CN115521257A - Alpha-substituted azolidone derivative and synthesis method thereof - Google Patents
Alpha-substituted azolidone derivative and synthesis method thereof Download PDFInfo
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- CN115521257A CN115521257A CN202211294346.8A CN202211294346A CN115521257A CN 115521257 A CN115521257 A CN 115521257A CN 202211294346 A CN202211294346 A CN 202211294346A CN 115521257 A CN115521257 A CN 115521257A
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- Prior art keywords
- substituted
- alpha
- reaction
- derivative according
- azolobenzophenone
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- BBXFVDGUPMYLQO-UHFFFAOYSA-N 2H-pyrrol-2-id-3-one Chemical class N1=[C-]C(C=C1)=O BBXFVDGUPMYLQO-UHFFFAOYSA-N 0.000 title claims abstract description 12
- 238000001308 synthesis method Methods 0.000 title abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 59
- 239000011734 sodium Substances 0.000 claims abstract description 26
- -1 sodium halide Chemical class 0.000 claims abstract description 18
- FTFFELNHZHIXAS-UHFFFAOYSA-N CC(=O)C1=CC=CC=C1.N1C=CC=C1 Chemical class CC(=O)C1=CC=CC=C1.N1C=CC=C1 FTFFELNHZHIXAS-UHFFFAOYSA-N 0.000 claims abstract description 10
- 150000007524 organic acids Chemical class 0.000 claims abstract description 6
- 229910052708 sodium Inorganic materials 0.000 claims abstract description 6
- 239000002994 raw material Substances 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 99
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 54
- 239000007787 solid Substances 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 17
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 16
- 239000012044 organic layer Substances 0.000 claims description 16
- 238000001035 drying Methods 0.000 claims description 15
- 238000001914 filtration Methods 0.000 claims description 15
- 238000010791 quenching Methods 0.000 claims description 15
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 11
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 11
- DQDCGTUHSVXZIS-UHFFFAOYSA-N iodobenzene;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F.IC1=CC=CC=C1 DQDCGTUHSVXZIS-UHFFFAOYSA-N 0.000 claims description 10
- ZBIKORITPGTTGI-UHFFFAOYSA-N [acetyloxy(phenyl)-$l^{3}-iodanyl] acetate Chemical compound CC(=O)OI(OC(C)=O)C1=CC=CC=C1 ZBIKORITPGTTGI-UHFFFAOYSA-N 0.000 claims description 8
- BERDEBHAJNAUOM-UHFFFAOYSA-N copper(I) oxide Inorganic materials [Cu]O[Cu] BERDEBHAJNAUOM-UHFFFAOYSA-N 0.000 claims description 8
- KRFJLUBVMFXRPN-UHFFFAOYSA-N cuprous oxide Chemical compound [O-2].[Cu+].[Cu+] KRFJLUBVMFXRPN-UHFFFAOYSA-N 0.000 claims description 8
- 229940112669 cuprous oxide Drugs 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 150000001879 copper Chemical class 0.000 claims description 6
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 239000007800 oxidant agent Substances 0.000 claims description 6
- 230000001590 oxidative effect Effects 0.000 claims description 6
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 4
- QPLDLSVMHZLSFG-UHFFFAOYSA-N Copper oxide Chemical compound [Cu]=O QPLDLSVMHZLSFG-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 claims description 4
- 125000004185 ester group Chemical group 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 239000011630 iodine Substances 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 3
- 229960003280 cupric chloride Drugs 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- VGJKBWPZBVBXGI-UHFFFAOYSA-N 1,2-dichloro-3-iodobenzene Chemical compound ClC1=CC=CC(I)=C1Cl VGJKBWPZBVBXGI-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 2
- 229910000366 copper(II) sulfate Inorganic materials 0.000 claims description 2
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 2
- 229940076286 cupric acetate Drugs 0.000 claims description 2
- 229960004643 cupric oxide Drugs 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- JYJVVHFRSFVEJM-UHFFFAOYSA-N iodosobenzene Chemical compound O=IC1=CC=CC=C1 JYJVVHFRSFVEJM-UHFFFAOYSA-N 0.000 claims description 2
- 239000010410 layer Substances 0.000 claims description 2
- 229910052751 metal Inorganic materials 0.000 claims description 2
- 239000002184 metal Substances 0.000 claims description 2
- FIYYMXYOBLWYQO-UHFFFAOYSA-N ortho-iodylbenzoic acid Chemical compound OC(=O)C1=CC=CC=C1I(=O)=O FIYYMXYOBLWYQO-UHFFFAOYSA-N 0.000 claims description 2
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical class O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims description 2
- XHFLOLLMZOTPSM-UHFFFAOYSA-M sodium;hydrogen carbonate;hydrate Chemical class [OH-].[Na+].OC(O)=O XHFLOLLMZOTPSM-UHFFFAOYSA-M 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims 7
- 150000001875 compounds Chemical class 0.000 abstract description 4
- 238000010499 C–H functionalization reaction Methods 0.000 abstract description 2
- 150000002148 esters Chemical group 0.000 abstract description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 28
- 239000012043 crude product Substances 0.000 description 27
- 238000005481 NMR spectroscopy Methods 0.000 description 26
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 20
- 239000000047 product Substances 0.000 description 19
- 238000003756 stirring Methods 0.000 description 16
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
- 239000003480 eluent Substances 0.000 description 14
- 238000002844 melting Methods 0.000 description 14
- 230000008018 melting Effects 0.000 description 14
