CN107082774A - The derivative of one class containing 1,2,4 nitrogen triazole type skeletons and its preparation method and application - Google Patents
The derivative of one class containing 1,2,4 nitrogen triazole type skeletons and its preparation method and application Download PDFInfo
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- ethyl acetate
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- 238000002360 preparation method Methods 0.000 title claims abstract description 51
- NLBPEJCENDHVEJ-UHFFFAOYSA-N [N].C1=CNN=N1 Chemical compound [N].C1=CNN=N1 NLBPEJCENDHVEJ-UHFFFAOYSA-N 0.000 title claims abstract description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 143
- 238000006243 chemical reaction Methods 0.000 claims description 90
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 71
- 238000001035 drying Methods 0.000 claims description 45
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 42
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 39
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- BLRHMMGNCXNXJL-UHFFFAOYSA-N 1-methylindole Chemical compound C1=CC=C2N(C)C=CC2=C1 BLRHMMGNCXNXJL-UHFFFAOYSA-N 0.000 claims description 38
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 33
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 32
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 31
- KMAKOBLIOCQGJP-UHFFFAOYSA-N indole-3-carboxylic acid Chemical compound C1=CC=C2C(C(=O)O)=CNC2=C1 KMAKOBLIOCQGJP-UHFFFAOYSA-N 0.000 claims description 29
- 239000012074 organic phase Substances 0.000 claims description 28
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 23
- 239000007787 solid Substances 0.000 claims description 19
- 235000019441 ethanol Nutrition 0.000 claims description 18
- 238000010992 reflux Methods 0.000 claims description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- QKFJKGMPGYROCL-UHFFFAOYSA-N phenyl isothiocyanate Chemical compound S=C=NC1=CC=CC=C1 QKFJKGMPGYROCL-UHFFFAOYSA-N 0.000 claims description 14
- 238000003756 stirring Methods 0.000 claims description 14
- 238000000967 suction filtration Methods 0.000 claims description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 14
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 13
- -1 sodium hydrides Chemical class 0.000 claims description 13
- 239000000047 product Substances 0.000 claims description 12
- 238000005292 vacuum distillation Methods 0.000 claims description 12
- 238000001816 cooling Methods 0.000 claims description 11
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 claims description 10
- OLNJUISKUQQNIM-UHFFFAOYSA-N indole-3-carbaldehyde Chemical compound C1=CC=C2C(C=O)=CNC2=C1 OLNJUISKUQQNIM-UHFFFAOYSA-N 0.000 claims description 10
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 10
- 239000012286 potassium permanganate Substances 0.000 claims description 10
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 9
- QXAUTQFAWKKNLM-UHFFFAOYSA-N methyl indole-3-carboxylate Chemical class C1=CC=C2C(C(=O)OC)=CNC2=C1 QXAUTQFAWKKNLM-UHFFFAOYSA-N 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 8
- 239000012141 concentrate Substances 0.000 claims description 7
- 239000012043 crude product Substances 0.000 claims description 7
- 229940117953 phenylisothiocyanate Drugs 0.000 claims description 7
- 239000000376 reactant Substances 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- 125000005909 ethyl alcohol group Chemical group 0.000 claims description 5
- 239000012453 solvate Substances 0.000 claims description 5
- 238000003810 ethyl acetate extraction Methods 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 3
- 230000000118 anti-neoplastic effect Effects 0.000 claims description 3
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical class COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 239000012312 sodium hydride Substances 0.000 claims description 3
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 2
- 230000006837 decompression Effects 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims 2
- 238000001953 recrystallisation Methods 0.000 claims 2
- 230000001476 alcoholic effect Effects 0.000 claims 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 claims 1
- 238000010189 synthetic method Methods 0.000 abstract description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 36
- 238000005160 1H NMR spectroscopy Methods 0.000 description 18
- 239000000843 powder Substances 0.000 description 18
- 235000011121 sodium hydroxide Nutrition 0.000 description 17
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 description 15
- 239000000243 solution Substances 0.000 description 8
- 150000002475 indoles Chemical class 0.000 description 5
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical class C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 4
- LCPVQAHEFVXVKT-UHFFFAOYSA-N 2-(2,4-difluorophenoxy)pyridin-3-amine Chemical compound NC1=CC=CN=C1OC1=CC=C(F)C=C1F LCPVQAHEFVXVKT-UHFFFAOYSA-N 0.000 description 3
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 150000003851 azoles Chemical class 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Substances [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 102000004243 Tubulin Human genes 0.000 description 2
- 108090000704 Tubulin Proteins 0.000 description 2
- UXHQMSUJQLPRAW-UHFFFAOYSA-N benzene;isothiocyanic acid Chemical compound N=C=S.C1=CC=CC=C1 UXHQMSUJQLPRAW-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- HVRCLXXJIQTXHC-UHFFFAOYSA-N 1-methylindole-3-carboxylic acid Chemical compound C1=CC=C2N(C)C=C(C(O)=O)C2=C1 HVRCLXXJIQTXHC-UHFFFAOYSA-N 0.000 description 1
- 125000006280 2-bromobenzyl group Chemical group [H]C1=C([H])C(Br)=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000006282 2-chlorobenzyl group Chemical group [H]C1=C([H])C(Cl)=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000005806 3,4,5-trimethoxybenzyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1C([H])([H])* 0.000 description 1
- 125000006186 3,5-dimethyl benzyl group Chemical group [H]C1=C(C([H])=C(C([H])=C1C([H])([H])[H])C([H])([H])*)C([H])([H])[H] 0.000 description 1
- 125000006279 3-bromobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(Br)=C1[H])C([H])([H])* 0.000 description 1
- 125000003852 3-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(Cl)=C1[H])C([H])([H])* 0.000 description 1
- OVDGUTHABMXVMI-UHFFFAOYSA-N 3-nitro-4-(propylamino)benzoic acid Chemical compound CCCNC1=CC=C(C(O)=O)C=C1[N+]([O-])=O OVDGUTHABMXVMI-UHFFFAOYSA-N 0.000 description 1
- ILUSBJDVXKZYEP-UHFFFAOYSA-N 4-(aminomethyl)oxan-4-ol;hydrochloride Chemical compound Cl.NCC1(O)CCOCC1 ILUSBJDVXKZYEP-UHFFFAOYSA-N 0.000 description 1
- 125000006281 4-bromobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Br)C([H])([H])* 0.000 description 1
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 description 1
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000006181 4-methyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])C([H])([H])* 0.000 description 1
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- TZYWCYJVHRLUCT-VABKMULXSA-N N-benzyloxycarbonyl-L-leucyl-L-leucyl-L-leucinal Chemical compound CC(C)C[C@@H](C=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OCC1=CC=CC=C1 TZYWCYJVHRLUCT-VABKMULXSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- CDMXXXZRZWQJQE-UHFFFAOYSA-N acetic acid;2-methylprop-2-enoic acid Chemical compound CC(O)=O.CC(=C)C(O)=O CDMXXXZRZWQJQE-UHFFFAOYSA-N 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 125000006278 bromobenzyl group Chemical group 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 230000029115 microtubule polymerization Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- YXCDJKQYFBEAOU-UHFFFAOYSA-N phenyl thiocyanate Chemical compound N#CSC1=CC=CC=C1 YXCDJKQYFBEAOU-UHFFFAOYSA-N 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses the derivative of a class containing 1,2,4 nitrogen triazole type skeletons and its preparation method and application, a class its structure containing the derivative of 1,2,4 nitrogen triazole type skeletons is as shown in formula：Wherein, R1It is selected from：‑H、‑F、‑Cl、‑Br；R2It is selected from：‑H、‑OCH3、‑Cl、‑Br、‑F；R3It is selected from：‑H、‑OCH3、‑Cl、‑Br、‑F、‑CH3、‑I、‑CF3；R4It is selected from：‑H、‑OCH3；R5It is selected from：‑H、‑F.The synthetic method craft of the present invention is simple, and step is less, and cost is relatively low, efficiently simple and direct, with good universality, can produce in batches.
