CN110437173A - A kind of diphenylethylene compounds and its synthetic method and application containing thiazole ring - Google Patents
A kind of diphenylethylene compounds and its synthetic method and application containing thiazole ring Download PDFInfo
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- CN110437173A CN110437173A CN201910791587.5A CN201910791587A CN110437173A CN 110437173 A CN110437173 A CN 110437173A CN 201910791587 A CN201910791587 A CN 201910791587A CN 110437173 A CN110437173 A CN 110437173A
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- phenyl
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- thiazole ring
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- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 title claims abstract description 49
- PJANXHGTPQOBST-UHFFFAOYSA-N stilbene Chemical group C=1C=CC=CC=1C=CC1=CC=CC=C1 PJANXHGTPQOBST-UHFFFAOYSA-N 0.000 title claims abstract description 40
- 238000010189 synthetic method Methods 0.000 title claims abstract description 17
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 32
- 125000001424 substituent group Chemical group 0.000 claims abstract description 21
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 12
- 239000001257 hydrogen Substances 0.000 claims abstract description 9
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 9
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 7
- 238000006467 substitution reaction Methods 0.000 claims abstract description 6
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 5
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 5
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 5
- 150000002367 halogens Chemical class 0.000 claims abstract description 5
- 238000002360 preparation method Methods 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 83
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 42
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 39
- 239000012141 concentrate Substances 0.000 claims description 22
- 239000007787 solid Substances 0.000 claims description 22
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 claims description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 16
- 238000001556 precipitation Methods 0.000 claims description 14
- 239000005457 ice water Substances 0.000 claims description 13
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzenecarboxaldehyde Natural products O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 12
- 239000012065 filter cake Substances 0.000 claims description 11
- -1 methoxyl group Chemical group 0.000 claims description 11
- 238000003756 stirring Methods 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims description 8
- 239000003208 petroleum Substances 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
- AJNKDGHQGKBHEG-UHFFFAOYSA-N 4-[4-(bromomethyl)phenyl]-2-(4-fluorophenyl)-1,3-thiazole Chemical compound C1=CC(F)=CC=C1C1=NC(C=2C=CC(CBr)=CC=2)=CS1 AJNKDGHQGKBHEG-UHFFFAOYSA-N 0.000 claims description 4
- 150000003935 benzaldehydes Chemical class 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 238000004440 column chromatography Methods 0.000 claims description 4
- 235000019441 ethanol Nutrition 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 238000000746 purification Methods 0.000 claims description 4
- 125000001246 bromo group Chemical group Br* 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 238000001953 recrystallisation Methods 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 claims description 3
- OTEKOJQFKOIXMU-UHFFFAOYSA-N 1,4-bis(trichloromethyl)benzene Chemical compound ClC(Cl)(Cl)C1=CC=C(C(Cl)(Cl)Cl)C=C1 OTEKOJQFKOIXMU-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- 239000002246 antineoplastic agent Substances 0.000 claims description 2
- 229940041181 antineoplastic drug Drugs 0.000 claims description 2
- 239000003480 eluent Substances 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- 229920002554 vinyl polymer Polymers 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims 2
- 238000002425 crystallisation Methods 0.000 claims 1
- 230000008025 crystallization Effects 0.000 claims 1
- 125000004494 ethyl ester group Chemical group 0.000 claims 1
- 238000001914 filtration Methods 0.000 claims 1
- 230000000259 anti-tumor effect Effects 0.000 abstract description 9
- 150000001875 compounds Chemical class 0.000 description 44
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 24
- 239000000243 solution Substances 0.000 description 18
- ATBBEUVVQCZWCQ-UHFFFAOYSA-N C1=CC(=CC=C1CBr)C2=CN=C(S2)C3=CC=C(C=C3)F Chemical compound C1=CC(=CC=C1CBr)C2=CN=C(S2)C3=CC=C(C=C3)F ATBBEUVVQCZWCQ-UHFFFAOYSA-N 0.000 description 12
- 102100024578 Tyrosyl-DNA phosphodiesterase 2 Human genes 0.000 description 11
- 101710205181 Tyrosyl-DNA phosphodiesterase 2 Proteins 0.000 description 11
- 230000002401 inhibitory effect Effects 0.000 description 11
- 238000012360 testing method Methods 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- 102100024579 Tyrosyl-DNA phosphodiesterase 1 Human genes 0.000 description 8
- 101710205182 Tyrosyl-DNA phosphodiesterase 1 Proteins 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 150000002148 esters Chemical class 0.000 description 8
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 8
- 238000010521 absorption reaction Methods 0.000 description 7
- 238000001514 detection method Methods 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 6
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- FNTWAZFXVIPFJF-UHFFFAOYSA-N NPPP Chemical compound NPPP FNTWAZFXVIPFJF-UHFFFAOYSA-N 0.000 description 4
- 239000007853 buffer solution Substances 0.000 description 4
- 230000009514 concussion Effects 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 3
- 241000196324 Embryophyta Species 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000010998 test method Methods 0.000 description 3
- PKZJLOCLABXVMC-UHFFFAOYSA-N 2-Methoxybenzaldehyde Chemical compound COC1=CC=CC=C1C=O PKZJLOCLABXVMC-UHFFFAOYSA-N 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- HDWLUGYOLUHEMN-UHFFFAOYSA-N Dinobuton Chemical group CCC(C)C1=CC([N+]([O-])=O)=CC([N+]([O-])=O)=C1OC(=O)OC(C)C HDWLUGYOLUHEMN-UHFFFAOYSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 108091034117 Oligonucleotide Proteins 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 230000001857 anti-mycotic effect Effects 0.000 description 2
- 239000002543 antimycotic Substances 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 229940125890 compound Ia Drugs 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 description 2