- 239000003208 petroleum Substances 0.000 description 14
- 239000007864 aqueous solution Substances 0.000 description 13
- 238000004440 column chromatography Methods 0.000 description 12
- LMHBYYNTCSUZKA-UHFFFAOYSA-N 2-(4-chloro-1H-pyrazol-5-yl)-1-phenylethanone Chemical compound ClC=1C(=NNC=1)CC(=O)C1=CC=CC=C1 LMHBYYNTCSUZKA-UHFFFAOYSA-N 0.000 description 7
- 239000011780 sodium chloride Substances 0.000 description 7
- 239000000203 mixture Substances 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 239000003429 antifungal agent Substances 0.000 description 3
- 229940121375 antifungal agent Drugs 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 description 2
- 101100232409 Drosophila melanogaster icln gene Proteins 0.000 description 2
- 206010017533 Fungal infection Diseases 0.000 description 2
- 208000031888 Mycoses Diseases 0.000 description 2
- 101100232415 Schizosaccharomyces pombe (strain 972 / ATCC 24843) saf5 gene Proteins 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 239000000975 dye Substances 0.000 description 2
- 229960004130 itraconazole Drugs 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- XPCRJEKXVCOLBZ-UHFFFAOYSA-N 1-phenyl-2-(1h-pyrazol-5-yl)ethanone Chemical compound C=1C=CC=CC=1C(=O)CC1=CC=NN1 XPCRJEKXVCOLBZ-UHFFFAOYSA-N 0.000 description 1
- UGNMPYJASACVFH-UHFFFAOYSA-N 2-(4-bromo-3,5-dimethylpyrazol-1-yl)-1-phenylethanone Chemical compound CC1=C(Br)C(C)=NN1CC(=O)C1=CC=CC=C1 UGNMPYJASACVFH-UHFFFAOYSA-N 0.000 description 1
- QWLMQJYXUPWMAH-UHFFFAOYSA-N 3,5-diphenyl-1H-pyrazole 1-phenylethanone Chemical compound C(C)(=O)C1=CC=CC=C1.C1(=CC=CC=C1)C1=NNC(=C1)C1=CC=CC=C1 QWLMQJYXUPWMAH-UHFFFAOYSA-N 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 206010014733 Endometrial cancer Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 229940046836 anti-estrogen Drugs 0.000 description 1
- 230000001833 anti-estrogenic effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000328 estrogen antagonist Substances 0.000 description 1
- 229960004884 fluconazole Drugs 0.000 description 1
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 239000008204 material by function Substances 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
- 229960004190 nomegestrol acetate Drugs 0.000 description 1
- IIVBFTNIGYRNQY-YQLZSBIMSA-N nomegestrol acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 IIVBFTNIGYRNQY-YQLZSBIMSA-N 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000000583 progesterone congener Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 229960004740 voriconazole Drugs 0.000 description 1
- BCEHBSKCWLPMDN-MGPLVRAMSA-N voriconazole Chemical compound C1([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)=NC=NC=C1F BCEHBSKCWLPMDN-MGPLVRAMSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole 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
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole 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
- C07D231/16—Halogen atoms or nitro radicals
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to an alpha-substituted azol acetophenone derivative and a synthesis method thereof. The invention takes cheap and easily obtained azolidone compounds and sodium halide or organic acid as raw materials, obtains a series of alpha-substituted (ester substituted or halogenated) azol acetophenones with high selectivity and high yield by C-H activation reaction under mild conditions, and the compounds are novel azol acetophenone derivatives and have better research and application values.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical and chemical intermediate synthesis, and particularly relates to an alpha-substituted azolidone derivative and a synthesis method thereof.
Background
Nitrogen-containing compounds exist in nature and are widely applied to the fields of medicines, antibacteria, pesticides and functional materials due to strong physiological activity and unique function; the research finds that: azole acetophenone is an active group playing a main role in certain drug molecules, and the compounds are concerned by the scientific community because of having remarkable curative effects in resisting fungi, HIV, lung cancer, depression, new crown and other diseases. Such as voriconazole (a second generation triazole antifungal agent acting on severe fungal infections); fluconazole (broad spectrum antifungal agent) for the treatment of fungal infections; and Itraconazole (Itraconazole) which is a highly effective broad-spectrum antifungal agent. The application values of the azolidone compounds and the derivatives thereof in the field of drug research are reflected. Meanwhile, the alpha-ester ketone compound has excellent performance in the field of anticancer, for example, nomegestrol acetate is a progestational drug, and can treat some estrogen-dependent tumors such as endometrial cancer, breast cancer and the like through the action of antiestrogen. Therefore, the α -ester-substituted azolidone derivative has great application potential in the field of pharmaceutical research, but how to construct the α -substituted (ester-substituted or halogenated) azolidone derivative in one step through green, simple and mild reaction conditions is a research difficulty in the field of organic synthesis.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention provides a simple, convenient and efficient alpha-substituted azoleacetone derivative and a synthesis method thereof.
