CN116462686A - 4-aryl (methyl) group-1, 4-benzoxazine imidazoline compound and preparation method and application thereof - Google Patents
4-aryl (methyl) group-1, 4-benzoxazine imidazoline compound and preparation method and application thereof Download PDFInfo
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 title claims description 19
- 238000002360 preparation method Methods 0.000 title abstract description 34
- -1 N- (2-bromoethyl) -1, 4-benzoxazine Chemical compound 0.000 claims abstract description 80
- 150000001875 compounds Chemical class 0.000 claims abstract description 25
- 239000003054 catalyst Substances 0.000 claims abstract description 20
- 235000007164 Oryza sativa Nutrition 0.000 claims abstract description 15
- 235000009566 rice Nutrition 0.000 claims abstract description 15
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 claims abstract description 11
- YRLORWPBJZEGBX-UHFFFAOYSA-N 3,4-dihydro-2h-1,4-benzoxazine Chemical compound C1=CC=C2NCCOC2=C1 YRLORWPBJZEGBX-UHFFFAOYSA-N 0.000 claims abstract description 11
- 241000233614 Phytophthora Species 0.000 claims abstract description 11
- 244000052769 pathogen Species 0.000 claims abstract description 10
- 241000223218 Fusarium Species 0.000 claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims description 76
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 48
- 239000002904 solvent Substances 0.000 claims description 47
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 38
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 33
- 238000004440 column chromatography Methods 0.000 claims description 32
- 239000012074 organic phase Substances 0.000 claims description 28
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 23
- 238000001035 drying Methods 0.000 claims description 19
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 18
- 239000000706 filtrate Substances 0.000 claims description 17
- 238000010992 reflux Methods 0.000 claims description 17
- 238000001914 filtration Methods 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 15
- 238000000605 extraction Methods 0.000 claims description 15
- 241000209094 Oryza Species 0.000 claims description 14
- 239000003513 alkali Substances 0.000 claims description 14
- 230000002401 inhibitory effect Effects 0.000 claims description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 12
- 238000005406 washing Methods 0.000 claims description 12
- 238000000926 separation method Methods 0.000 claims description 11
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 238000001816 cooling Methods 0.000 claims description 9
- 125000005843 halogen group Chemical group 0.000 claims description 9
- 241000894006 Bacteria Species 0.000 claims description 7
- 229940079593 drug Drugs 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 7
- 238000003756 stirring Methods 0.000 claims description 7
- 241001465180 Botrytis Species 0.000 claims description 6
- 239000012153 distilled water Substances 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 241000221662 Sclerotinia Species 0.000 claims description 5
- 241000233622 Phytophthora infestans Species 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- 239000005457 ice water Substances 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 238000000746 purification Methods 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 2
- 238000011282 treatment Methods 0.000 claims description 2
- 230000005764 inhibitory process Effects 0.000 abstract description 22
- 230000000694 effects Effects 0.000 abstract description 19
- 241000221696 Sclerotinia sclerotiorum Species 0.000 abstract description 6
- 230000001717 pathogenic effect Effects 0.000 abstract description 6
