CN111518117B - 1, 2-oxazinopyran compound and preparation method and application thereof - Google Patents
1, 2-oxazinopyran compound and preparation method and application thereof Download PDFInfo
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- CN111518117B CN111518117B CN202010524969.4A CN202010524969A CN111518117B CN 111518117 B CN111518117 B CN 111518117B CN 202010524969 A CN202010524969 A CN 202010524969A CN 111518117 B CN111518117 B CN 111518117B
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- dihydrochromone
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 50
- 238000002360 preparation method Methods 0.000 title abstract description 41
- 238000006243 chemical reaction Methods 0.000 claims abstract description 59
- -1 1, 2-oxazine pyran compound Chemical class 0.000 claims abstract description 45
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims abstract description 18
- 238000006146 oximation reaction Methods 0.000 claims abstract description 12
- 239000003054 catalyst Substances 0.000 claims abstract description 11
- 239000003446 ligand Substances 0.000 claims abstract description 6
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 6
- 150000002576 ketones Chemical class 0.000 claims abstract description 5
- 125000005646 oximino group Chemical group 0.000 claims abstract description 3
- 239000000047 product Substances 0.000 claims description 20
- UEXCJVNBTNXOEH-UHFFFAOYSA-N Ethynylbenzene Chemical group C#CC1=CC=CC=C1 UEXCJVNBTNXOEH-UHFFFAOYSA-N 0.000 claims description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- 238000003756 stirring Methods 0.000 claims description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- MSTDXOZUKAQDRL-UHFFFAOYSA-N 4-Chromanone Chemical compound C1=CC=C2C(=O)CCOC2=C1 MSTDXOZUKAQDRL-UHFFFAOYSA-N 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 9
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- ZPSJGADGUYYRKE-UHFFFAOYSA-N 2H-pyran-2-one Chemical compound O=C1C=CC=CO1 ZPSJGADGUYYRKE-UHFFFAOYSA-N 0.000 claims description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- 125000000304 alkynyl group Chemical group 0.000 claims description 6
- 238000004440 column chromatography Methods 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 5
- 238000005893 bromination reaction Methods 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 4
- 239000012043 crude product Substances 0.000 claims description 4
- 239000002994 raw material Substances 0.000 claims description 4
- 239000001632 sodium acetate Substances 0.000 claims description 4
- 235000017281 sodium acetate Nutrition 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- QXSWHQGIEKUBAS-UHFFFAOYSA-N 1-ethynyl-4-fluorobenzene Chemical group FC1=CC=C(C#C)C=C1 QXSWHQGIEKUBAS-UHFFFAOYSA-N 0.000 claims description 3
- KBIAVTUACPKPFJ-UHFFFAOYSA-N 1-ethynyl-4-methoxybenzene Chemical group COC1=CC=C(C#C)C=C1 KBIAVTUACPKPFJ-UHFFFAOYSA-N 0.000 claims description 3
- LWISLHRIEATKTM-UHFFFAOYSA-N 2-Ethynylthiophene Chemical compound C#CC1=CC=CS1 LWISLHRIEATKTM-UHFFFAOYSA-N 0.000 claims description 3
- KNTMEDNZPJADJU-UHFFFAOYSA-N 3,4-dihydro-2h-1-benzoxepin-5-one Chemical compound O=C1CCCOC2=CC=CC=C12 KNTMEDNZPJADJU-UHFFFAOYSA-N 0.000 claims description 3
- WRBICKOJBASGMC-UHFFFAOYSA-N 4-ethynylquinoline Chemical compound C1=CC=C2C(C#C)=CC=NC2=C1 WRBICKOJBASGMC-UHFFFAOYSA-N 0.000 claims description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 3
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical class [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
- 235000019441 ethanol Nutrition 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 239000005457 ice water Substances 0.000 claims description 3
- 239000011261 inert gas Substances 0.000 claims description 3
- 230000004224 protection Effects 0.000 claims description 3
- 238000010791 quenching Methods 0.000 claims description 3
- 230000000171 quenching effect Effects 0.000 claims description 3
- 238000004809 thin layer chromatography Methods 0.000 claims description 3
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical compound C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- GAZZTEJDUGESGQ-UHFFFAOYSA-N 1-ethynyl-4-nitrobenzene Chemical group [O-][N+](=O)C1=CC=C(C#C)C=C1 GAZZTEJDUGESGQ-UHFFFAOYSA-N 0.000 claims description 2
- CLRPXACRDTXENY-UHFFFAOYSA-N 3-ethynylpyridine Chemical compound C#CC1=CC=CN=C1 CLRPXACRDTXENY-UHFFFAOYSA-N 0.000 claims description 2
- KSZVOXHGCKKOLL-UHFFFAOYSA-N 4-Ethynyltoluene Chemical group CC1=CC=C(C#C)C=C1 KSZVOXHGCKKOLL-UHFFFAOYSA-N 0.000 claims description 2
- CZDQPKDUJDKJRF-UHFFFAOYSA-N 7-methoxy-3,4-dihydro-2h-1-benzoxepin-5-one Chemical compound O1CCCC(=O)C2=CC(OC)=CC=C21 CZDQPKDUJDKJRF-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 230000003211 malignant effect Effects 0.000 claims description 2
- NPTDXPDGUHAFKC-UHFFFAOYSA-N ethynylcyclopropane Chemical compound C#CC1CC1 NPTDXPDGUHAFKC-UHFFFAOYSA-N 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- 229920006395 saturated elastomer Polymers 0.000 claims 1
- 241000209140 Triticum Species 0.000 abstract description 19
- 235000021307 Triticum Nutrition 0.000 abstract description 19
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 8
- 241000221785 Erysiphales Species 0.000 abstract description 6
- 238000005905 alkynylation reaction Methods 0.000 abstract description 2