- 239000002547 new drug Substances 0.000 description 2
- 239000000575 pesticide Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000012089 stop solution Substances 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- SSZOCHFYWWVSAI-UHFFFAOYSA-N 1-bromo-2-ethenylbenzene Chemical compound BrC1=CC=CC=C1C=C SSZOCHFYWWVSAI-UHFFFAOYSA-N 0.000 description 1
- NVZWEEGUWXZOKI-UHFFFAOYSA-N 1-ethenyl-2-methylbenzene Chemical compound CC1=CC=CC=C1C=C NVZWEEGUWXZOKI-UHFFFAOYSA-N 0.000 description 1
- PECUPOXPPBBFLU-UHFFFAOYSA-N 1-ethenyl-3-methoxybenzene Chemical compound COC1=CC=CC(C=C)=C1 PECUPOXPPBBFLU-UHFFFAOYSA-N 0.000 description 1
- JZHGRUMIRATHIU-UHFFFAOYSA-N 1-ethenyl-3-methylbenzene Chemical compound CC1=CC=CC(C=C)=C1 JZHGRUMIRATHIU-UHFFFAOYSA-N 0.000 description 1
- WYKHSBAVLOPISI-UHFFFAOYSA-N 2-phenyl-1,3-thiazole Chemical compound C1=CSC(C=2C=CC=CC=2)=N1 WYKHSBAVLOPISI-UHFFFAOYSA-N 0.000 description 1
- WMPDAIZRQDCGFH-UHFFFAOYSA-N 3-methoxybenzaldehyde Chemical compound COC1=CC=CC(C=O)=C1 WMPDAIZRQDCGFH-UHFFFAOYSA-N 0.000 description 1
- JLBJTVDPSNHSKJ-UHFFFAOYSA-N 4-Methylstyrene Chemical compound CC1=CC=C(C=C)C=C1 JLBJTVDPSNHSKJ-UHFFFAOYSA-N 0.000 description 1
- UTQAIWNGUKJQEG-ONEGZZNKSA-N 4-[4-[(E)-2-(3,4-dimethoxyphenyl)ethenyl]phenyl]-2-(4-fluorophenyl)-1,3-thiazole Chemical compound COC1=C(C=C(C=C1)/C=C/C2=CC=C(C=C2)C3=CSC(=N3)C4=CC=C(C=C4)F)OC UTQAIWNGUKJQEG-ONEGZZNKSA-N 0.000 description 1
- 235000014489 Cinnamomum aromaticum Nutrition 0.000 description 1
- 244000037364 Cinnamomum aromaticum Species 0.000 description 1
- 241000195493 Cryptophyta Species 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 241000234280 Liliaceae Species 0.000 description 1
- 240000000249 Morus alba Species 0.000 description 1
- 235000008708 Morus alba Nutrition 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 241000219050 Polygonaceae Species 0.000 description 1
- 241000205407 Polygonum Species 0.000 description 1
- 101150098935 RFU1 gene Proteins 0.000 description 1
- 240000001341 Reynoutria japonica Species 0.000 description 1
- 235000018167 Reynoutria japonica Nutrition 0.000 description 1
- 241000362909 Smilax <beetle> Species 0.000 description 1
- PJANXHGTPQOBST-VAWYXSNFSA-N Stilbene Natural products C=1C=CC=CC=1/C=C/C1=CC=CC=C1 PJANXHGTPQOBST-VAWYXSNFSA-N 0.000 description 1
- 241000425573 Talanes Species 0.000 description 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 1
- 241000489523 Veratrum Species 0.000 description 1
- 241000607479 Yersinia pestis Species 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 150000003797 alkaloid derivatives Chemical group 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 229940121357 antivirals Drugs 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
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 239000013024 dilution buffer Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- FVKGRHSPCZORQC-UHFFFAOYSA-N formaldehyde;toluene Chemical compound O=C.CC1=CC=CC=C1 FVKGRHSPCZORQC-UHFFFAOYSA-N 0.000 description 1
- 239000010903 husk Substances 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- SFBTTWXNCQVIEC-UHFFFAOYSA-N o-Vinylanisole Chemical compound COC1=CC=CC=C1C=C SFBTTWXNCQVIEC-UHFFFAOYSA-N 0.000 description 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 1
- 230000000361 pesticidal effect Effects 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 230000008635 plant growth Effects 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 235000021286 stilbenes Nutrition 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 125000005504 styryl group Chemical group 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000009333 weeding Methods 0.000 description 1
Classifications
-
- 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
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D277/24—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
Abstract
The invention discloses a kind of diphenylethylene compounds containing thiazole ring and its synthetic method and application, the structural formula of the diphenylethylene compounds containing thiazole ring is as shown in the formula (I):In formula (I), substituent R1For Br or H；It is monosubstituted, polysubstituted or be not substituted that H on phenyl ring is substituted base R；The integer that n is 0 ~ 5, preferably 1 ~ 2 integer, n indicate the number of substituent R on phenyl ring；When n=0, indicate that the H on phenyl ring is not substituted；When n=1, it is monosubstituted to indicate that the H on phenyl ring is substituted base R；When n=2 ~ 5, indicate that the H on phenyl ring is substituted that base R is polysubstituted, and the substituent R on different the position of substitution is same or different；Substituent R is the alkoxy or halogen of hydrogen, the alkyl of C1 ~ C4, C1 ~ C3.The preparation method of diphenylethylene compounds provided by the invention containing thiazole ring is simple, and the diphenylethylene compounds containing thiazole ring show certain anti-tumor activity.
Description
Technical field
The present invention relates to a kind of diphenylethylene compounds containing thiazole ring and its synthetic method and applications.
Background technique
Diphenylethylene compounds, i.e. stilbene compound are a kind of objects with stibene parent nucleus or its polymer
The general name of matter.It is mainly distributed in the xylem parenchyma of plant, is plant by pest disease or other unfavorable stimulations
When generate stress product, be widely present in nature, such as polygonaceae plant hair black false hellebore, the fleece-flower root, polygonum cuspidate, Liliaceae smilax
Plant Smilax perfoliate, Cassia, Mulberry Roots etc..Diphenyl ethene compounds have extensive bioactivity, such as antitumor (Nutr.
Cancer, 2001,39:102-107), anti-leukocythemia (Phytochemistry, 1993,33:813-816), anti-blood it is small
Plate assemble (Chem. Pharm. Bull., 1987,35:887-890), it is anti-inflammatory (J. Immunol., 2005,175:
3339-3346), antibacterial (World. J. Microb. Biot., 2010,26 (8): 1533-1538) and anti-oxidant (J.
Biol. Chem., 2001,276:22586-22594) etc. medical physiological activity；Antimycotic (Plant Dis., 2019,
103 (7): 1674-1684), desinsection (J. Pest. Sci., 2018,91 (2): 897-906), kill algae (J. Agric.
Food Chem., 2008,56:9140-9145), mosquitocide (Chem. Biodivers., 2016,13,1165-1177)
Equal pesticide activities.Simultaneously because its structure is simple, and it is natural source skeleton structure, is a kind of ideal potential drug guide structure,
It is more and more paid close attention to by new drug development person.
