Synthesis and application of 4H-pyrido [1, 2-a] pyrimidine-4-one-1, 3, 5-triazine derivative

Abstract

The invention relates to the technical field of medicine synthesis, in particular to a synthesis method and application of a 4H-pyrido [1, 2-a] pyrimidine-4-one-1, 3, 5-triazine derivative. The structure of the target compound is shown as a formula I. The preparation method of the 4H-pyrido [1, 2-a] pyrimidine-4-ketone-1, 3, 5-triazine derivative comprises the following step: reacting a compound shown in a formula I with a compound shown in a formula II in the presence of acetonitrile, secondary amine and anhydrous potassium carbonate to obtain the 4H-pyrido [1, 2-a] pyrimidine-4-ketone-1, 3, 5-triazine derivative. The 4H-pyrido [1, 2-a] pyrimidine-4-ketone-1, 3, 5-triazine derivative disclosed by the invention has a relatively good anti-tumor effect, and is characterized by relatively strong tumor cell growth inhibition activity.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical synthesis technology, and particularly to methods for synthesizing a series of 4H-pyrido[1,2-a]pyrimidin-4-one-1,3,5-triazine derivatives and their applications. Background Technology

[0002] Cancer is a collective term for a complex group of diseases that can occur in almost any organ or tissue, and their development is often closely related to gene mutations. Cancer is now the second leading cause of death worldwide, after cardiovascular disease. A wide range of treatments are available for cancer, including surgery, radiation therapy, chemotherapy, targeted therapy, and immunotherapy. Chemotherapy is the primary clinical treatment for tumors; however, traditional chemotherapy drugs face many obstacles, such as cytotoxicity, drug resistance, and lack of sensitivity, thus limiting their application.

[0003] Nitrogen-containing heterocyclic compounds are cyclic compounds containing nitrogen atoms. In addition to carbon atoms, the rings contain at least one nitrogen atom, making them the most numerous class of organic compounds. They are widely found in nature and have important applications in drug development and materials science. The most common heteroatoms in heterocyclic compounds are nitrogen, sulfur, and oxygen atoms. They can be divided into two main categories: aliphatic heterocyclic compounds and aromatic heterocyclic compounds. Heterocyclic compounds are commonly found in the structures of drug molecules. The most common heterocyclic compounds are five-membered and six-membered heterocycles, as well as benzo[a]heterocyclic compounds. Five-membered heterocyclic compounds include furan, thiophene, and thiazole, while six-membered heterocyclic compounds include pyridine, pyrimidine, and pyridazine, and possess various activities such as antitumor, antiviral, antiparasitic, antioxidant, and antimalarial effects. 4H-pyrido[1,2-a]pyrimidin-4-one is a fused pyrimidine scaffold containing two nitrogen atoms and exhibits various biological activities such as antitumor, antioxidant, antiviral, and anti-inflammatory effects.

[0004] Triazine compounds are six-membered heterocyclic compounds containing three nitrogen atoms. They possess advantages such as easy hydrogen bonding and good stability, exhibiting multi-channel pharmacological properties and important industrial applications. Literature review shows that triazine derivatives have good antitumor activity. Summary of the Invention

[0005] The present invention aims to provide a series of novel 4H-pyrido[1,2-a]pyrimidin-4-one-1,3,5-triazine derivatives, and to provide efficient synthetic methods for the new compounds, as well as the application of the new compounds in antitumor drugs.

[0006] To achieve the above objectives, the present invention specifically adopts the following technical solution:

[0007] A novel 4H-pyrido[1,2-a]pyrimidin-4-one-1,3,5-triazine derivative, the general structural formula of which is shown in Formula I:

[0008]

[0009] In the structure shown in Formula I, R is selected from secondary amines.

[0010] Preferably, the 4H-pyrido[1,2-a]pyrimidin-4-one-1,3,5-triazine derivative is as follows:

[0011]

[0012] The synthetic method of the aforementioned 4H-pyrido[1,2-a]pyrimidin-4-one-1,3,5-triazine derivative is as follows:

[0013] In the final reaction, all NH2-R are selected from secondary amines, and the specific operation of the reaction is as follows:

[0014] 2-((4-chloro-6-phenyl-1,3,5-triazin-2-yl)oxy)-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one and 2 equivalents of anhydrous potassium carbonate were mixed with 5 ml of acetonitrile. 1.1 equivalents of secondary amine were slowly added dropwise at room temperature and stirred for 1 h. The reaction was monitored by TLC until it ended.

