CN110067006B - Method for electrochemically synthesizing sulfonyl hydrazino indole compound and application - Google Patents
Method for electrochemically synthesizing sulfonyl hydrazino indole compound and application Download PDFInfo
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- CN110067006B CN110067006B CN201910486584.0A CN201910486584A CN110067006B CN 110067006 B CN110067006 B CN 110067006B CN 201910486584 A CN201910486584 A CN 201910486584A CN 110067006 B CN110067006 B CN 110067006B
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- 238000000034 method Methods 0.000 title claims abstract description 16
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 8
- -1 sulfonyl hydrazino indole compound Chemical class 0.000 title claims description 32
- GJDAIEKGWDPCNE-UHFFFAOYSA-N N-(sulfonylamino)-1H-indol-2-amine Chemical class S(=O)(=O)=NNC=1NC2=CC=CC=C2C1 GJDAIEKGWDPCNE-UHFFFAOYSA-N 0.000 claims abstract description 12
- 230000000259 anti-tumor effect Effects 0.000 claims abstract description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 126
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 63
- 238000006243 chemical reaction Methods 0.000 claims description 45
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 42
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 40
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 27
- 239000002904 solvent Substances 0.000 claims description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- 238000010898 silica gel chromatography Methods 0.000 claims description 22
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 21
- 239000007832 Na2SO4 Substances 0.000 claims description 21
- 229910052786 argon Inorganic materials 0.000 claims description 21
- 238000001035 drying Methods 0.000 claims description 21
- 239000003480 eluent Substances 0.000 claims description 21
- 239000000203 mixture Substances 0.000 claims description 21
- 239000012044 organic layer Substances 0.000 claims description 21
- 239000003208 petroleum Substances 0.000 claims description 21
- 229910052697 platinum Inorganic materials 0.000 claims description 21
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 21
- 238000012544 monitoring process Methods 0.000 claims description 20
- 238000003756 stirring Methods 0.000 claims description 20
- 229910021397 glassy carbon Inorganic materials 0.000 claims description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- 150000001875 compounds Chemical class 0.000 claims description 18
- 238000004090 dissolution Methods 0.000 claims description 7
- 238000001308 synthesis method Methods 0.000 claims description 5
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 239000003792 electrolyte Substances 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 239000002246 antineoplastic agent Substances 0.000 claims description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- SWLVFNYSXGMGBS-UHFFFAOYSA-N ammonium bromide Chemical compound [NH4+].[Br-] SWLVFNYSXGMGBS-UHFFFAOYSA-N 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 235000010290 biphenyl Nutrition 0.000 claims description 2
- 239000004305 biphenyl Substances 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims 1
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 abstract description 30
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 abstract description 16
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 abstract description 15
- 239000007800 oxidant agent Substances 0.000 abstract description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 abstract description 4
- 230000001590 oxidative effect Effects 0.000 abstract description 4
- 239000003054 catalyst Substances 0.000 abstract description 3
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 abstract description 3
- ISNKSXRJJVWFIL-UHFFFAOYSA-N (sulfonylamino)amine Chemical compound NN=S(=O)=O ISNKSXRJJVWFIL-UHFFFAOYSA-N 0.000 abstract description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 2
- 239000006227 byproduct Substances 0.000 abstract description 2
- 230000006104 desulfonylation Effects 0.000 abstract description 2
- 238000005688 desulfonylation reaction Methods 0.000 abstract description 2
- 239000001257 hydrogen Substances 0.000 abstract description 2
- 230000005918 in vitro anti-tumor Effects 0.000 abstract description 2
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 2
- 238000007254 oxidation reaction Methods 0.000 abstract description 2
- 230000000144 pharmacologic effect Effects 0.000 abstract description 2
- 238000012216 screening Methods 0.000 abstract description 2
- 239000002184 metal Substances 0.000 abstract 1
- 230000003647 oxidation Effects 0.000 abstract 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 76
- 239000007787 solid Substances 0.000 description 38
- 210000004027 cell Anatomy 0.000 description 25
- VJRITMATACIYAF-UHFFFAOYSA-N benzenesulfonohydrazide Chemical compound NNS(=O)(=O)C1=CC=CC=C1 VJRITMATACIYAF-UHFFFAOYSA-N 0.000 description 23
- 230000015572 biosynthetic process Effects 0.000 description 22
- 238000003786 synthesis reaction Methods 0.000 description 22
- 238000012512 characterization method Methods 0.000 description 20
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 19
- 238000005160 1H NMR spectroscopy Methods 0.000 description 19
- ICGLPKIVTVWCFT-UHFFFAOYSA-N 4-methylbenzenesulfonohydrazide Chemical compound CC1=CC=C(S(=O)(=O)NN)C=C1 ICGLPKIVTVWCFT-UHFFFAOYSA-N 0.000 description 7
- 210000004881 tumor cell Anatomy 0.000 description 5
- ONYNOPPOVKYGRS-UHFFFAOYSA-N 6-methylindole Natural products CC1=CC=C2C=CNC2=C1 ONYNOPPOVKYGRS-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 150000002475 indoles Chemical group 0.000 description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine group Chemical group NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- YPKBCLZFIYBSHK-UHFFFAOYSA-N 5-methylindole Chemical compound CC1=CC=C2NC=CC2=C1 YPKBCLZFIYBSHK-UHFFFAOYSA-N 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 229940054051 antipsychotic indole derivative Drugs 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- ZQMIIPDQGBFDKT-UHFFFAOYSA-N 3-sulfonyl-1,2-dihydroindole Chemical class S(=O)(=O)=C1CNC2=CC=CC=C12 ZQMIIPDQGBFDKT-UHFFFAOYSA-N 0.000 description 1
- UIWFWZLAICURGT-UHFFFAOYSA-N 4-Methoxybenzenesulfonohydrazide Chemical compound COC1=CC=C(S(=O)(=O)NN)C=C1 UIWFWZLAICURGT-UHFFFAOYSA-N 0.000 description 1
- SQTLUXJWUCHKMT-UHFFFAOYSA-N 4-bromo-n,n-diphenylaniline Chemical compound C1=CC(Br)=CC=C1N(C=1C=CC=CC=1)C1=CC=CC=C1 SQTLUXJWUCHKMT-UHFFFAOYSA-N 0.000 description 1
- UXGNIMVLJMBZGY-UHFFFAOYSA-N 4-bromobenzenesulfonohydrazide Chemical compound NNS(=O)(=O)C1=CC=C(Br)C=C1 UXGNIMVLJMBZGY-UHFFFAOYSA-N 0.000 description 1
- 108091005435 5-HT6 receptors Proteins 0.000 description 1
- YYFFEPUCAKVRJX-UHFFFAOYSA-N 6-fluoro-1h-indole Chemical compound FC1=CC=C2C=CNC2=C1 YYFFEPUCAKVRJX-UHFFFAOYSA-N 0.000 description 1
- KGWPHCDTOLQQEP-UHFFFAOYSA-N 7-methylindole Chemical compound CC1=CC=CC2=C1NC=C2 KGWPHCDTOLQQEP-UHFFFAOYSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 229940122313 Nucleoside reverse transcriptase inhibitor Drugs 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 208000015114 central nervous system disease Diseases 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 229960003350 isoniazid Drugs 0.000 description 1
