CN113072470B - N-acetonitrile bis-benzenesulfonylimine derivative and preparation method and application thereof - Google Patents

N-acetonitrile bis-benzenesulfonylimine derivative and preparation method and application thereof Download PDF

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CN113072470B
CN113072470B CN202110342964.4A CN202110342964A CN113072470B CN 113072470 B CN113072470 B CN 113072470B CN 202110342964 A CN202110342964 A CN 202110342964A CN 113072470 B CN113072470 B CN 113072470B
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acetonitrile
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CN113072470A (en
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唐波
黄晓晴
曹文华
方杨
刘振华
高雯
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Shandong Normal University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/48—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups having nitrogen atoms of sulfonamide groups further bound to another hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
    • C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/42—Separation; Purification; Stabilisation; Use of additives
    • C07C303/44—Separation; Purification

Abstract

The disclosure belongs to the technical field of organic synthetic chemistry, and particularly provides an N-acetonitrile bis-benzenesulfonylimine derivative, and a preparation method and application thereof. The structure of the N-acetonitrile bis-benzenesulfonylimine derivative is shown as a formula (1),
Figure DDA0002999813000000011
wherein R or R 1 Are all selected from one of hydrogen, halogen, C1-C6 linear chain or branched chain alkyl, C1-C6 linear chain alkoxy, nitro, ester group, trifluoromethyl, trifluoromethoxy, acetyl, condensed ring group and heterocyclic group. The synthesis method comprises the following steps: the compound shown in the formula (1) is synthesized by taking a hydroxyl alkenyl azide and N-fluoro-bis-benzenesulfonamide as raw materials under the combined action of an additive and a catalyst. The method can quickly and effectively synthesize the N-acetonitrile bis-benzenesulfonylimide derivative, has mild reaction conditions and does not have toxic by-products.

Description

N-acetonitrile bis-benzenesulfonylimine derivative and preparation method and application thereof
Technical Field
The disclosure belongs to the technical field of organic synthetic chemistry, and particularly provides an N-acetonitrile bis-benzenesulfonylimine derivative, and a preparation method and application thereof.
Background
The statements herein merely provide background information related to the present disclosure and may not necessarily constitute prior art.
Nitrile compounds are compounds containing cyano groups (-CN), are widely present in natural products, play an important role in the aspects of medicine, functional materials, pesticide synthesis and the like, and play an important role in organic synthetic chemistry. The existing methods for synthesizing nitrile compounds include: 1. sandmeyer reaction, 1884, sandmeyer converted a diazonium salt to a cyano group using a Cu salt to form the corresponding cyano compound. 2. Rosememed-von Braun reaction, 1In 914, rosemmed reported that halogens could be converted to cyano groups under CuCN catalysis. 3. C-C coupling cyanation reaction, 2005, beller et al, was found in Cu (BF) 4 ) 2 ·6H 2 Non-toxic K in the presence of O 4 [Fe(CN) 6 ]Can be used as an anion source of cyano to perform anion exchange with aryl bromide to generate a corresponding cyanation product; in 2012, cheng topic group found that the cyano anion in DDQ was in Cu (OTf) 2 Catalytically, the catalyst can be exchanged with the boric acid ion of the arylboronic acid to form the corresponding cyanation product. 4. C-H bond cyanation reaction, 2014, liu reported that CuCN provides cyano anion, 2-aryl pyridine in Cu (OAC) 2 Cyanidation reaction under catalysis; in 2016, shen reported on Pd (OAC) 2 Cyanation reaction of α -iminonitrile as a source of cyano groups in the presence of a catalyst; in 2019, cheng topic group uses N-alkoxy phthalimide as a substrate, utilizes light and copper for co-catalysis, and realizes the remote asymmetric cyanation reaction of C-H bonds under the irradiation of blue light. Although the cyanation reaction is carried out in various ways, these methods have disadvantages such as: the reaction conditions are harsh, the steps are complicated, the method is harmful to health, pollutes the environment and the like, so that the development of a novel method for synthesizing the nitrile compound, which has mild reaction conditions and is environment-friendly, is very important.