- 241000123650 Botrytis cinerea Species 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 3
- 244000000037 crop pathogen Species 0.000 abstract description 2
- 240000007594 Oryza sativa Species 0.000 abstract 1
- 238000001308 synthesis method Methods 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 17
- 230000015572 biosynthetic process Effects 0.000 description 13
- 238000003786 synthesis reaction Methods 0.000 description 13
- 239000002244 precipitate Substances 0.000 description 12
- 229910052938 sodium sulfate Inorganic materials 0.000 description 12
- 235000011152 sodium sulphate Nutrition 0.000 description 12
- 230000000844 anti-bacterial effect Effects 0.000 description 11
- 238000002844 melting Methods 0.000 description 11
- 230000008018 melting Effects 0.000 description 11
- 238000000967 suction filtration Methods 0.000 description 11
- 239000007787 solid Substances 0.000 description 10
- 238000012360 testing method Methods 0.000 description 7
- 238000011160 research Methods 0.000 description 5
- DOLQYFPDPKPQSS-UHFFFAOYSA-N 3,4-dimethylaniline Chemical compound CC1=CC=C(N)C=C1C DOLQYFPDPKPQSS-UHFFFAOYSA-N 0.000 description 4
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
- 150000005130 benzoxazines Chemical group 0.000 description 4
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 4
- 150000002462 imidazolines Chemical class 0.000 description 4
- RNVCVTLRINQCPJ-UHFFFAOYSA-N o-toluidine Chemical compound CC1=CC=CC=C1N RNVCVTLRINQCPJ-UHFFFAOYSA-N 0.000 description 4
- RZXMPPFPUUCRFN-UHFFFAOYSA-N p-toluidine Chemical compound CC1=CC=C(N)C=C1 RZXMPPFPUUCRFN-UHFFFAOYSA-N 0.000 description 4
- 230000001580 bacterial effect Effects 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- BJFPYGGTDAYECS-UHFFFAOYSA-N (3-chlorophenyl)methanamine Chemical compound NCC1=CC=CC(Cl)=C1 BJFPYGGTDAYECS-UHFFFAOYSA-N 0.000 description 2
- RGXUCUWVGKLACF-UHFFFAOYSA-N (3-methylphenyl)methanamine Chemical compound CC1=CC=CC(CN)=C1 RGXUCUWVGKLACF-UHFFFAOYSA-N 0.000 description 2
- AKCRQHGQIJBRMN-UHFFFAOYSA-N 2-chloroaniline Chemical compound NC1=CC=CC=C1Cl AKCRQHGQIJBRMN-UHFFFAOYSA-N 0.000 description 2
- PNPCRKVUWYDDST-UHFFFAOYSA-N 3-chloroaniline Chemical compound NC1=CC=CC(Cl)=C1 PNPCRKVUWYDDST-UHFFFAOYSA-N 0.000 description 2
- AMKPQMFZCBTTAT-UHFFFAOYSA-N 3-ethylaniline Chemical compound CCC1=CC=CC(N)=C1 AMKPQMFZCBTTAT-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 230000001093 anti-cancer Effects 0.000 description 2
- 230000003276 anti-hypertensive effect Effects 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- 244000052616 bacterial pathogen Species 0.000 description 2
- 230000003385 bacteriostatic effect Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 125000002636 imidazolinyl group Chemical group 0.000 description 2
- NCBZRJODKRCREW-UHFFFAOYSA-N m-anisidine Chemical compound COC1=CC=CC(N)=C1 NCBZRJODKRCREW-UHFFFAOYSA-N 0.000 description 2
- VMPITZXILSNTON-UHFFFAOYSA-N o-anisidine Chemical compound COC1=CC=CC=C1N VMPITZXILSNTON-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- XUFXOAAUWZOOIT-SXARVLRPSA-N (2R,3R,4R,5S,6R)-5-[[(2R,3R,4R,5S,6R)-5-[[(2R,3R,4S,5S,6R)-3,4-dihydroxy-6-methyl-5-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)-1-cyclohex-2-enyl]amino]-2-oxanyl]oxy]-3,4-dihydroxy-6-(hydroxymethyl)-2-oxanyl]oxy]-6-(hydroxymethyl)oxane-2,3,4-triol Chemical compound O([C@H]1O[C@H](CO)[C@H]([C@@H]([C@H]1O)O)O[C@H]1O[C@@H]([C@H]([C@H](O)[C@H]1O)N[C@@H]1[C@@H]([C@@H](O)[C@H](O)C(CO)=C1)O)C)[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O XUFXOAAUWZOOIT-SXARVLRPSA-N 0.000 description 1
- FUNJHONCFBDKGW-UHFFFAOYSA-N 1,4-benzoxazin-2-one Chemical class C1=CC=C2OC(=O)C=NC2=C1 FUNJHONCFBDKGW-UHFFFAOYSA-N 0.000 description 1