Description
Technical field
The invention belongs to medicinal chemistry art, more particularly to derivative and its system of the class containing 1,2,4- nitrogen triazole type skeletons
Preparation Method and application.
Background technology
Research shows, in m period, and tubulin carries vital effect, and this is increasingly becoming researcher
Pay close attention to research antineoplastic important target.Have confirmed that some tubulin micromolecular inhibitors are facing at present
There is antitumor action on bed.
According to the literature, 1,2,4- nitrogen triazole derivatives have anti-tumour cell proliferative activity, suppress microtubule polymerization work
With and cell cycle and Apoptosis have an impact.The activity of some compounds is even better than current preferably microtubulin-resisting
The effective active compound Combretastatin A-4 (CA-4) of polymerization.In addition, can be carried with methyl substitution H in indoles -1
Its high activity simultaneously reduces cytotoxicity.
Based on this, 1,2,4- nitrogen triazole is introduced into our MOLECULE DESIGN by the present invention, and synthesis is a series of to contain 1,2,4-
The derivative of nitrogen triazole type skeleton, is desired to have more preferable antitumor activity.
The content of the invention
In order to overcome weak point of the prior art, simple it is an object of the invention to provide a class technique, cost is low
Derivative containing 1,2,4- nitrogen triazole type skeleton and its preparation method and application.
In order to realize above-mentioned technical purpose, the technical solution adopted by the present invention it is as follows：The class of the present invention contains 1,2,4-
Its structure of the derivative of nitrogen triazole type skeleton is as shown in formula：
Wherein, R1It is selected from：-H、-F、-Cl、-Br；
R2It is selected from：-H、-OCH3、-Cl、-Br、-F；
R3It is selected from：-H、-OCH3、-Cl、-Br、-F、-CH3、-I、-CF3；
R4It is selected from：-H、-OCH3；
R5It is selected from：-H、-F.
The preparation method of derivative of the class of the present invention containing 1,2,4- nitrogen triazole type skeletons, comprises the following steps：
(1) indole -3-formaldehyde is dissolved in acetone, adds potassium permanganate, be heated to reflux being maintained at 56 DEG C, stir 12h,
TLC tracking reactions, after reaction terminates, evaporated under reduced pressure removes acetone, and concentrate is extracted with ethyl acetate, and organic phase is collected, with nothing
After aqueous sodium persulfate is dried, carry out vacuum distillation and obtain indole -3-carboxylic acid；The mol ratio of the indole -3-formaldehyde and potassium permanganate
For 3.5:1, the volume ratio of ethyl acetate is 3 × 100mL；
(2) indole -3-carboxylic acid, absolute methanol are added in the round-bottomed flask of the 250mL with reflux, then slow drop
Enriching sulfuric acid, 80 DEG C of return stirrings, the reaction time is 8-11h, and TLC tracking reactions, reaction terminates to remove under the conditions of rear reduced vacuum
Methanol solvate is removed, is extracted with ethyl acetate；Anhydrous sodium sulfate drying ethyl acetate layer, vacuum distillation obtains indole -3-carboxylic acid first
Ester；The mol ratio of the indole -3-carboxylic acid and the concentrated sulfuric acid is 0.03:0.184；The absolute methanol volume is 20mL-100mL,
The volume ratio of ethyl acetate is 3 × 100 mL；
(3) indole -3-carboxylic acid methyl esters and tetrahydrofuran are added in 100mL round-bottomed flask, under the conditions of 0 DEG C, slowly
0.05mol sodium hydrides are added, 30min is stirred, reaction 5h, TLC tracking reaction is continued with after dropwise addition iodomethane under room temperature condition；
Stop reaction, tetrahydrofuran in reaction system is concentrated under reduced pressure removings, is extracted with ethyl acetate, organic phase is done with anhydrous sodium sulfate
1- Methvl-indole -3- methyl formates are concentrated under reduced pressure to give after dry；The indole -3-carboxylic acid methyl esters, sodium hydride and iodomethane rub
You are than being 0.5：1：1, the tetrahydrofuran volume is 20mL-50mL, and the volume of ethyl acetate is 3 × 100mL；
(4) by the product 1- Methvl-indole -3- methyl formates obtained in step (3) and 85% hydrazine hydrate, it is dissolved in second two
Back flow reaction 6h in alcohol, the round-bottomed flask being placed in, TLC tracking reaction, are evaporated after ethylene glycol, and ethyl acetate extraction will with ethanol
Crude product is recrystallized, filtering, and 1- Methvl-indole -3- formylhydrazines are obtained after drying；1- Methvl-indoles -3- the methyl formates with
The mol ratio of hydrazine hydrate is 1:3；The volume of the ethyl acetate is 3 × 100mL；；
(5) by 1- Methvl-indole -3- formylhydrazines and phenyl isothiocyanate, it is dissolved in 30mL absolute ethyl alcohols and is placed in round-bottomed flask
In, heating reflux reaction 4h is cooled to room temperature；By the solid suction filtration separated out in the round-bottomed flask after cooling, drying is stayed overnight, weighed
40mmol sodium hydroxide, is dissolved in 20mL water, the drying solid obtained by addition, the back flow reaction 0.5h at 90 DEG C, places cold
But, it is 5-6 the complete solution of above-mentioned reaction to be adjusted into pH with 10% watery hydrochloric acid, separates out a large amount of white solids, after suction filtration is dried, system
Obtain 1- Methvl-indoles and 4- phenyl -1,2,4- nitrogen Triazoles；1- Methvl-indoles -3- the formylhydrazines and isothiocyanic acid benzene
The mol ratio of ester is 1:1, the concentration of the sodium hydroxide is 2mmol/mL；
(6) by 1- Methvl-indoles and 4- phenyl -1,2,4- nitrogen Triazoles are dissolved in anhydrous acetonitrile, then added various
Bromobenzyl substituent and sodium hydroxide, wherein 90 DEG C of back flow reaction 12h, reactant 1- Methvl-indoles and 4- phenyl -1,2,4- nitrogen three
The mol ratio of azoles mercaptan, various substituted cylites and sodium hydroxide is 1:1:2；After reaction terminates, removal of solvent under reduced pressure acetonitrile,
It is extracted with ethyl acetate, merges organic phase and use anhydrous sodium sulfate drying, then by organic phase evaporated under reduced pressure, obtained product is used
Absolute ethyl alcohol is recrystallized, and the derivative containing 1,2,4- nitrogen triazole type skeletons is made.