[0015] This invention provides a series of novel synthetic methods for 4H-pyrido[1,2-a]pyrimidin-4-one-1,3,5-triazine derivatives. These methods are simple to operate, safe, produce few reaction byproducts, have high yields, and the products are easy to separate and purify.

[0016] The 4H-pyrido[1,2-a]pyrimidin-4-one-1,3,5-triazine derivative of the present invention exhibits strong inhibitory activity against SGC-7901, IC50. 50 The concentration reached 10.40 μM, which is superior to the positive control 5-fluorouracil (18.55 μM), and has broad application prospects in the treatment of tumors. Attached Figure Description

[0017] Figure 1 Example 1 final product 1 H-NMR spectrum; Figure 2 Example 1 final product 13 C-NMR spectrum;

[0018] Figure 3 Example 2 Final product 1 H-NMR spectrum; Figure 4 Example 2 Final product 13 C-NMR spectrum;

[0019] Figure 5 Example 3 Final product1 H-NMR spectrum; Figure 6 Example 3 Final product 13 C-NMR spectrum; Detailed Implementation

[0020] The technical solutions of the present invention will be clearly and completely described below in conjunction with specific embodiments. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. The following description of at least one exemplary embodiment is merely illustrative and is in no way intended to limit the present invention or its application or use. Other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are all within the scope of protection of the present invention.

[0021] Example 1: Preparation of 2-((4-(diethylamino)-6-phenyl-1,3,5-triazin-2-yl)oxy)-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one

[0022]

[0023] 2-Amino-5-fluoropyridine and bis(2,4,6-trichlorophenyl)malonate were dissolved in 120 mL of tetrahydrofuran and heated at 80 °C for 3 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to remove the tetrahydrofuran. The resulting solid was washed with petroleum ether to give 7-fluoro-2-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one, a pale yellow solid. 7-fluoro-2-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one and anhydrous K₂CO₃ were dissolved in an appropriate amount of DMF, and then 2,4-dichloro-6-phenyl-1,3,5-triazine dissolved in DMF was slowly added dropwise at 0 °C. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 1:1). After the reaction, the mixture was continuously extracted with saturated sodium bicarbonate solution and ethyl acetate. The ester was removed by rotary evaporation under vacuum, and 2-((4-chloro-6-phenyl-1,3,5-triazin-2-yl)oxy)-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one was obtained by column chromatography. 2-((4-chloro-6-phenyl-1,3,5-triazin-2-yl)oxy)-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one was dissolved in anhydrous K₂CO₃ in an appropriate amount of acetonitrile. A secondary amine was slowly added dropwise at room temperature. After determining the total conversion product by TLC analysis, the product was purified by column chromatography (petroleum ether: ethyl acetate) to obtain the target compound. White solid, yield: 67%, melting point: 142-144℃. 1H NMR (500MHz, CDCl3) δ9.05 (dd, J=4.5, 2.7Hz, 1H), 8.40-8.35 (m, 2H), 7.74 (ddd, J=9.3, 6.4, 2.7Hz, 1H), 7.66 (dd, J=9.8, 5.1Hz, 1H), 7.56- 7.49 (m, 1H), 7.44 (t, J = 7.7Hz, 2H), 6.39 (s, 1H), 3.80 (q, J = 7.1Hz, 2H), 3.58 (q, J = 7.1Hz, 2H), 1.31 (t, J = 7.1Hz, 3H), 1.18 (t, J = 7.1Hz, 3H). 13 C NMR (126MHz, CDCl3) δ173.0, 170.0, 165.9, 164.8, 159.2, 155.2, 153.2, 148.5, 136.0, 132 .0, 129.7, 129.5, 128.7, 128.3, 127.6, 127.5, 114.4, 114.0, 93.1, 42.4, 42.0, 13.1, 12.9.