- 102000010400 1-phosphatidylinositol-3-kinase activity proteins Human genes 0.000 description 1
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 1
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 1
- SFDGJDBLYNJMFI-UHFFFAOYSA-N 3,1-benzoxazin-4-one Chemical class C1=CC=C2C(=O)OC=NC2=C1 SFDGJDBLYNJMFI-UHFFFAOYSA-N 0.000 description 1
- 125000003852 3-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(Cl)=C1[H])C([H])([H])* 0.000 description 1
- 125000006180 3-methyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C(=C1[H])C([H])([H])[H])C([H])([H])* 0.000 description 1
- 101100136092 Drosophila melanogaster peng gene Proteins 0.000 description 1
- 102100024295 Maltase-glucoamylase Human genes 0.000 description 1
- BYBLEWFAAKGYCD-UHFFFAOYSA-N Miconazole Chemical compound ClC1=CC(Cl)=CC=C1COC(C=1C(=CC(Cl)=CC=1)Cl)CN1C=NC=C1 BYBLEWFAAKGYCD-UHFFFAOYSA-N 0.000 description 1
- 108091007960 PI3Ks Proteins 0.000 description 1
- 102000013530 TOR Serine-Threonine Kinases Human genes 0.000 description 1
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 description 1
- 229960002632 acarbose Drugs 0.000 description 1
- XUFXOAAUWZOOIT-UHFFFAOYSA-N acarviostatin I01 Natural products OC1C(O)C(NC2C(C(O)C(O)C(CO)=C2)O)C(C)OC1OC(C(C1O)O)C(CO)OC1OC1C(CO)OC(O)C(O)C1O XUFXOAAUWZOOIT-UHFFFAOYSA-N 0.000 description 1
- 108010028144 alpha-Glucosidases Proteins 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229960003405 ciprofloxacin Drugs 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229960002509 miconazole Drugs 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 229940083254 peripheral vasodilators imidazoline derivative Drugs 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229920002994 synthetic fiber Polymers 0.000 description 1
- 235000018553 tannin Nutrition 0.000 description 1
- 229920001864 tannin Polymers 0.000 description 1
- 239000001648 tannin Substances 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
- A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
- A01P3/00—Fungicides
Landscapes
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Environmental Sciences (AREA)
- Wood Science & Technology (AREA)
- Plant Pathology (AREA)
- Zoology (AREA)
- Engineering & Computer Science (AREA)
- Pest Control & Pesticides (AREA)
- General Health & Medical Sciences (AREA)
- Dentistry (AREA)
- Health & Medical Sciences (AREA)
- Agronomy & Crop Science (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention discloses a 4-aryl (methyl) -1, 4-benzoxazine imidazoline compound, and a preparation method and application thereof. The compound is prepared by taking 3, 4-dihydro-2H-1, 4-benzoxazine and 1, 2-dibromoethane as raw materials to react to generate N- (2-bromoethyl) -1, 4-benzoxazine, then reacting with arylamine compounds to generate corresponding N- (2-arylaminoethyl) -1, 4-benzoxazine, and then further reacting under the action of a catalyst to obtain the 4-aryl (methyl) -1, 4-benzoxazine imidazoline compounds. The raw materials used for synthesizing the compound are cheap and easy to obtain, and the synthesis method is simple. Meanwhile, the compound has good inhibition effect on the activity of crop pathogens, in particular to obvious inhibition activity on gibberella, rice blast pathogen, phytophthora, sclerotinia sclerotiorum, botrytis cinerea, sheath blight pathogen and the like.
Description
Technical Field
The invention relates to a benzoxazine-imidazoline compound, in particular to a 4-aryl (methyl) -1, 4-benzoxazine-imidazoline compound with antibacterial activity, and a preparation method and application thereof, and belongs to the technical field of agricultural medicines.