The vinyl azide is a molecule simultaneously containing conjugated olefin and azide groups, and the synergistic effect of the two functional groups ensures that the vinyl azide has unique properties which are not possessed by single olefin or azide groups, and can be used as an electrophilic reagent, a nucleophilic reagent, a free radical receptor and the like to participate in various reaction paths to generate various intermediates with high reactivity. Among them, the hydroxy alkenyl azide is a common reagent for cyanation reaction due to its simple and easily available structure, high reactivity, and the like. In 2017, the Cui topic group utilizes 2-methyl-3-butene-2-ol as a butyronitrile precursor to react with quinone methoxy compounds to synthesize a cyanation product. In 2020, 2-methyl-3-buten-2-ol is used as a substitute of acetonitrile carbon by the Cao project group, and Lewis acid and chiral transition metal iridium are used for catalyzing a hydroxyalkenyl azide and an asymmetric allyl electrophilic reagent to perform a coupling reaction to synthesize a nitrile compound. In recent years, research on hydroxyalkenyl azide compounds as cyanating agents has made great progress, however, the inventors of the present disclosure found in the course of research that the method for synthesizing nitriles using vinyl azide compounds is single in type and insufficient in product diversity, which seriously hinders the wide application of vinyl azide compounds as cyanating agents in organic synthesis.
Disclosure of Invention
Aiming at the problems of single type and insufficient product diversity of a method for synthesizing nitrile by using a vinyl azide in the prior art. The invention aims to provide a method for synthesizing an N-acetonitrile-based bis-benzenesulfonylimide derivative, which utilizes a novel material 2-methyl-3-butylene-2-alcohol as a substitute of acetonitrile carbon to react with N-fluoro-bis-benzenesulfonylimide under the combined action of an additive and a catalyst to quickly and effectively synthesize the N-acetonitrile-based bis-benzenesulfonylimide derivative, and has mild reaction conditions and no toxic side products.
In one or more embodiments of the present disclosure, an N-acetonitrile bis-benzenesulfonylimine derivative is provided, which has a structure shown in formula (1),
Figure BDA0002999812980000021
formula (1);
wherein, R or R1 is selected from one of hydrogen, halogen, C1-C6 linear chain or branched chain alkyl, C1-C6 linear chain alkoxy, nitryl, ester group, trifluoromethyl, trifluoromethoxy, acetyl, condensed ring group and heterocyclic group.
In one or some embodiments of the present disclosure, there is provided a method for synthesizing a compound of formula (1), the synthetic route of which is shown below,
Figure BDA0002999812980000022
in one or more embodiments of the present disclosure, there is provided a method for synthesizing a compound of formula (1), comprising the steps of: the compound shown in the formula (1) is synthesized by taking 2-methyl-3-butylene-2-alcohol and N-fluoro-bis-benzenesulfonamide as raw materials under the combined action of an additive and a catalyst.
In one or more embodiments of the present disclosure, there is provided the use of a compound as described above or a method of synthesizing a compound of formula (1) as described above for the preparation of an anti-inflammatory agent.
One or some of the above technical solutions have the following advantages or beneficial effects:
1) The method takes novel material 2-methyl-3-butylene-2-alcohol as raw material for the first time, and the raw material reacts with N-fluoro-diphenyl sulfonamide under the combined action of a catalyst and an additive to generate the N-acetonitrile-based diphenyl sulfonamide derivative. The method disclosed by the invention has the advantages of easily available raw materials, simplicity in operation, mild conditions, high yield, no toxic by-product generation, few reaction steps, environmental friendliness and suitability for large-scale industrial production.
2) The N-cyanobenzene sulfonyl imide is synthesized for the first time, and through detection, the N-cyanobenzene sulfonyl imide has anti-inflammatory activity, not only enriches the drug properties of the N-cyanobenzene sulfonyl imide derivative, but also gives full play to the advantages of the N-cyanobenzene sulfonyl imide derivative in the field of drug synthesis chemistry.
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The accompanying drawings, which are incorporated in and constitute a part of this disclosure, illustrate embodiments of the disclosure and, together with the description, serve to explain the disclosure and not to limit the disclosure.