- 230000004071 biological effect Effects 0.000 abstract description 2
- 201000010099 disease Diseases 0.000 abstract description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 2
- 239000000758 substrate Substances 0.000 abstract description 2
- 238000006555 catalytic reaction Methods 0.000 abstract 1
- 229940125782 compound 2 Drugs 0.000 description 29
- 230000000052 comparative effect Effects 0.000 description 27
- 239000011734 sodium Substances 0.000 description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 206010039509 Scab Diseases 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000001963 growth medium Substances 0.000 description 3
- 238000005580 one pot reaction Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 2
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000009036 growth inhibition Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 125000003544 oxime group Chemical group 0.000 description 2
- QRUBYZBWAOOHSV-UHFFFAOYSA-M silver trifluoromethanesulfonate Chemical compound [Ag+].[O-]S(=O)(=O)C(F)(F)F QRUBYZBWAOOHSV-UHFFFAOYSA-M 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- HPVXVIOTJPAXOH-UHFFFAOYSA-N 2-bromo-2H-pyran Chemical compound BrC1OC=CC=C1 HPVXVIOTJPAXOH-UHFFFAOYSA-N 0.000 description 1
- 241000223602 Alternaria alternata Species 0.000 description 1
- KYNSBQPICQTCGU-UHFFFAOYSA-N Benzopyrane Chemical compound C1=CC=C2C=CCOC2=C1 KYNSBQPICQTCGU-UHFFFAOYSA-N 0.000 description 1
- 241000123650 Botrytis cinerea Species 0.000 description 1
- VMQMZMRVKUZKQL-UHFFFAOYSA-N Cu+ Chemical compound [Cu+] VMQMZMRVKUZKQL-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 1
- 241000233614 Phytophthora Species 0.000 description 1
- 241000221696 Sclerotinia sclerotiorum Species 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000002300 anti-fibrosis Effects 0.000 description 1
- 230000002236 anti-hypertrophic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 239000003899 bactericide agent Substances 0.000 description 1
- 150000005130 benzoxazines Chemical class 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- HZAIHFIZXXSPFA-UHFFFAOYSA-N ethynylcyclopropane Chemical compound [C+]#CC1CC1 HZAIHFIZXXSPFA-UHFFFAOYSA-N 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000036543 hypotension Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004112 neuroprotection Effects 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 231100000241 scar Toxicity 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N55/00—Biocides, pest repellants or attractants, or plant growth regulators, containing organic compounds containing elements other than carbon, hydrogen, halogen, oxygen, nitrogen and sulfur
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
- C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
- C07F7/0814—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring said ring is substituted at a C ring atom by Si
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/0825—Preparations of compounds not comprising Si-Si or Si-cyano linkages
- C07F7/083—Syntheses without formation of a Si-C bond
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Dentistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Plant Pathology (AREA)
- General Health & Medical Sciences (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Environmental Sciences (AREA)
- Pest Control & Pesticides (AREA)
- Agronomy & Crop Science (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a 1, 2-oxazine pyran compound and a preparation method thereof, the compound takes a pyrone compound as a substrate, brominating reaction is carried out on alpha-site of ketone, the pyrone compound reacts with hydroxylamine hydrochloride to generate oximation product, finally, the oximation product is subjected to alkynylation reaction with alkynyl compound and cyclization reaction with oximino to obtain the 1, 2-oxazine pyran compound, and Pd (OAc) is used for the reaction 2 The yield of the 1, 2-oxazinopyran compound obtained by the co-catalysis of the catalyst/CuI is up to 94% by taking X-PHOS as a ligand, and the prepared oxazinopyran compound has good bactericidal activity on wheat gibberellic disease, wheat powdery mildew and wheat root rot, and has application potential in the aspect of agricultural biological activity.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a 1, 2-oxazinopyran compound, and a preparation method and application thereof.
Background
The benzopyran compound has the characteristics of anti-inflammatory activity, anti-fibrosis activity and anti-hypertrophic scar activity, has potential kidney retention capacity, and reduces the possibility of hypertension caused by the structural, pharmacological and physiological properties in the benzopyran compound, so the benzopyran compound has great significance for development.
Benzoxazine compounds also show medical activity as heterocyclic compounds, and are mainly used for rheumatism, hypotension, neuroprotection, thrombosis resistance, sterilization and the like, and the invention patent CN102408390B reports N-substituted-3, 4-dihydro-1, 4-benzoxazine compounds with bactericidal activity, and researches the bactericidal activity of the compounds on gibberellic disease, phytophthora blight, alternaria alternate, botrytis cinerea and sclerotinia sclerotiorum.