Further, in step (1), 0.035mol indole -3-formaldehydes are dissolved in 100mL acetone, 0.01mol is added
Potassium permanganate, be heated to reflux being maintained at 56 DEG C, stir 12h, TLC tracking reactions, after reaction terminates, evaporated under reduced pressure removes third
Ketone, concentrate is extracted with ethyl acetate, and collects organic phase, after anhydrous sodium sulfate drying, carries out vacuum distillation and obtains indoles -3-
Formic acid.
Further, in step (2), 0.03mol indole -3-carboxylic acids, 100mL absolute methanols are added with backflow dress
In the 250mL put round-bottomed flask, then be slowly added dropwise the 10mL concentrated sulfuric acids, 80 DEG C of return stirrings, the reaction time is 8-11h, TLC with
Track reacts, and reaction terminates to remove methanol solvate under the conditions of rear reduced vacuum, is extracted with ethyl acetate；Anhydrous sodium sulfate drying acetic acid
Methacrylate layer, vacuum distillation obtains indoles -3- methyl formates.
Further, in step (3), 0.025mol indole -3-carboxylic acids methyl esters and 50mL tetrahydrofurans are added
In 100mL round-bottomed flask, under the conditions of 0 DEG C, 0.05mol sodium hydrides are slowly added to, 30min are stirred, with after room temperature condition
Lower dropwise addition 0.05mol iodomethane continues to react 5h, TLC tracking reactions；Stop reaction, tetrahydrofuran decompression in reaction system is dense
Contracting is removed, and is extracted with ethyl acetate, and 1- Methvl-indole -3- formic acid is made with being concentrated under reduced pressure after anhydrous sodium sulfate drying in organic phase
Methyl esters.
Further, in step (4), by the mol of 1- Methvl-indole -3- methyl formates 0.02 obtained in previous step with
The hydrazine hydrates of 0.06mol 85%, are dissolved in ethylene glycol, back flow reaction 6h in the round-bottomed flask being placed in, TLC tracking reactions, are evaporated second
After glycol, crude product is recrystallized, filtered, 1- Methvl-indole -3- formylhydrazines are obtained after drying by ethyl acetate extraction with ethanol.
Further, in step (5), by the different of 0.015mol 1- Methvl-indole -3- formylhydrazines and 0 015mol
Thiocyanic acid phenyl ester, is dissolved in 30mL absolute ethyl alcohols and is placed in round-bottomed flask, and heating reflux reaction 4h is cooled to room temperature, after cooling
Round-bottomed flask in the solid suction filtration that separates out, drying stays overnight, weighs 40mmol sodium hydroxide, be dissolved in 20mL water, adds institute
The drying solid obtained, the back flow reaction 0.5h at 90 DEG C places cooling, is adjusted the complete solution of above-mentioned reaction with 10% watery hydrochloric acid
It is 5-6 to pH, separates out a large amount of white solids, suction filtration obtains 1- Methvl-indoles and 4- phenyl -1,2,4- nitrogen triazole sulphur after dries
Alcohol.
Further, in step (6), by 1- Methvl-indoles and 4- phenyl -1,2,4- nitrogen Triazoles are dissolved in anhydrous
In acetonitrile, various bromobenzyl substituents and sodium hydroxide, wherein 90 DEG C of back flow reaction 12h, reactant 1- Methvl-indoles are then added
And 4- phenyl -1,2, the mol ratio of 4- nitrogen Triazole and various substituted cylites and sodium hydroxide is 1:1:2；Reaction terminates
Afterwards, removal of solvent under reduced pressure acetonitrile, is extracted with ethyl acetate, and merges organic phase and uses anhydrous sodium sulfate drying, then by organic phase
Evaporated under reduced pressure, is made the derivative containing 1,2,4- nitrogen triazole type skeletons.
Further, the volume of the ethyl acetate is 3 × 100mL.
Application in derivative antineoplastic of the described class of the present invention containing 1,2,4- nitrogen triazole type skeletons.
Beneficial effect：The synthetic method craft of the present invention is simple, and step is less, and cost is relatively low, efficiently simple and direct, with fine
Universality, can produce in batches.
Embodiment
Following examples only exist in illustrative purpose, without being intended to limit the scope of the present invention.
A class its structure containing the derivative of 1,2,4- nitrogen triazole type skeletons of the present invention is as shown in formula：
Wherein, R1It is selected from：-H、-F、-Cl、-Br；
R2It is selected from：-H、-OCH3、-Cl、-Br、-F；
R3It is selected from：-H、-OCH3、-Cl、-Br、-F、-CH3、-I、-CF3；
R4It is selected from：-H、-OCH3；
R5It is selected from：-H、-F.
The preparation method of derivative of the class of the present invention containing 1,2,4- nitrogen triazole type skeletons, comprises the following steps：
(1) indole -3-formaldehyde is dissolved in acetone, adds potassium permanganate, be heated to reflux being maintained at 56 DEG C, stir 12h,
TLC tracking reactions, after reaction terminates, evaporated under reduced pressure removes acetone, and concentrate is extracted with ethyl acetate, and organic phase is collected, with nothing
After aqueous sodium persulfate is dried, carry out vacuum distillation and obtain indole -3-carboxylic acid；The mol ratio of the indole -3-formaldehyde and potassium permanganate
For 3.5:1, the volume of ethyl acetate is 3 × 100mL；
(2) indole -3-carboxylic acid, absolute methanol are added in the round-bottomed flask of the 250mL with reflux, then slow drop
Enriching sulfuric acid, 80 DEG C of return stirrings, the reaction time is 8-11h, and TLC tracking reactions, reaction terminates to remove under the conditions of rear reduced vacuum
Methanol solvate is removed, is extracted with ethyl acetate；Anhydrous sodium sulfate drying ethyl acetate layer, vacuum distillation obtains indole -3-carboxylic acid first
Ester；The mol ratio of the indole -3-carboxylic acid and the concentrated sulfuric acid is 0.03:0.184；The absolute methanol volume is 20mL-100mL,
The volume ratio of ethyl acetate is 3 × 100 mL；
(3) indole -3-carboxylic acid methyl esters and tetrahydrofuran are added in 100mL round-bottomed flask, under the conditions of 0 DEG C, slowly
0.05mol sodium hydrides are added, 30min is stirred, reaction 5h, TLC tracking reaction is continued with after dropwise addition iodomethane under room temperature condition；
Stop reaction, tetrahydrofuran in reaction system is concentrated under reduced pressure removings, is extracted with ethyl acetate, organic phase is done with anhydrous sodium sulfate
1- Methvl-indole -3- methyl formates are concentrated under reduced pressure to give after dry；The indole -3-carboxylic acid methyl esters, sodium hydride and iodomethane rub
You are than being 0.5：1：1, the tetrahydrofuran volume is：20mL-50mL, the volume of ethyl acetate are 3 × 100mL；
(4) by the product 1- Methvl-indole -3- methyl formates obtained in step (3) and 85% hydrazine hydrate, it is dissolved in second two
Back flow reaction 6h in alcohol, the round-bottomed flask being placed in, TLC tracking reaction, are evaporated after ethylene glycol, and ethyl acetate extraction will with ethanol