The technical scheme adopted by the invention is as follows:
an alpha-substituted azolidinone derivative has a structural formula as follows:
wherein R is 1 Is one of hydrogen, C1-C6 alkyl, halogen, C1-C6 alkoxy, cyano, aryl and nitro; r 2 Is one of hydrogen, aryl, nitro, halogen and alkyl; r 3 Is halogen or an ester group.
Preferably, R 3 When it is halogen, its structural formula is as follows:
wherein, X is one of chlorine, bromine and iodine.
Preferably, R 3 When it is an ester group, the structural formula is as followsShowing:
wherein R is 4 Is an alkyl or aryl group.
The invention also provides a synthesis method of the alpha-substituted azoleacetone derivative, which comprises the steps of taking an azoleacetone compound with a structural formula shown as (I) and sodium halide or organic acid as raw materials, taking copper salt as a metal catalyst, taking high-valence iodine as an oxidant, adding the raw materials into an organic solvent, carrying out post-treatment after the reaction to obtain the alpha-substituted azoleacetone derivative,
the synthetic route is as follows:
preferably, the molar ratio of the azole acetophenone compound to the sodium halide or the organic acid is 1:1 to 5.
Preferably, the copper salt is any one of cuprous iodide, cuprous bromide, cuprous oxide, cupric chloride, cupric oxide, cupric acetate, tetra (acetonitrile) copper tetrafluoroborate and cupric sulfate; the mol ratio of the azole acetophenone compound to the copper salt is 1:0.01 to 0.1.
Preferably, the oxidant is any one of iodobenzene diacetate, dichloroiodobenzene, iodosobenzene, iodobenzene bistrifluoroacetate and 2-iodoxybenzoic acid; the mol ratio of the azolidone compounds to the oxidant is 1:1 to 4.
Preferably, the organic solvent is any one of dichloromethane, 1,2-dichloroethane, ethyl acetate, ethanol, acetonitrile, N-dimethylformamide, tetrahydrofuran and dimethyl sulfoxide, and the mass ratio of the organic solvent to the azole acetophenone compound is 10-100: 1, the reaction time is 1-60 minutes.
Preferably, the post-treatment is: adding saturated sodium bicarbonate water solution to quench reaction, adding an organic extractant to extract and separate layers, drying an organic layer by anhydrous magnesium sulfate or anhydrous sodium sulfate, filtering, and purifying by a column to obtain light yellow solid alpha-substituted azolidone derivatives.
Preferably, the organic extractant is ethyl acetate or dichloromethane.
The invention has the beneficial effects that:
the invention takes cheap and easily obtained azolidone compounds and sodium halide or organic acid as raw materials, obtains a series of alpha-substituted (ester substituted or halogenated) azol acetophenones with high selectivity and high yield by C-H activation reaction under mild conditions, and the compounds are novel azol acetophenone derivatives and have better research and application values.
Detailed Description
The invention is further illustrated by the following examples, without limiting the scope of the invention. Those skilled in the art can and should understand that any simple changes or substitutions based on the spirit of the present invention should fall within the protection scope of the present invention.
Example 1
4-Chloropyrazoleacetophenone (2.20g, 10mmol), sodium chloride (1.16g, 20mmol), cuprous iodide (38mg, 0.2mmol) and iodobenzene bistrifluoroacetate (8.6g, 20mmol) were added to a reaction flask, and dichloromethane (50 g) was added thereto and dissolved, and the mixture was stirred at room temperature for 5 minutes. After the reaction is finished, adding saturated sodium bicarbonate aqueous solution (50 g) to quench the reaction, adding dichloromethane (50 g), fully stirring, standing for layering, drying an organic layer over anhydrous magnesium sulfate, filtering, and concentrating to obtain a brown crude product, and purifying the crude product by a column chromatography (eluent: ethyl acetate/petroleum ether =1:20, v/v) to obtain a light yellow solid target product, wherein the yield is 2.41g, and the melting point is 60-62 ℃. 1 H NMR(500MHz,CDCl 3 )δ8.03(dd,J＝8.3,1.0Hz,2H),7.96(s,1H),7.69–7.64(m,1H),7.55–7.51(m,3H),7.42(s,1H)；13C NMR(126MHz,CDCl3)δ186.18,139.76,134.90,132.34,129.26,129.19,128.52,113.48,69.43；HRMS(ESI+):Calculated for C 11 H 8 C l2 N 2 ONa:[M+Na] + 276.9911,Found 276.9918.