- QRXWMOHMRWLFEY-UHFFFAOYSA-N isoniazide Chemical compound NNC(=O)C1=CC=NC=C1 QRXWMOHMRWLFEY-UHFFFAOYSA-N 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 1
- 229960001156 mitoxantrone Drugs 0.000 description 1
- 229940042402 non-nucleoside reverse transcriptase inhibitor Drugs 0.000 description 1
- 239000002726 nonnucleoside reverse transcriptase inhibitor Substances 0.000 description 1
- 238000005691 oxidative coupling reaction Methods 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000006103 sulfonylation Effects 0.000 description 1
- 238000005694 sulfonylation reaction Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C25—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES; APPARATUS THEREFOR
- C25B—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES FOR THE PRODUCTION OF COMPOUNDS OR NON-METALS; APPARATUS THEREFOR
- C25B3/00—Electrolytic production of organic compounds
- C25B3/20—Processes
- C25B3/23—Oxidation
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Electrochemistry (AREA)
- Materials Engineering (AREA)
- Metallurgy (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
- Electrolytic Production Of Non-Metals, Compounds, Apparatuses Therefor (AREA)
Abstract
The invention discloses a method for electrochemically synthesizing sulfonyl hydrazino indole compounds, which is characterized in that the sulfonyl hydrazino indole compounds are synthesized by a method without metal and oxidant, indole is selectively sulfonylated and hydrazinized by sulfonyl hydrazine under mild electrochemical conditions to obtain a series of sulfonyl hydrazino indole compounds with pharmacological activity, and the synthesized sulfonyl hydrazino indole compounds are found to have good anti-tumor activity by in vitro anti-tumor activity screening. The process of the invention is carried out in a diaphragm-free electrolytic cell using constant current instead of exogenous oxidant, the by-products being hydrogen and nitrogen. In addition, under the mild electrochemical condition without a catalyst, the problem of sulfonyl desulfonylation or over oxidation is effectively avoided.
Description
Technical Field
The invention relates to a synthesis method of a compound, in particular to a method for electrochemically synthesizing sulfonyl hydrazino indole compounds and application thereof.
Background
Indole backbones are widely found in various natural products and are considered to be "dominant structures" in a broad class of compounds associated with medicine due to their specific chemical and biological properties. Since the development of synthetic chemistry, the functionalization and synthesis of indole derivatives has attracted great interest to organic chemists, and effective methods for the synthesis of indoles have been reported in the literature. However, most of these methods require an equivalent amount of oxidant or an excess amount of catalyst.
In addition, sulfonyl-containing indole derivatives are widely found in natural products and drug molecules. For example, 3-sulfonyl-1H-indoles are HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) and 5-HT6 receptor ligands and have superior efficacy in treating central nervous system disorders (schizophrenia, depression, and Alzheimer's disease) (J.Med.chem.,1993,36, 1291; bioorg.Med.chem.Lett.,2004,14, 5499).
Currently, commercially available drugs such as isoniazid, mitoxantrone, hydrazinozine and besirazine all contain hydrazine functional groups. Hydrazine scaffolds have a variety of biological activities such as anti-schistosome activity, anti-cancer activity, antibacterial activity, anti-inflammatory activity, and antioxidant activity (res.2014,113, 437; bioorg.med.chem.lett., 2015,23, 1651; e.j.mol.struct., 2014,1075,566; bioorg.med.chem.lett., 2015,25, 1420; med.chem., 2014,10, 521). Therefore, the introduction of hydrazine functional groups into indole rings is an interesting task, but is not reported in the literature at present.
Disclosure of Invention
The invention aims to provide a method for electrochemically synthesizing sulfonyl hydrazino indole compounds and application thereof.
The technical scheme for realizing the purpose of the invention is as follows:
a method for electrochemically synthesizing sulfonyl hydrazino indole compounds has the following general formula:
wherein R is1Is H, F, Cl, CH3And OCH3；
R2Are benzyl, tolyl and biphenyl;
the electrolyte is as follows: NH (NH)4I、NH4Br、Bu4NPF6、NH4Cl or KI and the like;
the solvent is as follows: acetonitrile, methanol or ethanol, and the like.
The synthesis method of the sulfonyl hydrazino indole compound comprises the following steps:
(A) respectively adding 0.5mmol of the compound of the formula (1), 1mmol of the compound of the formula (2) and 1mmol of electrolyte into a 10mL three-necked flask, adding 8mL of solvent for dissolution, using reticular vitreous carbon RVC as an anode and a platinum sheet Pt as a cathode, carrying out stirring reaction for 3-5h in a diaphragm-free electrolytic cell under the conditions of constant current of 10-30mA and argon protection at 50-70 ℃, and monitoring the reaction process by TLC;
(B) after completion of the reaction, the mixture was extracted with 10mL of ethyl acetate, and the organic layer was washed with anhydrous Na2SO4Drying, removing solvent by rotary evaporator, purifying residue by flash silica gel column chromatography to obtain product (3).
And (B) purifying by using a flash silica gel column chromatography, wherein the volume ratio of the eluent is ethyl acetate to petroleum ether is 1: 3-6.
The invention also discloses application of the compound shown in the formula 3 or pharmaceutically acceptable salt thereof in preparing antitumor drugs.
The invention also discloses an antitumor drug prepared by using the compound shown in the formula 3 or pharmaceutically acceptable salt thereof as an active ingredient.
According to the method, under mild electrochemical conditions, sulfonyl hydrazine is used for carrying out selective sulfonylation and hydrazidation on indole to synthesize a series of sulfonyl hydrazino indole compounds, and the synthesized sulfonyl hydrazino indole compounds are found to have good antitumor activity through in vitro antitumor activity screening. Among the numerous oxidizing agents used in oxidative coupling reactions, electric current is one of the cheapest, most effective and environmentally friendly oxidizing agents. The process of the invention is carried out in a diaphragm-free electrolytic cell using constant current instead of exogenous oxidant, the by-products being hydrogen and nitrogen. In addition, under mild electrochemical conditions without catalysts, the problems of sulfonyl desulfonylation or over-oxidation are effectively avoided, and a series of sulfonyl hydrazino indole compounds which are not reported in documents are obtained. Compared with the traditional synthesis method, the method is more environment-friendly.