Crude product is recrystallized, filtering, and 1- Methvl-indole -3- formylhydrazines are obtained after drying；1- Methvl-indoles -3- the methyl formates with
The mol ratio of hydrazine hydrate is 1:3；The volume of the ethyl acetate is 3 × 100mL；
(5) by 1- Methvl-indole -3- formylhydrazines and phenyl isothiocyanate, it is dissolved in 30mL absolute ethyl alcohols and is placed in round-bottomed flask
In, heating reflux reaction 4h is cooled to room temperature；By the solid suction filtration separated out in the round-bottomed flask after cooling, drying is stayed overnight, weighed
40mmol sodium hydroxide, is dissolved in 20mL water, the drying solid obtained by addition, the back flow reaction 0.5h at 90 DEG C, places cold
But, it is 5-6 the complete solution of above-mentioned reaction to be adjusted into pH with 10% watery hydrochloric acid, separates out a large amount of white solids, after suction filtration is dried, system
Obtain 1- Methvl-indoles and 4- phenyl -1,2,4- nitrogen Triazoles；1- Methvl-indoles -3- the formylhydrazines and isothiocyanic acid benzene
The mol ratio of ester is 1:1, the concentration of the sodium hydroxide is 2mmol/mL；
(6) by 1- Methvl-indoles and 4- phenyl -1,2,4- nitrogen Triazoles are dissolved in anhydrous acetonitrile, then added various
Bromobenzyl substituent and sodium hydroxide, wherein 90 DEG C of back flow reaction 12h, reactant 1- Methvl-indoles and 4- phenyl -1,2,4- nitrogen three
The mol ratio of azoles mercaptan, various substituted cylites and sodium hydroxide is 1:1:2；After reaction terminates, removal of solvent under reduced pressure acetonitrile,
It is extracted with ethyl acetate, merges organic phase and use anhydrous sodium sulfate drying, then by organic phase evaporated under reduced pressure, obtained product is used
Absolute ethyl alcohol is recrystallized, and the derivative containing 1,2,4- nitrogen triazole type skeletons is made.
Embodiment 1
(1) 0.035mol indole -3-formaldehydes are dissolved in 100mL acetone, add 0.01mol potassium permanganate, heat back
Stream is maintained at 56 DEG C, stirring 12h (TLC tracking reaction).After reaction terminates, evaporated under reduced pressure removes acetone, concentrate acetic acid second
Ester is extracted, and collects organic phase, after anhydrous sodium sulfate drying, is carried out vacuum distillation and is obtained indole -3-carboxylic acid.
(2) round bottom that 0.03mol indole -3-carboxylic acids, 100mL absolute methanols are added into the 250mL with reflux burns
In bottle, then the 10mL concentrated sulfuric acids, 80 DEG C of return stirrings is slowly added dropwise, the reaction time is 8-11h (TLC tracking reaction).Reaction terminates
Methanol solvate is removed under the conditions of reduced vacuum afterwards, is extracted with ethyl acetate (3 × 100mL).Anhydrous sodium sulfate drying ethyl acetate
Layer, vacuum distillation obtains indole -3-carboxylic acid methyl esters.
(3) 0.025mol indole -3-carboxylic acids methyl esters and 50mL tetrahydrofurans are added in 100mL round-bottomed flask, at 0 DEG C
Under the conditions of, 0.05mol sodium hydrides are slowly added to, 30min is stirred, continued with after dropwise addition 0.05mol iodomethane under room temperature condition
React 5h (TLC tracking reaction).Stop reaction, tetrahydrofuran in reaction system be concentrated under reduced pressure removing, with ethyl acetate (3 ×
100mL) extract, organic phase is with being concentrated under reduced pressure to give 1- Methvl-indole -3- methyl formates after anhydrous sodium sulfate drying.
(4) by the product 0.02mol obtained in previous step and the hydrazine hydrates of 0.06mol 85%, ethylene glycol is dissolved in, is placed in
Back flow reaction 6h (TLC tracking reaction) in round-bottomed flask.It is evaporated after ethylene glycol, ethanol is used in ethyl acetate (3 × 100mL) extraction
Crude product is recrystallized, filtered, 1- Methvl-indole -3- formylhydrazines are obtained after drying.
(5) by 0.015mol 1- Methvl-indole -3- formylhydrazines and 0 015mol phenyl isothiocyanate, it is dissolved in 30mL
Absolute ethyl alcohol is placed in round-bottomed flask, heating reflux reaction 4h, is cooled to room temperature, by consolidating for being separated out in the round-bottomed flask after cooling
Body suction filtration, drying is stayed overnight, and weighs 40mmol sodium hydroxide, is dissolved in 20mL water, the drying solid obtained by addition.At 90 DEG C
Lower back flow reaction 0.5h, places cooling.The complete solution of above-mentioned reaction is adjusted to pH=5-6 with 10% watery hydrochloric acid, separated out a large amount of
White solid, suction filtration obtains 1- Methvl-indoles and 4- phenyl -1,2,4- nitrogen Triazoles after drying.
(6) by 1- Methvl-indoles and 4- phenyl -1,2,4- nitrogen Triazoles are dissolved in anhydrous acetonitrile, then added various
Bromobenzyl substituent and sodium hydroxide, 90 DEG C of back flow reaction 12h.Wherein reactant 1- Methvl-indoles and 4- phenyl -1,2,4- nitrogen three
The mol ratio of azoles mercaptan, various substituted cylites and sodium hydroxide is 1:1:2.After reaction terminates, removal of solvent under reduced pressure acetonitrile,
Extracted with ethyl acetate (3 × 100mL), merge organic phase and use anhydrous sodium sulfate drying, then by organic phase evaporated under reduced pressure, obtain
To product recrystallized with absolute ethyl alcohol, be made containing 1,2,4- nitrogen triazole type skeletons derivative.
In some specific embodiment, preparation process of the invention and the structural formula of associated products are as described below：
Embodiment 2
The preparation of 3- (5- (benzylthio) -4- phenyl -4H-1,2,4- nitrogen triazole -3- bases) -1- Methyl-1H-indoles (B1)
20mL acetone solutions indole -3-formaldehyde (16mmol) is added into round-bottomed flask, potassium permanganate (5 mmol) is being returned
Stirred 12 hours under the conditions of stream.After reaction terminates, evaporated under reduced pressure removes acetone, and concentrate is extracted with ethyl acetate, and collects organic
Phase, after anhydrous sodium sulfate drying, carries out vacuum distillation and obtains crude product 5b.The compound 5b (1mmol) of above-mentioned synthesis is molten
In 20mL absolute methanol, the 1mL concentrated sulfuric acids are added dropwise under stirring condition, stirred at reflux condition reacts 8-11 hours, question response
Liquid is cooled to room temperature, is washed three times with saturated aqueous common salt, ethyl acetate (each 100mL), anhydrous sodium sulfate drying ethyl acetate layer subtracts
Pressure distillation obtains 5c.Tetrahydrofuran solution 10mL is added into round-bottomed flask, the compound 5c (1mmol) of synthesis, hydrogen is added
Change sodium (2mmol).30min is stirred, continues to react 5h with after dropwise addition 2mmol iodomethane under room temperature condition.