The invention aims to develop a method for generating a benzopyran oxazine compound, namely a 1, 2-oxazine pyran compound, by reacting a bromo-pyran oximation product with an alkynyl compound in a one-pot method, and research the bactericidal activity of the benzopyran oximation product on wheat scab, wheat powdery mildew and wheat root rot.
Disclosure of Invention
The invention aims to provide a 1, 2-oxazinopyran compound, a preparation method thereof and a research on bactericidal activity in wheat scab and wheat powdery mildew.
The 1, 2-oxazine pyran compound has the following structural formula:
1, 2-oxazinopyran compounds, which comprises the product obtained by the following method:
a, (1) the alpha-position of ketone in the pyrone compound is subjected to bromination reaction, and the bromopyrone compound reacts with hydroxylamine hydrochloride to generate an oximation product;
(2) carrying out an ethynylation reaction on bromine and an alkynyl compound of an oximation product, and then carrying out a ring-forming reaction on the product and an oximino group to obtain a 1, 2-oxazine pyran compound;
or
B, (1) carrying out bromination reaction on alpha-site of ketone in the pyrone compound, and carrying out ethynylation reaction on the bromopyrone compound and an alkynyl compound to obtain a pyrone ethynylation product;
(2) and (3) performing oximation reaction on carbonyl in the alkynyl product, and then directly performing ring formation with alkynyl to generate the 1, 2-oxazine pyran compound.
Preferably, the pyrone compound is 2, 3-dihydrobenzopyran-4-one, 6-methyl-4-dihydrochromone, 6-ethyl-4-dihydrochromone, 8-methyl-4-dihydrochromone, 6, 8-dimethyl-4-dihydrochromone, 7-methoxy-6-methyl-4-dihydrochromone, 7-methoxy-4-dihydrochromone, 8-tert-butyl-4-dihydrochromone, 6-benzyloxy-4-dihydrochromone, 3, 4-dihydro-2H-benzoxepin-5-one, 7-methoxy-3, 4-dihydro-2H-benzoxepin-5-one, or a mixture thereof, 2, 3-dihydro-4H-naphthopyran-4-one, 2-phenyl-4-dihydrochromone;
preferably, the alkynyl compound is phenylacetylene, 4-methoxyphenylacetylene, 4-methylphenylacetylene, 4-fluorophenylacetylene, 4-nitrophenylacetylene, 5-ethynyl-1, 3-benzodioxazole, 3-ethynylpyridine, 4-ethynylquinoline, 2-ethynylthiophene, ethynylcyclopropane, ethynyltrimethylsilane.
The preparation method of the 1, 2-oxazine pyran compound comprises the following steps:
firstly, dissolving pyrone raw material A in anhydrous ether, and stirring the solution Br at 0 DEG C 2 Added dropwise to the solution, after whichGradually heating to room temperature, continuously stirring for 3-4h, quenching the reaction by using saturated sodium bisulfite after the reaction is finished, extracting by using ethyl acetate, washing by using saturated saline solution, drying by using anhydrous sodium sulfate, and separating and purifying a crude product after decompression and concentration by using column chromatography to obtain a compound B;
dissolving the compound B in an absolute ethyl alcohol solution, adding an ethyl alcohol solution of sodium acetate and hydroxylamine hydrochloride into an ice water bath, gradually heating to room temperature, stirring for reaction for 1-3 hours, adding water to stop the reaction after the reaction is finished, extracting with ethyl acetate, drying with anhydrous sodium sulfate, concentrating under reduced pressure, drying, crystallizing and purifying to obtain a compound C;
dissolving a catalyst and a ligand in a solvent under the protection of inert gas, stirring for reaction for 1-2h, then adding a compound C, an alkynyl compound and alkali into a reaction solution, stirring for reaction for 12-20h at 60-100 ℃, detecting by TLC (thin layer chromatography), filtering by using kieselguhr after the reaction is finished, concentrating under reduced pressure, and separating and purifying by using column chromatography to obtain the 1, 2-oxazine pyran compound.
Preferably, the molar mass ratio of the pyrone raw material A to the liquid bromine in the first step is 1: 0.8-0.9;
preferably, the molar mass ratio of the compound B to the hydroxylamine hydrochloride and the sodium acetate in the step two is 1:1.5-2.0: 1.5-2.0;
preferably, the benign and malignant solvents used for crystallizing the compound C in the step two are dichloromethane and n-hexane respectively;
preferably, the molar mass ratio of the compound C to the alkynyl compound, the catalyst, the ligand and the base in the third step is 1.2-1.5: 1.0:0.15-0.25:0.05-0.10: 1.5-2.0; the catalyst in the third step is Pd (OAc) 2 CuI, the ratio is 2-4: 1; the ligand is X-PHOS, the alkali is cesium carbonate, and the solvent is anhydrous tetrahydrofuran.
The general formula of the synthetic reaction of the 1, 2-oxazine pyran compound is as follows:
the method comprises the steps of taking a pyrone compound as a substrate, reacting a brominated product obtained by bromination of carbonyl a-H with hydroxylamine hydrochloride to obtain an oximation product, carrying out an ethynylation reaction on the oximation product under the action of a mixed catalyst, forming a complex by alkynyl and metal in the alkynylation product, attacking alkynyl by nucleophilic group hydroxyl in an oxime group to form a cyclization intermediate, and then removing protons to obtain a target product.
