Synthesis method of 6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione compound

Abstract

The invention discloses a method for synthesizing a 6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione compound. The method comprises: uniformly mixing 1,2,4-triazine-3,5(2H,4H)-dione, sodium difluoromethanesulfonate, a photooxidant and a solvent to obtain a first solution; reacting the first solution under stirring at 25-50 DEG C and irradiation with a blue laser; monitoring the reaction by thin layer chromatography; and performing column chromatography to obtain the 6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione compound. The method comprises: at least two light sources emitting the blue laser are provided, at least one light source is provided on opposite sides of the first solution, and two light sources located on opposite sides of the first solution are provided opposite to each other.

Description

Technical Field

[0001] The invention belongs to the technical field of fine chemical synthesis, and specifically relates to a method for synthesizing a 6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione compound. Background Art

[0002] Organofluorine compounds have been widely used in medicine, agriculture and materials science due to their unique physical and biological properties. The introduction of fluorine atoms or fluorine-containing groups into organic molecules can usually significantly affect the lipophilicity, permeability and metabolic stability of the parent molecule. Among the many fluorine-containing groups, difluoromethyl (CF 2 H) as a possible lipophilic hydrogen bond donor, is a potential bioisostere of hydroxyl, amino or thiol groups. In recent years, compounds containing difluoromethyl groups have played an important role in the fields of medicine, pesticides and materials science, especially difluoromethyl-substituted nitrogen-containing heterocyclic compounds. For example, pyraclostrobin belongs to the pyrazoleamide fungicide and is also a new generation of SDHI fungicide. It has the excellent characteristics of broad spectrum, high efficiency and long-lasting effect; thiamethoxam is a good herbicide; deracoxib is a class of non-steroidal, non-narcotic anti-inflammatory drugs; ZSTK474 is an orally available, ATP-competitive class I PI3K selective inhibitor (W.Zhang.et.al.Nat.commun.2020,11,638). The structural formulas of pyraclostrobin, thiamethoxam, deracoxib and ZSTK474 are shown in Figure 1 shown.

[0003] In the past few decades, chemists have focused their attention on fluorine-containing compounds (CPA et al. Chem. Rev. 2015, 115, 9073–9174.; CM Get. al. Chem. Rev. 2015, 115, 612–633.; FT et. al. Nature. 2011, 473, 470–477.; LT et. al. Angew. Chem. Int. Ed. 2013, 52, 8214–8264.) and trifluoromethyl-containing compounds (CJ et. al. Chem. Rev. 2015, 115, 650–682.; ME et. al. .Chem.Soc.Rev.2014,43,6598–6608.;EHet.al.Angew.Chem.Int.Ed.2014,53,8294–8308.;CLet.al.Acc.Chem.Res.2014,47,1513–1522.;YXet.al.Chem.Rev.2015,115,826–870.;ACet.al.Chem.Rev.2015,115,1847–1935.;NCet.al.Chem.Rev.2015,115,765–825.) In contrast, there is little research on difluoromethyl compounds. Existing literature shows that difluoromethyl thymidine has stronger tumor cell inhibition ability than the marketed drug trifluorothymidine, and the IC50 value for tumor cells HCT116 and HepG2 cells reaches the low micromolar level (W. Zhang. et. al. Nat. Commun. 2020, 11, 638), which is enough to show that difluoromethyl compounds have potential application value. Therefore, it is crucial to develop an efficient method for synthesizing difluoromethyl nitrogen heterocyclic compounds.

[0004] 1,2,4-Triazine-3,5(2H,4H)-dione is a degradable, non-polluting, environmentally friendly small molecule compound (CN 107821408A). It is related to enzyme inhibitors in purine and pyrimidine biosynthesis and can, to a certain extent, lead to changes in the level of nucleotide pools in the body. Currently, 1,2,4-triazine-3,5(2H,4H)-dione has been widely used to study transcriptional regulation, especially in model microorganism yeast. Due to its antiviral activity, it can also be used as a bactericide. Therefore, the introduction of a difluoromethyl group into 1,2,4-triazine-3,5(2H,4H)-dione is expected to significantly change the biological activity.

