CDCl₃) δ 165.3, 163.2, 160.7, 159.9, 145.3, 144.1, 134.5, 133.6, 131.5, 130.5, 130.3, 127.8, 121.5, 107.6, 62.9, 62.6, 62.4, 14.1, 14.0, 13.5; HRMS (ESI-TOF⁺) m/z: calcd for C₂₀H₂₁ClNO₇ ⁺ [(M + H)⁺], 422.1001; found, 422.1002.

Triethyl 1-(3-chlorophenyl)-4-oxo-1,4-dihydropyridine-2,3,5- tricarboxylate (5h)：Pale yellow oil; yield 93%; ¹H NMR (400 MHz, CDCl₃) δ7.43–7.32 (m, 2H, Ph-H), 7.22 (t, J = 1.8 Hz, 1H, Ph-H), 7.14–7.08 (m, 1H, Ph-H), 6.77 (s, 1H, CH), 4.30 (q, J = 7.2 Hz, 2H, OCH₂), 4.20 (q, J = 7.1 Hz, 2H, OCH₂), 3.97–3.90 (m, 2H, OCH₂), 1.30 (t, J = 7.2 Hz, 3H, CH₃), 1.22 (t, J= 7.2 Hz, 3H, CH₃), 0.94 (t, J = 7.2 Hz, 3H, CH₃); ¹³C NMR (100 MHz, CDCl₃) δ165.2, 163.2, 160.8, 160.6, 145.2, 143.9, 137.5, 135.1, 130.5, 130.4, 129.0, 127.0, 121.6, 107.7, 63.1, 62.6, 62.4, 14.1, 14.0, 13.5; HRMS (ESI-TOF⁺) m/z: calcd for C₂₀H₂₁ClNO₇ ⁺ [(M + H)⁺], 422.1001; found, 422.1003.

Triethyl 4-oxo-1-(2-(trifluoromethyl)phenyl)-1,4-dihydropyridine-2,3, 5-tricarboxylate (5i)：Yellow oil; yield 80%; ¹H NMR (400 MHz, CDCl₃) δ 7.80 (dd, J = 7.5, 1.5 Hz, 1H, Ph-H), 7.71–7.59 (m, 2H, Ph-H), 7.31 (d, J = 7.3 Hz, 1H, Ph-H), 6.86 (s, 1H, CH), 4.37 (q, J = 7.2 Hz, 2H, OCH₂), 4.26 (q, J = 7.1 Hz, 2H, OCH₂), 3.94 (q, J = 7.1 Hz, 2H, OCH₂), 1.38 (t, J = 7.2 Hz, 3H, CH₃), 1.29 (t, J = 7.2 Hz, 3H, CH₃), 0.95 (t, J = 7.2 Hz, 3H, CH₃); ¹³C NMR (100 MHz, CDCl₃) δ 165.2, 163.4, 160.8, 160.7, 144.8, 143.9, 133.1, 131.2, 130.8, 128.2, 128.2, 121.7, 108.3, 63.0, 62.7, 62.4, 14.2, 14.0, 13.5; ¹⁹F NMR (311 MHz, CDCl₃) δ -60.3 (s, 3F); HRMS (ESI-TOF⁺) m/z: calcd for C₂₁H₂₁F₃NO₇ ⁺[(M + H)⁺], 456.1265; found, 456.1266.

Triethyl 1-(3-nitrophenyl)-4-oxo-1,4-dihydropyridine-2,3,5- tricarboxylate (5j)：Drak yellow oil; yield 85%; ¹H NMR (400 MHz, CDCl₃) δ8.40–8.30 (m, 1H, Ph-H), 8.18 (t, J = 2.0 Hz, 1H, Ph-H), 7.70 (t, J = 8.1 Hz, 1H, Ph-H), 7.66–7.61 (m, 1H, Ph-H), 6.87 (d, J = 0.7 Hz, 1H, CH), 4.38 (q, J= 7.1 Hz, 2H, OCH₂), 4.27 (q, J = 7.1 Hz, 2H, OCH₂), 3.99 (q, J = 7.1 Hz, 2H, OCH₂), 1.38 (t, J = 7.1 Hz, 3H, CH₃), 1.30 (d, J = 7.1 Hz, 3H, CH₃), 1.00 (t, J = 7.2 Hz, 3H, CH₃); ¹³C NMR (100 MHz, CDCl₃) δ 163.8, 162.0, 159.6, 159.3, 147.5, 143.4, 142.9, 136.4, 133.8, 129.3, 123.8, 122.9, 120.6, 107.2, 62.2, 61.6, 61.4, 13.0, 12.8, 12.4; HRMS (ESI-TOF⁺) m/z: calcd for C₂₀H₂₁N₂O₉ ⁺ [(M + H)⁺], 433.1242; found, 433.1244.

Triethyl 1-(3,4-difluorophenyl)-4-oxo-1,4-dihydropyridine-2,3,5- tricarboxylate (5k)：Yellow oil; yield 87%; ¹H NMR (400 MHz, CDCl₃) δ 7.27 (q, J = 9.1 Hz, 1H, Ph-H), 7.20–7.09 (m, 1H, Ph-H), 7.04–7.01 (m, 1H, Ph-H), 6.82 (s, 1H, CH), 4.36 (q, J = 7.2 Hz, 2H, OCH₂), 4.26 (q, J = 7.1 Hz, 2H, OCH₂), 4.03 (q, J = 7.2 Hz, 2H, OCH₂), 1.36 (t, J = 7.2 Hz, 3H, CH₃), 1.28 (t, J = 7.2 Hz, 3H, CH₃), 1.05 (t, J = 7.2 Hz, 3H, CH₃); ¹³C NMR (100 MHz, CDCl₃) δ165.1, 163.2, 160.8, 160.6, 145.1, 144.0, 125.4, 125.3,125.3, 121.6, 118.8, 118.7, 118.6, 118.1, 118.1, 118.0, 118.0, 107.8, 63.2, 62.7, 62.5, 14.2, 14.0, 13.6; ¹⁹F NMR (311 MHz, CDCl₃) δ -133.91 (s, 1F), -133.91 (s, 1F); HRMS (ESI-TOF⁺) m/z: calcd for C₂₀H₂₀F₂NO₇ ⁺ [(M + H)⁺], 424.1202; found, 424.1205。