Nitrogen-containing heterocycle compound has high, the environment phase to target specificity since it is similar to alkaloid structure in organism
The good feature of capacitive, it has also become the mainstream research field of new drug initiative.As nitrogenous heterocyclic important a member, thiazole heterocycle class
Close object because its extensive bioactivity medicine and pesticide field have broad application prospects.According to the literature, in medicine
Field has anticancer (Bioorg. Med. Chem. Lett., 2011,21 (7): 1965-1968), anti-inflammatory (Bioorgan.
Med. Chem., 2011,19 (10): 3135-3140), it is antimycotic (Eur. J. Med. Chem., 2011,46 (9):
3681-3689), anti-oxidant (Chemistry Select, 2019,4 (19): 5570-5576) isoreactivity；In pesticide field
With weeding (organic chemistry, 2009,29 (6): 924-928), sterilization (J. Enzym. Inhib. Med. CH.,
2019,34 (1): 898-908), desinsection (J. Agric. Food Chem, 2011,59 (9): 2932-2937), anti-
Viral (Bioorg Med Chem, 2011,19 (12): 3845-3854), plant growth regulating (Chin Chem Lett,
2010,21 (3): 283-286) etc. bioactivity.(WO 2001068589,2001-09-20 according to the literature；WO
2004035554,2004-04-29) and the previous work of the applicant (organic chemistry, 2009,29 (12): 2000-
2004) show that fluorine-containing phenyl thiazole is also a kind of with the active structural unit of good biological.
Good bioactivity is all had in view of diphenylethylene compounds and thiazole heterocycle class compound, it is new in order to find
The drug leads of grain husk, the present invention by biologically active talan skeleton and are contained using the method for active substructure splicing
Fluorophenyl thiazole structure mutually splices, and design has synthesized a kind of novel diphenyl ethene compounds containing thiazole ring, is expected to have preferable
Bioactivity.
The serial diphenyl ethene compounds containing thiazole ring that the present invention designs and synthesizes, structure and bioactivity research
It is showed no document report.
Summary of the invention
The purpose of the present invention is to provide a kind of diphenylethylene compounds containing thiazole ring and its synthetic method and application,
The preparation method of diphenylethylene compounds provided by the invention containing thiazole ring is simple, and the talan containing thiazole ring
Class compound shows certain anti-tumor activity.
A kind of diphenylethylene compounds containing thiazole ring, it is characterised in that its structural formula is as shown in the formula (I):
In formula (I), substituent R1For Br or H；It is monosubstituted, polysubstituted or be not substituted that H on phenyl ring is substituted base R；N is 0 ~ 5
Integer, preferably 1 ~ 2 integer, n indicate phenyl ring on substituent R number；When n=0, indicate that the H on phenyl ring is not substituted；n
When=1, it is monosubstituted to indicate that the H on phenyl ring is substituted base R；When n=2 ~ 5, indicate that the H on phenyl ring is substituted that base R is polysubstituted, and difference takes
It is same or different to subrogate the substituent R set；The substituent R is the alkoxy or halogen of hydrogen, the alkyl of C1 ~ C4, C1 ~ C3
Element.
A kind of diphenylethylene compounds containing thiazole ring, it is characterised in that the substituent R be hydrogen, methyl,
Tert-butyl, methoxyl group or bromine.
A kind of diphenylethylene compounds containing thiazole ring, it is characterised in that in formula (I), R (n) is hydrogen, adjacent first
Base, methyl, to methyl, O-methoxy, meta-methoxy, to tert-butyl, adjacent bromine or 3,4- dimethoxy.
The synthetic method of a kind of diphenylethylene compounds containing thiazole ring, it is characterised in that including following step
It is rapid:
1) (4- (bromomethyl) phenyl) -2- (4- fluorophenyl) thiazole of the bromo- 4- of 5- as shown in formula (II) with as shown in formula (III)
Triethyl phosphite is reacted under heating, and TLC is monitored to after reaction, and extra phosphorous acid is sloughed in reaction solution concentration
Triethyl obtains concentrate；
2) solvent DMF, sodium hydroxide and the substituted benzaldehyde as shown in formula (IV) are added in the concentrate obtained by step 1), in room
The lower reaction of temperature, TLC are monitored to after reaction, reaction solution is post-treated and the hexichol second containing thiazole ring as shown in the formula are made
Vinyl compound；
In formula (IV), it is monosubstituted, polysubstituted or be not substituted that H on phenyl ring is substituted base R；The integer that n is 0 ~ 5, preferably 1 ~ 2
Integer, n indicate phenyl ring on substituent R number；When n=0, indicate that the H on phenyl ring is not substituted；When n=1, indicate on phenyl ring
H be substituted base R it is monosubstituted；When n=2 ~ 5, polysubstituted, the substitution on different the position of substitution that indicates that the H on phenyl ring is substituted base R
Base R is same or different；Substituent R in formula (IV) is the alkoxy or halogen of hydrogen, the alkyl of C1 ~ C4, C1 ~ C3.
The synthetic method of a kind of diphenylethylene compounds containing thiazole ring, it is characterised in that as shown in formula (II)
The bromo- 4- of 5- (4- (bromomethyl) phenyl) -2- (4- fluorophenyl) thiazole, triethyl phosphite as shown in the formula (III), such as formula
(IV) the ratio between amount for the substance that feeds intake of substituted benzaldehyde and sodium hydroxide shown in is 1:1.0~30.0:1.0~8.0:1.0
~20.0, preferably 1: 1.5~20.0: 1.0~3.0: 1.0~5.0.
The synthetic method of a kind of diphenylethylene compounds containing thiazole ring, it is characterised in that as shown in formula (II)
The bromo- 4- of 5- (4- (bromomethyl) phenyl) -2- (4- fluorophenyl) thiazole and solvent DMF mass ratio be 1: 2.0~20, preferably
It is 1: 4.0~10.0.
The synthetic method of a kind of diphenylethylene compounds containing thiazole ring, it is characterised in that in step 1), add
The temperature of thermal response is 120 ~ 155 DEG C, and the time for heating reaction is 1 ~ 5 hour；In step 2, time of room temperature reaction is 1.5 ~
4 hours.