Detailed Description
The present invention will be further described with reference to the synthesis, structure and characterization of sulfonyl hydrazinoindoles in the following examples, which are not intended to limit the scope of the present invention.
Example 1:
synthesis and characterization of 4-methyl-N' - (3-p-toluenesulfonyl-1H-indol-2-yl) benzenesulfonylhydrazide (3 aa):
0.5mmol of indole, 1mmol of p-toluenesulfonyl hydrazide and 1mmol of NH were added respectively4I is added into a 10mL three-necked flask, dissolved by adding 8mL acetonitrile and dissolved by using a reticular glassTaking bulk carbon RVC as an anode and a platinum sheet Pt as a cathode, stirring and reacting for 3 hours in a diaphragm-free electrolytic cell under the conditions of constant current of 10mA and argon protection at 50 ℃, and monitoring the reaction process by TLC;
after completion of the reaction, the mixture was extracted with 10mL of ethyl acetate, and the organic layer was washed with anhydrous Na2SO4Drying, removing the solvent by rotary evaporator, purifying the residue by flash silica gel column chromatography (eluent volume ratio of ethyl acetate: petroleum ether: 1:3) to obtain white solid 3 aa;
White solid(85％,193.4mg).mp:125.0–125.6℃,1H NMR(400MHz,DMSO-d6)11.73(s,1H),9.97(s,1H),7.92(s,1H),7.85–7.75(m,2H),7.72–7.65(m,2H),7.58–7.50(m,2H),7.48–7.40(m,1H),7.38–7.32(m,2H),7.30–7.24(m,1H),7.10–6.90(m,2H),2.44(s,3H),2.33(s,3H).13C NMR(100MHz,DMSO-d6)148.3,144.4,142.9,141.2,133.9,132.0,129.9,129.6,128.0,125.3,124.7,121.3,120.7,116.1,111.3,89.8,21.1,20.9.HRMS(m/z)(ESI):calcd for C22H22N3O4S2[M+H]+456.1052,found 456.1036。
example 2:
synthesis and characterization of N' - (3- (benzenesulfonyl) -1H-indol-2-yl) benzenesulfonylhydrazide (3 ab):
0.5mmol of indole, 1mmol of benzenesulfonyl hydrazide and 1mmol of NH respectively4Adding Br into a 10mL three-necked flask, adding 8mL methanol for dissolution, using reticular vitreous carbon RVC as an anode and a platinum sheet Pt as a cathode, stirring and reacting for 4h in a diaphragm-free electrolytic cell under the conditions of constant current of 15mA and argon protection at 55 ℃, and monitoring the reaction process by TLC;
after completion of the reaction, the mixture was extracted with 10mL of ethyl acetate, and the organic layer was washed with anhydrous Na2SO4Drying, removing solvent by rotary evaporator, purifying residue by flash silica gel column chromatography (eluent volume ratio is ethyl acetate: petroleum ether-1: 4) to obtain white solid 3 ab;
White solid(78％,166.5mg).mp:112.4–113.7℃,1H NMR(500MHz,DMSO-d6)11.77(s,1H),10.08(s,1H),8.04(s,1H),7.91–7.87(m,2H),7.81–7.75(m,3H),7.74–7.68(m,2H),7.60–7.52(m,3H),7.47–7.43(M,1H),7.28–7.24(m,1H),7.04–6.94(m,2H).13C NMR(125MHz,DMSO-d6)148.5,144.0,136.9,133.9,132.5,132.0,129.4,129.2,127.9,125.2,124.7,121.3,120.8,116.1,111.3,89.4.HRMS(m/z)(ESI):calcd for C20H18N3O4S2[M+H]+428.0739,found 428.0725。
example 3:
synthesis and characterization of 2-methyl-N' - (3- (o-toluenesulfonyl) -1H-indol-2-yl) benzenesulfonylhydrazide (3 ac):
0.5mmol of indole, 1mmol of o-toluenesulfonyl hydrazide and 1mmol of Bu are reacted respectively4NPF6Adding into a 10mL three-necked bottle, adding 8mL ethanol for dissolving, using reticular vitreous carbon RVC as an anode and a platinum sheet Pt as a cathode, stirring and reacting for 5h in a diaphragm-free electrolytic cell under the conditions of constant current of 20mA and argon protection and 60 ℃, and monitoring the reaction process by TLC;
after completion of the reaction, the mixture was extracted with 10mL of ethyl acetate, and the organic layer was washed with anhydrous Na2SO4Drying, removing the solvent by a rotary evaporator, and purifying the residue by flash silica gel column chromatography (eluent volume ratio is ethyl acetate: petroleum ether: 1:5) to obtain a white solid 3 ac;
White solid(45％,102.4mg).mp:131.5–132.9℃,1H NMR(400MHz,DMSO-d6)11.78(s,1H),10.02(s,1H),8.00-7.90(m,1H),7.82(s,1H),7.75–7.70(m,2H),7.52–7.45(m,3H),7.44–7.38(m,1H),7.34–7.28(m,2H),7.14–7.08(m,1H),7.02–6.88(m,2H),2.42(s,3H),2.35(s,3H).13C NMR(100MHz,DMSO-d6)149.0,144.3,141.2,136.8,133.9,132.6,132.5,132.0,129.9,127.9,127.8,126.3,124.7,121.2,120.8,115.8,111.4,87.8,21.1,19.4.HRMS(m/z)(ESI):calcd for C22H22N3O4S2[M+H]+456.1052,found 456.1038。
example 4:
synthesis and characterization of 3-methyl-N' - (3- (m-toluenesulfonyl) -1H-indol-2-yl) benzenesulfonylhydrazide (3 ad):
respectively adding 0.5mmol of indole, 1mmol of m-toluenesulfonylhydrazide and 1mmol of KI into a 10mL three-necked bottle, adding 8mL of acetonitrile for dissolving, using reticular vitreous carbon RVC as an anode and a platinum sheet Pt as a cathode, stirring and reacting for 3h in a diaphragm-free electrolytic cell under the conditions of constant current of 25mA and argon protection and 65 ℃, and monitoring the reaction process by TLC;
after completion of the reaction, the mixture was extracted with 10mL of ethyl acetate, and the organic layer was washed with anhydrous Na2SO4Drying, removing the solvent by a rotary evaporator, and purifying the residue by flash silica gel column chromatography (eluent volume ratio is ethyl acetate: petroleum ether: 1:6) to obtain white solid 3 ad;