Tetrahydrofuran in reaction system is concentrated under reduced pressure removing, extracted with ethyl acetate (3 × 100mL), organic phase nothing
Aqueous sodium persulfate is concentrated under reduced pressure to give 5d after drying.Obtained product 5d (1mmol) and the hydrazine hydrates of 3mmol 85%, second two is dissolved in
Back flow reaction 6h. is evaporated after ethylene glycol in alcohol, the round-bottomed flask being placed in.Ethyl acetate (3 × 100mL) is extracted, will be thick with ethanol
Product is recrystallized, filtering, and 5e is obtained after drying.By 1.5mmol 5e and 1.5mmol phenyl isothiocyanate, be dissolved in 10mL without
Water-ethanol is placed in round-bottomed flask, heating reflux reaction 4h, is cooled to room temperature, the solid that will be separated out in the round-bottomed flask after cooling
Suction filtration, drying is stayed overnight, and adds sodium hydrate aqueous solution, and the back flow reaction 0.5h at 90 DEG C places cooling.With 10% watery hydrochloric acid
Solution is adjusted to pH=5-6, a large amount of white solids are separated out, suction filtration obtains 5f after drying.5f is dissolved in anhydrous acetonitrile, then
Add benzyl bromine and sodium hydroxide, 90 DEG C of back flow reaction 12h.The mol ratio of wherein reactant 5f, bromobenzyl and sodium hydroxide is 1：1：
2.After reaction terminates, removal of solvent under reduced pressure acetonitrile is extracted with ethyl acetate (3 × 100mL), is merged organic phase and is used anhydrous slufuric acid
Sodium is dried, and then by organic phase evaporated under reduced pressure, obtained product is recrystallized to give target compound B1 with absolute ethyl alcohol.
Obtain white powder, yield 47.7%, m.p.150-151 DEG C；1H NMR(400MHz,DMSO-d6) δ(ppm):
8.16 (d, J=7.8Hz, 1H), 7.67-7.53 (m, 4H), 7.46 (d, J=8.2Hz, 1H), 7.38-7.23 (m, 7H),
7.26-7.15(m,1H),6.49(s,1H),4.37(s,2H).3.62(m,3H).MS (ESI):397.1[M+H]+；
Anal.Calcd for C24H20N4S.
Embodiment 3
3- (5- ((2,6- difluorobenzyl) sulfenyl) -4- phenyl -4H-1,2,4- nitrogen triazole -3- bases) -1- methyl isophthalic acid H- Yin
The preparation of diindyl (B2)
Preparation method reference implementation example 1.Obtain pale yellow powder, yield 38.4%, m.p.177-178 DEG C；1H NMR
(400MHz,DMSO-d6)δ(ppm):8.16 (d, J=8.0Hz, 1H), 7.68-7.55 (m, 4H), 7.51-7.34 (m, 3H),
(s, the 2H) .3.61 of 7.26 (t, J=7.3Hz, 1H), 7.14 (dt, J=31.8,7.9Hz, 3H), 6.51 (s, 1H), 4.27 (s,
3H).MS(ESI):433.1[M+H]+；Anal.Calcd for C24H18F2N4S
Embodiment 4
3- (5- ((the chloro- 4- luorobenzyls of 3-) sulfenyl) -4- phenyl -4H-1,2,4- nitrogen triazole -3- bases) -1- methyl isophthalic acid H- Yin
The preparation of diindyl (B3)
Preparation method reference implementation example 1.Obtain yellow powder, yield 52.3%, m.p.183-184 DEG C；1H NMR
(400MHz,DMSO-d6)δ(ppm):8.15 (d, J=7.9Hz, 1H), 7.66-7.55 (m, 5H), 7.46 (d, J=8.2Hz,
1H), 7.42-7.33 (m, 3H), 7.25 (t, J=7.1Hz, 1H), 7.17 (t, J=7.9Hz, 1H), 6.51 (s, 1H), 4.37
(s,2H).3.63(s,3H).MS(ESI):449.1[M+H]+；Anal.Calcd for C24H18ClFN4S.
Embodiment 5
3- (5- ((4- methoxy-benzyls) sulfenyl) -4- phenyl -4H-1,2,4- nitrogen triazole -3- bases) -1- methyl isophthalic acid H- Yin
The preparation of diindyl (B4)
Preparation method reference implementation example 1.Obtain pale yellow powder, yield 69.1%, m.p.155-156 DEG C；1H NMR
(400MHz,DMSO-d6)δ(ppm):8.20 (d, J=8.0Hz, 1H), 7.87-7.70 (m, 2H), 7.50 (d, J=8.2Hz,
2H), 7.35 (dd, J=8.0,1.3Hz, 2H), 7.24 (dd, J=17.1,7.6Hz, 4H), 7.22-7.08 (m, 2H), 6.50
(s,1H),4.33(s,2H),3.87(s,3H)3.73(s,3H).MS (ESI):427.2[M+H]+；Anal.Calcd for
C25H22N4OS.
Embodiment 6
3- (5- ((3,5- dimethyl benzyls) sulfenyl) -4- phenyl -4H-1,2,4- nitrogen triazole -3- bases) -1- methyl isophthalic acids H-
The preparation of indoles (B5)
Preparation method reference implementation example 1.Obtain white powder, yield 55.6%, m.p, 175-176 DEG C；1H NMR
(400MHz,DMSO-d6)δ(ppm):7.95 (dt, J=7.9,1.0Hz, 1H), 7.64-7.54 (m, 5H), 7.58-7.43 (m,
4H), 7.24 (ddd, J=8.3,7.0,1.3Hz, 1H), 7.12 (ddd, J=8.0,7.0,1.0Hz, 1H), 6.85 (s, 1H),
4.45(s,2H)3.70(s,6H),3.63(s,3H).MS(ESI):457.2[M+H]+； Anal.Calcd for
C26H24N4O2S.
Embodiment 7
1- methyl -3- (4- phenyl -5- ((3,4,5- trimethoxy benzyls) sulfenyl) -4H-1,2,4- nitrogen triazole -3- bases) -
The preparation of 1H- indoles (B6)
Preparation method reference implementation example 1.Obtain pale yellow powder, yield 66.3%, m.p.189-190 DEG C；1H NMR
(600MHz,DMSO-d6):δ(ppm):8.14 (d, J=8.0Hz, 1H), 7.61 (t, J=7.4Hz, 1H), 7.56 (t, J=
7.6Hz, 2H), 7.46 (d, J=8.2Hz, 1H), 7.25 (dd, J=12.8,7.3Hz, 3H), 7.17 (t, J=7.5Hz, 1H),
(d, J=3.8Hz, the 6H) .MS (ESI) of 6.57 (s, 2H), 6.50 (s, 1H), 4.26 (s, 2H), 3.69 (s, 6H), 3.63:
487.2[M+H]+；Anal.Calcd for C27H26N4O3S.
