Alpha-dideuterium methylated sulfone compound as well as synthesis method and application thereof

Abstract

The invention discloses an alpha-dideuterium methylated sulfone compound as well as a synthesis method and application thereof, and belongs to the field of organic chemistry. In an air atmosphere, benzyl methyl sulfone and 2-((3, 5-dimethyl-4-methoxypyridine-2-yl) methylsulfonyl)-5-methoxy-1H-benzo [d] imidazole are used as substrates, in the presence of a catalyst [Cp * IrCl2] 2 and cesium carbonate, deuterated paraformaldehyde is used as a carbon source, sodium formate is used as an additive, and the alpha-dideuterium methylated sulfone compound is obtained through a reaction in an acetonitrile solvent at 120 DEG C. The reaction does not need to use a ligand and hydrogen, the reaction is simple and efficient, the potential value of the compound in medicinal chemistry is shown, and the compound has a certain inhibition effect on H3N2 subtype influenza viruses and has remarkable application potential.

Description

Technical Field

[0001] This invention belongs to the field of organic chemistry, specifically relating to α-dideuterium methyl sulfone compounds, their synthesis methods, and applications. Background Technology

[0002] In the field of organic chemistry, α-methylation of compounds holds significant academic importance and practical value, particularly in medicinal chemistry where it occupies a central position. Among these, α-deuterium methylation plays a unique role in drug research, not only in exploring drug metabolic pathways and helping to elucidate the formation mechanisms of metabolites, but also in improving drug metabolic stability and prolonging drug half-life, thereby enhancing drug efficacy and safety. Therefore, conducting research on compound methylation and α-deuterium methylation is of great significance and practical value.

[0003] There are various methods for synthesizing methyl-containing compounds through direct methylation. Traditional methods for methylating amines, ketones, or other methylene compounds often rely on toxic and hazardous reagents, such as iodomethane, diazomethane, dimethyl sulfate, and dimethyl carbonate, as methyl sources in conjunction with an excess of base. These methods typically have limitations regarding the substrates used. Methanol, carbon dioxide, formic acid, and paraformaldehyde are considered green alternatives for methylation and have received considerable attention in recent decades; however, research on tritium-labeled methyl chemicals remains very limited.

[0004] The methylation of sulfonic acid compounds still faces many challenges, such as high catalyst loading, the need for expensive ligands, and long reaction times. Furthermore, research on the deuteration methylation of sulfonic acid compounds remains largely unexplored. To address these issues, this invention designs and synthesizes several anti-influenza virus prodrugs and develops an iridium-catalyzed α-deuteration methylation reaction of benzylphenyl sulfone derivatives. This method uses deuterated paraformaldehyde as the C1 source, can occur under relatively mild conditions, is simple and easy to perform, has a wide range of applications, and possesses practical value. It also provides a new method for the deuteration methylation of sulfonic acid compounds. Summary of the Invention

[0005] To overcome the aforementioned technical deficiencies, this invention provides α-dideuterium methyl sulfone compounds and investigates their synthesis methods and active applications. The synthesis method of this invention involves, in an air atmosphere, using benzyl methyl sulfone or 2-((3,5-dimethyl-4-methoxypyridin-2-yl)methylsulfonyl)-5-methoxy-1H-benzo[d]imidazole as a substrate, in the presence of the catalyst [Cp*IrCl2]2 and cesium carbonate, deuterated paraformaldehyde as a carbon source, sodium formate as an additive, and acetonitrile solvent at 120 °C. oThe C-reaction yields α-dideuterium methyl sulfone compounds. This reaction requires no ligands or hydrogen, is simple and efficient, demonstrating its potential value in medicinal chemistry, and exhibits some inhibitory effect on the H3N2 subtype influenza virus, showing significant application potential.

[0006] The α-dideuterium methyl sulfone compounds of this invention have the following structural formula:

[0007] ,

[0008] This invention also provides a method for synthesizing the above-mentioned α-dideuterium methyl sulfone compounds, comprising the following steps: using benzyl methyl sulfone or 2-((3,5-dimethyl-4-methoxypyridin-2-yl)methylsulfonyl)-5-methoxy-1H-benzo[d]imidazole as a substrate, deuterated paraformaldehyde as a carbon source, and sodium formate as an additive, reacting in the presence of catalyst [Cp*IrCl2]2 and cesium carbonate to obtain α-dideuterium methyl sulfone compounds; the reaction equation is as follows:

[0009]

[0010] Furthermore, in the above technical solution, the ratio of benzyl methyl sulfone or 2-((3,5-dimethyl-4-methoxypyridin-2-yl)methylsulfonyl)-5-methoxy-1H-benzo[d]imidazolium, cesium carbonate, sodium formate, [Cp*IrCl2]2 and deuterated paraformaldehyde is 1: 1: 4: 0.001: 1.