Compared with the prior art, the invention has the following advantages:
1. when the 1, 2-oxazine pyran compound is prepared, the one-pot method is adopted to ensure that the bromo-compound is subjected to an ethynylation reaction and then directly subjected to a ring-forming reaction with an oxime group to obtain a target product, and the yield of the one-pot reaction is up to 94%.
2. The 1, 2-oxazine pyran compound prepared by the invention has good bactericidal activity to wheat scab, wheat powdery mildew and wheat root rot.
Detailed Description
The technical solutions of the present invention are further described in detail with reference to specific examples so that those skilled in the art can better understand the present invention and can implement the present invention, but the examples are not intended to limit the present invention.
The invention relates to a 1, 2-oxazine pyran compound, the structural formula of which is as follows:
example 1
Preparation of compound 2 a:
40mmol of 2, 3-dihydrobenzopyran-4-one are dissolved in 150mL of anhydrous diethyl ether, and 2mL of solution Br are added with stirring at 0 DEG C 2 Slowly adding the mixture dropwise into the solution, gradually increasing to room temperature, continuously stirring for 3-4h, quenching the reaction by using saturated sodium bisulfite after the reaction is finished until the reaction solution turns clear from brown, extracting by using ethyl acetate, washing by using saturated saline solution, drying by using anhydrous sodium sulfate, and separating and purifying a crude product after decompression concentration by using column chromatography to obtain a compound B; dissolving 10mmol of compound B in anhydrous ethanol solution, adding 15mmol of vinegar in ice water bathReacting sodium acid and 15mmol of ethanol solution of hydroxylamine hydrochloride, gradually raising the temperature to room temperature, continuously stirring for 2 hours, cooling to room temperature after the reaction is finished, adding water to stop the reaction, extracting with EA, drying with anhydrous sodium sulfate, concentrating under reduced pressure, drying, and crystallizing a crude product with dichloromethane and n-hexane to obtain a pure compound C; under the protection of inert gas, 0.6mmol Pd (OAc) 2 dissolving/CuI (3:1) and 0.2mmol X-PHOS in anhydrous tetrahydrofuran, stirring for reaction for 1-2h, adding 4.8mmol compound C, 4mmol phenylacetylene and 6mmol cesium carbonate into the reaction solution, stirring for reaction for 15h at 80 ℃, detecting by TLC, filtering with diatomite after the reaction is finished, concentrating under reduced pressure, and separating and purifying by column chromatography to obtain the target product 1, 2-oxazinopyran compound.
The structural formula of the target compound obtained by the reaction is characterized as follows:
Analytical data:yield:88％； 1 H NMR(400MHz,CDCl3)δ7.38–7.06(m,9H),5.63(d,J＝ 4.9Hz,1H),4.34(m,1H),4.13–4.05(m,1H),3.89–3.81(m,1H). 13 C NMR(101MHz,CDCl3) δ174.53,173.29,158.53,134.17,132.12,129.93,129.58,128.22,127.02,122.44,119.94,119.65, 100.89,70.70,32.39.HRMS(ESI):calcd for C 17 H 13 NNaO 2 + [M+Na] + 286.0838,found 286.0841.
example 2
Preparation of compound 2 b:
the 2, 3-dihydrobenzopyran-4-one in example 1 was changed to 6-methyl-4-dihydrochromone, and the remaining compounds were unchanged, the specific preparation method being referred to that of compound 2 a.
The structural formula of the target compound obtained by the reaction is characterized as follows:
Analytical data:yield:85％； 1 H NMR(400MHz,CDCl 3 )δ7.10(m,2H),7.05–6.92(m,5H), 6.78(d,J＝1.2Hz,1H),5.48(d,J＝4.9Hz,1H),4.22–4.16(m,1H),3.94(m,1H),3.70(m,1H), 2.13(s,3H). 13 C NMR(100MHz,CDCl 3 )δ174.72,173.08,154.93,133.57,131.91,130.59, 129.72,129.37,128.59,126.81,120.03,118.22,100.68,70.49,32.18,21.45.HRMS(ESI):calcd for C 18 H 15 NNaO 2 + [M+Na] + 300.0995,found.300.0998.
example 3
Preparation of compound 2 d:
the 2, 3-dihydrobenzopyran-4-one in example 1 was replaced with 6-chloro-4-dihydrochromone, and the remaining compounds were unchanged, the specific preparation method being referred to that of compound 2 a.
The structural formula of the target compound obtained by the reaction is characterized as follows:
Analytical data:yield:73％； 1 H NMR(400MHz,CDCl3)δ7.09(dd,J＝6.0,1.2Hz,1H), 7.01(m,2H),6.98–6.84(m,5H),5.39(d,J＝5.4Hz,1H),4.11–4.06(m,1H),3.85(m,1H),3.61 (m,1H). 13 C NMR(100MHz,CDCl3)δ172.97,171.33,153.92,131.72,130.16,127.97,127.62, 125.52,125.13,125.06,118.60,118.51,98.93,68.74,30.43.HRMS(ESI):calcd for C 17 H 21 ClNNaO 2 + [M+Na] + 320.0449,found.320.0447.
example 4
Preparation of compound 2 e:
the 2, 3-dihydrobenzopyran-4-one in example 1 was replaced with 6-benzyloxy-4-dihydrochromone, and the remaining compounds were not changed, and the specific preparation method was according to the preparation method of compound 2 a.
