A method for preparing on-dna dithio-carbamate structured compounds

Abstract

The application belongs to the field of DEL library construction, and particularly relates to a method for preparing On-DNA dithio-carbamate structural compounds. The method comprises the following steps: reacting On-DNA secondary amine, carbon disulfide and halide under certain temperature and solvent conditions to generate On-DNA dithio-carbamate structural compounds. The preparation method can obtain rich-structure On-DNA dithio-carbamate structural compounds at one time, the applicable range of raw materials is significantly widened on the basis of the prior art, the reaction condition is mild, and the conversion rate can be more than 90%.

Description

Technical Field

[0001] This application belongs to the field of lead compound library construction in pharmaceutical research, specifically involving a method for synthesizing On-DNA dithiocarbamate structure compounds. Background Technology

[0002] Currently, there are numerous known compounds with dithiocarbamate structures and diverse mechanisms of action. Among the following compounds, compounds 1 to 14 are marketed drugs and natural products with dithiocarbamate structures; compounds 15 to 27 are naturally derived dithiocarbamate compounds with anticancer activity; compounds 28 to 34 are representative targeted anticancer drugs among dithiocarbamate compounds; compounds 35 to 42 are anticancer compounds with various structural types; and compounds 43 to 51 are dithiocarbamate-metal complexes with anticancer activity.

[0003]

[0004]

[0005] Carcinogenic dithiocarbamate compounds have diverse mechanisms of action, such as topoisomerase II inhibitors and aldehyde dehydrogenase ALDH inhibitors (Disulfiram).

[0006] Compounds 52 to 65 have antifungal or antibacterial activity; compounds 66 to 69 are representative of dithiocarbamate compounds with anti-Alzheimer's disease activity; compounds 70 to 72 have anti-tuberculosis activity; compounds 73 to 75 have sperm-inhibiting activity; compounds 76 and 77 have anti-glaucoma activity; 78 and 79 have anticholinergic activity; 80 and 81 have hypoglycemic activity; 82 and 83 have anti-inflammatory activity; and 84 has anti-influenza activity (An insight into medicinal attributes of dithiocarbamates: Bird's eye view, Bioorganic Chemistry, 105(2020)104346).

[0007] This demonstrates the diversity and rich mechanisms of action of drugs containing dithiocarbamates. However, their applications extend beyond pharmaceuticals, extending to other chemical fields. For example, disulfiram (compound 1) can be used as a super-accelerator and vulcanizing agent for natural rubber, styrene-butadiene rubber, nitrile rubber, butyl rubber, cis-butadiene rubber, and latex, as well as as a bactericide and insecticide. Therefore, traditional chemical synthesis methods are clearly insufficient for screening these compounds. In recent years, DNA-encoded compound library technology (DEL technology) has emerged, enabling the synthesis of libraries containing hundreds of millions of compounds in a very short time. In the field of new drug development, high-throughput screening targeting biological targets is one of the main methods for rapidly obtaining lead compounds. DNA-encoded compound library technology significantly improves the efficiency and likelihood of lead compound discovery.

[0008] After extensive searching, the inventors of this application did not find any literature reports on the preparation of dithiocarbamate compounds using DEL technology. Among existing small molecule synthesis techniques, Daoshan Yang et al. (《Photocatalyst-Free Visible-Light-Promoted C(sp 2 (S-Coupling: A Strategy for the Preparation of S-Aryl Dithiocarbamates, Organic Letters, 2019, 21(19), 7938-7942) Dithiocarbamate compounds were prepared by reacting haloalkanes, carbon disulfide and secondary amines; the reaction conditions were light, Cs2CO3 (base) and DMSO as solvent. However, after analysis, it was found that the existing technical methods have the following technical problems: (1) low conversion rate, especially when the haloalkanes are brominated, the conversion rate is the highest at 43%; (2) low universality, that is, the substrate haloalkanes can only be aryl haloalkanes; (3) long reaction time. In particular, the long reaction time and the fact that only one type of small molecule compound can be synthesized at a time cannot meet the requirements of high throughput screening. Therefore, it is urgent to develop a method with broad applicability, rapid and large-scale preparation of dithiocarbamate compounds to meet the needs of constructing and screening lead compound libraries with dithiocarbamate structures. Summary of the Invention

[0009] To address the aforementioned technical problems, this application provides a method that, compared to the prior art, has broad substrate applicability, short reaction time, high conversion rate, and can synthesize large quantities of dithiocarbamate compounds in a single step.