[0011] Furthermore, in the above technical solution, the organic solvent is acetonitrile, and the reaction temperature is 100-120°C. o C.

[0012] Furthermore, in the above technical solution, the reaction takes place in air.

[0013] The present invention also provides the application of the aforementioned α-dideuterium methylated benzylphenyl sulfone derivatives in the preparation of antiviral drugs.

[0014] Furthermore, in the above technical solution, the virus is the H3N2 subtype influenza virus.

[0015] Beneficial effects of this invention:

[0016] 1. This invention requires no ligands or hydrogen, has green and mild reaction conditions, is simple and safe to operate, and has a wide range of substrate applicability and good functional group compatibility.

[0017] 2. This invention uses benzyl methyl sulfone and 2-((3,5-dimethyl-4-methoxypyridin-2-yl)methylsulfonyl)-5-methoxy-1H-benzo[d]imidazole as substrates, [Cp*IrCl2]2 as catalyst, deuterated paraformaldehyde as the C1 source, and sodium formate as a safe and stable hydrogen source, reacting in acetonitrile solvent in the presence of cesium carbonate to obtain the target compound. This reaction method achieves α-dideuterium methylation of benzyl phenyl sulfone derivatives, and the reacted derivatives show significant inhibitory effects against H3N2 subtype influenza virus. Attached Figure Description

[0018] Figure 1 Experimental steps for preliminary screening of compounds that inhibit H3N2 subtype influenza virus;

[0019] Figure 2 This serves as a preliminary screening for the activity of compounds 1a and 2a against H3N2 subtype IV at a single concentration (25 μM).

[0020] Figure 3 EC for compound ZMD-34 50 (Compound ZMD-34 EC) 50 =2.756 μM);

[0021] Figure 4 CC of compound ZMD-34 50 (compound ZMD-34 CC) 50 =230.3 μM);

[0022] Figure 5 EC for compound ZMD-37 50 (Compound ZMD-37 EC) 50 =1.483 μM);

[0023] Figure 6 CC of compound ZMD-37 50 (Compound ZMD-37 CC) 50 =55.74μM). Specific Implementation

[0024] The present invention will be further illustrated below with specific examples. These embodiments should be understood as illustrative only and not as limiting the scope of protection of the present invention. After reading the description of the present invention, those skilled in the art can make various alterations or modifications to the present invention, and these equivalent changes and modifications also fall within the scope defined by the claims of the present invention.

[0025] Example 1

[0026]

[0027] Under air atmosphere, ZMD-34-S1 (0.2 mmol, 1.0 equiv), cesium carbonate (65.2 mg, 0.2 mmol), sodium formate (54.4 mg, 0.8 mmol), [Cp*IrCl2]2 (0.16 mg, 0.0002 mmol), and deuterated paraformaldehyde (19.6 mg, 0.2 mmol) were sequentially added to a 10 mL Shrek sealed tube, followed by 2.0 mL of acetonitrile. The tube was then placed at 120°C. o The mixture was stirred continuously at C for 12 hours and monitored by TLC. After the reaction was complete, the mixture was separated by column chromatography with PE / EA = 8 / 1 as the mobile phase to obtain product ZMD-34. 1 H NMR (400 MHz, CDCl3) δ 7.55-7.30 (m, 4H), 4.18 (d, J = 6.8 Hz, 1H), 2.64 (s, 3H), 1.82-1.73 (m, 1H). 13 C NMR (101 MHz, CDCl3)δ 134.5, 129.2, 129.0, 128.9, 64.7, 37.8, 13.3 (m). HRMS (ESI) m / z: [M+ Na] + Calcd for C9H 10 D2NaO2S + 209.0 576, Found: 209.0574.