The structural formula of the target compound obtained by the reaction is characterized as follows:
Analytical data:yield:81％； 1 H NMR(400MHz,CDCl 3 )δ7.33–7.12(m,11H),7.05(m, 1H),6.83(d,J＝1.8Hz,1H),5.69(d,J＝4.6Hz,1H),5.18(s,2H),4.40(m,1H),4.13(m,1H), 3.89(m,1H). 13 C NMR(100MHz,CDCl 3 )δ174.77,173.13,154.25,153.07,137.39,131.97, 129.78,129.42,129.42,128.62,128.62,128.47,128.47,128.46,126.86,126.86,123.37,122.65, 119.02,112.30,100.73,71.14,70.55,32.24.HRMS(ESI):calcd for C 24 H 19 NNaO 3 + [M+Na] + 392.1257,found.392.1260.
example 5
Preparation of compound 2 h:
the 2, 3-dihydrobenzopyran-4-one in example 1 was changed to 7-methoxy-6-methyl-4-dihydrochromone, and the remaining compounds were not changed, and the specific preparation method was according to the preparation method of compound 2 a.
The structural formula of the target compound obtained by the reaction is characterized as follows:
Analytical data:yield:87％； 1 H NMR(400MHz,CDCl 3 )δ7.32(dd,J＝7.2,1.1Hz,2H), 7.29–7.13(m,3H),6.91(s,1H),6.62(s,1H),5.71(d,J＝4.9Hz,1H),4.41(m,1H),4.16(m,1H), 3.92(m,1H),3.82(s,3H),2.27(s,3H). 13 C NMR(100MHz,CDCl 3 )δ175.03,173.39,162.57, 155.03,132.22,131.27,130.03,129.68,127.12,123.97,113.11,100.99,97.87,70.80,57.34,32.49, 16.55.HRMS(ESI):calcd for C 19 H 17 NNaO 3 + [M+Na] + 330.1101,found.330.1104.
example 6
Preparation of compound 2 j:
the 2, 3-dihydrobenzopyran-4-one in example 1 was replaced with 8-tert-butyl-4-dihydrochromone, and the remaining compounds were unchanged, the specific preparation method being referred to that of compound 2 a.
The structural formula of the target compound obtained by the reaction is characterized as follows:
Analytical data:yield:80％； 1 H NMR(400MHz,CDCl 3 )δ7.38–7.16(m,8H),5.72(d,J＝ 6.0Hz,1H),4.45(m,1H),4.18(dd,J＝9.7,6.5Hz,1H),3.94(m,1H),1.43(s,9H). 13 C NMR(100 MHz,CDCl 3 )δ175.47,173.09,154.67,137.14,131.92,129.73,129.46,129.38,126.81,126.08, 124.10,116.91,100.68,71.31,35.23,32.19,31.47.HRMS(ESI):calcd for C 21 H 21 NNaO 2 + [M+ Na] + 342.1465,found.342.1465.
example 7
Preparation of compound 2 k:
the 2, 3-dihydrobenzopyran-4-one in example 1 was changed to 2-phenyl-4-dihydrochromone, and the remaining compounds were not changed, and the specific preparation method was referred to the preparation method of compound 2 a.
The structural formula of the target compound obtained by the reaction is characterized as follows:
Analytical data:yield:70％； 1 H NMR(400MHz,CDCl 3 )δ7.40(dd,J＝5.7,1.7Hz,1H), 7.37–7.08(m,13H),5.84(d,J＝8.5Hz,1H),5.67(m,1H),4.68(m,1H). 13 C NMR(100MHz, CDCl 3 )δ169.40,168.68,156.12,139.02,133.15,131.16,128.97,128.62,128.03,127.55,127.25, 126.06,126.04,122.87,118.79,118.53,97.40,79.77,42.46.HRMS(ESI):calcd for C 23 H 17NNa O 2 + [M+Na] + 362.1151,found.362.1154.
example 8
Preparation of compound 2 l:
the 2, 3-dihydrobenzopyran-4-one in example 1 was changed to 3, 4-dihydro-2H-benzoxepin-5-one, and the remaining compounds were not changed, and the specific preparation method was according to the preparation method of Compound 2 a.
The structural formula of the target compound obtained by the reaction is characterized as follows:
Analytical data:yield:74％； 1 H NMR(400MHz,CDCl 3 )δ7.68–7.62(m,1H),7.46–7.14 (m,8H),5.76(d,J＝6.2Hz,1H),4.10(m,1H),4.02(m,1H),3.66(dd,J＝10.7,5.6Hz,1H),2.08 –2.01(m,1H),1.84–1.77(m,1H). 13 C NMR(100MHz,CDCl 3 )δ170.26,158.78,132.55,132.11, 131.78,129.59,129.24,126.68,122.98,121.93,115.44,99.53,69.18,30.18.HRMS(ESI):calcd for C 18 H 15 NNaO 2 + [M+Na] + 300.0995,found.300.0996.
example 9
Preparation of compound 2 n:
the 2, 3-dihydrobenzopyran-4-one in example 1 was changed to 2, 3-dihydro-4H-naphthopyran-4-one, and the remaining compounds were not changed, and the specific preparation method was referred to the preparation method of Compound 2 a.