FIG. 1 is a drawing of compound 1c prepared according to examples 1 to 5 of the present disclosure 1 Nuclear magnetic resonance spectrum of H-NMR;
FIG. 2 is a drawing of compound 1c prepared in examples 1-5 of the present disclosure 13 Nuclear magnetic resonance spectrum of C-NMR;
Detailed Description
The technical solutions in the embodiments of the present disclosure will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present disclosure, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments of the disclosure without making any creative effort, shall fall within the protection scope of the disclosure.
Aiming at the problems of single type and insufficient product diversity of a method for synthesizing nitrile by using a vinyl azide in the prior art. The invention aims to provide a method for synthesizing an N-acetonitrile-based bis-benzenesulfonylimine derivative, which utilizes a novel material 2-methyl-3-butylene-2-alcohol as a substitute of acetonitrile carbon to react with N-fluoro-bis-benzenesulfonylimine under the combined action of an additive and a catalyst to quickly and effectively synthesize the N-acetonitrile-based bis-benzenesulfonylimine derivative, and has the advantages of mild reaction conditions and no toxic side products.
In one or more embodiments of the present disclosure, an N-acetonitrile bis-benzenesulfonylimide derivative is provided, which has a structure shown in formula (1),
Figure BDA0002999812980000041
formula (1);
wherein, R or R1 is selected from one of hydrogen, halogen, C1-C6 linear chain or branched chain alkyl, C1-C6 linear chain alkoxy, nitro, ester group, trifluoromethyl, trifluoromethoxy, acetyl, condensed ring group and heterocyclic group.
Preferably, the halogen is selected from one of F, cl, br and I;
or, said C 1 -C 6 The linear alkyl is selected from one of methyl, ethyl, n-propyl and n-butyl;
or, the branched alkyl is selected from one of tert-butyl and n-pentyl;
or, said C 1 -C 2 The linear alkoxy is selected from one of methoxy and ethoxy.
In one or some embodiments of the present disclosure, there is provided a method for synthesizing a compound of formula (1), the synthetic route of which is shown below,
Figure BDA0002999812980000042
in one or more embodiments of the present disclosure, there is provided a method for synthesizing a compound of formula (1), comprising the steps of: the compound shown in the formula (1) is synthesized by taking 2-methyl-3-butylene-2-alcohol and N-fluoro-diphenyl sulfonamide as raw materials under the combined action of an additive and a catalyst.
The chemical formula of the 2-methyl-3-butylene-2-alcohol is
Figure BDA0002999812980000043
The chemical formula of the N-fluoro-diphenyl sulfonamide is
Figure BDA0002999812980000044
Preferably, the additive is one of 1, 10-phenanthroline (Phen), benzoic acid (PhCOOH) and trifluoroacetic acid (TFA); preferably, the additive is Phen; when Phen is added, the conversion of the starting material and the yield of the product can be increased.
Or the catalyst is cuprous chloride (CuCl), cuprous iodide (CuI), or cupric chloride (CuCl) 2 ) Copper acetate (Cu (OAc) 2 ) One of copper oxide (CuO), cuprous cyanide (CuCN), and cuprous bromide (CuBr); preferably, the catalyst is CuCl. When the catalyst is CuCl, the conversion rate of raw materials and the yield of products can be improved.
The N-acetonitrile bisbenzenesulfonylimine derivative is prepared by taking novel materials 2-methyl-3-butylene-2-alcohol and N-fluoro bisbenzenesulfonyl amide as raw materials under the catalysis of cuprous. The method disclosed by the invention has the advantages of few steps, simplicity in operation, easiness in obtaining raw materials, mild reaction conditions, high yield and no toxic by-product.
Preferably, the reaction temperature is 20-60 ℃, and preferably, the reaction temperature is 50 ℃; the reaction temperature is 20-60 ℃. This temperature can increase the conversion of the feedstock while increasing the yield of the product. When the reaction is carried out at 50 ℃, the conversion of the raw material and the yield of the product can be further improved.
Or the reaction time is 0-24 h and is not 0; preferably, the reaction time is 16. + -. 0.1h.