Example 2
Pyrazoloacetophenone (1.86g, 10 mmol), sodium chloride (1.16g, 20 mmol), cuprous iodide (38mg, 0.2 mmol) and iodobenzene bis (trifluoroacetic acid) (8.6g, 20 mmol) were put into a reaction flask, dissolved in dichloromethane (50 g), and reacted at room temperature for 5 minutes with stirring. After the reaction is finished, adding saturated sodium bicarbonate aqueous solution (50 g) to quench the reaction, adding dichloromethane (50 g), fully stirring, standing for layering, drying an organic layer by anhydrous magnesium sulfate, filtering and concentrating to obtain a brown crude product, and purifying the crude product by a column method (eluent: ethyl acetate/petroleum ether =1, 20, v/v) to obtain a light yellow solid target product, wherein the yield is 92 percent, and the melting point is 64-66 ℃. 1 H NMR(500MHz,CDCl 3 )δ8.02(dd,J＝8.4,1.1Hz,2H),7.92(d,J＝2.6Hz,1H),7.66–7.61(m,2H),7.57(s,1H),7.51(t,J＝7.8Hz,2H),6.46–6.43(m,1H)； 13 C NMR(126MHz,CDCl 3 )δ186.46,141.25,134.66,132.68,130.49,129.22,129.10,109.03,69.77；HRMS(ESI+):Calculated for C 11 H 9 ClN 2 ONa:[M+Na] + 243.0301,Found 243.0305.
Example 3
4-methylpyrazole acetophenone (2.00g, 10mmol), sodium chloride (1.16g, 20mmol), cuprous iodide (38mg, 0.2mmol) and iodobenzene bistrifluoroacetate (8.6g, 20mmol) were charged into a reaction flask, and dichloromethane (50 g) was added to dissolve them, and the reaction was stirred at room temperature for 5 minutes. After the reaction is finished, adding saturated waterThe reaction was quenched with aqueous sodium bicarbonate (50 g), dichloromethane (50 g) was added, the mixture was stirred well and allowed to stand for layering, the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to give a brown crude product, which was purified by column chromatography (eluent: ethyl acetate/petroleum ether =1, 20, v/v) to give 2.20g of the target product as a pale yellow solid, yield 94%, melting point 62-64 ℃. 1 H NMR(500MHz,CDCl 3 )δ7.78(dd,J＝8.4,1.1Hz,2H),7.50(s,1H),7.46(s,1H),7.42(d,J＝1.5Hz,1H),7.36(t,J＝7.9Hz,2H),6.04(s,1H),2.33(s,3H)；13C NMR(126MHz,CDCl3)δ184.45,140.41,139.35,133.11,132.24,128.00,127.92,107.74,72.15,10.46；HRMS(ESI+):Calculated for C 12 H 11 ClN 2 ONa:[M+Na] + 257.0458,Found257.0458.
Example 4
3,5-diphenylpyrazole acetophenone (3.38g, 10 mmol), sodium chloride (1.16g, 20 mmol), cuprous iodide (38mg, 0.2 mmol) and iodobenzene bistrifluoroacetate (8.6g, 20 mmol) were charged into a reaction flask, dissolved in dichloromethane (50 g), and the reaction was stirred at room temperature for 5 minutes. After the reaction is finished, adding saturated sodium bicarbonate aqueous solution (50 g) to quench the reaction, adding dichloromethane (50 g), fully stirring, standing for layering, drying an organic layer over anhydrous magnesium sulfate, filtering, and concentrating to obtain a brown crude product, and purifying the crude product by a column chromatography (eluent: ethyl acetate/petroleum ether =1:20, v/v) to obtain a light yellow solid target product, namely 3.57g, the yield is 96%, and the melting point is 82-84 ℃. 1 H NMR(500MHz,CDCl 3 )δ7.73(d,J＝7.2Hz,2H),7.69(d,J＝6.7Hz,2H),7.61–7.51(m,5H),7.45(t,J＝7.4Hz,1H),7.37–7.27(m,6H),6.68(s,1H)； 13 C NMR(126MHz,CDCl 3 )δ184.95,153.87,146.13,133.77,133.53,132.07,129.89,129.36,129.05,128.96,128.66,128.54,128.53,128.37,126.05,105.54,73.66；HRMS(ESI+):Calculated for C 23 H 17 ClN 2 ONa:[M+Na] + 395.0927,Found 395.0921.