The synthetic method of a kind of diphenylethylene compounds containing thiazole ring, it is characterised in that in step 2, instead
Answer the step that liquid is post-treated are as follows: after reaction, a large amount of ice water are added into reaction solution, stir, if having solid precipitation, mistake
Filter, the recrystallization purification of filter cake organic solvent obtain the diphenylethylene compounds as shown in the formula (I) containing thiazole ring；If without solid
Body is precipitated, then is extracted with ethyl acetate, after precipitation, the residual liquid after precipitation uses column chromatography to obtain as shown in the formula (I)
Diphenylethylene compounds containing thiazole ring；Wherein, the bromo- 4- of 5- (4- (bromomethyl) benzene that the ice water of addition and step 1) are added
Base) -2- (4- fluorophenyl) thiazole mass ratio be 33 ~ 50:1.
The synthetic method of a kind of diphenylethylene compounds containing thiazole ring, it is characterised in that recrystallization purification is adopted
Organic solvent is the mixed liquor of one or more of ethyl alcohol, ethyl acetate, n-hexane；Used in column chromatography for separation
Eluant, eluent is the mixed liquor of the ethyl acetate that volume ratio is 1: 1 ~ 10 and petroleum ether.
A kind of diphenylethylene compounds application in preparation of anti-tumor drugs containing thiazole ring.
During synthesizing the diphenylethylene compounds containing thiazole ring, the present invention has found in an experiment: if phosphorous acid
Triethyl dosage is less, and (triethyl phosphite dosage is that the bromo- 4- of 5- (4- (bromomethyl) phenyl) -2- (4- fluorophenyl) thiazole rubs
Within 5 times of your amount) and substituent R when reaction temperature lower (120 DEG C), in structural formula of compound shown in formula (I)1Essentially
Br；If triethyl phosphite dosage is more, (triethyl phosphite dosage is the bromo- 4- of 5- (4- (bromomethyl) phenyl) -2- (4- fluorobenzene
Base) other than 10 times of mole of thiazole) and when reaction temperature higher (reflux temperature), in structural formula of compound shown in formula (I)
Substituent R1Essentially H can take off 5- bromines of thiazole ring this is because triethyl phosphite has certain reproducibility
It goes.
Compared with prior art, the beneficial effects of the present invention are embodied in:
The present invention provides a kind of novel diphenylethylene compounds containing thiazole ring, the preparation method letters of such compound
It is single, and certain anti-tumor activity is shown, the anti-tumor activity for having carried out TDP1 and TDP2 in an embodiment of the present invention is surveyed
It is fixed, the experimental results showed that, compound represented of embodiment of the present invention Ia-Ii has certain antitumor work in 50 μM of concentration
Property, Compound Ig per has been above 50% to the inhibiting rate of TDP2 to TDP1 and compound Ib, Ie, has reached medium suppression level；Its
Middle compound Ib has preferable inhibitory activity, inhibiting rate 60.3% to TDP2.
Specific embodiment
The present invention is further explained in the light of specific embodiments, but the scope of protection of the present invention is not limited thereto.
In following embodiment, the structural formula of compound Ia-Ii is as shown in the formula (I),, and corresponding substituent R is disclosed in table 11With R's (n)
Type.
1 compound Ia(R of embodiment1=Br, R(n)=H) synthesis:
Phosphorous triethylenetetraminehexaacetic acid is added in the bromo- 4- of 5- (4- (bromomethyl) phenyl) -2- (4- fluorophenyl) thiazole (4.2 g, 10 mmol)
In ester (2.6 mL, 15 mmol), 120 DEG C of reactions are heated to, TLC detects reaction process, end of reaction after about 1 h.Concentration is de-
Extra triethyl phosphite is removed, concentrate is obtained；Be added in gained concentrate DMF (20 mL, 19.0 g), benzaldehyde
(1.3g, 12 mmol) and sodium hydroxide (0.9 g, 22 mmol) react at room temperature.TLC detects reaction process, about 3 small
Shi Fanying terminates, and reaction solution is poured into 139 g ice water, and stirring has solid precipitation, filters, filter cake re-crystallizing in ethyl acetate
2.4 g of yellow solid is obtained, as (E) the bromo- 2- of -5- (4- fluorophenyl) -4- (4- styryl phenyl) thiazole (and be labeled as compound
Ia), calculating its yield is 54.5%.m.p.: 208-210℃；
1H NMR (500 MHz, Chloroform-d) δ 8.06 (ddt, J = 8.0, 5.0, 3.0 Hz, 2H),
7.92 (d, J = 8.5 Hz, 2H), 7.61 (d, J = 8.5 Hz, 2H), 7.56 (d, J = 7.0 Hz, 2H),
7.40 (t, J = 7.0 Hz, 2H), 7.32 (d, J = 7.5 Hz, 1H), 7.21 – 7.16 (m, 3H), 7.15
(d, J= 16.0 Hz, 1H)；
HRMS (ESI) calcd C23H16BrFNS [M+H]+ 436.0165, found 436.0185。
2 compound Ib(R of embodiment1=Br, R(n)=4-CH3) synthesis:
Phosphorous triethylenetetraminehexaacetic acid is added in the bromo- 4- of 5- (4- (bromomethyl) phenyl) -2- (4- fluorophenyl) thiazole (4.2 g, 10 mmol)
In ester (5.1 mL, 30.0 mmol), 120 DEG C of reactions are heated to, TLC detects reaction process, end of reaction after about 1.5 h.It is dense
Extra triethyl phosphite is sloughed in contracting, obtains concentrate；DMF (18 mL, 17.1 g), to first are added in gained concentrate
Benzaldehyde (1.2g, 10 mmol) and sodium hydroxide (1.5 g, 36.9 mmol) react at room temperature.TLC detection was reacted
Journey, about 3.5 hour reactions terminate, reaction solution are poured into 160 g ice water, stirs, there is solid precipitation, is filtered, filter cake second