[0024] Example 2: Preparation of 7-fluoro-2-((4-phenyl-6-(pyrrolidone-1-yl)-1,3,5-triazine-2-oxy)-4H-pyrido[1,2-a]pyrimidin-4-one)

[0025]

[0026] The preparation method is the same as in Example 1. A white solid was obtained, with a yield of 66% and a melting point of 137-139°C. 1 H NMR (400MHz, CDCl3) δ9.04 (dd, J=4.5, 2.7Hz, 1H), 8.41-8.34 (m, 2H), 7.73 (ddd, J=9.4, 6.4, 2.8Hz, 1H), 7.66 (dd, J=9.7, 5.2 Hz, 1H), 7.56-7.49 (m, 1H), 7.45-7.40 (m, 2H), 6.39 (s, 1H), 3.80 (t, J=6.5Hz, 2H), 3.58 (t, J=6.3Hz, 2H), 2.05-1.97 (m, 4H). 13 C NMR (151MHz, CDCl3) δ172.9, 169.7, 164.8, 164.7, 159.2, 155.0, 153.4, 148.5, 135.9, 132. 1, 129.7, 129.5, 128.8, 128.3, 127.7, 127.6, 114.3, 114.1, 93.0, 46.9, 46.5, 25.18, 25.15.

[0027] Example 3: Preparation of 7-fluoro-2-((4-morpholino-6-phenyl-1,3,5-triazin-2-yl)oxy)-4H-pyrido[1,2-a]pyrimidin-4-one

[0028]

[0029] The preparation method is the same as in Example 1. A white solid was obtained, with a yield of 60% and a melting point of 215-217°C. 1 H NMR (400MHz, CDCl3) δ9.05 (dd, J=4.4, 2.8Hz, 1H), 8.39-8.31 (m, 2H), 7.75 (ddd, J=9.4, 6.5, 2.8Hz, 1H), 7.67 (dd, J=9.7, 5.1H z, 1H), 7.58-7.49 (m, 1H), 7.46-7.42 (m, 2H), 6.37 (s, 1H), 4.09 (t, J=4.9Hz, 2H), 3.81 (t, J=4.6Hz, 4H), 3.75 (q, J=4.1Hz, 2H). 13 C NMR (151MHz, CDCl3) δ173.5, 170.2, 166.4, 164.5, 159.1, 155.1, 153.5, 148.5, 135.6, 132. 4, 129.9, 129.7, 128.8, 128.3, 127.64, 127.60, 114.4, 114.1, 93.1, 66.7, 66.6, 44.2, 43.9.

[0030] Example 4: Determination of the antitumor activity of the 20 4H-pyrido[1,2-a]pyrimidine-4-one derivatives mentioned above in this patent.

[0031] This invention tested the antitumor activity of 20 4H-pyrido[1,2-a]pyrimidine-4-one derivatives.

[0032] The synthesized 4H-pyrido[1,2-a]pyrimidin-4-one derivative was tested for its antitumor activity using the MTT assay. The specific method is as follows:

[0033] SGC-7901 cells were cultured in DMEM high-glucose medium supplemented with 10% fetal bovine serum (FBS) and 1% penicillin / streptomycin at 37°C in a 5% CO2 incubator. The antiproliferative activity of the target compound was detected by MTT assay. SGC-7901 cells were seeded into 96-well plates (1×10⁶ cells / wells). 4Cells were then placed in a solution of 6.25–200 μM of the drug for one day. After treatment, the supernatant was removed, and cells treated with MTT (5 mg / mL) for 4 hours were added to 100 μL of DMSO to dissolve the formed crystals. The absorbance was measured at 450 nm using a microplate reader (BioTek Instruments, USA). All experiments were performed three times.

[0034] The antitumor activities of 20 compounds were determined and are shown in Table 1.

[0035] Table 1

[0036] Antiproliferative activity of the target compound against human gastric cancer cells SGC-7901

[0037]

[0038] The embodiments described above are merely examples of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these modifications and improvements all fall within the scope of protection of the present invention.

Claims

1. Synthesis of a series of 4H-pyrido[1,2-a]pyrimidin-4-one-1,3,5-triazine derivatives, the structures of which are shown below:

2. The use of the 4H-pyrido[1,2-a]pyrimidine-4-one-1,3,5-triazine derivative of claim 1 in the preparation of antitumor drugs, characterized in that the 4H-pyrido[1,2-a]pyrimidine-4-one-1,3,5-triazine derivative has antitumor activity.

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