The structural formula of the target compound obtained by the reaction is characterized as follows:
Analytical data:yield:65％； 1 H NMR(400MHz,CDCl 3 )δ7.92(d,J＝2.4Hz,1H),7.82– 7.71(m,2H),7.43–7.34(m,3H),7.31(m,2H),7.29–7.14(m,3H),5.72(d,J＝6.2Hz,1H),4.48 (m,1H),4.26(m,1H),4.02(m,1H). 13 C NMR(100MHz,CDCl 3 )δ172.36,171.60,151.30,136.20, 131.19,130.03,129.70,129.00,128.65,128.28,127.37,126.43,126.09,123.39,121.63,102.95, 99.96,69.77,31.46.HRMS(ESI):calcd for C 21 H 15 NNaO 2 + [M+Na] + 336.0995,found.336.0999.
example 10
Preparation of compound 2 o:
the phenylacetylene in example 1 was changed to 4-methoxy-phenylacetylene, and the remaining compounds were not changed, and the specific production method was referred to the production method of compound 2 a.
The structural formula of the target compound obtained by the reaction is characterized as follows:
Analytical data:yield:71％； 1 H NMR(400MHz,CDCl 3 )δ7.47–7.28(m,5H),7.24(m,1H), 6.89(d,J＝6.0Hz,2H),5.43(d,J＝7.4Hz,1H),4.39(m,1H),4.18(m,1H),3.94(m,1H),3.84(s, 3H). 13 C NMR(100MHz,CDCl 3 )δ174.32,173.08,159.80,158.32,133.96,128.11,128.01, 124.46,122.23,119.73,119.44,114.51,100.68,70.49,56.28,32.18.HRMS(ESI):calcd for C 18 H 15 NNaO 3 + [M+Na] + 316.0944,found.316.0945.
example 11
Preparation of compound 2 q:
the phenylacetylene in example 1 was changed to 4-fluoro-phenylacetylene, and the remaining compounds were not changed, and the specific production method was referred to the production method of compound 2 a.
The structural formula of the target compound obtained by the reaction is characterized as follows:
Analytical data:yield:92％； 1 H NMR(400MHz,CDCl 3 )δ7.51–7.30(m,5H),7.26(m,1H), 7.04(t,J＝7.8Hz,2H),5.50(d,J＝8/2Hz,1H),4.43(m,1H),4.20(m,1H),3.96(m,1H). 13 C NMR(100MHz,CDCl 3 )δ174.00,172.76,163.32,161.23,158.00,133.64,129.36,129.30,127.69, 127.64,127.61,121.91,119.41,119.12,115.81,115.59,100.36,70.17,31.86. 19 F NMR(376MHz, CDCl 3 )δ-106.74,-107.15.HRMS(ESI):calcd for C 17 H 12 FNNaO 2 + [M+Na] + 304.0744, found.304.0746.
example 12
Preparation of compound 2 s:
the phenylacetylene in example 1 was replaced with 5-ethynyl-1, 3-benzodioxazole, and the remaining compounds were unchanged, the concrete preparation method was according to that of compound 2 a.
The structural formula of the target compound obtained by the reaction is characterized as follows:
Analytical data:yield:82％； 1 H NMR(400MHz,CDCl 3 )δ7.33(m,3H),7.18(dd,J＝8.4,3.0 Hz,1H),6.89(m,2H),6.75–6.70(m,1H),5.87(s,2H),5.39(d,J＝6.2Hz,1H),4.33(m,1H), 4.12(m,1H),3.88(m,1H). 13 C NMR(100MHz,CDCl 3 )δ174.02,171.31,158.02,150.22,148.24, 133.66,127.71,124.15,121.93,121.19,119.43,119.14,109.72,108.81,102.07,101.02,70.19, 31.88.HRMS(ESI):calcd for C 18 H 13 NNaO 4 + [M+Na] + 330.0737,found.330.0738.
example 13
Preparation of compound 2 u:
the phenylacetylene in example 1 was replaced with 4-ethynylquinoline, and the remaining compounds were unchanged, the specific preparation method being referred to the preparation method of compound 2 a.
The structural formula of the target compound obtained by the reaction is characterized as follows:
Analytical data:yield:92％； 1 H NMR(400MHz,CDCl 3 )δ8.62(d,J＝10.5Hz,1H),7.95(dd, J＝7.4,2.3Hz,1H),7.42(m,1H),7.33(m,1H),7.29–7.09(m,5H),6.99(dd,J＝7.3,1.0Hz,1H), 4.90(d,J＝7.6Hz,1H),4.28(m,1H),3.99(m,1H),3.73(m,1H). 13 C NMR(100MHz,CDCl 3 )δ 173.68,171.31,157.68,148.61,146.00,133.32,132.89,130.07,127.37,126.83,126.64,126.33, 123.80,121.59,119.09,118.84,118.80,105.17,69.85,31.54.HRMS(ESI):calcd for C 20 H 14 N 2 NaO 2 + [M+Na] + 337.0947,found.337.0951.
example 14
Preparation of compound 2 v:
the phenylacetylene in example 1 was replaced with 2-ethynylthiophene, and the remaining compounds were unchanged, and the specific preparation method was referred to the preparation method of compound 2 a.