Alcohol recrystallizes to obtain 2.7 g of yellow solid, as (E) the bromo- 2- of -5- (4- fluorophenyl) -4- (4- (4- methyl styrene base) phenyl)
Thiazole (is labeled as compound Ib), and calculating its yield is 60.5%. m.p.: 196-198℃；
1H NMR (500 MHz, Chloroform-d) δ8.09 – 8.04 (m, 2H), 7.91 (d, J = 8.5 Hz,
2H), 7.59 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.23 – 7.16 (m, 5H),
7.10 (d, J = 16.0 Hz, 1H), 2.39 (s, 3H);
HRMS (ESI) calcd C24H18BrFNS [M+H]+ 450.0322, found 450.0319。
3 compound Ic(R of embodiment1=Br, R(n)=4- tert-butyl) synthesis:
Phosphorous triethylenetetraminehexaacetic acid is added in the bromo- 4- of 5- (4- (bromomethyl) phenyl) -2- (4- fluorophenyl) thiazole (4.2 g, 10 mmol)
In ester (6.9 mL, 40 mmol), 120 DEG C of reactions are heated to, TLC detects reaction process, end of reaction after about 2 h.Concentration is de-
Extra triethyl phosphite is removed, concentrate is obtained；DMF (30 mL, 28.4 g), to tert-butyl are added in gained concentrate
Benzaldehyde (3.2 g, 20 mmol) and sodium hydroxide (2.0 g, 50 mmol) react at room temperature.TLC detects reaction process,
About 2.5 hour reactions terminate, and reaction solution is poured into 180 g ice water, stirs, there is solid precipitation, is filtered, filter cake n-hexane
2.8 g of yellow solid is recrystallized to obtain, as (E) the bromo- 4- of -5- (4- (4- (tert-butyl) styryl) phenyl) -2- (4- fluorobenzene
Base) thiazole (being labeled as compound Ic), calculating its yield is 56.8%. m.p.: 183-185℃；
1H NMR (500 MHz, Chloroform-d) δ 8.06 (ddd, J = 6.5, 5.5, 2.0 Hz, 2H),
7.91 (d, J = 8.5 Hz, 2H), 7.59 (d, J = 8.5 Hz, 2H), 7.50 (d, J = 8.5 Hz, 2H),
7.42 (d, J = 8.5 Hz, 2H), 7.23 – 7.16 (m, 3H), 7.11 (d, J = 16.5 Hz, 1H),
1.36 (s, 9H)；
HRMS (ESI) calcd C27H24BrFNS [M+H]+ 492.0791, found 492.0801。
4 compound Id(R of embodiment1=Br, R(n) =3-CH3) synthesis:
Phosphorous triethylenetetraminehexaacetic acid is added in the bromo- 4- of 5- (4- (bromomethyl) phenyl) -2- (4- fluorophenyl) thiazole (4.2 g, 10 mmol)
In ester (5.1 mL, 30 mmol), 120 DEG C of reactions are heated to, TLC detects reaction process, end of reaction after about 2 h.Concentration is de-
Extra triethyl phosphite is removed, concentrate is obtained；Be added in gained concentrate DMF (44 mL, 42.0 g), methylbenzene
Formaldehyde (3.6 g, 30 mmol) and sodium hydroxide (1.2 g, 30 mmol) react at room temperature.TLC detects reaction process, about
2.5 hour reactions terminate, and reaction solution is poured into 200 g ice water, stirs, there is solid precipitation, is filtered, filter cake ethyl acetate
With n-hexane mixed liquor (V ethyl acetate: n-hexane=1 V: 1) recrystallizing to obtain 2.4 g of yellow solid, as (E) -5- is bromo-
2- (4- fluorophenyl) -4- (4- (3- methyl styrene base) phenyl) thiazole (is labeled as compound Id), and calculating its yield is
52.4%.m.p.: 163-165℃；
1H NMR (500 MHz, Chloroform-d) δ 8.06 (ddd, J = 8.5, 5.5, 2.5 Hz, 2H),
7.93 – 7.89 (m, 2H), 7.59 (d, J = 8.5 Hz, 2H), 7.40 – 7.34 (m, 2H), 7.29 (d,J = 15.0 Hz, 1H), 7.22 – 7.16 (m, 3H), 7.13 (d, J = 16.5 Hz, 1H), 2.41 (s,
3H).
HRMS (ESI) calcd C24H18BrFNS [M+H]+ 450.0322, found 450.0334。
5 compound Ie(R of embodiment1=H, R(n) =2-CH3) synthesis:
Triethyl phosphite is added in the bromo- 4- of 5- (4- (bromomethyl) phenyl) -2- (4- fluorophenyl) thiazole (4.2 g, 10 mmol)
In (34.3 mL, 200 mmol), it is heated to back flow reaction, TLC detects reaction process, end of reaction after about 3 h.Concentration is sloughed
Extra triethyl phosphite, obtains concentrate；Be added in gained concentrate DMF (40 mL, 37.9 g), o-methyl-benzene first
Aldehyde (3.0 g, 25 mmol) and sodium hydroxide (1.6 g, 40 mmol) react at room temperature.TLC detects reaction process, about
1.5 hour reactions terminate, and reaction solution is poured into 210 g ice water, stirs, there is solid precipitation, is filtered, filter cake is tied again with ethyl alcohol
It is brilliant to obtain 2.2 g of yellow solid, as (E) -2- (4- fluorophenyl) -4- (4- (2-methyl styrene base) phenyl) thiazole (is labeled as
Compound Ie), calculating its yield is 58.9%.m.p.: 130-133℃；
1H NMR (500 MHz, Chloroform-d) δ 8.05 (d, J = 8.5 Hz, 2H), 8.03 – 7.97
(m, 2H), 7.63 (t, J = 8.0 Hz, 3H), 7.45 (d, J = 16.0 Hz, 1H), 7.43 (s, 1H),
7.23 (dt, J = 5.1, 2.5 Hz, 2H), 7.20 – 7.11 (m, 1H), 7.06 (d, J = 16.2 Hz,
1H), 2.49 (s, 2H)；
HRMS (ESI) calcd C24H19FNS [M+H]+ 372.1217, found 372.1228。
6 compound If(R of embodiment1=H, R(n) =3-OCH3) synthesis:
Phosphorous triethylenetetraminehexaacetic acid is added in the bromo- 4- of 5- (4- (bromomethyl) phenyl) -2- (4- fluorophenyl) thiazole (4.2 g, 10 mmol)
In ester (25.7 mL, 150 mmol), it is heated to back flow reaction, TLC detects reaction process, end of reaction after about 4 h.Concentration is de-
Extra triethyl phosphite is removed, concentrate is obtained；Be added in gained concentrate DMF (25 mL, 23.7 g), meta-methoxy
Benzaldehyde (3.4 g, 25 mmol) and sodium hydroxide (0.8 g, 20 mmol) react at room temperature.TLC detects reaction process,
About 4 hour reactions terminate, and reaction solution is poured into 200 g ice water, stirs, there is solid precipitation, is filtered, filter cake n-hexane weight
2.5 g of yellow solid is crystallized to obtain, as (E) -2- (4- fluorophenyl) -4- (4- (3- methoxyl-styrene) phenyl) thiazole (mark
It is denoted as compound If), calculating its yield is 65.3%.m.p.: 143-145℃；