White solid(78％,177.5mg).mp:125.3–125.8℃,1H NMR(400MHz,DMSO-d6)11.76(s,1H),10.04(s,1H),8.01(s,1H),7.77–7.66(m,3H),7.65–7.61(m,1H),7.62–7.53(m,2H),7.47–7.37(m,3H),7.31–7.25(m,1H),7.06–6.97(m,2H),2.37(s,3H),2.34(s,3H).13C NMR(100MHz,DMSO-d6)148.5,144.0,139.2,139.0,136.8,134.4,133.2,132.1,129.3,129.0,128.1,125.4,124.9,124.7,122.5,121.3,120.9,116.2,111.3,89.5,20.9,20.8.HRMS(m/z)(ESI):calcd for C22H22N3O4S2[M+H]+456.1052,found 456.1038。
example 5:
synthesis and characterization of 4-fluoro-N' - (3- (4-fluorophenyl) sulfonyl-1H-indol-2-yl) benzenesulfonylhydrazide (3 ae):
0.5mmol of indole, 1mmol of p-fluorobenzenesulfonyl hydrazide and 1mmol of NH respectively4Adding the I into a 10mL three-necked bottle, adding 8mL methanol for dissolution, using reticular vitreous carbon RVC as an anode and a platinum sheet Pt as a cathode, stirring and reacting for 4h in a diaphragm-free electrolytic cell under the conditions of constant current of 30mA and argon protection at 70 ℃, and monitoring the reaction process by TLC;
after completion of the reaction, the mixture was extracted with 10mL of ethyl acetate, and the organic layer was washed with anhydrous Na2SO4Drying, removing solvent with rotary evaporator, and purifying the residue by flash silica gel column chromatography (eluent volume ratio of ethyl acetate: petroleum ether: 1:3) to obtain white solid 3 ae;
White solid(65％,150.5mg).mp:165.1–162.8℃,1H NMR(500MHz,DMSO-d6)11.76(s,1H),10.14(s,1H),8.31(s,1H),7.99–7.92(m,2H),7.91–7.85(m,2H),7.62–7.56(m,2H),7.52–7.38(m,3H),7.32–7.24(m,1H),7.06–6.98(m,2H).13C NMR(125MHz,DMSO-d6)165.7(d,J＝252.1Hz),164.7(d,J＝251.1Hz),148.9,141.0(d,J＝3.1Hz),133.9(d,J＝2.7Hz),132.4,131.7(d,J＝9.9Hz),128.5(d,J＝9.7Hz),125.1,121.7,121.2,117.0(d,J＝23.1Hz),116.8(d,J＝22.9Hz),116.4,111.7,89.69.HRMS(m/z)(ESI):calcd for C20H14F2N3O4S2[M–H]-462.0394,found 462.0395。
example 6:
synthesis and characterization of 4-chloro-N' - (3- (4-chlorophenyl) sulfonyl-1H-indol-2-yl) benzenesulfonylhydrazide (3 af):
0.5mmol of indole, 1mmol of p-chlorobenzenesulfonyl hydrazide and 1mmol of NH respectively4Adding Br into a 10mL three-necked flask, adding 8mL ethanol for dissolution, using reticular vitreous carbon RVC as an anode and a platinum sheet Pt as a cathode, stirring and reacting for 5h in a diaphragm-free electrolytic cell under the conditions of constant current of 10mA and argon protection and 50 ℃, and monitoring the reaction process by TLC;
to be reversedAfter completion of the reaction, the mixture was extracted with 10mL of ethyl acetate, and the organic layer was washed with anhydrous Na2SO4Drying, removing the solvent by rotary evaporator, purifying the residue by flash silica gel column chromatography (eluent volume ratio of ethyl acetate: petroleum ether: 1:4) to obtain 3af as a white solid;
White solid(75％,175.6mg).mp:209.2–210.0℃,1H NMR(500MHz,DMSO-d6)11.78(s,1H),10.22(s,1H),8.44(s,1H),7.92–7.87(m,2H),7.86–7.80(m,4H),7.70–7.64(m,2H),7.52–7.47(m,1H),7.32–7.27(m,1H),7.08–6.98(m,2H).13C NMR(125MHz,DMSO-d6)148.8,143.0,138.7,137.5,136.1,132.1,130.0,129.5,129.4,127.1,124.7,121.5,120.9,116.1,111.4,89.1.HRMS(m/z)(ESI):calcd for C20H14Cl2N3O4S2[M–H]-493.9803,found 493.9805。
example 7:
synthesis and characterization of 4-bromo-N' - (3- (4-bromophenyl) sulfonyl-1H-indol-2-yl) benzenesulfonylhydrazide (3 ag):
0.5mmol of indole, 1mmol of p-bromobenzenesulfonyl hydrazide and 1mmol of Bu4NPF6Adding into a 10mL three-necked bottle, adding 8mL acetonitrile for dissolving, using reticular vitreous carbon RVC as an anode and a platinum sheet Pt as a cathode, stirring and reacting for 3h in a diaphragm-free electrolytic cell under the conditions of constant current of 15mA and argon protection and at 55 ℃, and monitoring the reaction process by TLC;
after completion of the reaction, the mixture was extracted with 10mL of ethyl acetate, and the organic layer was washed with anhydrous Na2SO4Drying, removing the solvent by a rotary evaporator, and purifying the residue by flash silica gel column chromatography (eluent volume ratio is ethyl acetate: petroleum ether: 1:5) to obtain yellow solid 3 ag;
Yellow solid(60％,175.5mg).mp:219.5–221.0℃,1H NMR(500MHz,DMSO-d6)11.76(s,1H),10.21(s,1H),8.42(s,1H),7.98–7.93(m,2H),7.82–7.78(m,4H),7.78–7.73(m,2H),7.50–7.43(m,1H),7.32–7.26(m,1H),7.06–6.98(m,2H).13C NMR(125MHz,DMSO-d6)148.8,143.4,136.6,132.4,132.3,132.1,130.0,127.8,127.2,126.4,124.7,121.5,120.9,116.1,111.4,89.0.HRMS(m/z)(ESI):HRMS(m/z)(ESI):calcd for C20H14Br2N3O4S2[M–H]-583.8772,found 583.8774。
example 8:
synthesis and characterization of 4-methoxy-N' - (3- (4-methoxyphenyl) sulfonyl-1H-indol-2-yl) benzenesulfonylhydrazide (3 ah):
respectively adding 0.5mmol of indole, 1mmol of p-methoxybenzenesulfonyl hydrazide and 1mmol of KI into a 10mL three-necked bottle, adding 8mL of methanol for dissolving, using reticular vitreous carbon RVC as an anode and a platinum sheet Pt as a cathode, stirring and reacting for 4 hours in a diaphragm-free electrolytic cell under the conditions of constant current of 20mA and argon protection and 60 ℃, and monitoring the reaction process by TLC;