Example 5
3,5-dimethyl-4-bromopyrazoleacetophenone (2.92g, 10mmol), sodium chloride (1.116g, 20mmol), cuprous iodide (38mg, 0.20mmol) and iodobenzene bistrifluoroacetate (8.6g, 20mmol) were added to a reaction bottle, and dichloromethane (50 g) was added to dissolve the mixture, and the mixture was stirred at room temperature for 5 minutes to react. After the reaction is finished, adding saturated sodium bicarbonate aqueous solution (50 g) to quench the reaction, adding dichloromethane (50 g), fully stirring, standing for layering, drying an organic layer over anhydrous magnesium sulfate, filtering, and concentrating to obtain a brown crude product, and purifying the crude product by a column chromatography (eluent: ethyl acetate/petroleum ether =1:20, v/v) to obtain a light yellow solid target product, wherein the yield is 2.96g, and the melting point is 72-74 ℃. 1 H NMR(500MHz,CDCl 3 )δ7.91–7.86(m,2H),7.59(t,J＝7.4Hz,1H),7.46(t,J＝7.8Hz,2H),7.41(s,1H),2.33(s,3H),2.19(s,3H)； 13 C NMR(126MHz,CDCl 3 )δ185.38,149.54,139.21,134.32,133.06,129.12,129.01,98.61,73.44,12.47,10.97；HRMS(ESI+):Calculated for C 13 H 12 BrClN 2 ONa:[M+Na] + 348.9719,Found 348.9724.
Example 6
4-chloropyrazoleacetophenone (2.20g, 10mmol), sodium bromide (2.04g, 20mmol), cuprous iodide (38mg, 0.2mmol) and iodobenzene bistrifluoroacetate (8.6g, 20mmol) were charged into a reaction flask, and dichloromethane (50 g) was added to dissolve them, and the reaction was stirred at room temperature for 5 minutes. After the reaction is finished, adding saturated sodium bicarbonate aqueous solution (50 g) to quench the reaction, adding dichloromethane (50 g), fully stirring, standing for layering, drying an organic layer over anhydrous magnesium sulfate, filtering, and concentrating to obtain a brown crude product, and purifying the crude product by a column chromatography (eluent: ethyl acetate/petroleum ether =1:20, v/v) to obtain a light yellow solid target product, wherein the yield is 2.70g, and the melting point is 68-72 ℃. 1 H NMR(500MHz,CDCl 3 )δ8.18(s,1H),8.08–8.02(m,2H),7.67(t,J＝7.4Hz,1H),7.62(s,1H),7.54(dd,J＝9.7,5.9Hz,3H)； 13 C NMR(126MHz,CDCl 3 )δ186.35,139.84,134.83,132.01,129.73,129.18,129.15,113.72,57.54；HRMS(ESI+):Calculated for C 11 H 8 IClN 2 ONa:[M+Na] + 320.9406,Found 320.9406.
Example 7
4-chloropyrazoleacetophenone (2.20g, 10mmol), sodium iodide (2.98g, 20mmol), cuprous iodide (38mg, 0.2mmol) and iodobenzene bistrifluoroacetate (8.6g, 20mmol) were charged into a reaction flask, and dichloromethane (50 g) was added to dissolve them, and the reaction was stirred at room temperature for 5 minutes. After the reaction is finished, adding saturated sodium bicarbonate aqueous solution (50 g) to quench the reaction, adding dichloromethane (50 g), fully stirring, standing for layering, drying an organic layer by anhydrous magnesium sulfate, filtering and concentrating to obtain a brown crude product, and purifying the crude product by a column method (eluent: ethyl acetate/petroleum ether =1, 20, v/v) to obtain a light yellow solid target product, wherein the yield is 3.10g, and the melting point is 68-72 ℃. 1 H NMR(500MHz,CDCl 3 )δ8.03(d,J＝7.4Hz,2H),7.96(s,1H),7.67(t,J＝7.4Hz,1H),7.57–7.50(m,3H),7.42(s,1H)； 13 C NMR(126MHz,CDCl 3 )δ186.18,139.76,134.91,132.34,129.26,129.19,128.52,113.48,69.41；HRMS(ESI+):Calculated for C 11 H 8 IClN 2 ONa:[M+Na] + 368.9268,Found 368.9268.
Example 8
4-Chloropyrazoleacetophenone (2.20g, 10mmol), sodium chloride (2.320g, 40mmol), cuprous iodide (38mg, 0.2mmol) and iodobenzene bistrifluoroacetate (17.2g, 40mmol) were added to a reaction flask, and dichloromethane (50 g) was added thereto to dissolve the mixture, and the reaction was stirred at room temperature for 10 minutesA clock. After the reaction is finished, adding saturated sodium bicarbonate aqueous solution (50 g) to quench the reaction, adding dichloromethane (50 g), fully stirring, standing for layering, drying an organic layer over anhydrous magnesium sulfate, filtering and concentrating to obtain a brown crude product, and purifying the crude product by a column chromatography method (eluent: ethyl acetate/petroleum ether =1:20, v/v) to obtain a light yellow solid, namely 2.62g of an alpha, alpha-dichloro target product, wherein the yield is 91%, and the melting point is 64-67 ℃. 1 H NMR(500MHz,CDCl 3 )δ8.20(d,J＝0.5Hz,1H),7.75(dd,J＝8.5,1.2Hz,2H),7.58–7.54(m,1H),7.52(s,1H),7.43–7.37(m,2H)； 13 C NMR(126MHz,CDCl 3 )δ180.87,141.19,134.00,130.73,130.47,128.54,127.08,114.43,94.11；HRMS(ESI+):Calculated for C 11 H 7 Cl 3 N 2 ONa:[M+Na] + 310.9522,Found310.9527.