1H NMR (500 MHz, Chloroform-d) δ 8.04 (d, J = 8.5 Hz, 2H), 7.99 (ddd, J =
8.5, 5.5, 3.0 Hz, 2H), 7.61 (d, J = 8.5 Hz, 2H), 7.41 (s, 1H), 7.32 (t, J =
8.0 Hz, 1H), 7.22 – 7.12 (m, 5H), 7.11 – 7.09 (m, 1H), 6.87 (dd, J = 8.0, 3.0
Hz, 1H), 3.88 (s, 3H).；
HRMS (ESI) calcd C24H19FNOS [M+H]+ 388.1166, found 388.1145。
7 Compound Ig per (R of embodiment1=H, R(n) = 2-OCH3) synthesis:
Phosphorous triethylenetetraminehexaacetic acid is added in the bromo- 4- of 5- (4- (bromomethyl) phenyl) -2- (4- fluorophenyl) thiazole (4.2 g, 10 mmol)
In ester (34.3 mL, 200 mmol), it is heated to back flow reaction, TLC detects reaction process, end of reaction after about 3 h.Concentration is de-
Extra triethyl phosphite is removed, concentrate is obtained；Be added in gained concentrate DMF (20 mL, 19.0 g), O-methoxy
Benzaldehyde (1.6 g, 12 mmol) and sodium hydroxide (0.4 g, 10 mmol) react at room temperature.TLC detects reaction process,
About 3 hour reactions terminate, and reaction solution is poured into 210 g ice water, stirs, there is solid precipitation, is filtered, filter cake ethyl acetate
With petroleum ether mixed liquor (V ethyl acetate: petroleum ether=1 V: 10) column chromatographic elution obtains 2.7 g of yellow solid, as (E)-
2- (4- fluorophenyl) -4- (4- (2- methoxyl-styrene) phenyl) thiazole (is labeled as Compound Ig per), yield 68.9%.m.p.:
115-116℃；
1H NMR (500 MHz, Chloroform-d) δ 8.07 – 7.97 (m, 4H), 7.63 (q, J = 8.5
Hz, 4H), 7.37 (s, 1H), 7.33 – 7.29 (m, 1H), 7.21 – 7.15 (m, 3H), 7.03 (t, J =
7.5 Hz, 1H), 6.95 (d, J= 8.0 Hz, 1H), 3.93 (s, 3H).；
HRMS (ESI) calcd C24H19FNOS [M+H]+ 388.1166, found 388.1176。
8 compound Ih(R of embodiment1=H, R(n)=2-Br) synthesis:
Phosphorous triethylenetetraminehexaacetic acid is added in the bromo- 4- of 5- (4- (bromomethyl) phenyl) -2- (4- fluorophenyl) thiazole (4.2 g, 10 mmol)
In ester (17.1 mL, 100 mmol), it is heated to back flow reaction, TLC detects reaction process, end of reaction after about 5 h.Concentration is de-
Extra triethyl phosphite is removed, concentrate is obtained；Be added in gained concentrate DMF (20 mL, 19.0 g), o-bromobenzaldehye
(2.8 g, 15 mmol) and sodium hydroxide (0.8 g, 20 mmol) react at room temperature.TLC detection reaction process, about 3.5
Reaction in a hour terminates, and reaction solution is poured into 180 g ice water, stirring, have solid precipitation, filter, filter cake ethyl acetate and
Petroleum ether mixed liquor (V ethyl acetate: petroleum ether=1 V: 1) column chromatographic elution obtains 2.5 g of yellow solid, as (E)-2-
(4- fluorophenyl) -4- (4- (2- bromstyrol base) phenyl) thiazole (is labeled as compound Ih), yield 58.6%.m.p.: 134-
135℃；
1H NMR (500 MHz, Chloroform-d) δ 8.18 (s, 1H), 8.11 (ddd, J = 8.5, 5.0,
2.5 Hz, 2H), 8.07 (d, J = 8.5 Hz, 2H), 7.90 (dd, J = 8.0, 1.5 Hz, 1H), 7.77
(d, J = 8.5 Hz, 2H), 7.69 (dd, J = 8.0, 1.0 Hz, 1H), 7.51 (d, J = 16.5 Hz,
1H), 7.45 (t, J = 7.5 Hz, 1H), 7.40 – 7.30 (m, 3H), 7.26 (td, J = 8.0, 1.5
Hz, 1H).；
HRMS (ESI) calcd C23H16BrFNS [M+H]+ 436.0165, found 436.0169。
9 compound Ii(R of embodiment1=H, R(n)=3,4- dimethoxy) synthesis:
Phosphorous triethylenetetraminehexaacetic acid is added in the bromo- 4- of 5- (4- (bromomethyl) phenyl) -2- (4- fluorophenyl) thiazole (4.2 g, 10 mmol)
In ester (25.7 mL, 150 mmol), it is heated to back flow reaction, TLC detects reaction process, end of reaction after about 3 h.Concentration is de-
Extra triethyl phosphite is removed, concentrate is obtained；Be added in gained concentrate DMF (28 mL, 26.5 g), 3,4- diformazan
Oxygroup benzaldehyde (3.0 g, 18 mmol) and sodium hydroxide (1.2 g, 30 mmol) react at room temperature.TLC detection reaction
Process, about 3 hour reactions terminate, reaction solution are poured into 150 g ice water, stirs, there is solid precipitation, is filtered, filter cake second
(V ethyl acetate: petroleum ether=1 V: 5) column chromatographic elution must obtain yellow solid 2.8g, i.e., for acetoacetic ester and petroleum ether mixed liquor
For (E) -2- (4- fluorophenyl) -4- (4- (3,4- dimethoxy-styryl) phenyl) thiazole (being labeled as compound Ii), yield
67.7%.m.p.: 147-150℃；
1H NMR (500 MHz, Chloroform-d) δ 8.05 – 7.96 (m, 4H), 7.57 (d, J = 8.5
Hz, 2H), 7.38 (s, 1H), 7.18 – 7.06 (m, 5H), 7.00 (d, J = 16.5 Hz, 1H), 6.88
(d, J= 8.0 Hz, 1H), 3.97 (s, 3H), 3.92 (s, 3H)；
HRMS (ESI) calcd C25H21FNO2S [M+H]+ 418.1272, found 418.1266。
The test of 10 anti-tumor activity of embodiment:
The diphenylethylene compounds containing thiazole ring that embodiment 1 ~ 9 is synthesized are labeled as untested compound.To untested compound
The inhibitory activity for having carried out tyrosyl-DNA phosphodiesterase 1 (TDP1) and tyrosyl-DNA phosphodiesterase 2 (TDP2) is surveyed
Examination.Its test method is as follows:
(1) test of tyrosyl-DNA phosphodiesterase 1 (TDP1) inhibitory activity
Reaction system (40 μ L): 100 nM TDP1 Dilution Buffer (200 nM TDP1,10 mM Tris-HCl,
50 mM KCl, 1 mM EDTA, 2 mM DTT, pH=7.5) 20 μ L, 2 μ of DMSO solution of the untested compound of 50 μM of concentration
L supplies volume with buffer solution (10 mM Tris-HCl, 50 mM KCl, 1 mM EDTA, pH=7.5).Shake 30 s mixing
Afterwards, Linear is added using the background fluorescence activity at microplate reader detection Ex485 nm/Em510 nm in 37 DEG C of 30 min of incubation
20 μ L of Oligonucleotide, concussion mix the reaction fluorescent value at detection Ex485 nm/Em510 nm, that is, measure
Compound group fluorescent value.