[0010] The specific method for preparing the On-DNA dithiocarbamate structured compound includes the steps of reacting an On-DNA secondary amine with carbon disulfide and a halogenated product under certain temperature and solvent conditions to generate the On-DNA dithiocarbamate structured compound. The specific reaction equation is as follows: Among them, -R 1 -NH- represents dimethylamine, cyclopentylamine, cyclohexylcyclopentylamine, 7-azaspiro[3,4]octane, cyclohexylamine, 1,2,5,6-tetrahydropyridine, phenylcyclohexylamine; R 2 C 2-5 Straight-chain alkyl, isobutyl, isopentyl, allyl, 1-butenyl, 1-butynyl, hydroxyethyl, trifluoropropyl, acetate, cyclopropylmethyl, cyclobutylmethyl, oxacyclobutanemethyl, isopropyl, sec-butyl, ethyl propionate, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydro-2H-pyranyl, tetrahydro-2H-thiaranyl, 2-oxaspiro[3.3]heptyl, benzyl; X is chlorine, bromine, iodine;

[0011] Preferably, the final concentration of carbon disulfide in the reaction is greater than or equal to 12.5 mmol / L, more preferably greater than or equal to 25.0 mmol / L; preferably R 2 The final concentration of halide X is greater than or equal to 25.0 mmol / L, and the optimal concentration is greater than or equal to 50.0 mmol / L;

[0012] The solvent includes water and an organic solvent, wherein the organic solvent is one or more of N,N-dimethylformamide (DMF), ethanol, dimethyl sulfoxide (DMSO) or dimethylacetamide (DMA); preferably, the volume ratio of water to DMF is 1:4 to 1:2; preferably, the volume ratio of water to DMF is 1:3.

[0013] The temperature is not higher than 100°C, preferably the reaction temperature is not higher than 90°C, and more preferably not higher than 60°C;

[0014] Preferably, to improve the conversion rate, an alkali is added to the reaction system. The alkali is bicycloamidine (abbreviated as DBU, also known as 1,8-diazabicyclo[5.4.0]undec-7-ene), Na2CO3, NaHCO3, K2CO3, KHCO3, Cs2CO3, NaOH, KOH, N,N-diisopropylethylamine (DIEA), 1,4-diazabicyclo[2.2.2]octane (DABCO), and a borate buffer solution with pH = 9.5. The alkali is preferably DBU, DABCO, and DIEA; more preferably DBU and DABCO. The final concentration of the alkali is greater than or equal to 12.5 mmol / L.

[0015] In some embodiments of this application, the inventors experimented with final carbon disulfide concentrations of 12.5 mmol / L, 25.0 mmol / L, 50.0 mmol / L, 100.0 mmol / L, and 150.0 mmol / L. The experimental results showed that, under the condition that other factors remained unchanged, simply examining the effect of the reaction concentration of carbon disulfide on the conversion rate, it was found that when the final concentration of carbon disulfide was 12.5 mmol / L, the conversion rate reached 70%, and reached its highest point when it was increased to 25.0 mmol / L. When it was further increased to 150.0 mmol / L, the conversion rate remained unchanged at the highest point. Therefore, it is preferable that the final reaction concentration of carbon disulfide is greater than or equal to 12.5 mmol / L, and more preferably greater than or equal to 25.0 mmol / L.

[0016] In some embodiments of this application, the inventors experimented with multiple final reaction concentrations of the halogenated compounds: 25.0 mmol / L, 30.0 mmol / L, 40.0 mmol / L, 50.0 mmol / L, 100.0 mmol / L, 125.0 mmol / L, and 150.0 mmol / L. The experimental results showed that when the reaction concentration of the halogenated compound was 25.0 mmol / L, the conversion rate was as high as 65%. When the reaction concentration of the halogenated compound was in the range of 25.0 mmol / L to 150.0 mmol / L, it first increased and then slightly decreased with the increase of the reaction concentration of the halogenated compound. Therefore, it is preferred that the reaction concentration of the halogenated compound is greater than or equal to 25.0 mmol / L, more preferably greater than or equal to 30.0 mmol / L, more preferably 40.0 mmol / L, and most preferably greater than or equal to 50.0 mmol / L.