Preferably, the raw materials are added into a solvent to be dissolved, then the additive and the catalyst are added, and the reaction is carried out in a heating environment;
preferably, the solvent is dimethyl sulfoxide (DMSO), acetonitrile (CH) 3 CN), N-Dimethylformamide (DMF), toluene (PhMe) and Dichloromethane (DCM);
further preferably, the solvent is DCM.
Preferably, the molar ratio of the 2-methyl-3-buten-2-ol to the N-fluorobisbenzenesulfonamide is 1 to 2:1 to 3. Further preferred, the molar ratio of 2-methyl-3-buten-2-ol to N-fluorobisbenzenesulfonamide is 1:1.5.
preferably, the amount of the catalyst added is 0 to 1 time the molar mass of the hydroxyalkenyl azide compound. More preferably, the amount of the catalyst added is 0.2 times the molar mass of the hydroxyalkenyl azide compound.
Preferably, the additive is added in an amount of 1 to 3 times the molar mass of 2-methyl-3-buten-2-ol. More preferably, the additive is added in an amount of 2 times the molar mass of 2-methyl-3-buten-2-ol.
Preferably, adding an extraction solvent into the solution after the reaction for extraction to obtain an organic phase, removing the solvent in the organic phase, and performing silica gel column chromatography to obtain the N-acetonitrile bis-benzenesulfonylimide derivative;
preferably, the extraction solvent adopted in the extraction is ethyl acetate;
preferably, the extraction is carried out for 1 to 3 times, and 5 to 20mL of extraction solvent is used each time;
preferably, the obtained organic phase is dried by adopting anhydrous sodium sulfate, and then the organic solvent is removed;
preferably, the eluent of the silica gel column chromatography is petroleum ether and ethyl acetate;
preferably, the volume ratio of the petroleum ether to the ethyl acetate is 1-30;
preferably, the volume ratio of petroleum ether to ethyl acetate is 20.
In one or more embodiments of the present disclosure, there is provided the use of a compound as described above or a method of synthesizing a compound of formula (1) as described above for the preparation of an anti-inflammatory agent.
Example 1
The compound 1a (0.2 mmol), compound1b (0.3 mmol,1.5 eq) was dissolved in 3mL DCM and then CuCl (0.04mmol, 0.2eq), phen (0.4mmol, 2eq) were added and reacted at 50 ℃ for 16h. The reaction was monitored by TLC and was terminated when the starting material had reacted. Pouring the reaction solution into 30mL of water, extracting with ethyl acetate (3X 10 mL), combining organic phases, drying with anhydrous sodium sulfate, filtering, removing the organic solvent by reduced pressure distillation, and performing silica gel column chromatography (eluent V) Petroleum ether :V Ethyl acetate = 20).
Example 2
Compound 1a (0.2 mmol), compound 1b (0.3 mmol,1.5 eq) were dissolved in 3mL DMF, followed by addition of CuCl (0.04mmol, 0.2eq), phen (0.4 mmol, 2eq) and reaction at 50 ℃ for 16h. The reaction was monitored by TLC and was terminated when the starting material had reacted. Pouring the reaction solution into 30mL of water, extracting with ethyl acetate (3X 10 mL), combining organic phases, drying with anhydrous sodium sulfate, filtering, removing organic solvent by reduced pressure distillation, and performing silica gel column chromatography (eluent is V) Petroleum ether :V Ethyl acetate = 20).
Example 3
Compound 1a (0.2 mmol), compound 1b (0.3 mmol,1.5 eq) were dissolved in 3mL of CCM, followed by addition of CuI (0.04mmol, 0.2eq), phen (0.4 mmol, 2eq) and reaction at 50 ℃ for 16h. The reaction was monitored by TLC and the reaction was terminated when the starting material had reacted. Pouring the reaction solution into 30mL of water, extracting with ethyl acetate (3X 10 mL), combining organic phases, drying with anhydrous sodium sulfate, filtering, removing organic solvent by reduced pressure distillation, and performing silica gel column chromatography (eluent is V) Petroleum ether :V Ethyl acetate = 20).