The structural formula of the target compound obtained by the reaction is characterized as follows:
Analytical data:yield:90％； 1 H NMR(400MHz,CDCl 3 )δ7.43–7.25(m,4H),7.18(dd,J＝ 9.4,1.6Hz,2H),7.04(t,J＝7.5Hz,1H),5.50(d,J＝6.2Hz,1H),4.37(d,J＝6.3Hz,1H),4.17– 4.09(m,1H),3.93–3.86(m,1H). 13 C NMR(100MHz,CDCl 3 )δ171.76,162.38,157.83,137.37, 133.47,129.80,127.52,127.16,122.40,121.74,119.24,118.95,94.60,70.00,31.68.HRMS(ESI): calcd for C 15 H 11 NNaO 2 S + [M+Na] + 292.0403,found.291.0403.
example 15
Preparation of compound 2 x:
the phenylacetylene in example 1 was replaced with ethynyltrimethylsilane, and the remaining compounds were unchanged, the specific preparation method was referenced to the preparation method of compound 2 a.
The structural formula of the target compound obtained by the reaction is characterized as follows:
Analytical data:yield:94％； 1 H NMR(400MHz,CDCl 3 )δ7.45–7.34(m,3H),7.22(dd,J＝ 7.5,1.4Hz,1H),5.38(td,J＝7.5,6.4Hz,1H),4.16(dd,J＝12.5,7.5Hz,1H),3.89(dd,J＝12.4, 7.4Hz,1H),0.13(s,9H). 13 C NMR(100MHz,CDCl 3 )δ168.97,156.64,132.70,132.28,132.22, 126.33,120.55,118.05,117.76,68.81,33.26,-4.71.HRMS(ESI):calcd for C 14 H 17 NNaO 2 Si + [M+ Na] + 282.0921,found.282.0923.
comparative example 1
Comparing with example 1, the catalyst Pd (OAc) in the reaction system 2 Change of/CuI to Pd (OAc) 2 ，CuI， CuCN，CuCl，AgOTf，Pd 2 (dba) 3 ，Pd 2 (dba) 3 One of the/CuI and the rest of the reaction conditions are unchanged.
| Catalyst and process for preparing same | Yield of | |
| Example 1 | Pd(OAc) 2 /CuI | 88％ |
| Comparative example 11 | Pd(OAc) 2 | 41％ |
| Comparative example 12 | CuI | 16％ |
| Comparative example 13 | CuCN | — |
| Comparative example 14 | CuCl | trace |
| Comparative example 15 | AgOTf | — |
| Comparative example 16 | Pd 2 (dba) 3 | 23％ |
| Comparative example 17 | Pd 2 (dba) 3 /CuI | 64％ |
Comparative example 2
Compared with the example 1, the solvent anhydrous tetrahydrofuran in the reaction system is changed into one of dichloromethane, toluene, 1, 4-dioxane and N, N-dimethylformamide (all the solvents are anhydrous solvents), and the rest reaction conditions are not changed.
| Solvent(s) | Yield of | |
| Example 1 | THF | 88％ |
| Comparative example 21 | CH 2 Cl 2 | 30％ |
| Comparative example 22 | Toluene | 45％ |
| Comparative example 23 | 1,4-Dioxane | — |
| Comparative example 24 | DMF | — |
Comparative example 3
Comparing with example 1, alkali Cs in the reaction system 2 CO 3 Change to K 2 CO 3 ，Na 2 CO 3 ，K 3 PO 4 One of CsF and NaOH, and the rest of the reaction conditions are unchanged.
| Alkali | Yield of | |
| Example 1 | Cs 2 CO 3 | 88％ |
| Comparative example 31 | K 2 CO 3 | 66％ |
| Comparative example 32 | Na 2 CO 3 | 59％ |
| Comparative example 33 | K 3 PO 4 | 43％ |
| Comparative example 34 | CsF | 71％ |
| Comparative example 35 | NaOH | 78％ |
Comparative example 4
Comparative examples 41 to 43 As compared with example 1, catalysts Pd (OAc) in the reaction System 2 The ratio of/CuI was changed to 1:1, 2:1, 4:1, or comparative examples 44 to 45 alkali Cs 2 CO 3 The quantitative ratio of (A) to (B) was changed to 4mmol and 8mmol, and the remaining reaction conditions were not changed.
| Catalyst and base | Yield of | |
| Example 1 | 3:1 and 6mmol | 88％ |
| Comparative example 41 | 1:1 and 6mmol | 68％ |
| Comparative example 42 | 2:1 and 6mmol | 76％ |
| Comparative example 43 | 4:1 and 6mmol | 72％ |
| Comparative example 44 | 3:1 and 4mmol | 77％ |
| Comparative example 45 | 3:1 and 8mmol | 81％ |
The 1, 2-oxazine pyran compound is tested for bactericidal activity, and the tested materials are wheat scab, wheat powdery mildew and wheat root rot. According to the requirements of Good Laboratory Practice (GLP) of pesticides, by the standard operation specification of indoor biological activity test of bactericides, a PDA culture medium without medicine is used as a blank control, the concentration of a culture medium containing the medicine is 100 mug/mL, pathogenic bacteria cakes (with the diameter of 5mm) are respectively inoculated on the culture medium, and the culture is carried out for 3 days at the temperature of 25 ℃. The colony diameter is measured by a cross method, and the hypha growth inhibition rate is calculated. The growth inhibition (%) was (control colony diameter-treated colony diameter)/(control colony diameter-cake diameter) × 100%. The test results are shown in Table 1.