Example 9
Experimental procedure for example 9 example 1 was repeated except that "the charge of sodium chloride was replaced by 10mmol so that the molar ratio of 4-chloropyrazoleacetophenone was 1: 1', the other operations were performed in the same manner as in example 1 to obtain 1.45g of the objective product as a pale yellow solid with a yield of 57%.
Example 10
Example 10 experimental procedure example 1 was repeated except for "replacing the dichloromethane reaction solvent with the same mass of the dimethylsulfoxide reaction solvent", and the other procedures as in example 1 gave 2.26g of the objective product as a pale yellow solid with a yield of 89%.
Example 11
EXAMPLE 11 Experimental procedure example 1 was repeated except for "changing the reaction time from 5 minutes to 10 minutes" and the other operations were the same as in example 1 to finally obtain 2.24g of the objective product as a pale yellow solid with a yield of 88%.
The novel alpha-halogenated azole acetophenone derivative obtained by the embodiment of the invention has potential application prospects in the fields of pharmaceutical chemicals, materials, dyes and the like.
Example 12
4-Chloropyrazoleacetophenone (2.20g, 10mmol), acetic acid (1.20g, 20mmol), cuprous oxide (28mg, 0.2mmol) and iodobenzene diacetate (6.4g, 20mmol) were charged into a reaction flask, and methylene chloride (50 g) was added thereto to dissolve them, and the reaction mixture was stirred at room temperature for 10 minutes. After the reaction is finished, adding saturated sodium bicarbonate aqueous solution (50 g) to quench the reaction, adding dichloromethane (50 g), fully stirring, standing for layering, drying an organic layer over anhydrous magnesium sulfate, filtering, concentrating to obtain a brown crude product, and purifying the crude product by a column chromatography method (eluent: ethyl acetate/petroleum ether =1:20, v/v) to obtain a light yellow solid target product, wherein the yield is 2.64g, and the melting point is 75-78 ℃. 1 H NMR(500MHz,CDCl 3 )δ7.91(dd,J＝8.4,1.1Hz,2H),7.70(s,1H),7.63(s,1H),7.61–7.57(m,1H),7.54(s,1H),7.47–7.44(m,2H),2.22(s,3H)； 13 C NMR(126MHz,CDCl 3 )δ187.26,169.36,140.32,134.57,133.13,129.05,128.80,127.66,113.01,81.53,20.54；HRMS(ESI+):Calculated for C 13 H 11 ClN 2 O 3 Na:[M+Na] + 301.0356,Found301.0356.
Example 13
Pyrazoleacetophenone (1.86g, 10mmol), acetic acid (1.20g, 20mmol), cuprous oxide (28mg, 0.2mmol) and iodobenzene diacetate (6.4g, 20mmol) were put into a reaction flask, and dichloromethane (50 g) was added thereto to dissolve them, followed by reaction for 10 minutes with stirring at room temperature. After the reaction is finished, adding saturated sodium bicarbonate aqueous solution (50 g) to quench the reaction, adding dichloromethane (50 g), fully stirring, standing for layering, drying an organic layer over anhydrous magnesium sulfate, filtering, and concentrating to obtain a brown crude product, and purifying the crude product by a column chromatography (eluent: ethyl acetate/petroleum ether =1:20, v/v) to obtain a light yellow solid target product, wherein the yield is 2.48g, and the melting point is 74-76 ℃. 1 H NMR(500MHz,CDCl 3 )δ7.89(dd,J＝8.4,1.1Hz,2H),7.78(s,1H),7.63(d,J＝1.6Hz,1H),7.62(d,J＝2.5Hz,1H),7.57(t,J＝7.4Hz,1H),7.43(t,J＝7.9Hz,2H),6.38–6.34(m,1H),2.22(s,3H)； 13 C NMR(126MHz,CDCl 3 )δ187.61,169.59,141.84,134.31,133.36,129.84,128.92,128.75,108.35,99.99,81.54,20.60；HRMS(ESI+):Calculated for C 16 H 18 N 2 O 2 Na:[M+Na] + 293.1260,Found 293.1264.