[0005] In 2020, Li Xin's research group (W. Zhang. et al. Nat. Commun. 2020, 11, 638) reported a direct CH bond difluoromethylation reaction of nitrogen-containing heterocyclic compounds through organic photocatalysis, synthesizing 6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione compounds (such as Figure 2 ), but the reaction time of this method is long (12h) and the yield is not high (73%). In the same year, Yu Tao et al. (WO 2020 / 239076 Al) published a patent on pyridazinone derivatives of thyroid receptor-β agonists and their applications. In Example 3 of their patent, some steps involved the synthesis of 6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione compounds (such as Figure 3 As shown in the figure, the reaction requires the addition of precious metal catalyst DPPF palladium dichloride (poor raw material economy), diethylaminosulfur trifluoride (DAST) and hazardous chemical cerium ammonium nitrate (CAN) (not environmentally friendly), and the reaction conditions are relatively severe (80°C) and complex (requiring Ar protection), and the reaction steps are relatively cumbersome (4 steps).

[0006] In 2021, Zhou Jingye et al. (WO 2021 / 143706 Al) reported a patent on the synthesis of substituted triazinones as thyroid hormone receptor agonists. In Example 2 of their patent, a 6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione compound (such as Figure 4 The reaction requires 9 steps, with many reaction steps, long reaction time, low yield (1.3%), and the reaction conditions of some steps are relatively severe and use of hazardous chemical ammonium cerium nitrate (not environmentally friendly).

[0007] In 2023, Shi Jingjing et al. (CN 115650928 A) reported a patent for a polycyclic thyroid hormone beta receptor agonist and its use. In Example 19 of their patent, they reported the synthesis of 6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione compounds (such as Figure 5 ), but the reaction time is long (10h) and the yield is low (23.6%). In the same year, Shi Jingjing et al. (CN 116836158 A) reported a patent for a compound as a thyroid hormone beta receptor agonist and its use. On page 38 of the specification, a synthetic route involving 6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione compound was reported (such as Figure 6 However, this reaction requires 4 steps and takes a long time.

[0008] In summary, the above method requires the use of highly corrosive reagents, has complicated reaction steps, long reaction time, low efficiency and harsh reaction conditions, which is not conducive to later industrial applications. Summary of the invention

[0009] In view of the shortcomings of the prior art, the object of the present invention is to provide a new green cleaning method, by using blue laser as the reaction light source, to achieve efficient and highly selective 1,2,4-triazine-3,5(2H,4H)-dione compound CH bond difluoromethylation reaction to prepare 6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione compound.

[0010] The purpose of the present invention is achieved through the following technical solutions.

[0011] A method for synthesizing a 6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione compound comprises: uniformly mixing 1,2,4-triazine-3,5(2H,4H)-dione, sodium difluoromethanesulfonate, a photooxidant and a solvent to obtain a first solution; reacting the first solution under stirring at 25-50°C and under blue laser irradiation; monitoring the reaction by thin layer chromatography; and performing column chromatography to obtain the 6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione compound, wherein the number of light sources emitting the blue laser is at least two, at least one light source is arranged on opposite sides of the first solution, the two light sources located on opposite sides of the first solution are arranged opposite to each other, and the ratio of the 1,2,4-triazine-3,5(2H,4H)-dione, sodium difluoromethanesulfonate and the photooxidant is 0.4:0.8:2 in terms of the amount of the substances.

[0012] In the above technical solution, the solvent is dimethyl sulfoxide.

[0013] In the above technical solution, the photo-oxidant is 2,3-butanedione.

[0014] In the above technical solution, the power of each blue laser is 5W.

[0015] In the above technical solution, the ratio of the amount of the substance of 1,2,4-triazine-3,5(2H,4H)-dione to the volume of the solvent is 0.4:1, the unit of the amount of the substance is mmol, and the unit of the volume is mL.

[0016] In the above technical solution, the minimum distance between each of the light sources and the first solution is 1 to 3 cm.

[0017] Compared with the prior art, the present invention has the following beneficial effects:

[0018] 1. The present invention introduces a blue laser as a light source, uses the blue laser as a light source to mediate the efficient synthesis of 6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione, and designs the angle and amount of blue laser irradiation so that the 6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione compound can be efficiently constructed in one step under illumination conditions.

[0019] 2. The present invention uses 1,2,4-triazine-3,5(2H,4H)-dione and sodium difluoromethanesulfonate as reaction raw materials, and reacts in the presence of a photooxidant (such as 2,3-butanedione) to synthesize 6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione. The reaction step only requires one step, which greatly shortens the reaction step compared to the prior art.