Embodiment 8
3- (5- ((2- luorobenzyls) sulfenyl) -4- phenyl -4H-1,2,4- nitrogen triazole -3- bases) -1- Methyl-1H-indoles
(B7) preparation
Preparation method reference implementation example 1.Obtain yellow powder, yield 53.3%, m.p.170-171 DEG C；1H NMR
(400MHz,DMSO-d6)δ(ppm):8.17 (d, J=7.9Hz, 1H), 7.60 (dt, J=14.4,6.9Hz, 3H), 7.50-
7.38 (m, 2H), 7.34 (d, J=6.9Hz, 3H), 7.28-7.12 (m, 4H) .6.49 (s, 1H), 4.37 (s, 2H), 3.67 (s,
3H).MS(ESI):415.1[M+H]+；Anal.Calcd for C24H19FN4S.
Embodiment 9
3- (5- ((2- chlorobenzyls) sulfenyl) -4- phenyl -4H-1,2,4- nitrogen triazole -3- bases) -1- Methyl-1H-indoles
(B8) preparation
Preparation method reference implementation example 1.Obtain pale yellow powder, yield 36.4%, m.p.162-163 DEG C；1H NMR
(400MHz,DMSO-d6)δ(ppm):8.16 (d, J=7.9Hz, 1H), 7.59 (dt, J=14.4,6.9 Hz, 5H), 7.48
(dd, J=13.7,7.6Hz, 4H), 7.36-7.21 (m, 2H), 7.17 (t, J=7.5Hz, 1H), 6.50 (s, 1H), 4.45 (s,
2H).3.63(s,3H).MS(ESI):431.1[M+H]+；Anal.Calcd for C24H19ClN4S.
Embodiment 10
3- (5- ((2- bromobenzyls) sulfenyl) -4- phenyl -4H-1,2,4- nitrogen triazole -3- bases) -1- Methyl-1H-indoles
(B9) preparation
Preparation method reference implementation example 1.Obtain pale yellow powder, yield 41.8%, m.p.160-161 DEG C；1H NMR
(400MHz,DMSO-d6)δ(ppm):8.17 (d, J=7.9Hz, 1H), 7.65-7.54 (m, 4H), 7.50-7.38 (m, 2H),
7.34 (d, J=6.8Hz, 3H), 7.25 (t, J=7.6Hz, 1H), 7.24-7.10 (m, 2H), 6.50 (s, 1H), 4.38 (s,
2H),3.62(s,3H).MS(ESI):477.1[M+H]+；Anal.Calcd for C24H19BrN4S.
Embodiment 11
3- (5- ((3- luorobenzyls) sulfenyl) -4- phenyl -4H-1,2,4- nitrogen triazole -3- bases) -1- Methyl-1H-indoles
(B10) preparation
Preparation method reference implementation example 1.Obtain yellow powder, yield 40.1%, m.p.171-172 DEG C；1H NMR
(400MHz,DMSO-d6)δ(ppm):8.16 (d, J=7.9Hz, 1H), 7.68-7.52 (m, 3H), 7.47 (d, J=8.1Hz,
1H),7.46-7.30(m,3H),7.34-7.06(m,5H),6.51(s,1H),4.39(s,2H),3.63 (s,3H).MS
(ESI):415.1[M+H]+；Anal.Calcd for C24H19FN4S.
Embodiment 12
3- (5- ((3- chlorobenzyls) sulfenyl) -4- phenyl -4H-1,2,4- nitrogen triazole -3- bases) -1- Methyl-1H-indoles
(B11) preparation
Preparation method reference implementation example 1.Obtain pale yellow powder, yield 56.4%, m.p.166-167 DEG C；1H NMR
(400MHz,DMSO-d6)δ(ppm):8.15 (d, J=8.0Hz, 1H), 7.68-7.54 (m, 3H), 7.50-7.41 (m, 2H),
7.40-7.29 (m, 5H), 7.25 (s, 1H), 7.21 (dt, J=32.1,7.2Hz, 1H), 6.50 (d, J=1.9Hz, 1H),
4.37 (d, J=1.9Hz, 2H), 3.62 (m, 3H) .MS (ESI):431.1[M +H]+；Anal.Calcd for C24H19ClN4S.
Embodiment 13
3- (5- ((3- bromobenzyls) sulfenyl) -4- phenyl -4H-1,2,4- nitrogen triazole -3- bases) -1- Methyl-1H-indoles
(B12) preparation
Preparation method reference implementation example 1.Obtain white powder, yield 47.7%, m.p.164-166 DEG C；1H NMR
(400MHz,DMSO-d6)δ(ppm):8.76 (s, 1H), 7.95 (dd, J=8.0,1.1Hz, 1H), 7.66-7.54 (m, 3H),
7.58-7.41 (m, 3H), 7.24 (d, J=7.0Hz, 2H), 7.12 (dt, J=7.5,7.0,1.1Hz, 3H), 6.85 (s, 1H),
4.46(s,2H),3.70(s,3H).MS(ESI):477.1[M+H]+；Anal.Calcd for C24H19BrN4S.
Embodiment 14
3- (5- ((2- luorobenzyls) sulfenyl) -4- phenyl -4H-1,2,4- nitrogen triazole -3- bases) -1- Methyl-1H-indoles
(B13) preparation
Preparation method reference implementation example 1.Obtain yellow powder, yield 46.7%, m.p.169-170 DEG C；1H NMR
(400MHz,DMSO-d6)δ(ppm):8.18 (d, J=7.9Hz, 1H), 7.61-7.55 (m, 3H), 7.50-7.38 (m, 2H),
7.34 (d, J=6.9Hz, 3H), 7.23-7.09 (m, 4H) .6.52 (s, 1H), 4.40 (s, 2H), 3.61 (s, 3H) .MS
(ESI):415.1[M+H]+；Anal.Calcd for C24H19FN4S.
Embodiment 15
3- (5- ((4- chlorobenzyls) sulfenyl) -4- phenyl -4H-1,2,4- nitrogen triazole -3- bases) -1- Methyl-1H-indoles
(B14) preparation
Preparation method reference implementation example 1.Obtain pale yellow powder, yield 36.4%, m.p.165-166 DEG C；1H NMR
(400MHz,DMSO-d6)δ(ppm):8.16 (d, J=8.0Hz, 1H), 7.68-7.55 (m, 3H), 7.49 (dd, J=18.3,
8.3Hz, 3H), 7.35 (dd, J=13.1,7.6Hz, 4H), 7.25 (t, J=7.0Hz, 1H), 7.17 (t, J=7.5Hz, 1H),
6.50(s,1H),4.35(s,2H),3.63(s,3H).MS(ESI):449.1 [M+H]+；Anal.Calcd for
C24H19ClN4S.