Example 14
3,5-dimethyl-4-bromopyrazolylacetophenone (2.92g, 10mmol), acetic acid (1.20g, 20mmol), cuprous oxide (28mg, 0.2mmol) and iodobenzene diacetate (6.4g, 20mmol) were charged into a reaction flask, and dichloromethane (50 g) was added to dissolve them, and the reaction was stirred at room temperature for 10 minutes. After the reaction is finished, adding saturated sodium bicarbonate aqueous solution (50 g) to quench the reaction, adding dichloromethane (50 g), fully stirring, standing for layering, drying an organic layer over anhydrous magnesium sulfate, filtering, and concentrating to obtain a brown crude product, and purifying the crude product by a column chromatography (eluent: ethyl acetate/petroleum ether =1:20, v/v) to obtain a light yellow solid target product, wherein the yield is 91%, and the melting point is 92-94 ℃. 1 H NMR(500MHz,CDCl 3 )δ7.84–7.78(m,2H),7.63(s,1H),7.56(t,J＝7.4Hz,1H),7.42(t,J＝7.8Hz,2H),2.30(s,3H),2.24(s,3H),2.17(s,3H)； 13 C NMR(126MHz,CDCl 3 )δ187.21,169.40,149.37,138.85,134.08,133.50,128.89,128.72,97.71,81.01,20.62,12.46,10.41；HRMS(ESI+):Calculated for C 15 H 15 BrN 2 O 3 Na:[M+Na] + 373.0164,Found 373.0157.
Example 15
4-chloropyrazole-4-methylacetophenone (2.34g, 10 mmol), acetic acid (1.20g, 20 mmol), cuprous oxide (28mg, 0.2mmol) and iodobenzene diacetate (6.4g, 20 mmol) were charged into a reaction flask, and dichloromethane (50 g) was added to dissolve the mixture to obtain a solutionThe reaction was stirred at room temperature for 10 minutes. After the reaction is finished, adding saturated sodium bicarbonate aqueous solution (50 g) to quench the reaction, adding dichloromethane (50 g), fully stirring, standing for layering, drying an organic layer over anhydrous magnesium sulfate, filtering, concentrating to obtain a brown crude product, and purifying the crude product by a column chromatography method (eluent: ethyl acetate/petroleum ether =1:20, v/v) to obtain a light yellow solid target product, namely 2.77g, the yield is 95%, and the melting point is 92-94 ℃. 1 H NMR(500MHz,CDCl 3 )δ7.81(d,J＝8.2Hz,2H),7.69(s,1H),7.62(s,1H),7.53(s,1H),7.25(d,J＝8.1Hz,2H),2.40(s,3H),2.21(s,3H)； 13 C NMR(126MHz,CDCl 3 )δ186.79,169.35,145.86,140.21,130.59,129.76,128.93,127.61,112.91,81.51,21.83,20.56；HRMS(ESI+):Calculated for C 14 H 13 ClN 2 O 3 Na:[M+Na] + 315.0512,Found315.0518.
Example 16
4-chloropyrazole-4-methoxyacetophenone (2.50g, 10 mmol), acetic acid (1.20g, 20 mmol), cuprous oxide (28mg, 0.2mmol) and iodobenzene diacetate (6.4g, 20 mmol) were charged into a reaction flask, and dichloromethane (50 g) was added to dissolve them, followed by reaction for 10 minutes under stirring at room temperature. After the reaction is finished, adding saturated sodium bicarbonate aqueous solution (50 g) to quench the reaction, adding dichloromethane (50 g), fully stirring, standing for layering, drying an organic layer over anhydrous magnesium sulfate, filtering, concentrating to obtain a brown crude product, and purifying the crude product by a column chromatography method (eluent: ethyl acetate/petroleum ether =1:20, v/v) to obtain a light yellow solid target product, wherein the yield is 2.99g, and the melting point is 88-92 ℃. 1 H NMR(500MHz,CDCl 3 )δ7.91(d,J＝9.0Hz,2H),7.67(s,1H),7.61(s,1H),7.54(s,1H),6.92(d,J＝9.0Hz,2H),3.86(s,3H),2.21(s,3H)； 13 C NMR(126MHz,CDCl 3 )δ185.64,169.35,164.67,140.14,131.34,127.55,125.97,114.34,112.87,81.48,55.62,20.57；HRMS(ESI+):Calculated for C 14 H 13 ClN 2 O 4 Na:[M+Na] + 331.0462,Found 331.0462.
Example 17
4-chloropyrazole-2-methylacetophenone (2.34g, 10 mmol), acetic acid (1.20g, 20mmol), cuprous oxide (28mg, 0.2mmol) and iodobenzene diacetate (6.4g, 20mmol) were charged into a reaction flask, and methylene chloride (50 g) was added thereto to dissolve them, and the reaction was stirred at room temperature for 10 minutes. After the reaction is finished, adding saturated sodium bicarbonate aqueous solution (50 g) to quench the reaction, adding dichloromethane (50 g), fully stirring, standing for layering, drying an organic layer over anhydrous magnesium sulfate, filtering and concentrating to obtain a brown crude product, and purifying the crude product by a column chromatography method (eluent: ethyl acetate/petroleum ether =1:20, v/v) to obtain a light yellow solid, namely 2.80g of an alpha, alpha-dichloro target product, wherein the yield is 96 percent, and the melting point is 64-67 ℃. 1 H NMR(500MHz,CDCl 3 )δ7.64–7.58(m,2H),7.55(s,1H),7.50(s,1H),7.40(t,J＝7.5Hz,1H),7.29–7.26(m,1H),7.23(t,J＝7.6Hz,1H),2.54(s,3H),2.20(s,3H)； 13 C NMR(126MHz,CDCl 3 )δ189.95,169.51,140.53,140.30,133.18,132.81,132.43,128.45,127.82,125.87,112.73,82.25,21.28,20.52；HRMS(ESI+):Calculated for C 14 H 13 ClN 2 O 3 Na:[M+Na] + 315.0512,Found 315.0518.