The test method step of Control group fluorescent value repeats the test process of above-mentioned Compound group fluorescent value, different
Place is: the DMSO solution of the untested compound of 50 μM of concentration is replaced with to the DMSO solvent of peer accumulated amount.Other operations
Condition finally measures Control group fluorescent value with Compound group fluorescent value test process.
The test process of Blank group fluorescent value is as follows: reaction system (40 μ L), 2 μ L of DMSO solvent, with buffer solution (10
MM Tris-HCl, 50 mM KCl, 1 mM EDTA, pH=7.5) complement to the volume of 40 μ L.After shaking 30 s mixing, in 37
DEG C be incubated for 30 min, use microplate reader detection Ex485 nm/Em510 nm place background fluorescence activity, addition Linear
20 μ L of Oligonucleotide, concussion mix the reaction fluorescent value at detection Ex485 nm/Em510 nm, that is, measure Blank
Group fluorescent value.
By comparing Control group, the difference of Blank group fluorescent value, the inhibiting rate of each untested compound is calculated, is inhibited
Rate calculation formula are as follows:
Wherein: RFU1 is that Control group reaction fluorescent value subtracts background fluorescence activity；
RFU2 is that Compound group reaction fluorescent value subtracts background fluorescence activity；
RFU3 is that Blank group reaction fluorescent value subtracts background fluorescence activity.
(2) test of tyrosyl-DNA phosphodiesterase 2 (TDP2) inhibitory activity
Reaction system (40 μ L): buffer solution (25 mM Hepes, 10 mM MgCl are first added2, 130 mM KCl, pH=8.0)
9 μ L, add the 1 μ L of DMSO solution of the untested compound of 50 μM of concentration, and concussion uses microplate reader at 405 nm after mixing
Background absorbance is measured, 300 nM TDP2,10 μ L is added, 20 μ L NPPP Solution are added after mixing, shakes 1 min
Afterwards, it is put in 37 DEG C of constant incubators and cultivates 90 min, then 5 μ L EDTA Stop Solution termination is added in every hole
TDP2 is reacted with NPPP's.The ultraviolet absorptivity A that each hole at this time is measured at 405 nm, that is, measure the ultraviolet suction of Compound group
Receipts degree.
The test method step of Control group ultraviolet absorptivity repeats the test of above-mentioned Compound group ultraviolet absorptivity
Journey, the difference is that: the DMSO solution of the untested compound of 50 μM of concentration is replaced with to the DMSO solvent of peer accumulated amount.
Other operating conditions finally measure the ultraviolet absorptivity of Control group with the test process of Compound group ultraviolet absorptivity.
The test process of Blank group ultraviolet absorptivity is as follows: buffer solution (25 mM Hepes, 10 mM are first added
MgCl2, 130 mM KCl, pH=8.0) 19 μ L, add 1 μ L of DMSO solvent, concussion mix after using microplate reader in 405 nm
20 μ L NPPP Solution are added in lower measurement background absorbance after mixing, after shaking 1 min, be put in 37 DEG C of constant temperature incubations
90 min are cultivated in case, then every hole is added 5 μ L EDTA Stop Solution and terminates reacting for TDP2 and NPPP.In
The ultraviolet absorptivity A that each hole at this time is measured at 405 nm, finally measures the ultraviolet absorptivity of Blank group.
By comparing Control group, the difference of Blank group ultraviolet absorption value, the inhibiting rate of each compound is calculated, is inhibited
Rate calculation formula are as follows:
Wherein: A1 is that Control group reaction UV absorption subtracts background UV absorption；
A2 is that Compound group reaction UV absorption subtracts background UV absorption；
A3 is that Blank group reaction UV absorption subtracts background UV absorption.
Test result is shown in Table 1.
The anti-tumor activity of compound Ia-Ii under 1 50 μM of concentration of table
As shown in Table 1, compound represented of embodiment of the present invention Ia-Ii has certain anti-tumor activity in 50 μM of concentration,
Compound Ig per has been above 50% to the inhibiting rate of TDP2 to TDP1 and Ib, Ie, has reached medium suppression level.Wherein compound
Ib has preferable inhibitory activity to TDP2, and inhibiting rate is up to 60.3%.
Content described in this specification is only to enumerate to inventive concept way of realization, and protection scope of the present invention is not answered
When the concrete form for being seen as limited by embodiment and being stated.
Claims (10)
1. a kind of diphenylethylene compounds containing thiazole ring, it is characterised in that its structural formula is as shown in the formula (I):
In formula (I), substituent R1For Br or H；
It is monosubstituted, polysubstituted or be not substituted that H on phenyl ring is substituted base R；The integer that n is 0 ~ 5, preferably 1 ~ 2 integer, n
Indicate the number of substituent R on phenyl ring；When n=0, indicate that the H on phenyl ring is not substituted；When n=1, indicate that the H on phenyl ring is substituted
Base R is monosubstituted；When n=2 ~ 5, it is polysubstituted to indicate that the H on phenyl ring is substituted base R, the substituent R on different the position of substitution it is identical or
Person is different；
The substituent R is the alkoxy or halogen of hydrogen, the alkyl of C1 ~ C4, C1 ~ C3.