Embodiment 16
3- (5- ((4- bromobenzyls) sulfenyl) -4- phenyl -4H-1,2,4- nitrogen triazole -3- bases) -1- Methyl-1H-indoles
(B15) preparation
Preparation method reference implementation example 1.Obtain white yellow powder, yield 55.1%, m.p.161-162 DEG C；1H NMR
(400MHz,DMSO-d6)δ(ppm):8.15 (d, J=7.8Hz, 1H), 7.68-7.55 (m, 4H), 7.49 (dd, J=18.1,
8.3Hz, 3H), 7.35 (dd, J=13.0,7.6Hz, 3H), 7.21 (dt, J=32.7,7.0 Hz, 2H)), 6.55 (s, 1H),
4.46 4.35(s,2H),3.63(s,3H).MS(ESI):477.1[M+H]+； Anal.Calcd for C24H19BrN4S.
Embodiment 17
3- (5- ((4- iodine benzyl) sulfenyl) -4- phenyl -4H-1,2,4- nitrogen triazole -3- bases) -1- Methyl-1H-indoles
(B16) preparation
Preparation method reference implementation example 1.Obtain yellow powder, yield 40.7%, m.p.197-198 DEG C；1H NMR
(400MHz,DMSO-d6)δ(ppm):8.15 (d, J=7.9Hz, 1H), 7.71-7.55 (m, 6H), 7.46 (d, J=8.1Hz,
1H), 7.36 (d, J=6.8Hz, 2H), 7.25 (t, J=7.0Hz, 1H), 7.18 (d, J=8.3Hz, 2H), 6.50 (s, 1H),
4.33(s,2H),3.63(s,3H).MS(ESI):523.0[M+H]+；Anal.Calcd for C24H19IN4S.
Embodiment 18
1- methyl -3- (5- ((4- methyl-benzyls) sulfenyl) -4- phenyl -4H-1,2,4- nitrogen triazole -3- bases) -1H- indoles
(B17) preparation
Preparation method reference implementation example 1.Obtain pale yellow powder, yield 69.1%, m.p.155-156 DEG C；1H NMR
(400MHz,DMSO-d6)δ(ppm):8.16 (d, J=7.9Hz, 1H), 7.67-7.54 (m, 3H), 7.46 (d, J=8.2Hz,
1H), 7.33 (dd, J=8.0,1.3Hz, 2H), 7.24 (dd, J=17.1,7.6Hz, 3H), 7.22-7.08 (m, 3H), 6.50
(s,1H),4.33(s,2H),3.63(s,3H),2.27(s,3H).MS (ESI):411.2[M+H]+；Anal.Calcd for
C25H22N4S.
Embodiment 19
1- methyl -3- (4- phenyl -5- ((4- (trifluoromethyl) benzyl) sulfenyl) -4H-1,2,4- nitrogen triazole -3- bases) -
The preparation of 1H- indoles (B18)
Preparation method reference implementation example 1.Obtain pale yellow powder, yield 47.3%, m.p.178-179 DEG C；1H NMR
(400MHz,DMSO-d6)δ:7.73 (s, 1H), 7.60 (dd, J=23.2,9.2Hz, 7H), 7.46 (d, J=8.1Hz, 1H),
(s, the 3H) .MS of 7.31 (d, J=7.6Hz, 2H), 7.29-7.14 (m, 2H), 6.49 (s, 1H), 4.46 (s, 2H), 3.36
(ESI):465.1[M+H]+；Anal.Calcd for C25H19F3N4S.
Specific embodiment described herein is only to spirit explanation for example of the invention.Technology neck belonging to of the invention
The technical staff in domain can be made various modifications or supplement to described specific embodiment or be replaced using similar mode
Generation, but without departing from the spiritual of the present invention or surmount scope defined in appended claims.
Claims (10)
1. a class contains the derivative of 1,2,4- nitrogen triazole type skeletons, its structure is as shown in formula：
Wherein, R1It is selected from：-H、-F、-Cl、-Br；
R2It is selected from：-H、-OCH3、-Cl、-Br、-F；
R3It is selected from：-H、-OCH3、-Cl、-Br、-F、-CH3、-I、-CF3；
R4It is selected from：-H、-OCH3；
R5It is selected from：-H、-F.
2. the preparation method of derivative of the class containing 1,2,4- nitrogen triazole type skeletons, it is characterised in that comprise the following steps：
(1) indole -3-formaldehyde is dissolved in acetone, adds potassium permanganate, be heated to reflux being maintained at 56 DEG C, stir 12h, TLC with
Track reacts, after reaction terminates, and evaporated under reduced pressure removes acetone, and concentrate is extracted with ethyl acetate, and collects organic phase, uses anhydrous slufuric acid
After sodium is dried, carry out vacuum distillation and obtain indole -3-carboxylic acid；The mol ratio of the indole -3-formaldehyde and potassium permanganate is 3.5:
1；The volume ratio of ethyl acetate is 3 × 100mL；
(2) indole -3-carboxylic acid, absolute methanol are added in the round-bottomed flask of the 250mL with reflux, then be slowly added dropwise dense
Sulfuric acid, 80 DEG C of return stirrings, the reaction time is 8-11h, and TLC tracking reactions, reaction terminates to remove first under the conditions of rear reduced vacuum
Alcoholic solvent, is extracted with ethyl acetate；Anhydrous sodium sulfate drying ethyl acetate layer, vacuum distillation obtains indole -3-carboxylic acid methyl esters；Institute
The mol ratio for stating indole -3-carboxylic acid and the concentrated sulfuric acid is 0.03:0.184；The absolute methanol volume is 20mL-100mL, acetic acid second
The volume ratio of ester is 3 × 100mL；
(3) indole -3-carboxylic acid methyl esters and tetrahydrofuran are added in 100mL round-bottomed flask, under the conditions of 0 DEG C, are slowly added to
0.05mol sodium hydrides, stir 30min, continue to react 5h with after dropwise addition iodomethane under room temperature condition, TLC tracks reaction；Stop
Reaction, tetrahydrofuran in reaction system is concentrated under reduced pressure removing, is extracted with ethyl acetate, after organic phase anhydrous sodium sulfate drying
It is concentrated under reduced pressure to give 1- Methvl-indole -3- methyl formates；The mol ratio of the indole -3-carboxylic acid methyl esters, sodium hydride and iodomethane
For 0.5：1：1, the tetrahydrofuran volume is 20mL-50mL, and the volume of ethyl acetate is 3 × 100mL；
(4) by the product 1- Methvl-indole -3- methyl formates obtained in step (3) and 85% hydrazine hydrate, ethylene glycol is dissolved in, is put
In round-bottomed flask in back flow reaction 6h, TLC tracking reactions are evaporated after ethylene glycol, ethyl acetate extraction, with ethanol by crude product
Recrystallization, filtering obtains 1- Methvl-indole -3- formylhydrazines after drying；1- Methvl-indoles -3- the methyl formates and hydrazine hydrate
Mol ratio be 1:3；The volume of the ethyl acetate is 3 × 100mL；；
(5) by 1- Methvl-indole -3- formylhydrazines and phenyl isothiocyanate, it is dissolved in 30mL absolute ethyl alcohols and is placed in round-bottomed flask, plus
Hot back flow reaction 4h, is cooled to room temperature；By the solid suction filtration separated out in the round-bottomed flask after cooling, drying is stayed overnight, weighed
40mmol sodium hydroxide, is dissolved in 20mL water, the drying solid obtained by addition, the back flow reaction 0.5h at 90 DEG C, places cold
But, it is 5-6 the complete solution of above-mentioned reaction to be adjusted into pH with 10% watery hydrochloric acid, separates out a large amount of white solids, after suction filtration is dried, system
Obtain 1- Methvl-indoles and 4- phenyl -1,2,4- nitrogen Triazoles；1- Methvl-indoles -3- the formylhydrazines and phenyl isothiocyanate
Mol ratio be 1:1, the concentration of the sodium hydroxide is 2mmol/mL；
(6) by 1- Methvl-indoles and 4- phenyl -1,2,4- nitrogen Triazoles are dissolved in anhydrous acetonitrile, then add various bromobenzyls
Substituent and sodium hydroxide, wherein 90 DEG C of back flow reaction 12h, reactant 1- Methvl-indoles and 4- phenyl -1,2,4- nitrogen triazole sulphur
The mol ratio of alcohol, various substituted cylites and sodium hydroxide is 1:1:2；After reaction terminates, removal of solvent under reduced pressure acetonitrile uses second
Acetoacetic ester is extracted, and is merged organic phase and is simultaneously used anhydrous sodium sulfate drying, then by organic phase evaporated under reduced pressure, obtained product is with anhydrous
Ethyl alcohol recrystallization, is made the derivative containing 1,2,4- nitrogen triazole type skeletons.