Background
The benzoxazine compound and the imidazoline compound have good biological activity, and become one of hot spots for pesticide and medicine research. For example, the benzoxazine compound has antibacterial, anti-tumor and antioxidant activities, and can be used as anticancer drugs, protease inhibitors, etc. The imidazoline compound has antifungal, antihypertensive, anti-inflammatory and other biological activities, and can be used as a medicament for depression, anticancer, depressurization, analgesia and the like, so that the research on the benzoxazine compound and the imidazoline compound is very important and is attracting attention. In 2014, wasilowska et al reported a series of substituted imidazoline derivatives, some of which were found to have good antihypertensive effects and to be potential antihypertensive agents. In 2017, rajitha Bollu et al synthesized a series of substituted triazolyl 1, 4-benzoxazinones and tested the antibacterial activity of gram positive and gram negative strains with miconazole and ciprofloxacin as controls, finding that most compounds had moderate to good activity against the detected pathogenic bacteria. In 2019, the tannin et al synthesized a series of imidazoline compounds, and found that some of the compounds had good antibacterial activity. 2021, farooq et al synthesized a series of 1-arylaminomethyl-2-phenylimidazoline derivatives, some of which were found to have antioxidant activity. In 2019, yan et al studied to synthesize a series of 1, 4-benzoxazinone compounds, and activity tests show that part of the compounds are effective PI3K/mTOR dual inhibitors and can be used as anti-cancer candidate drugs. 2023, zhang Peng et al reported a series of 4H-3, 1-benzoxazin-4-one derivatives, and experiments found that some compounds had strong affinity with alpha-glucosidase and activity significantly better than the positive control acarbose.
However, the whole of these compounds has a disadvantage in terms of bacteriostatic effect on crops (bacteriostatic effect is relatively low), and there is also a great room for improvement. Furthermore, it has been found through studies that no related literature has been reported so far in the prior art on a compound in which a benzoxazine ring and an imidazoline ring are bonded together and its antibacterial activity. So we design and synthesize the 4-aryl (methyl) -1, 4-benzoxazine-imidazoline compound containing benzoxazine ring and imidazoline ring structure. And the inhibitory activity of these compounds against gibberella, phytophthora, rice blast, sclerotinia sclerotiorum, botrytis cinerea or sheath blight is studied.
Disclosure of Invention
Aiming at the defect that the bacteriostasis effect of the existing benzoxazine compounds and imidazoline compounds in the prior art is generally low, the invention provides the 4-aryl (methyl) group-1, 4-benzoxazine imidazoline compounds, the synthetic material of the compounds is cheap and easy to obtain, the synthetic method is simple, the compounds have good bacteriostasis activity on the activity of crop pathogens, and particularly have remarkable activity inhibition effect on pathogens such as gibberella, phytophthora, rice blast, sclerotinia sclerotiorum, botrytis or sheath blight. The invention also provides a preparation method and application of the 4-aryl (methyl) group-1, 4-benzoxazine imidazoline compound in bactericidal activity.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
according to a first embodiment of the present invention, there is provided a 4-aryl (meth) 1, 4-benzoxazinoimidazoline compound:
a 4-aryl (methyl) -1, 4-benzoxazinoimidazoline compound which is a compound with a structural general formula (IV) shown below:
in the formula (IV), n is an integer of 0-12, and R is one or more selected from H, alkyl, alkoxy and halogen atoms.
Preferably, n is an integer of 0 to 6, and R is H, C 1 -C 8 Alkyl of (2)、C 1 -C 8 One or more of alkoxy groups, halogen atoms.
Preferably, n is 0 or 1, wherein:
when n=0, the R is H, C 1 -C 4 Alkyl, C of (2) 1 -C 4 Preferably R is H, 2-CH 3 、3-Cl、4-CH 3 、2-OCH 3 、3-OCH 3 、2-Cl、3,4-(CH 3 ) 2 、3-CH 2 CH 3 One of them.
When n=1, the R is H, C 1 -C 2 Preferably, R is H, 3-CH 3 One of 3-Cl.