[0017] In some embodiments of this application, the inventors have experimented with organic solvents such as N,N-dimethylformamide (DMF), ethanol, methanol, 1,4-dioxane, tetrahydrofuran, acetonitrile (MeCN), dimethyl sulfoxide (DMSO), and dimethylacetamide (DMA). Experimental results show that, under the same conditions except for the organic solvent, the conversion rate is zero when the volume ratio of water to methanol, or water to 1,4-dioxane, or water to tetrahydrofuran, or water to acetonitrile (MeCN) is 1:3; the conversion rate is 5% when the volume ratio of water to ethanol is 1:3; and the conversion rates are 14% and 19% respectively when the volume ratio of water to DMA or DMSO is 1:3. Therefore, the solvent includes water and an organic solvent, wherein the organic solvent is one or more of N,N-dimethylformamide (DMF), ethanol, dimethyl sulfoxide (DMSO), or dimethylacetamide (DMA); preferably, the volume ratio of water to DMF is 1:4 to 1:2; preferably, the volume ratio of water to DMF is 1:3.

[0018] In some embodiments of this application, the reaction temperature is set to room temperature, 40°C, 60°C, 90°C, and 100°C, respectively. Experimental results show that the above temperatures are the temperatures at which the conversion rate reaches more than 90% and the DNA strand does not break. The above temperature range has little impact on the conversion rate. For ease of operation, those skilled in the art can arbitrarily choose the temperature without creative effort. That is, the temperature is not higher than 100°C, preferably not higher than 90°C, and more preferably not higher than 60°C.

[0019] During the experiment, the inventors of this application also discovered that adding a base to the reaction system is not necessary. Under the condition that other conditions remain unchanged, the conversion rate of product 3e can reach 45% without adding a base. When a base is added, the conversion rate is significantly increased to over 70%. To improve the conversion rate, the bases added to the reaction system by the inventors include: bicycloamidine (abbreviated as DBU, also known as 1,8-diazabicyclo[5.4.0]undec-7-ene), Na2CO3, NaHCO3, K2CO3, KHCO3, Cs2CO3, NaOH, KOH, N,N-diisopropylethylamine (DIEA), 1,4-diazabicyclo[2.2.2]octane (DABCO)), and borate buffer solution with pH = 9.5. The experimental results show that when the base is DBU and DABCO, the conversion rate can reach over 80%. Therefore, the preferred types of base are DBU and DABCO, and the final concentration of the base is greater than or equal to 12.5 mmol / L.

[0020] The above experimental results show that the conversion rate of this application is significantly higher than that investigated in the prior art (Daoshan Yang et al.). To investigate the reason or mechanism, the inventors of this application added the free radical scavenger TEMPO (tetramethylpiperidine oxide) to the reaction system to a final concentration of 50.0 mmol / L, but this had no effect on the conversion rate. Therefore, the applicant infers that the reaction described in this application is a non-free radical reaction. The reaction described by Daoshan Yang et al. (《Photocatalyst-Free Visible-Light-Promoted C(sp...)》) 2The paper "S-Aryl Coupling: A Strategy for the Preparation of S-Aryl Dithiocarbamates", Organic Letters, 2019, 21(19), 7938-7942, describes a reaction in which carbon disulfide reacts with amines in the presence of Cs₂CO₃ to generate the corresponding thiolate intermediates. Subsequently, the aryl halide and the thiolate anion bind through an electron donor-acceptor (EDA) complex. This complex undergoes a single electron transfer (SET) under visible light irradiation, promoting the transfer of electrons from the thiolate anion to the aryl halide, simultaneously generating sulfur radicals, halide anions, and aryl radicals. Finally, the aryl radicals couple with the sulfur radicals to form the target coupling product. Therefore, the reaction described by Daoshan Yang et al. is a radical reaction, and the reaction in this application is fundamentally different from existing technologies.