after completion of the reaction, the mixture was extracted with 10mL of ethyl acetate, and the organic layer was washed with anhydrous Na2SO4Drying, removing the solvent by a rotary evaporator, and purifying the residue by flash silica gel column chromatography (eluent volume ratio is ethyl acetate: petroleum ether: 1:6) to obtain a white solid 3 ah;
White solid(72％,175.3mg).mp:189.1–189.9℃,1H NMR(500MHz,DMSO-d6)11.71(s,1H),9.90(s,1H),7.90–7.83(m,3H),7.80–7.70(m,2H),7.46–7.40(m,1H),7.30–7.22(m,3H),7.12–7.05(m,2H),7.04–6.96(m,2H),3.87(s,3H),3.79(s,3H).13C NMR(125MHz,DMSO-d6)163.3,162.4,148.1,135.9,132.1,130.3,128.2,127.5,124.7,121.2,120.7,116.1,114.7,114.4,111.3,90.2,55.9,55.7.HRMS(m/z)(ESI):calcd for C22H22N3O6S2[M+H]+488.0950found 488.0932。
example 9:
synthesis and characterization of 4-tert-butyl-N' - (3- (4- (tert-butyl) phenyl) sulfonyl-1H-indol-2-yl) benzenesulfonylhydrazide (3 ai):
0.5mmol of indole, 1mmol of p-tert-butylbenzenesulfonyl hydrazide and 1mmol of NH were added to the reaction mixture4Adding Cl into a 10mL three-necked bottle, adding 8mL ethanol for dissolving, using reticular vitreous carbon RVC as an anode and a platinum sheet Pt as a cathode, stirring and reacting for 5h in a diaphragm-free electrolytic cell under the conditions of constant current of 25mA and argon protection at 65 ℃, and monitoring the reaction process by TLC;
after completion of the reaction, the mixture was extracted with 10mL of ethyl acetate, and the organic layer was washed with anhydrous Na2SO4Drying, removing solvent by rotary evaporator, purifying residue by flash silica gel column chromatography (eluent volume ratio is ethyl acetate: petroleum ether: 1:3) to obtain white solid 3 ai;
White solid(63％,169.8mg).mp:193.5–194.0℃,1H NMR(500MHz,DMSO-d6)11.71(s,1H),10.01(s,1H),8.02(s,1H),7.90–7.80(m,2H),7.77–7.65(m,4H),7.60–7.50(m,2H),7.50–7.40(m,1H),7.30–7.20(m,1H),7.05–6.90(m,2H),1.29(s,9H),1.26(s,9H).13C NMR(125MHz,DMSO-d6)156.9,155.6,148.2,141.2,134.0,132.0,127.9,126.2,126.0,125.7,125.5,125.1,124.6,121.2,120.7,116.1,111.3,89.7,35.0,34.8,34.7,30.8,30.7,30.7.HRMS(m/z)(ESI):calcd for C28H33N3O4S2[M–H]-538.1834found 538.1832。
example 10:
synthesis and characterization of N ' - (3- ([1,1' -biphenyl ] -4-sulfonyl) -1H-indol-2-yl) - [1,1' -biphenyl ] -4-benzenesulfonylhydrazide (3 aj):
0.5mmol of indole, 1mmol of 4-biphenylsulfonyl hydrazide and 1mmol of NH respectively4Adding Br into a 10mL three-necked flask, adding 8mL acetonitrile to dissolve, using reticular vitreous carbon RVC as an anode and a platinum sheet Pt as a cathode, stirring and reacting for 3h in a diaphragm-free electrolytic cell under the conditions of constant current of 30mA and argon protection at 70 ℃, and monitoring the reaction process by TLC;
after completion of the reaction, the mixture was extracted with 10mL of ethyl acetate, and the organic layer was washed with anhydrous Na2SO4Drying, removing the solvent by rotary evaporator, purifying the residue by flash silica gel column chromatography (eluent volume ratio of ethyl acetate: petroleum ether: 1:4) to obtain white solid 3 aj;
White solid(60％,173.7mg).mp:220.4–221.0℃,1H NMR(500MHz,DMSO-d6)11.81(s,1H),10.15(s,1H),8.25(s,1H),8.10–7.95(m,4H),7.93–7.89(m,2H),7.87–7.83(m,2H),7.80–7.76(m,2H),7.71–7.67(m,2H),7.57–7.49(m,4H),7.48–7.39(m,4H),7.35–7.25(m,1H),7.10–6.95(m,1H).13C NMR(125MHz,DMSO-d6)148.6,145.2,144.2,142.8,138.5,138.2,135.8,132.1,129.2,129.1,128.8,128.7,128.5,127.5,127.2,127.1,125.9,124.8,121.4,120.9,116.2,111.4,99.5,89.56.HRMS(m/z)(ESI):calcd for C32H24N3O4S2[M–H]-578.1208found 578.1210。
example 11:
synthesis and characterization of N' - (3- (2-naphthalenesulfonyl) -1H-indol-2-yl) -2-naphthalenesulfonyl hydrazide (3 ak):
0.5mmol of indole, 1mmol of 2-naphthalenesulfonyl hydrazide and 1mmol of Bu respectively4NPF6Adding into a 10mL three-necked bottle, adding 8mL methanol for dissolving, using reticular vitreous carbon RVC as an anode and a platinum sheet Pt as a cathode, stirring and reacting for 4h in a diaphragm-free electrolytic cell under the conditions of constant current of 10mA and argon protection and 50 ℃, and monitoring the reaction process by TLC;
after completion of the reaction, the mixture was extracted with 10mL of ethyl acetate, and the organic layer was washed with anhydrous Na2SO4Drying, removing the solvent by rotary evaporator, purifying the residue by flash silica gel column chromatography (eluent volume ratio is ethyl acetate: petroleum ether: 1:5) to obtain white solid 3 ak;
White solid(65％,171.3mg).mp:209.7–210.3℃,1H NMR(500MHz,DMSO-d6)11.82(s,1H),10.25(s,1H),8.65–8.60(m,1H),8.55–8.50(m,1H),8.31(s,1H),8.26–8.22(m,1H),8.19–8.14(m,1H),8.13–8.07(m,2H),8.07–8.03(m,1H),8.02–7.92(m,2H),7.78–7.70(m,3H),7.69–7.60(m,2H),7.54–7.48(m,1H),7.35–7.25(m,1H),7.05–6.90(m,2H).13C NMR(125MHz,DMSO-d6)148.8,140.9,134.8,134.2,132.1,131.7,131.7,129.6,129.4,129.4,129.4,129.2,128.7,128.0,127.8,127.6,125.7,124.7,122.9,121.3,120.8,116.1,111.3,89.3.HRMS(m/z)(ESI):calcd for C28H21N3O4S2[M–H]-526.0895found 526.0892。