2. a kind of diphenylethylene compounds containing thiazole ring as described in claim 1, it is characterised in that the substituent R is
Hydrogen, methyl, tert-butyl, methoxyl group or bromine.
3. a kind of diphenylethylene compounds containing thiazole ring as described in claim 1, it is characterised in that in formula (I), R (n)
For hydrogen, adjacent methyl, methyl, to methyl, O-methoxy, meta-methoxy, to tert-butyl, adjacent bromine or 3,4- dimethoxy.
4. a kind of synthetic method of the diphenylethylene compounds containing thiazole ring as described in claim 1, it is characterised in that packet
Include following steps:
1) (4- (bromomethyl) phenyl) -2- (4- fluorophenyl) thiazole of the bromo- 4- of 5- as shown in formula (II) with as shown in formula (III)
Triethyl phosphite is reacted under heating, and TLC is monitored to after reaction, and extra phosphorous acid is sloughed in reaction solution concentration
Triethyl obtains concentrate；
2) solvent DMF, sodium hydroxide and the substituted benzaldehyde as shown in formula (IV) are added in the concentrate obtained by step 1), in room
The lower reaction of temperature, TLC are monitored to after reaction, reaction solution is post-treated and the hexichol second containing thiazole ring as shown in the formula are made
Vinyl compound；
In formula (IV), it is monosubstituted, polysubstituted or be not substituted that H on phenyl ring is substituted base R；The integer that n is 0 ~ 5, preferably 1 ~ 2
Integer, n indicate phenyl ring on substituent R number；When n=0, indicate that the H on phenyl ring is not substituted；When n=1, indicate on phenyl ring
H be substituted base R it is monosubstituted；When n=2 ~ 5, polysubstituted, the substitution on different the position of substitution that indicates that the H on phenyl ring is substituted base R
Base R is same or different；
Substituent R in formula (IV) is the alkoxy or halogen of hydrogen, the alkyl of C1 ~ C4, C1 ~ C3.
5. a kind of synthetic method of the diphenylethylene compounds containing thiazole ring as claimed in claim 4, it is characterised in that such as
The bromo- 4- of 5- shown in formula (II) (4- (bromomethyl) phenyl) -2- (4- fluorophenyl) thiazole, phosphorous acid three as shown in the formula (III)
The ratio between amount for the substance that feeds intake of ethyl ester, substituted benzaldehyde and sodium hydroxide as shown in formula (IV) is 1: 1.0~30.0:
1.0~8.0: 1.0~20.0, preferably 1: 1.5~20.0: 1.0~3.0: 1.0~5.0.
6. a kind of synthetic method of the diphenylethylene compounds containing thiazole ring as claimed in claim 4, it is characterised in that such as
(4- (bromomethyl) phenyl) -2- (4- fluorophenyl) thiazole of the bromo- 4- of 5- shown in formula (II) and the mass ratio of solvent DMF are 1:
2.0~20, preferably 1: 4.0~10.0.
7. a kind of synthetic method of the diphenylethylene compounds containing thiazole ring as claimed in claim 4, it is characterised in that step
It is rapid 1) in, heat reaction temperature be 120 ~ 155 DEG C, heat reaction time be 1 ~ 5 hour；In step 2, room temperature reaction
Time is 1.5 ~ 4 hours.
8. a kind of synthetic method of the diphenylethylene compounds containing thiazole ring as claimed in claim 4, it is characterised in that step
It is rapid 2) in, the post-treated step of reaction solution are as follows: after reaction, a large amount of ice water are added into reaction solution, stir, if there is solid
It is precipitated, filtering, the recrystallization purification of filter cake organic solvent obtains the diphenylethylene chemical combination as shown in the formula (I) containing thiazole ring
Object；If no solid is precipitated, it is extracted with ethyl acetate, after precipitation, the residual liquid after precipitation uses column chromatography to obtain such as formula
(I) containing the diphenylethylene compounds of thiazole ring shown in；Wherein, the bromo- 4- (4- of 5- that the ice water of addition and step 1) are added
(bromomethyl) phenyl) -2- (4- fluorophenyl) thiazole mass ratio be 33 ~ 50:1.
9. a kind of synthetic method of the diphenylethylene compounds containing thiazole ring as claimed in claim 8, it is characterised in that weight
The organic solvent that crystallization and purification uses is the mixed liquor of one or more of ethyl alcohol, ethyl acetate, n-hexane；Column chromatography
Separation eluant, eluent used is the mixed liquor of ethyl acetate and petroleum ether that volume ratio is 1: 1 ~ 10.
10. a kind of diphenylethylene compounds containing thiazole ring as described in claim 1 answering in the preparation of antitumor drugs
With.
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| CN110476994A (en) * | 2019-08-26 | 2019-11-22 | 浙江工业大学 | A kind of application of diphenylethylene compounds containing thiazole ring as fungicide |
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| CN104860900A (en) * | 2014-02-25 | 2015-08-26 | 中国药科大学 | Thiazole compounds, and preparation method and application thereof in pharmacy |
| CN108727294A (en) * | 2018-06-19 | 2018-11-02 | 浙江工业大学 | A kind of class diphenyl ethene compounds and its synthetic method and application containing thiazole ring |
| CN108863977A (en) * | 2018-06-19 | 2018-11-23 | 浙江工业大学 | The class diphenyl ethene compounds and its synthetic method of a kind of thiazole ring containing bromo and application |
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| EP2612861A1 (en) * | 2010-09-02 | 2013-07-10 | Universitat de Barcelona | Fluorinated thiazoles for use in treating cancer |
| US20130190367A1 (en) * | 2010-09-02 | 2013-07-25 | Universitat De Barcelona | Fluorinated thiazoles for use in treating cancer |
| CN104860900A (en) * | 2014-02-25 | 2015-08-26 | 中国药科大学 | Thiazole compounds, and preparation method and application thereof in pharmacy |
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| CN110476994A (en) * | 2019-08-26 | 2019-11-22 | 浙江工业大学 | A kind of application of diphenylethylene compounds containing thiazole ring as fungicide |
| CN110476994B (en) * | 2019-08-26 | 2021-09-14 | 浙江工业大学 | Application of toluylene compound containing thiazole ring as bactericide |
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