[0028] Example 2

[0029]

[0030] Under air atmosphere, ZMD-37-S1 (0.2 mmol, 1.0 equiv), cesium carbonate (65.2 mg, 0.2 mmol), sodium formate (54.4 mg, 0.8 mmol), [Cp*IrCl2]2 (0.16 mg, 0.0002 mmol), and deuterated paraformaldehyde (19.6 mg, 0.2 mmol) were sequentially added to a 10 mL Shrek sealed tube, followed by 2.0 mL of acetonitrile. The tube was then placed at 120°C. o The mixture was stirred continuously at C for 12 hours and monitored by TLC. After the reaction was complete, the mixture was separated by column chromatography with PE:EA = 8:1 as the mobile phase to obtain product ZMD-37. 1H NMR (400 MHz, CDCl3) δ 11.46 (s, 1H), 8.19 (s,1H), 7.77 (s, 1H), 7.26 (s, 1H), 6.97 (d, J = 48.4 Hz, 2H), 3.86 (s, 3H), 3.53 (s, 3H), 2.25 (s, 3H), 2.17 (s, 3H), 1.79 (d, J = 6.9 Hz, 1H). 13 C NMR (101 MHz, CDCl3) δ 164.4, 158.4, 150.7, 149.8, 145.8, 127.5, 126.8, 115.9,62.7, 59.8, 55.8, 14.0 (m), 13.2, 11.4. HRMS (ESI) m / z: [M+ Na] + Calcd forC 18 H 19 D2N3NaO4S + 400.1271, Found: 400.1261

[0031] Example 3

[0032] This embodiment presents the preliminary detection process and results of the inhibition of H3N2 subtype influenza virus by compounds ZMD-34 and ZMD-37 described in Examples 1 and 2 at the cellular level. Unless otherwise specified, all materials and consumables listed in this embodiment are commercially available. Cells and viruses are from cell and microbial resource banks of CTCC or other relevant institutions. The experimental methods in this embodiment are standard molecular biology, cell biology, or virology procedures, which researchers in the field can easily understand and operate. The specific steps are as follows:

[0033] 1. Cells and viruses

[0034] MDCK (canine kidney cells), culture conditions: DMEM medium 90% + 10% bovine serum + 1% penicillin-streptomycin;

[0035] The H3N2 subtype influenza virus A / Swine / Guangdong / SQQMA / 2024(H3N2) (abbreviated as: H3N2-SQQMA) is lethal to mice, and its hemagglutination titer after proliferation in chicken embryos is 2. 10 HAU / 50 µL.

[0036] 2. Main reagents:

[0037] DMEM (Gibco, cat: C11995500BT);

[0038] Fetal bovine serum FBS (Gibco, cat:10270-106);

[0039] Pen-Strep (10,000 U / mL) (M&C gene biotechnology, cat: G2723M3);

[0040] Antiviral drug that has shown positive results for influenza virus: Oseltamivir phosphate (Solarbio, cat: IO0490);

[0041] MUNANA (Sigma, cat: M8639);

[0042] MTT:(3-(4,5-Dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide)(Tetramethylazozolium salt)(MCE, cat: HY-15924);

[0043] DMSO (Solarbio, cat: D8370).

[0044] 4. Experimental steps:

[0045] Step 1: As Figure 1 As shown, the activity of the compound in inhibiting H3N2 influenza virus was detected: MDCK cells were used at 1×10⁻⁶ cells. 5 Cells / wells were seeded in 12-well plates the following day; when cell confluence reached 90-95%, the original culture medium was discarded, and 900 μL of DMEM and 100 μL of the test compound (250 μM) or positive control drug (Oselta mivir phosphate, 100 μM) were added to bring the final concentration of the test compound to 25 μM and the final concentration of the positive control drug to 10 μM; 37 o Incubate at 37°C for 4 h, discard the supernatant, and add 100 μL of H3N2-SQQ MA virus solution at MOI=0.01; incubate at 37°C for 2 h, wash away free virus, and add 900 μL of cell maintenance medium DMEM and 100 μL of the test compound (250 μM) or positive control drug (100 μM); incubate at 37°C for 2 h, wash away free virus, and add 37°C. o After culturing at C for 48 hours, the cell culture supernatant was collected; cells with only DMEM were used as a blank control (Mock), and the inhibitory rate of the compound against influenza virus was determined by NA activity.

[0046] The experiment included three control groups:

[0047] Positive drug group: Added virus and added Oseltamivir phosphate at a final concentration of 10 µM;

[0048] Virus control group: Group with only virus added, no compound added;

[0049] Normal cell group: No virus or drug added.

[0050] Step 2, NA activity assay: Add 50 μL of cell culture supernatant to each well of a 96-well black microplate, and perform at least two assays for each compound; add 50 μL of influenza virus NA substrate MUNANA to each well in the dark; incubate at 37°C in the dark. o After incubation in a C incubator for 30 min, 100 μL of 0.2 M Na2CO3 stop solution was added to each well; the fluorescence value was measured using a multifunctional microplate reader: excitation wavelength 355 nm, emission wavelength 485 nm, and the fluorescence value was read. The compound inhibition rate (%) = [1 - (OD compound - OD blank) / (OD virus control - OD blank)] * 100. A preliminary screening of anti-H3N2 subtype IV activity at a single concentration (25 μM) was obtained, such as... Figure 2 As shown, the compound concentration was 25 μM, and the control drug concentration was 10 μM.