example 12:
synthesis and characterization of N' - (3- (2-thiophenesulfonyl) -1H-indol-2-yl) -2-thiophenesulfonylhydrazide (3 al):
respectively adding 0.5mmol of indole, 1mmol of 2-thiophenesulfonyl hydrazide and 1mmol of KI into a 10mL three-necked bottle, adding 8mL of ethanol for dissolving, using reticular vitreous carbon RVC as an anode and a platinum sheet Pt as a cathode, stirring and reacting for 5 hours in a diaphragm-free electrolytic cell under the conditions of constant current of 15mA and argon protection and at 55 ℃, and monitoring the reaction process by TLC;
after completion of the reaction, the mixture was extracted with 10mL of ethyl acetate, and the organic layer was washed with anhydrous Na2SO4Drying, removing solvent by rotary evaporator, purifying residue by flash silica gel column chromatography (eluent volume ratio is ethyl acetate: petroleum ether: 1:6) to obtain white solid 3 al;
White solid(86％,188.72mg).mp:203.4–203.9℃,1H NMR(500MHz,DMSO-d6)11.82(s,1H),10.21(s,1H),8.18–8.12(m,2H),7.89–7.83(m,1H),7.79–7.73(m,1H),7.67–7.63(m,1H),7.52–7.46(m,1H),7.37–7.32(m,1H),7.32–7.27(m,1H),7.16–7.11(m,1H),7.10–7.00(m,2H).13C NMR(125MHz,DMSO-d6)148.2,145.6,136.8,135.2,134.2,132.5,132.1,130.3,128.2,127.8,124.5,121.4,121.0,116.3,111.4,90.1.HRMS(m/z)(ESI):calcd for C16H12N3O4S4[M–H]-437.9711found 437.9712。
example 13:
synthesis and characterization of N' - (3- (benzylsulfonyl) -1H-indol-2-yl) -1-benzylsulfonyl (3 am):
0.5mmol of indole, 1mmol of benzylsulfonylhydrazide and 1mmol of NH respectively4Adding Cl into a 10mL three-necked bottle, adding 8mL acetonitrile to dissolve, using reticular vitreous carbon RVC as an anode and a platinum sheet Pt as a cathode, stirring and reacting for 5h in a diaphragm-free electrolytic cell under the conditions of constant current of 20mA and argon protection and 60 ℃, and monitoring the reaction process by TLC;
after completion of the reaction, the mixture was extracted with 10mL of ethyl acetate, and the organic layer was washed with anhydrous Na2SO4Drying, removing the solvent by a rotary evaporator, and purifying the residue by flash silica gel column chromatography (eluent volume ratio is ethyl acetate: petroleum ether: 1:3) to obtain yellow solid 3 am;
Yellow solid(40％,91.0mg).mp:197.1-198.9℃,1H NMR(400MHz,DMSO-d6)11.54(s,1H),9.64(s,1H),8.17(s,1H),7.48–7.43(m,1H),7.41–7.37(m,5H),7.31–7.27(m,1H),7.26–7.22(m,3H),7.19-7.13(m,2H),7.01–6.93(m,2H),4.45-4.40(m,4H).13C NMR(100MHz,DMSO-d6)149.3,131.7,131.1,130.9,130.8,129.6,128.7,128.6,128.4,128.1,125.8,121.0,120.4,116.4,111.1,87.4,61.7,55.5.HRMS(m/z)(ESI):calcd for C22H20N3O4S2[M–H]-454.0895found 454.0899。
example 14:
synthesis and characterization of 4-methyl-N' - (5-methyl-3-tosyl-1H-indol-2-yl) benzenesulfonylhydrazide (3 ba):
0.5mmol of 5-methylindole, 1mmol of p-toluenesulfonylhydrazide and 1mmol of NH were added respectively4Br was added to a 10mL three-necked flask, dissolved in 8mL of methanol, and applied to a glass netGlass carbon RVC is taken as an anode, a platinum sheet Pt is taken as a cathode, the reaction is stirred and reacted for 4 hours in a diaphragm-free electrolytic cell under the conditions of constant current of 25mA and argon protection at 65 ℃, and the reaction process is monitored by TLC;
after completion of the reaction, the mixture was extracted with 10mL of ethyl acetate, and the organic layer was washed with anhydrous Na2SO4Drying, removing the solvent by rotary evaporator, purifying the residue by flash silica gel column chromatography (eluent volume ratio of ethyl acetate: petroleum ether: 1:4) to obtain white solid 3 ba;
White solid(77％,180.6mg).mp:184.3–185.2℃,1H NMR(400MHz,DMSO-d6)11.61(s,1H),9.93(s,1H),7.85(s,1H),7.82–7.76(m,2H),7.70–7.64(m,2H),7.56–7.50(m,2H),7.39–7.34(m,2H),7.26–7.22(m,1H),7.18–7.13(m,1H),6.84–6.78(m,1H),2.44(s,3H),2.34(s,3H),2.31(s,3H).13C NMR(100MHz,DMSO-d6)148.3,144.4,142.9,141.3,133.9,130.2,130.0,129.9,129.6,127.9,125.2,124.9,121.9,116.1,111.0,89.4,21.3,21.1,20.9.HRMS(m/z)(ESI):calcd for C23H22N3O4S2[M–H]-468.1052found 468.1053。
example 15:
synthesis and characterization of 4-methyl-N' - (6-methyl-3-tosyl-1H-indol-2-yl) benzenesulfonyl hydrazide (3 ca):
0.5mmol of 6-methylindole, 1mmol of p-toluenesulfonylhydrazide and 1mmol of Bu are reacted respectively4NPF6Adding into a 10mL three-necked bottle, adding 8mL ethanol for dissolving, using reticular vitreous carbon RVC as an anode and a platinum sheet Pt as a cathode, stirring and reacting for 5h in a diaphragm-free electrolytic cell under the conditions of constant current of 30mA and argon protection and 70 ℃, and monitoring the reaction process by TLC;
after completion of the reaction, the mixture was extracted with 10mL of ethyl acetate, and the organic layer was washed with anhydrous Na2SO4Drying, removing solvent by rotary evaporator, and purifying the residue by flash silica gel column chromatography (eluent volume ratio of ethyl acetate: petroleum ether: 1:5) to obtain white productA solid 3 ca;