Example 18
Experimental procedure for example 18 example 12 was repeated with the only difference that "the charge of acetic acid was replaced by 10mmol each, so that the molar ratio of 4-chloropyrazoleacetophenone was 1: 1', the other operations were performed in the same manner as in example 12 to obtain 2.09g of the objective product as a pale yellow solid with a yield of 75%.
Example 19
EXAMPLE 19 Experimental procedure example 12 was repeated except that "cuprous iodide was replaced with cupric chloride" and other operations were the same as in example 12 to finally obtain 2.50g of a pale yellow solid as a target product with a yield of 90%.
The novel alpha-ester substituted azole acetophenone derivative obtained by the embodiment of the invention has potential application prospects in the fields of pharmaceutical chemicals, materials, dyes and the like.
It should be noted that the present disclosure is only illustrative of the implementation of the inventive concept and the scope of the present disclosure should not be considered as being limited to the specific forms set forth in the examples. It will be apparent to those skilled in the art that various changes and modifications can be made without departing from the spirit and scope of the invention.
Claims (10)
1. An alpha-substituted azoleacetone derivative is characterized in that the structural formula is as follows:
wherein R is 1 Is one of hydrogen, C1-C6 alkyl, halogen, C1-C6 alkoxy, cyano, aryl and nitro; r 2 Is one of hydrogen, aryl, nitro, halogen and alkyl; r 3 Is halogen or an ester group.
2. The α -substituted azolobenzophenone derivative according to claim 1, wherein: r 3 When the halogen is contained, the structural formula is as follows:
wherein, X is one of chlorine, bromine and iodine.
3. The α -substituted azolobenzophenone derivative according to claim 1, wherein: r 3 When the ester group is used, the structural formula is shown as follows:
wherein R is 4 Is an alkyl or aryl group.
4. The method for synthesizing the α -substituted azolidinone derivative according to claim 1, wherein: taking azole acetophenone compounds with a structural formula shown in (I) and sodium halide or organic acid as raw materials, copper salt as a metal catalyst, high-valence iodine as an oxidant, adding into an organic solvent, carrying out post-treatment after the reaction to obtain alpha-substituted azole acetophenone derivatives,
5. the method for synthesizing the alpha-substituted azolobenzophenone derivative according to claim 4, wherein the method comprises the following steps: the mol ratio of the azole acetophenone compound to the sodium halide or the organic acid is 1:1 to 5.
6. The method for synthesizing the α -substituted azolobenzophenone derivative according to claim 4, wherein: the copper salt is any one of cuprous iodide, cuprous bromide, cuprous oxide, cupric chloride, cupric oxide, cupric acetate, tetra (acetonitrile) copper tetrafluoroborate and cupric sulfate; the mol ratio of the azole acetophenone compound to the copper salt is 1:0.01 to 0.1.
7. The method for synthesizing the α -substituted azolobenzophenone derivative according to claim 4, wherein: the oxidant is any one of iodobenzene diacetate, dichloroiodobenzene, iodosobenzene, iodobenzene bistrifluoroacetate and 2-iodoxybenzoic acid; the mol ratio of the azolidone compounds to the oxidant is 1:1 to 4.
8. The method for synthesizing the alpha-substituted azolobenzophenone derivative according to claim 4, wherein the method comprises the following steps: the organic solvent is any one of dichloromethane, 1,2-dichloroethane, ethyl acetate, ethanol, acetonitrile, N-dimethylformamide, tetrahydrofuran and dimethyl sulfoxide, and the mass ratio of the organic solvent to the azole acetophenone compound is 10-100: 1, the reaction time is 1-60 minutes.
9. The method for synthesizing the alpha-substituted azolobenzophenone derivative according to claim 4, wherein the post-treatment comprises: adding saturated sodium bicarbonate water solution to quench reaction, adding an organic extractant to extract and separate layers, drying an organic layer by anhydrous magnesium sulfate or anhydrous sodium sulfate, filtering, and purifying by a column to obtain light yellow solid alpha-substituted azolidone derivatives.
10. The method for synthesizing the α -substituted azolobenzophenone derivative according to claim 9, wherein: the organic extractant is ethyl acetate or dichloromethane.
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