[0021] In summary, the preparation method of this application can obtain On-DNA dithiocarbamate structural compounds with rich structures in a single step. It not only significantly broadens the applicable range of raw materials compared to existing technologies, but also provides mild reaction conditions and achieves a conversion rate of over 90%. Furthermore, the method for preparing On-DNA dithiocarbamate structural compounds in this application not only fills the current gap in methods for preparing On-DNA dithiocarbamate structural compounds, but also enriches the library of On-DNA dithiocarbamate structural compounds and the methods for preparing On-DNA dithiocarbamate structural compounds. Attached Figure Description

[0022] Figures 1 to 4 LC-MC chromatogram of On-DNA secondary amines 1a to 1g;

[0023] Figures 5 to 17 LC-MC Detection Chromatography of On-DNA Dithiocarbamates 3a-3z

[0024] Figures 18 to 20 LC-MC chromatograms of On-DNA dithiocarbamates 3aa to 3af. Detailed Implementation

[0025] Unless otherwise specified, all reagents or compounds used in this application are commercially available products, and all self-made products have preparation method instructions.

[0026] DMSO: Dimethyl sulfoxide;

[0027] DMF: N,N-dimethylformamide;

[0028] MeCN: Acetonitrile;

[0029] EtOH: Ethanol;

[0030] MeOH: Methanol;

[0031] 1,4-Dioxane: 1,4-dioxane;

[0032] THF: Tetrahydrofuran;

[0033] DBU: Bicyclic amidine, also known as 1,8-diazabicyclic[5.4.0]undec-7-ene;

[0034] DIEA: N,N-diisopropylethylamine;

[0035] DABCO: 1,4-diazabicyclo[2.2.2]octane;

[0036] TEMPO: Tetramethylpiperidine oxide;

[0037] HFIP: Hexafluoroisopropanol;

[0038] TEAA: Triethylammonium acetate;

[0039] EDTA: Ethylenediaminetetraacetic acid.

[0040] The LC-MS (electrospray ionization mass spectrometry) analysis conditions used in this application were as follows: The sample (approximately 100.0 picomoles, diluted with 40.0 μL of water) was injected into a reversed-phase column (XBridge Oligonucleotide BEH C18 column, 1.7 μm, 2.1 × 50 mm) and eluted with a gradient (solvent B increased from 10% to 90% within 1.2 min at a flow rate of 0.60 mL / min; solvent A: 0.75% hexafluoroisopropanol (HFIP) / 0.38% triethylammonium acetate (TEAA) / 10.0 μM ethylenediaminetetraacetic acid (EDTA) dissolved in deionized water; solvent B: 0.75% v / v HFIP / 0.38% v / v TEAA / 10.0 μM EDTA dissolved in 90 / 10 methanol / deionized water). The monitoring wavelength was UV 260.0 nm and the total ion current (TIC) was monitored.

[0041] The structure and synthesis method of DNA-NH2 are consistent with the previous patent, namely, (1) preparing HP-Linker-NHFmoc from HP-NH2 (commercially available reagent), and (2) preparing HP-Linker-NH2 from HP-Linker-NHFmoc. This application uses the exact same method as CN118461019A to prepare HP-Linker-NH2, therefore omitting the synthesis steps of HP-NH2, HP-Linker-NHFmoc, and HP-Linker-NH2, as well as the structural confirmation map.

[0042] Experimental example. Preparation of 1a-1g of On-DNA secondary amine compound:

[0043] This application prepares On-DNA secondary amine compounds by reacting Fmoc-protected amino acids listed in Table 1 with HP-Linker-NH2.

[0044] Table 1. Fmoc-protected amino acids

[0045] The compounds listed in Table 1 are Fmoc-protected amino acids, and all of them are secondary amines, which are commercially available products.