White solid(67％,157.1mg).mp:145.2–145.9℃,1H NMR(400MHz,DMSO-d6)11.61(s,1H),9.94(s,1H),7.85–7.75(m,3H),7.70–7.62(m,2H),7.60–7.50(m,2H),7.40–7.25(m,3H),7.08(s,1H),6.90–6.80(m,1H),2.43(s,3H),2.33(s,3H),2.30(s,3H).13C NMR(100MHz,DMSO-d6)148.0,144.4,142.9,141.2,133.9,132.4,129.9,129.9,129.6,128.0,125.2,122.5,122.4,115.9,111.4,89.5,21.2,21.1,20.9.HRMS(m/z)(ESI):calcd for C23H24N3O4S2[M+H]+470.1208found 470.1198。
example 16:
synthesis and characterization of 4-methyl-N' - (7-methyl-3-tosyl-1H-indol-2-yl) benzenesulfonylhydrazide (3 da):
respectively adding 0.5mmol of 7-methylindole, 1mmol of p-toluenesulfonylhydrazide and 1mmol of KI into a 10mL three-necked bottle, adding 8mL of acetonitrile for dissolving, using reticular vitreous carbon RVC as an anode and a platinum sheet Pt as a cathode, stirring and reacting for 3 hours in a diaphragm-free electrolytic cell under the conditions of constant current of 10mA and argon protection and 50 ℃, and monitoring the reaction process by TLC;
after completion of the reaction, the mixture was extracted with 10mL of ethyl acetate, and the organic layer was washed with anhydrous Na2SO4Drying, removing the solvent by rotary evaporator, and purifying the residue by flash silica gel column chromatography (eluent volume ratio of ethyl acetate: petroleum ether: 1:6) to obtain 3da of white solid;
White solid(58％,136.0mg).mp:134.3–135.0℃,1H NMR(400MHz,DMSO-d6)11.32(s,1H),9.86(s,1H),7.83(s,1H),7.80–7.73(m,2H),7.72–7.65(m,2H),7.50–7.42(m,2H),7.40–7.32(m,2H),7.30–7.20(m,1H),6.95–6.87(m,1H),6.85–6.75(m,1H),2.38(s,6H),2.33(s,3H).13C NMR(100MHz,DMSO-d6)148.2,144.4,143.0,141.0,134.0,131.0,129.8,129.6,127.9,125.3,124.4,122.3,121.5,120.8,113.8,90.4,21.1,20.9,17.0.HRMS(m/z)(ESI):calcd for C23H22N3O4S2[M–H]-468.1052found 468.1054。
example 17:
synthesis and characterization of N' - (5-methoxy-3-tosyl-1H-indol-2-yl) -4-toluenesulfonylhydrazide (3 ea):
0.5mmol of 5-methylindole, 1mmol of p-toluenesulfonylhydrazide and 1mmol of NH were added respectively4Adding Cl into a 10mL three-necked bottle, adding 8mL methanol for dissolution, using reticular vitreous carbon RVC as an anode and a platinum sheet Pt as a cathode, stirring and reacting for 3h in a diaphragm-free electrolytic cell under the conditions of constant current of 15mA and argon protection and at 55 ℃, and monitoring the reaction process by TLC;
after completion of the reaction, the mixture was extracted with 10mL of ethyl acetate, and the organic layer was washed with anhydrous Na2SO4Drying, removing the solvent by rotary evaporator, and purifying the residue by flash silica gel column chromatography (eluent volume ratio of ethyl acetate: petroleum ether: 1:3) to obtain white solid 3 ea;
White solid(54％,131.0mg).mp:156.9–157.6℃,1H NMR(400MHz,DMSO-d6)11.57(s,1H),9.94(s,1H),7.87(s,1H),7.83–7.77(m,2H),7.72–7.66(m,2H),7.57–7.50(m,2H),7.40–7.34(m,2H),7.20–7.14(m,1H),6.99–6.93(m,1H),6.67–6.57(m,1H),3.72(s,3H),2.44(s,3H),2.34(s,3H).13C NMR(100MHz,DMSO-d6)154.9,148.5,144.4,143.0,141.2,134.0,129.9,129.6,128.0,126.6,125.6,125.2,112.0,108.6,100.2,89.9,55.4,21.1,20.9.HRMS(m/z)(ESI):calcd for C23H22N3O5S2[M–H]-484.1001found 484.1003。
example 18:
synthesis and characterization of N' - (6-chloro-3-tosyl-1H-indol-2-yl) -4-toluenesulfonylhydrazide (3 fa):
respectively adding 0.5mmol of6-Chloroindole, 1mmol of p-toluenesulfonylhydrazide and 1mmol of NH4Adding Br into a 10mL three-necked flask, adding 8mL ethanol for dissolution, using reticular vitreous carbon RVC as an anode and a platinum sheet Pt as a cathode, stirring and reacting for 4h in a diaphragm-free electrolytic cell under the conditions of constant current of 20mA and argon protection and 60 ℃, and monitoring the reaction process by TLC;
after completion of the reaction, the mixture was extracted with 10mL of ethyl acetate, and the organic layer was washed with anhydrous Na2SO4Drying, removing the solvent by rotary evaporator, and purifying the residue by flash silica gel column chromatography (eluent volume ratio of ethyl acetate to petroleum ether: 1:4) to obtain white solid 3 fa;
White solid(75％,183.4mg).mp:132.3–132.9℃,1H NMR(400MHz,DMSO-d6)11.82(s,1H),10.03(s,1H),8.12(s,1H),7.81–7.76(m,2H),7.72–7.67(m,2H),7.58–7.50(m,2H),7.46–7.41(m,1H),7.39–7.34(m,2H),7.29–7.26(m,1H),7.08–7.02(m,1H),2.44(s,3H),2.34(s,3H).13C NMR(100MHz,DMSO-d6)148.9,144.4,143.2,140.9,133.9,132.7,129.8,129.7,128.0,125.3,125.0,123.6,121.4,117.3,111.0,89.9,21.1,20.9.HRMS(m/z)(ESI):calcd for C22H19ClN3O4S2[M-H]-488.0505,found 488.0508。
example 19:
synthesis and characterization of N' - (6-fluoro-3-tosyl-1H-indol-2-yl) -4-toluenesulfonylhydrazide (3 ga):
0.5mmol of 6-fluoroindole, 1mmol of p-toluenesulfonylhydrazide and 1mmol of Bu were added respectively4NPF6Adding into a 10mL three-necked bottle, adding 8mL acetonitrile for dissolving, using reticular vitreous carbon RVC as an anode and a platinum sheet Pt as a cathode, stirring and reacting for 5h in a diaphragm-free electrolytic cell under the conditions of constant current of 25mA and argon protection at 65 ℃, and monitoring the reaction process by TLC;