Example 4:
compound 1a (0.2 mmol), compound 1b (0.3 mmol,1.5 eq) were dissolved in 3mL of CCM, followed by addition of CuCl (0.04mmol, 0.2eq), phCOOH (0.4 mmol, 2eq) and reaction at 50 ℃ for 16h. The reaction was monitored by TLC and the reaction was terminated when the starting material had reacted. The reaction mixture was poured into 30mL of water, extracted with ethyl acetate (3X 10 mL), and combinedDrying the organic phase with anhydrous sodium sulfate, vacuum filtering, distilling under reduced pressure to remove organic solvent, and performing silica gel column chromatography (eluent is V) Petroleum ether :V Ethyl acetate = 20).
Example 5
Compound 1a (0.2 mmol), compound 1b (0.3 mmol,1.5 eq) were dissolved in 3mL of CCM, followed by addition of CuCl (0.04mmol, 0.2eq), phen (0.4 mmol, 2eq) and reaction at 30 ℃ for 16h. The reaction was monitored by TLC and was terminated when the starting material had reacted. Pouring the reaction solution into 30mL of water, extracting with ethyl acetate (3X 10 mL), combining organic phases, drying with anhydrous sodium sulfate, filtering, removing organic solvent by reduced pressure distillation, and performing silica gel column chromatography (eluent is V) Petroleum ether :V Ethyl acetate = 20).
The reactions of examples 1 to 5 are shown by the following formulae:
Figure BDA0002999812980000071
compound 1c:
1 H NMR(400MHz,CDCl 3 )δ7.97–7.89(m,4H),7.58(t,J＝7.5Hz,2H),7.46(t,J＝7.8Hz,4H),4.50(s,2H). 13 C NMR(101MHz,CDCl 3 )δ136.92,133.89,128.45,127.28,113.15,34.25.HRMS(ESI)m/z calculated for C 14 H 13 N 2 O 4 S 2 [M+H] + :337.0317,found:337.0329.
example 6
Compound 1a (0.2 mmol), compound 2b (0.3 mmol,1.5 eq) were dissolved in 3mL of CCM, followed by addition of CuCl (0.04mmol, 0.2eq), phen (0.4 mmol, 2eq) and reaction at 50 ℃ for 16h. The reaction was monitored by TLC and the reaction was terminated when the starting material had reacted. Pouring the reaction solution into 30mL of water, extracting with ethyl acetate (3X 10 mL), combining organic phases, drying with anhydrous sodium sulfate, filtering, removing organic solvent by reduced pressure distillation, and performing silica gel column chromatography (eluent is V) Petroleum ether :V Acetic acidEthyl ester = 20).
The reaction formula is as follows:
Figure BDA0002999812980000081
compound 2c:
HRMS(ESI)m/z calculated for C 14 H 10 Cl 2 N 2 O 4 S 2 [M+H] + :403.9459,found:403.9427.
example 7
Compound 1a (0.2 mmol), compound 3b (0.3 mmol,1.5 eq) were dissolved in 3mL of CCM, followed by addition of CuCl (0.04mmol, 0.2eq), phen (0.4 mmol, 2eq) and reaction at 50 ℃ for 16h. The reaction was monitored by TLC and the reaction was terminated when the starting material had reacted. Pouring the reaction solution into 30mL of water, extracting with ethyl acetate (3X 10 mL), combining organic phases, drying with anhydrous sodium sulfate, filtering, removing the organic solvent by reduced pressure distillation, and performing silica gel column chromatography (eluent V) Petroleum ether :V Ethyl acetate = 20).
The reaction formula is as follows:
Figure BDA0002999812980000082
compound 3c:
HRMS(ESI)m/z calculated for C 14 H 11 N 3 O 6 S 2 [M+H] + :381.0089,found:301.0034.
example 8
Compound 1a (0.2 mmol), compound 4b (0.3 mmol,1.5 eq) were dissolved in 3mL of CCM, followed by addition of CuCl (0.04mmol, 0.2eq), phen (0.4 mmol, 2eq) and reaction at 50 ℃ for 16h. The reaction was monitored by TLC and the reaction was terminated when the starting material had reacted. The reaction mixture was poured into 30mL of water, extracted with ethyl acetate (3X 10 mL), the organic phases were combined, dried over anhydrous sodium sulfate and filtered with suction, and then distilled off under reduced pressureRemoving organic solvent, and performing silica gel column chromatography (eluent is V) Petroleum ether :V Acetic acid ethyl ester = 20).