[0020] 3. The raw materials used in the synthesis method of the present invention are cheap and easily available, have stable chemical properties, low production costs, mild reaction conditions, high reaction efficiency (reaction time is 3 hours), high reaction yield (isolation yield is as high as 80%), are green and pollution-free, and are expected to be applied to large-scale industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 are the structural formulas of pyraclostrobin, thiabendazim, deracoxib and ZSTK474;

[0022] Figure 2 A route for synthesizing 6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione compounds by direct CH bond difluoromethylation reaction of nitrogen-containing heterocyclic compounds catalyzed by visible light;

[0023] Figure 3 A synthetic route for the 6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione compound in WO 2020 / 239076 Al;

[0024] Figure 4 A synthetic route for the 6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione compound in WO 2021 / 143706 Al;

[0025] Figure 5 It is a synthetic route for the 6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione compound in CN 115650928 A;

[0026] Figure 6 The synthetic route of the 6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione compound in CN 116836158 A;

[0027] Figure 7 The synthetic route of the 6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione compound in Example 1;

[0028] Figure 8 is the H NMR spectrum of the 6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione compound in Example 1;

[0029] Fig. 9 is the NMR carbon spectrum of the 6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione compound in Example 1;

[0030] Fig.10 is the NMR fluorine spectrum of the 6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione compound in Example 1;

[0031] Fig.11 is a schematic diagram of the synthesis method in Example 1;

[0032] Fig.12 Schematic diagram of the synthesis method in Comparative Example 4. DETAILED DESCRIPTION

[0033] The technical solution of the present invention is further described below in conjunction with specific embodiments.

[0034] The raw material information involved in the following examples is as follows:

[0035] 1,2,4-Triazine-3,5(2H,4H)-dione and sodium difluoromethanesulfonate were purchased from Bidex Pharmaceuticals.

[0036] In the following embodiments, the blue laser was purchased from Tansen official flagship store, model TS-017, the peak wavelength of the blue laser is 450nm, and the cross-section of the blue laser along the vertical direction after being emitted from the light source is a rectangle with a length of 2cm and a width of 0.5cm.

[0037] In the following examples, the diameter of the quartz tube is 2 cm. When reacting under the irradiation of blue laser, the width direction of the quartz tube is completely covered by the blue laser emitted by the light source.

[0038] Example 1

[0039] like Figure 7 As shown, the synthetic route of the 6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione compound in Example 1 is as follows ("1" represents 1,2,4-triazine-3,5(2H,4H)-dione, "2" represents sodium difluoromethanesulfonate, and "3" represents 6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione compound):

[0040]

[0041] A method for synthesizing a 6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione compound comprises: placing 1,2,4-triazine-3,5(2H,4H)-dione (45.2 mg), sodium difluoromethanesulfonate (i.e. sodium difluoromethanesulfinate) and a photooxidant in a quartz tube of 10 mL in sequence, adding a solvent, mixing evenly to obtain a first solution, reacting the first solution at 25° C. under stirring conditions and under blue laser irradiation, monitoring the reaction by thin layer chromatography (the reaction is complete in 3 hours), and performing column chromatography using a silica gel column (using a mixture of petroleum ether and ethyl acetate as a flushing agent, petroleum ether and acetic acid by volume). The ratio of ethyl ester is 12:1), and the colorless oily compound is 6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione compound (52.2 mg, isolated yield is 80%), wherein the photooxidant is 2,3-butanedione, the solvent is dimethyl sulfoxide, and the ratio of 1,2,4-triazine-3,5(2H,4H)-dione, sodium difluoromethanesulfonate and the photooxidant is 0.4:0.8:2, and the ratio of the amount of 1,2,4-triazine-3,5(2H,4H)-dione to the volume of the solvent is 0.4:1. The unit of the amount of the substance is mmol, and the unit of the volume is mL.

[0042] like Fig.11 As shown, there are two light sources emitting blue lasers, and the power of each blue laser is 5 W. A light source is arranged on opposite sides of the first solution in the horizontal direction (i.e., the two light sources are located on the same horizontal line), the two light sources located on opposite sides of the first solution are opposite (i.e., the two light sources located on opposite sides of the first solution are located on the same straight line), and the minimum distance between each light source and the first solution is 1 cm.