3. the preparation method of derivative of the class according to claim 2 containing 1,2,4- nitrogen triazole type skeletons, its feature exists
In：In step (1), 0.035mol indole -3-formaldehydes are dissolved in 100mL acetone, 0.01mol potassium permanganate is added, plus
Heat backflow is maintained at 56 DEG C, stirs 12h, TLC tracking is reacted, after reaction terminates, and evaporated under reduced pressure removes acetone, concentrate acetic acid
Ethyl ester is extracted, and collects organic phase, after anhydrous sodium sulfate drying, is carried out vacuum distillation and is obtained indole -3-carboxylic acid.
4. the preparation method of derivative of the class according to claim 3 containing 1,2,4- nitrogen triazole type skeletons, its feature exists
In：In step (2), 0.03mol indole -3-carboxylic acids, 100mL absolute methanols are added to the circle of the 250mL with reflux
In the flask of bottom, then the 10mL concentrated sulfuric acids, 80 DEG C of return stirrings is slowly added dropwise, the reaction time is 8-11h, TLC tracking reactions, reaction knot
Methanol solvate is removed after beam under the conditions of reduced vacuum, is extracted with ethyl acetate；Anhydrous sodium sulfate drying ethyl acetate layer, decompression is steamed
Evaporate and obtain indole -3-carboxylic acid methyl esters.
5. the preparation method of derivative of the class according to claim 4 containing 1,2,4- nitrogen triazole type skeletons, its feature exists
In：In step (3), 0.025mol indole -3-carboxylic acids methyl esters and 50mL tetrahydrofurans are added in 100mL round-bottomed flask,
Under the conditions of 0 DEG C, 0.05mol sodium hydrides are slowly added to, 30min is stirred, with after dropwise addition 0.05mol iodomethane under room temperature condition
Continue to react 5h, TLC tracking reactions；Stop reaction, tetrahydrofuran in reaction system is concentrated under reduced pressure removing, extracted with ethyl acetate
Take, 1- Methvl-indole -3- methyl formates are made with being concentrated under reduced pressure after anhydrous sodium sulfate drying in organic phase.
6. the preparation method of derivative of the class according to claim 5 containing 1,2,4- nitrogen triazole type skeletons, its feature exists
In：In step (4), by the 1- Methvl-indoles -3- methyl formates 0.02mol obtained in previous step and the water of 0.06mol 85%
Hydrazine is closed, ethylene glycol is dissolved in, back flow reaction 6h (TLC tracking reaction), is evaporated after ethylene glycol, ethyl acetate in the round-bottomed flask being placed in
Extraction, is recrystallized crude product with ethanol, is filtered, and 1- Methvl-indole -3- formylhydrazines are obtained after drying.
7. the preparation method of derivative of the class according to claim 6 containing 1,2,4- nitrogen triazole type skeletons, its feature exists
In：In step (5), 0.015mol 1- Methvl-indole -3- formylhydrazines and 0 015mol phenyl isothiocyanate are dissolved in
30mL absolute ethyl alcohols are placed in round-bottomed flask, heating reflux reaction 4h, are cooled to room temperature, will be separated out in the round-bottomed flask after cooling
Solid suction filtration, drying stays overnight, weighs 40mmol sodium hydroxide, be dissolved in 20mL water, the drying solid obtained by addition, 90
Back flow reaction 0.5h at DEG C, places cooling, it is 5-6 that the complete solution of above-mentioned reaction is adjusted into pH with 10% watery hydrochloric acid, separates out big
White solid is measured, suction filtration obtains 1- Methvl-indoles and 4- phenyl -1,2,4- nitrogen Triazoles after drying.
8. the preparation method of derivative of the class according to claim 7 containing 1,2,4- nitrogen triazole type skeletons, its feature exists
In：In step (6), by 1- Methvl-indoles and 4- phenyl -1,2,4- nitrogen Triazoles are dissolved in anhydrous acetonitrile, then added
Various bromobenzyl substituents and sodium hydroxide, wherein 90 DEG C of back flow reaction 12h, reactant 1- Methvl-indoles and 4- phenyl -1,2,4-
The mol ratio of nitrogen Triazole, various substituted cylites and sodium hydroxide is 1:1:2；After reaction terminates, removal of solvent under reduced pressure
Acetonitrile, is extracted with ethyl acetate, and merges organic phase and uses anhydrous sodium sulfate drying, then by organic phase evaporated under reduced pressure, is made and contains
The derivative of 1,2,4- nitrogen triazole type skeleton.
9. the preparation method of derivative of the class according to claim 8 containing 1,2,4- nitrogen triazole type skeletons, its feature exists
In：The volume of the ethyl acetate is 3 × 100mL.
10. in derivative antineoplastic of the class containing 1,2,4- nitrogen triazole type skeletons described in any one of claim 1 to 9
Using.
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| CN103373987A (en) * | 2012-04-12 | 2013-10-30 | 南京大学 | Pyrazine ring-containing triazole derivatives, preparation method and applications |
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| CN103373987A (en) * | 2012-04-12 | 2013-10-30 | 南京大学 | Pyrazine ring-containing triazole derivatives, preparation method and applications |
| CN104529867A (en) * | 2015-01-26 | 2015-04-22 | 中国科学院西北高原生物研究所 | Synthesis method of bisindolyl acylhydrazone compound |
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| CN113402473A (en) * | 2021-06-22 | 2021-09-17 | 四川省医学科学院·四川省人民医院 | Thiotriazole compound, preparation method and application thereof |
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