The reaction formula is as follows:
Figure BDA0002999812980000091
compound 4c:
HRMS(ESI)m/z calculated for C 15 H 14 N 2 O 4 S 2 [M+H] + :350.0395,found:350.0347.
example 9
Compound 1a (0.2 mmol), compound 5b (0.3 mmol,1.5 eq) were dissolved in 3mL of CCM, followed by addition of CuCl (0.04mmol, 0.2eq), phen (0.4 mmol, 2eq) and reaction at 50 ℃ for 16h. The reaction was monitored by TLC and was terminated when the starting material had reacted. Pouring the reaction solution into 30mL of water, extracting with ethyl acetate (3X 10 mL), combining organic phases, drying with anhydrous sodium sulfate, filtering, removing organic solvent by reduced pressure distillation, and performing silica gel column chromatography (eluent is V) Petroleum ether :V Acetic acid ethyl ester = 20).
The reaction formula is as follows:
Figure BDA0002999812980000092
compound 5c:
HRMS(ESI)m/z calculated for C 18 H 20 N 2 O 4 S 2 [M+H] + :392.0864,found:3592.0843.
example 10
This example provides an effect test of compounds 1c, 2c, 3c, 4c, and 5c in inhibiting the activity of hepatoma cells, comprising the following steps: 1. liver cancer HepG2 cells were seeded at a cell density of 6X 104/mL in a culture plate at a concentration of 100. Mu.L per well, 37 ℃ C., 5% CO 2 And incubated overnight under saturated humidity conditions.
2. After the adhesion of the membrane, the compounds 1c, 2c, 3c, 4c and 5c were added to the membrane respectively to achieve final concentrations of 1. Mu.g/ml, 2. Mu.g/ml, 3. Mu.g/ml, 4. Mu.g/ml and 5. Mu.g/ml, each set of 5 multiple wells with a final volume of 200. Mu.L per well. The control group was added with an equal amount of DMEM medium.
3. After 24 hours and 48 hours of incubation, 30. Mu.L of MTT (5 mg/mL)) was added to each well and incubation was continued for 6 hours.
4. The supernatant was centrifuged off and 150. Mu.L of DMSO was added to each well to dissolve the crystalline particles.
5. And (3) measuring the absorbance (D) by the enzyme-labeling instrument at the wavelength of 580nm, calculating the proliferation inhibition rate of the cervical cancer HeLa cells by the adriamycin with different time and different concentration, and repeating the experiment for 3 times.
6. The growth inhibition rate = [ (control D570 — experimental D570)/control D570] × 100% was calculated. IC50 refers to the concentration of drug required to reduce the number of cells that survive a drug administration by half. In the MTT method, the IC50 is the concentration of the drug required to reduce the OD value of the absorbance of the control group by half.
In addition, the meaning of median inhibitory concentration corresponds to the average of the minimum lethal doses of drugs on cultured cells, and is widely used in screening various drugs as a quantitative index reflecting the drug efficacy.
Specifically, according to the formula: inhibition = 1-addition group OD value/control group OD value, calculated IC50 values of the compounds tested, all compounds had IC50 values below 6.3 μ g/kg,
the disclosure of the present invention is not limited to the specific embodiments, but rather to the specific embodiments, the disclosure is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

Claims (14)

1. A synthetic method of a compound shown in a formula (1) of an N-acetonitrile-based bis-benzenesulfonylimine derivative is characterized in that the structure of the N-acetonitrile-based bis-benzenesulfonylimine derivative is shown in the formula (1),
Figure DEST_PATH_IMAGE001
formula (1);
wherein, R or R1 is selected from one of hydrogen, halogen, C1-C6 linear chain or branched chain alkyl, C1-C6 linear chain alkoxy, nitro, trifluoromethyl, trifluoromethoxy and acetyl;
the halogen is selected from one of F, cl, br and I;
the C1-C6 linear alkyl is selected from one of methyl, ethyl, n-propyl, n-butyl and n-pentyl;
the branched alkyl is tert-butyl;
the straight chain alkoxy of the C1-C2 is selected from one of methoxy and ethoxy;
the synthetic route of the compound represented by the formula (1) is shown below,
Figure 785885DEST_PATH_IMAGE002
the synthesis method of the compound shown in the formula (1) comprises the following steps:
taking 1a and N-fluoro-diphenyl sulfonamide as raw materials, adding the raw materials into a solvent for dissolving, then adding an additive and a catalyst, and reacting in a heating environment to synthesize a compound shown in a formula (1);
the additive is 1, 10-phenanthroline;
the solvent is dichloromethane;
the catalyst is cuprous chloride.