[0046] The reaction equation for the preparation of On-DNA secondary amine compounds is as follows: The specific experimental method involved mixing Fmoc-protected secondary amino acid S2 (200.0 mmol / L dissolved in DMSO, 10.0 μL, 40.0 equivalence) with DMT-MM (200.0 mmol / L aqueous solution, 10.0 μL, 40.0 equivalence), followed by the addition of DNA-NH2 (1 mmol / L aqueous solution, 50.0 μL, 50.0 nanomoles, 1.0 equivalence) and borate buffer (250 mmol / L, pH 9.5, 50.0 μL). The reaction was quenched after 1 hour at 25°C and precipitated with cold ethanol.

[0047] The resulting precipitate was dissolved in 50.0 μL of deionized water, and then 18.0 μL of a 10% piperidine aqueous solution was added. The mixture was thoroughly combined and reacted at 25°C for 1 hour. After the reaction was complete, 10% (by volume) of a 5.0 mol / L sodium chloride solution was added to the reaction solution. Then, three times the total volume of anhydrous ethanol was added, and the mixture was shaken thoroughly. The reaction mixture was then frozen at -80°C for 2 hours. Afterward, the mixture was centrifuged at 4000.0 rpm for half an hour, and the supernatant was discarded. The remaining precipitate was dissolved in deionized water and analyzed by LC-MS. The On-DNA secondary amine compounds 1a-1g prepared by the above method are shown in Table 2.

[0048] Table 2. On-DNA secondary amine compounds 1a-1g

[0049]

[0050] Examples 1-32: Exploration of reaction conditions for the preparation of On-DNA dithiocarbamate compounds

[0051] Taking the preparation of product 3e as an example, the specific reaction equation is as follows: The specific experimental conditions are shown in Table 3.

[0052] Table 3. Exploration of reaction conditions for the preparation of On-DNA dithiocarbamate compounds

[0053]

[0054] a. final concentration;

[0055] b. Conversion rate was determined by LC-MS;

[0056] c pH=9.5 borate buffer solution;

[0057] d. Reaction conditions: 1e (5.0 nanomoles, 1.0 equivalent, final concentration 0.25 mmol / L aqueous solution), DBU (final concentration 25.0 mmol / L DMF solution), and CS2 (final concentration 25.0 mmol / L DMF solution), reacted at 25°C for 0.5 hours. Then, 2 ag (final concentration 50.0 mmol / L DMF solution) was added to the reaction mixture, and the reaction was carried out at 25°C for 3 hours.

[0058] The reaction temperature is 40℃;

[0059] The reaction temperature is 60℃.

[0060] Add TEMPO (tetramethylpiperidine oxide) to a final concentration of 50.0 mmol / L.

[0061] Examples 1-8 explored different bases, and the above are only some representative examples. Since no special explanation is needed, sodium carbonate and sodium bicarbonate are representative of potassium carbonate, potassium bicarbonate, sodium hydroxide, and potassium hydroxide. In addition, Example 8 was carried out under the condition of no base. By comparing the results, we can see that the base is not necessary, and under the condition that other reaction conditions remain unchanged, the 3e conversion rate is better than that of inorganic bases when organic bases DBU, DABCO, and DIEA are used as bases.

[0062] Comparing Examples 1 and 9-15, we can see that, under unchanged reaction conditions, the conversion rate is zero when the volume ratio of water to methanol, or water to 1,4-dioxane, or water to tetrahydrofuran, or water to acetonitrile (MeCN) is 1:3. Therefore, this reaction cannot be carried out in all of the commonly used organic solvents mentioned above. When the volume ratio of water to ethanol is 1:3, the conversion rate is 5%; when the volume ratio of water to DMA or DMSO is 1:3, the conversion rates are 14% and 19%, respectively. Therefore, the solvents required for this reaction include water and organic solvents, wherein the organic solvent is one or more of N,N-dimethylformamide (DMF), ethanol, dimethyl sulfoxide (DMSO), or dimethylacetamide (DMA); when the organic solvent is DMF, the 3e conversion rate is better than that of other organic solvents. Furthermore, by comparing Examples 1 and 16-17, we can see that, under the condition that other reaction conditions remain unchanged, the preferred volume ratio of water to DMF is 1:4 to 1:2; more preferably, the volume ratio of water to DMF is 1:3.