[0051] Step 3: Replace the 250 µM test compound from Step 1 with test compounds at final concentrations of 0.8 μM, 4 μM, 20 μM, 100 μM, and 500 μM. Following Steps 1 and 2, first calculate the inhibition rate of different concentrations of the compound against the influenza virus. Then, based on the inhibition rate, use GraphPad Prism software to derive the EC50 (exponential coefficient of performance) for inhibiting viral replication. 50 For details, please see the results. Figure 3 and Figure 5 .Depend on Figure 3 It can be seen that the EC of compound ZMD-34 50 =2.756 μM, from Figure 5 It can be seen that the EC of compound ZMD-37 50 =1.483 μM.

[0052] Step 4: MTT assay for cytotoxicity: 5 × 10⁻⁶ 4Cells were seeded in 96-well cell culture plates containing 100 μL of cell culture medium. The medium was discarded, and 100 μL of a gradient concentration compound solution was added to achieve final concentrations of 0.8 μM, 4 μM, 20 μM, 100 μM, and 500 μM, respectively. Each concentration was repeated in triplicate. A control without the compound was also included. After 72 h of cell culture, 100 μL of supernatant was discarded, and 20 μL of MTT (5 mg / mL) was added. The cells were incubated at 37°C for 4 h. After centrifugation, 100 μL of supernatant was discarded, and 100 μL of DMSO was added. The cells were incubated at room temperature in the dark, and shaken for 15 minutes until the blue formazene dissolved. Cell viability was measured using a microplate reader at OD595 (OD630 as a reference wavelength). The CC value was calculated based on the cell viability, and the CC was determined using GraphPad Prism software. 50 For details, please see the results. Figure 4 , Figure 6 .Depend on Figure 4 It can be seen that the C2C of compound ZMD-34 50 =230.3μM, from Figure 6 It can be seen that the CC of compound ZMD-37 50 =55.74μM.

[0053] Step 5: Calculation of the Selective Index (SI) of the drug's anti-influenza virus activity: Selective Index (SI) = CC 50 / EC 50 .

[0054] 5. Test Results:

[0055] Conclusion: Compounds ZMD-34 and ZMD-37 exhibit antiviral activity against the proliferation of H3N2 subtype influenza virus. The selective index (SI) for antiviral activity was 83.56 and 37.59, respectively (the selective index for the control drug Osel tamivir phosphate was 3233.8).

[0056] The above description is merely a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.

Claims

1. An α-dideuterium methyl sulfone compound, characterized in that, The specific structural formula is as follows: 、 。 2. The method for synthesizing α-dideuterium methyl sulfone compounds as described in claim 1, characterized in that, The reaction includes the following steps: using benzyl methyl sulfone or 2-((3,5-dimethyl-4-methoxypyridin-2-yl)methylsulfonyl)-5-methoxy-1H-benzo[d]imidazole as a substrate, deuterated paraformaldehyde as a carbon source, and sodium formate as an additive, in the presence of catalyst [Cp*IrCl2]2 and cesium carbonate, to obtain α-dideuterium methyl sulfone compounds; the reaction equation is as follows: 。 3. The method for synthesizing α-dideuterium methyl sulfone compounds according to claim 2, characterized in that: The ratio of benzyl methyl sulfone or 2-((3,5-dimethyl-4-methoxypyridin-2-yl)methylsulfonyl)-5-methoxy-1H-benzo[d]imidazolium, cesium carbonate, sodium formate, [Cp*IrCl2]2 to deuterated paraformaldehyde is 1: 1: 4: 0.001:

1.

4. The method for synthesizing α-dideuterium methyl sulfone compounds according to claim 2, characterized in that: The organic solvent is acetonitrile.

5. The method for synthesizing α-dideuterium methyl sulfone compounds according to claim 2, characterized in that: The reaction temperature is 100-120°C. o C.

6. The method for synthesizing α-dideuterium methyl sulfone compounds according to claim 2, characterized in that: The reaction takes place in air.

7. The use of the α-dideuterium methyl sulfone compound according to claim 1 in the preparation of antiviral drugs.

8. The use of the α-dideuterium methyl sulfone compound according to claim 7 in the preparation of antiviral drugs, characterized in that, The virus in question is the H3N2 subtype of influenza virus.

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