after completion of the reaction, the mixture was extracted with 10mL of ethyl acetate, and the organic layer was washed with anhydrous Na2SO4Drying, removing solvent with rotary evaporator, and collecting residueThe residue was purified by flash column chromatography on silica gel (eluent volume ratio ethyl acetate: petroleum ether: 1:5) to give 3ga as a white solid;
White solid(55％,130.1mg).mp:127.5–128.2℃,1H NMR(400MHz,DMSO-d6)11.80(s,1H),9.99(s,1H),8.00(s,1H),7.81–7.76(m,2H),7.72–7.65(m,2H),7.60–7.50(m,2H),7.44–7.34(m,3H),7.10–7.00(m,1H),6.92–6.84(m,1H),2.44(s,3H),2.34(s,3H).13C NMR(100MHz,DMSO-d6)158.5(d,J＝234.6Hz),157.3,149.3(d,J＝1.8Hz),144.8,143.5,141.4,134.4,132.7(d,J＝12.5Hz),130.3,130.1,128.4,125.7,121.6,117.3(d,J＝9.7Hz),109.2(d,J＝23.5Hz),98.7(d,J＝26.9Hz),90.00,21.5,21.3.HRMS(m/z)(ESI):calcd for C22H19FN3O4S2[M-H]-472.0801,found 472.0802。
EXAMPLES 1-19 study of pharmacological Activity of Compounds
MTT was used to screen the in vitro inhibitory activity of compounds 3aa-3am and 3ba-3ga against 4 cancer cell lines (MGC-803, T-24, HepG-2, and SK-OV-3) and 1 human normal cell (WI-38). 5-FU was used as a positive control. The experimental result shows that most of the compounds have good inhibitory activity to tumor cell strains, wherein the compound 3ae has the best inhibitory effect on the tumor cell strains. As shown in Table 1, IC of compound 3ae for T-24 and HepG-250The values were 12.4. + -. 1.4 and 15.3. + -. 0.9. mu.M, respectively. In addition, the inhibition effect of the compound 3ae on tumor cells is more obvious than that of a normal human WI-38 cell line.
TABLE 1 IC of Compounds on five cell lines50Value (μ M)
| MGC-803 | T-24 | HepG-2 | SK-OV-3 | WI-38 | |
| 3aa | >40 | 30.5±1.4 | 25.5±1.7 | 35.9±1.8 | >40 |
| 3ab | 20.4±1.2 | 29.8±0.9 | 21.6±0.5 | 39.5±1.1 | 39.1±0.3 |
| 3ac | 27.8±0.4 | 28.1±0.5 | >40 | >40 | >40 |
| 3ad | 25.3±0.8 | >40 | >40 | >40 | >40 |
| 3ae | 20.7±0.7 | 12.4±1.4 | 15.3±0.9 | 25.1±2.3 | >40 |
| 3af | >40 | >40 | >40 | >40 | >40 |
| 3ag | >40 | >40 | >40 | >40 | >40 |
| 3ah | 29.2±2.3 | 32.9±1.6 | >40 | 35.7±0.3 | 37.9±1.5 |
| 3ai | >40 | >40 | >40 | >40 | >40 |
| 3aj | >40 | >40 | >40 | >40 | >40 |
| 3ak | 23.7±0.6 | 27.2±1.9 | 32.9±1.8 | >40 | 35.4±1.7 |
| 3al | >40 | 29.4± | >40 | 38.1±1.8 | >40 |
| 3am | >40 | >40 | >40 | >40 | >40 |
| 3ba | 21.5±1.2 | 25.3±0.5 | 34.5±0.7 | >40 | >40 |
| 3ca | 19.4±0.9 | 33.2±1.6 | >40 | >40 | >40 |
| 3da | >40 | >40 | >40 | 32.5±0.9 | >40 |
| 3ea | >40 | 30.7±1.5 | >40 | >40 | >40 |
| 3fa | >40 | >40 | >40 | >40 | >40 |
| 3ga | 17.6±1.5 | 27.1±2.2 | >40 | 34.0±0.6 | >40 |
| 5-FU | 35.2±0.8 | 38.4±1.1 | >40 | >40 | >40 |
The MTT method is utilized to research the anti-tumor activity of all compounds, and the experimental result shows that most compounds have good inhibition activity on tumor cell strains, wherein the inhibition effect of the compound 3ae on the tumor cell strains is the best.
Claims (5)
1. The method for electrochemically synthesizing the sulfonyl hydrazino indole compound is characterized in that the general formula of the synthesis method is as follows:
wherein,
R1is H, F, Cl, CH3And OCH3；
R2Are benzyl, tolyl and biphenyl;
the electrolyte is as follows: NH (NH)4I、NH4Br、Bu4NPF6、NH4Cl or KI;
the solvent is as follows: acetonitrile, methanol or ethanol;
the synthesis method of the sulfonyl hydrazino indole compound comprises the following steps:
(A) respectively adding 0.5mmol of the compound of the formula (1), 1mmol of the compound of the formula (2) and 1mmol of electrolyte into a 10mL three-necked flask, adding 8mL of solvent for dissolution, using reticular vitreous carbon RVC as an anode and a platinum sheet Pt as a cathode, carrying out stirring reaction for 3-5h in a diaphragm-free electrolytic cell under the conditions of constant current of 10-30mA and argon protection at 50-70 ℃, and monitoring the reaction process by TLC;
(B) after completion of the reaction, the mixture was extracted with 10mL of ethyl acetate, and the organic layer was washed with anhydrous Na2SO4Drying, removing solvent by rotary evaporator, purifying residue by flash silica gel column chromatography to obtain product (3).
2. The method for electrochemically synthesizing sulfonyl hydrazinoindoles as claimed in claim 1, wherein: and (B) purifying by using a flash silica gel column chromatography, wherein the volume ratio of the eluent is ethyl acetate to petroleum ether is 1: 3-6.
3. The sulfonyl hydrazino indole compound is characterized in that the structure of the sulfonyl hydrazino indole compound is as follows:
4. the use of a sulfonylhydrazinoindole compound or a pharmaceutically acceptable salt thereof according to claim 3 in the preparation of an anti-tumor medicament.
5. An antitumor agent prepared by using the sulfonyl hydrazino indole compound or the pharmaceutically acceptable salt thereof as an active ingredient according to claim 3.
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