[0063] Comparing Examples 1 and 18-21, we can see that, under the condition that other reaction conditions remain unchanged, the 3e conversion rate is consistent when the final concentration of CS2 is 25.0 to 150.0 mmol / L; when the final concentration of CS2 is reduced to 12.5 mmol / L, the 3e conversion rate can still reach a relatively high conversion rate of 70%; therefore, it is more preferable that the final concentration of CS2 is greater than or equal to 25.0 mmol / L.

[0064] Comparing Examples 20 and 22-25, we can see that, under the condition that other reaction conditions remain unchanged, when the final concentration of DBU is 12.5 mmol / L, the 3e conversion rate is as high as 87%, and the final concentration of the base is preferably greater than or equal to 12.5 mmol / L.

[0065] Comparing Examples 20 and 26-29, we can see that, under the condition that other reaction conditions remain unchanged, when the final concentration of 2ag of halogenated product is 25.0 mmol / L, the conversion rate is as high as 65%. When the reaction concentration of halogenated product is in the range of 25.0 mmol / L to 150.0 mmol / L, it first increases and then slightly decreases with the increase of the reaction concentration of halogenated product. Therefore, it is preferred that the reaction concentration of halogenated product is greater than or equal to 25.0 mmol / L, more preferably greater than or equal to 30.0 mmol / L, more preferably 40.0 mmol / L, and most preferably greater than or equal to 50.0 mmol / L.

[0066] Comparing Examples 28 and 30-31, we can see that, under the condition that other reaction conditions remain unchanged, the 3e conversion rate is consistent within the reaction temperature range of 25℃ to 60℃. Based on years of experiments, we have found that the On-DNA reaction substrate is stable at a reaction temperature not exceeding 100℃. Therefore, considering the economic efficiency of the reaction, a reaction temperature not exceeding 90℃ is more preferable. Technicians can choose within the above range without making any creative effort.

[0067] The inventors of this application, through analysis of experimental results, found that compared with the experiments of Daoshan Yang et al., the reaction conditions were milder, and the conversion rate could still reach over 90%. To explore the fundamental reason, the free radical scavenger TEMPO was added to the reaction to a final concentration of 50.0 mmol / L (represented by Example 32). Comparing Examples 28 and 32, we can see that the reaction was not affected when the free radical scavenger TEMPO was added to a final concentration of 50.0 mmol / L, indicating that this reaction is not a free radical reaction. In contrast, the experiment of Daoshan Yang et al. involved the reaction of carbon disulfide with amine compounds in the presence of Cs2CO3 to generate the corresponding thiolate intermediates. Subsequently, the aryl halide and the thiolate anion combined through an electron donor-acceptor (EDA) complex. This complex under visible light irradiation underwent a single electron transfer (SET), promoting the transfer of electrons from the thiolate anion to the aryl halide, simultaneously generating sulfur free radicals, halide anions, and aryl free radicals. Finally, the aryl free radicals and sulfur free radicals coupled to form the target coupling product. Therefore, it can be seen that the reaction described by Daoshan Yang et al. is a free radical reaction, and the inventors of this application infer that the reaction of this application is fundamentally different from that of the prior art in terms of reaction mechanism.

[0068] Examples 33-64: Preparation of On-DNA dithiocarbamate compounds 3a to 3af

[0069] The secondary On-DNA amines used in the preparation of On-DNA dithiocarbamate compounds 3a to 3af are shown in Table 2 or appendix. Figures 1-4 As shown in Table 4, all of the halogenated products used are commercially available.

[0070] Table 4. Halogenated compounds used in the preparation of On-DNA dithiocarbamate compounds 3a to 3af

[0071]

[0072] The specific reaction equations for preparing On-DNA dithiocarbamate compounds 3a to 3af are as follows: The specific operating procedure is as follows: Take a 0.2 mL octet PCR tube and add DNA starting material 1 (5.0 nmol, 1.0 equivalent, 1.0 mmol / L aqueous solution, 5.0 μL, final concentration 0.25 mmol / L), DBU (1,8-diazabispyrocyclo[5.4.0]undecyl-7-ene, 200.0 mmol / L DMF solution, 2.5 μL, final concentration 25.0 mmol / L) and CS2 (carbon disulfide, 200.0 mmol / L DMF solution, 2.5 μL, final concentration 25.0 mmol / L). After vortexing the reaction mixture, react at 25°C for 0.5 hours. Then add the halogenated product (100.0 mmol / L DMF solution, 10.0 μL, final concentration 50.0 mmol / L), vortex, and react at 25°C for 3 hours. After the reaction is complete, perform ethanol precipitation and LC-MS analysis. The reaction conversion rate was confirmed based on LC-MS measurements, as shown in the attached figure. Figures 5 to 20 As shown.