[0043] The H NMR spectrum, C NMR spectrum and F NMR spectrum of the 6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione compound in Example 1 are as follows: Figure 8 , Fig. 9 and Fig.10 As shown. The NMR of 6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione is: 1 H NMR (400MHz, DMSO-d6) δ12.75 (s, 1H), 12.31 (s, 1H), 6.77 (t, J = 52.7Hz, 1H); 13C NMR (101MHz, DMSO-d6) δ155.1, 149.0, 135.9 (t, J = 23.7Hz), 110.7 (t, J = 237.9Hz); 19 F NMR (376MHz, DMSO-d6) δ-117.4 (d, J = 52.7Hz, 2F); HRMS (ESI)

[0044] calculated for C 4 H 2 F 2 N 3 O 2 [M+H + ]:162.0115,found:162.0124.

[0045] Comparative Example 1

[0046] A method for synthesizing a 6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione compound is basically the same as that in Example 1, except that only one light source emitting blue laser (the power of the blue laser is 5 W) is arranged on the side of the first solution, the direction in which the light source emits the blue laser is parallel to the horizontal plane, and the minimum distance between the light source and the first solution is 1 cm.

[0047] The isolated yield was 74% at 6.5 h of reaction monitoring by thin layer chromatography.

[0048] Comparative Example 2

[0049] A method for synthesizing a 6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione compound is basically the same as Example 1, with the only difference being that the directions in which the two light sources emit blue lasers are perpendicular to each other and are both directed toward the first solution (the power of each blue laser is 5 W), the directions in which the two light sources emit blue lasers are parallel to the horizontal plane (the two light sources are located in the same plane), and the minimum distance between each light source and the first solution is 1 cm.

[0050] The isolated yield was 69% when the reaction was monitored by thin layer chromatography at 3 h.

[0051] Comparative Example 3

[0052] A method for synthesizing a 6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione compound is basically the same as that in Example 1, except that: the angle between the directions in which the two light sources emit blue lasers is 120° and both are directed toward the first solution (the power of each blue laser is 5 W), the directions in which the two light sources emit blue lasers are parallel to the horizontal plane (the two light sources are located in the same plane), and the minimum distance between each light source and the first solution is 1 cm.

[0053] The isolated yield was 54% when the reaction was monitored by thin layer chromatography at 3 h.

[0054] Comparative Example 4

[0055] A method for synthesizing a 6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione compound is basically the same as that in Example 1, except that: Fig.12 As shown, two light sources (each with a blue laser power of 5 W) are symmetrically arranged on a plane where the diameter of the quartz tube is located, the angle between the directions in which the two light sources emit blue lasers is 120° and both are directed toward the first solution, the height of each light source gradually decreases from the end away from the quartz tube to the end close to the quartz tube, the angle between the direction in which each light source emits blue lasers and the horizontal plane is 30°, and the minimum distance between each light source and the first solution is 1 cm.

[0056] The isolated yield was 60% when the reaction was monitored by thin layer chromatography at 3 h.

[0057] The present invention is described above by way of example. It should be noted that, without departing from the core of the present invention, any simple deformation, modification or other equivalent replacement that can be made by those skilled in the art without inventive effort falls within the protection scope of the present invention.

Claims

1. A method for synthesizing a 6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione compound, characterized in that: include: 1,2,4-triazine-3,5(2H,4H)-dione, sodium difluoromethanesulfonate, a photooxidant and a solvent are uniformly mixed to obtain a first solution, the first solution is reacted at 25-50° C. under stirring conditions and irradiated with a blue laser, the reaction is monitored by thin layer chromatography, and column chromatography is performed to obtain a 6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione compound, wherein the number of light sources emitting the blue laser is at least two, at least one light source is arranged on each of the two opposite sides of the first solution, and the two light sources located on the two opposite sides of the first solution are arranged opposite to each other, and the ratio of the 1,2,4-triazine-3,5(2H,4H)-dione, sodium difluoromethanesulfonate and the photooxidant is 0.4:0.8:2 in terms of the amount of the substance, and the photooxidant is 2,3-butanedione.

2. The synthesis method according to claim 1, characterized in that The solvent is dimethyl sulfoxide.

3. The synthesis method according to claim 1, characterized in that The power of each blue laser is 5W.

4. The synthesis method according to claim 1, characterized in that The ratio of the amount of the substance of the 1,2,4-triazine-3,5(2H,4H)-dione to the volume of the solvent is 0.4:1, the unit of the amount of the substance is mmol, and the unit of the volume is mL.

5. The synthesis method according to claim 1, characterized in that The minimum distance between each of the light sources and the first solution is 1 to 3 cm.

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