2. The method for synthesizing a compound represented by the formula (1) which is an N-acetonitrile bisbenzenesulfonylimide derivative according to claim 1, wherein the reaction temperature is 20 to 60 ℃, the reaction time is 0 to 24h, and the reaction time is not 0.
3. The method for synthesizing the compound of formula (1) of N-acetonitrile bis-benzenesulfonylimide derivative according to claim 1, wherein the reaction temperature is 50 ℃ and the reaction time is 16 ± 0.1h.
4. The method for synthesizing the compound of the N-acetonitrile-based bisbenzenesulfonylimide derivative represented by the formula (1) according to claim 1, wherein the molar ratio of 1a to N-fluorobenzenesulfonamide is 1 to 2:1 to 3; the addition amount of the catalyst is 0 to 1 time of the 1a molar mass, and the addition amount is not 0; the additive is added in an amount of 1 to 3 times the molar mass of 1 a.
5. The method for synthesizing the compound of formula (1) which is an N-acetonitrile bisbenzenesulfonylimide derivative according to claim 4, wherein the molar ratio of 1a to N-fluorobisbenzenesulfonylimide is 1:1.5.
6. the method for synthesizing the compound represented by the formula (1) of the N-acetonitrile-based bisbenzenesulfonylimide derivative of claim 4, wherein the amount of the catalyst added is 0.2 times the molar mass of 1 a.
7. The method for synthesizing a compound represented by the formula (1) of an N-acetonitrile-based bisbenzenesulfonylimide derivative as claimed in claim 4, wherein the amount of the additive added is 2 times the molar mass of 1 a.
8. The method for synthesizing the compound represented by the formula (1) of the N-acetonitrile-based bisbenzenesulfonylimide derivative according to claim 1, wherein the solution after the reaction is added with an extraction solvent to extract the solution to obtain an organic phase, the solvent in the organic phase is removed, and silica gel column chromatography is performed to obtain the N-acetonitrile-based bisbenzenesulfonylimide derivative.
9. The method for synthesizing the compound represented by the formula (1) of the N-acetonitrile-based bis-benzenesulfonylimine derivative according to claim 8, wherein the extraction solvent used for the extraction is ethyl acetate.
10. The method for synthesizing the compound of formula (1) of N-acetonitrile bisbenzenesulfonylimide derivative according to claim 8, wherein the extraction is performed 1 to 3 times by using 5 to 20mL of the extraction solvent each time.
11. The method for synthesizing the compound represented by the formula (1) of the N-acetonitrile bisbenzenesulfonylimide derivative of claim 8, wherein the organic phase obtained is dried over anhydrous sodium sulfate, and the organic solvent is removed.
12. The method for synthesizing the compound represented by the formula (1) of the N-acetonitrile bisbenzenesulfonylimide derivative according to claim 8, wherein the eluent for the silica gel column chromatography is petroleum ether or ethyl acetate.
13. The method for synthesizing the compound of formula (1) of the N-acetonitrile bisbenzenesulfonylimide derivative according to claim 12, wherein the volume ratio of petroleum ether to ethyl acetate is 1 to 30.
14. The method for synthesizing the compound of formula (1) of the N-acetonitrile bisbenzenesulfonylimide derivative according to claim 12, wherein the volume ratio of petroleum ether to ethyl acetate is 20.
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