[0073] Table 5. Structure and conversion rate of On-DNA dithiocarbamate compounds

[0074]

[0075] Halogenated compound R was discovered through examples 33 to 64. 2 X is no longer limited to aromatic halogenated compounds, but can also be C. 2-5 Straight-chain alkyl, isobutyl, isopentyl, allyl, 1-butenyl, 1-butynyl, and other aliphatic halides can be synthesized, with yields ranging from a minimum of 55% to a maximum of 99%. Therefore, compared to existing small-molecule synthesis techniques, this method significantly broadens the range of applicable raw materials and, compared to existing aryl halides, the conversion rate is also significantly higher. 2 When X is a brominated derivative, the highest conversion rate is only 43%, while the 3s conversion rate of this application is 84%; in the prior art, when the halogenated derivative R... 2 When X is an iodinated derivative, the conversion rate is only 81%, while that of this application is 99% (3g). Based on this, the method of this application for preparing dithiocarbamates can significantly accelerate the preparation of such compounds, thereby accelerating the screening of such pharmacologically active compounds.

[0076] This specific embodiment is merely an explanation of this application and is not intended to limit it. After reading this specification, those skilled in the art can make modifications to this embodiment without contributing any inventive step, but such modifications are protected by patent law as long as they fall within the scope of the claims of this application.

Claims

1. A method for preparing On-DNA dithiocarbamate compounds, characterized in that, The process includes the reaction of an On-DNA secondary amine with carbon disulfide and a halogenated derivative to generate an On-DNA dithiocarbamate compound, and the specific reaction equation is as follows: Among them, -R 1 -NH- represents 7-azaspiro[3.4]octane, cyclohexylamine, 1,2,5,6-tetrahydropyridine, and phenylcyclohexylamine; wherein R 2 X is a halogenated product, R 2 The following are C2-5 straight-chain alkyl groups: isobutyl, isopentyl, allyl, 1-butenyl, 1-butynyl, hydroxyethyl, trifluoropropyl, acetate, cyclopropylmethyl, cyclobutylmethyl, oxecyclobutanemethyl, isopropyl, sec-butyl, ethyl propionate, cyclopentyl, tetrahydro-2H-pyranyl, tetrahydro-2H-thiaranyl, 2-oxespiro[3.3]heptyl, benzyl, and X is chlorine, bromine, or iodine; The temperature shall not exceed 60°C; The solvent is a mixed solution of water and N,N-dimethylformamide, and the volume ratio of water to N,N-dimethylformamide is 1:3; The final concentration of carbon disulfide in the reaction is greater than 12.5 mmol / L and less than or equal to 150 mmol / L; The final concentration of the halogenated compound is greater than 25.0 mmol / L and less than or equal to 150 mmol / L; The reaction conditions for the On-DNA secondary amine to react with carbon disulfide and the halogenated product also include a base, wherein the base is bicycloamidine, N,N-diisopropylethylamine, or 1,4-diazabicyclo[2.2.2]octane, and the concentration of the base is greater than or equal to 12.5 mmol / L and less than or equal to 150 mmol / L.

2. The method for preparing On-DNA dithiocarbamate compounds according to claim 1, characterized in that, The final concentration of carbon disulfide in the reaction is greater than or equal to 25.0 mmol / L and less than or equal to 150 mmol / L.

3. The method for preparing On-DNA dithiocarbamate compounds according to claim 1, characterized in that, The final concentration of the halogenated compound is greater than or equal to 50.0 mmol / L and less than or equal to 150 mmol / L.

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