TABLE 1
As can be seen from the data in Table 1, the 1, 2-oxazinopyran compounds have certain inhibiting effect on wheat scab, wheat powdery mildew and wheat root rot, have better inhibiting effect on wheat root rot on the whole, the highest inhibiting effect is 76.2%, and the inhibiting effect on wheat scab is slightly weaker but has better inhibiting effect.
The above description is only a preferred embodiment of the present invention, and not intended to limit the scope of the present invention, and all modifications of equivalent structures and equivalent processes, which are made by the present specification, or directly or indirectly applied to other related technical fields, are included in the scope of the present invention.
Claims (6)
1. 1, 2-oxazinopyran compounds selected from the following:
2. the method for preparing 1, 2-oxazinopyran compounds according to claim 1, comprising the steps of:
a, (1) the alpha-position of ketone in the pyrone compound is subjected to bromination reaction, and the bromopyrone compound reacts with hydroxylamine hydrochloride to generate an oximation product;
(2) carrying out an ethynylation reaction on bromine of an oximation product and an alkynyl compound, and then directly carrying out a cyclization reaction on the product and an oximino to obtain a 1, 2-oxazine pyran compound; or
B, (1) carrying out bromination reaction on alpha-site of ketone in the pyrone compound, and carrying out ethynylation reaction on the bromopyrone compound and an alkynyl compound to obtain a pyrone ethynylation product;
(2) the carbonyl in the alkynyl product is subjected to oximation reaction and then directly cyclized with alkynyl to generate a 1, 2-oxazine pyran compound,
the pyrone compound is 2, 3-dihydrobenzopyran-4-one, 6-methyl-4-dihydrochromone, 6-ethyl-4-dihydrochromone, 8-methyl-4-dihydrochromone, 6, 8-dimethyl-4-dihydrochromone, 7-methoxy-6-methyl-4-dihydrochromone, 7-methoxy-4-dihydrochromone, 8-tert-butyl-4-dihydrochromone, 6-benzyloxy-4-dihydrochromone, 3, 4-dihydro-2H-benzoxepin-5-one, 7-methoxy-3, 4-dihydro-2H-benzoxepin-5-one, or, 2, 3-dihydro-4H-naphthopyran-4-one, 2-phenyl-4-dihydrochromone,
the alkynyl compound is phenylacetylene, 4-methoxy phenylacetylene, 4-methyl phenylacetylene, 4-fluoro phenylacetylene, 4-nitro phenylacetylene, 5-ethynyl-1, 3-benzodioxazole, 3-ethynylpyridine, 4-ethynylquinoline, 2-ethynyl thiophene, ethynyl cyclopropane and ethynyl trimethylsilane.
3. The method according to claim 2, characterized in that it comprises the following reaction steps:
firstly, dissolving a pyrone raw material A in anhydrous ether, dropwise adding Br2 into the solution under stirring at 0 ℃, gradually increasing the temperature to room temperature, continuously stirring for 3-4 hours, quenching the reaction with saturated sodium bisulfite after the reaction is finished, extracting with ethyl acetate, washing with saturated salt water, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and separating and purifying a crude product through column chromatography to obtain a compound B;
dissolving the compound B in an absolute ethyl alcohol solution, adding an ethyl alcohol solution of sodium acetate and hydroxylamine hydrochloride into an ice water bath, gradually raising the temperature to room temperature, stirring and reacting for 1-3 hours, adding water to stop the reaction after the reaction is finished, extracting with ethyl acetate, drying with anhydrous sodium sulfate, concentrating under reduced pressure, drying, crystallizing and purifying to obtain a compound C;
dissolving a catalyst and a ligand in a solvent under the protection of inert gas, stirring for reaction for 1-2h, then adding a compound C, an alkynyl compound and alkali into a reaction solution, stirring for reaction for 12-20h at 60-100 ℃, detecting by TLC (thin layer chromatography), filtering by using kieselguhr after the reaction is finished, concentrating under reduced pressure, separating and purifying by using column chromatography to obtain a 1, 2-oxazine-pyran compound,
the catalyst is Pd (OAc)2/CuI, and the ligand is X-PHOS.
4. The method according to claim 3, wherein the molar mass ratio of the pyrone raw material A to the liquid bromine in the first step is 1: 0.8-0.9.
5. The method as claimed in claim 3, wherein the molar mass ratio of the compound B to the hydroxylamine hydrochloride and the sodium acetate in the second step is 1:1.5-2.0: 1.5-2.0.
6. The method of claim 3, wherein the benign and malignant solvents used for crystallizing compound C in step two are dichloromethane and n-hexane, respectively.
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