Preferably, the 4-aryl (methyl) -1, 4-benzoxazine-imidazoline compound with the structural formula (IV) is selected from one or more of the following compounds:
4-phenyl-1, 4-benzoxazinoimidazoline:
4- (2-methylphenyl) -1, 4-benzoxazinoimidazoline:
4- (3-chlorophenyl) -1, 4-benzoxazinoimidazoline:
4- (4-methylphenyl) -1, 4-benzoxazinoimidazoline:
4- (2-methoxyphenyl) -1, 4-benzoxazinoimidazoline:
4- (3-methoxyphenyl) -1, 4-benzoxazinoimidazoline:
4- (2-chlorophenyl) -1, 4-benzoxazinoimidazoline:
4- (3, 4-dimethylphenyl) -1, 4-benzoxazinoimidazoline:
4- (3-ethylphenyl) -1, 4-benzoxazinoimidazoline:
4-benzyl-1, 4-benzoxazinoimidazoline:
4- (3-methylbenzyl) -1, 4-benzoxazinoimidazoline:
4- (3-chlorobenzyl) -1, 4-benzoxazinoimidazoline:
according to a second embodiment of the present invention, there is provided a process for preparing 4-aryl (meth) 1, 4-benzoxazinoimidazolins:
a process for preparing 4-aryl (meth) 1, 4-benzoxazinoimidazolins or for preparing 4-aryl (meth) 1, 4-benzoxazinoimidazolins according to the first embodiment, the process comprising the steps of:
s1) reacting 3, 4-dihydro-2H-1, 4-benzoxazine having the structural formula (I) with 1, 2-dibromoethane in the presence of a base in a first solvent to obtain N- (2-bromoethyl) -1, 4-benzoxazine having the structural formula (II):
S2) reacting N- (2-bromoethyl) -1, 4-benzoxazine with a structural formula (II) with an arylamine compound with a structural formula (V) in the presence of alkali and a first catalyst in a second solvent to obtain the N- (2-arylaminoethyl) -1, 4-benzoxazine compound with a structural formula (III):
s3) reacting the N- (2-arylaminoethyl) -1, 4-benzoxazine compound with the structural formula (III) in the presence of a second catalyst in a third solvent to obtain the 4-aryl (methyl) group-1, 4-benzoxazine-imidazoline compound with the structural formula (IV):
wherein: and n is an integer of 0-12, and R is one or more selected from H, alkyl, alkoxy and halogen atoms. Preferably, said n is 0 to 6An integer, R is H, C 1 -C 8 Alkyl, C of (2) 1 -C 8 One or more of alkoxy groups, halogen atoms.
Preferably, n is 0 or 1, wherein:
when n=0, the R is H, C 1 -C 4 Alkyl, C of (2) 1 -C 4 Preferably R is H, 2-CH 3 、3-Cl、4-CH 3 、2-OCH 3 、3-OCH 3 、2-Cl、3,4-(CH 3 ) 2 、3-CH 2 CH 3 One of them.
When n=1, the R is H, C 1 -C 2 Preferably, R is H, 3-CH 3 One of 3-Cl.
Preferably, in step S1): the first solvent is an organic solvent, preferably the organic solvent is N, N-Dimethylformamide (DMF). The alkali is NaH.
Preferably, in step S2): the second solvent is an organic solvent, preferably acetonitrile. The alkali is Na 2 CO 3 、K 2 CO 3 And one or both, preferably K 2 CO 3 . The first catalyst is one or two of KI and NaI, preferably NaI.
Preferably, in step S3): the third solvent is an organic solvent, preferably the organic solvent is N, N-Dimethylformamide (DMF). The second catalyst is Cu (OAc) 2 、Ag 2 CO 3 One or both of them, preferably Cu (OAc) 2 And Ag 2 CO 3 Is a mixture of (a) and (b).
Preferably, in step S1): the molar ratio of the 3, 4-dihydro-2H-1, 4-benzoxazine with the structural formula (I), the 1, 2-dibromoethane and the alkali is 1:8-20:4-12, preferably 1:10-15:6-10.
Preferably, in step S2): the molar ratio of the N- (2-bromoethyl) -1, 4-benzoxazine with the structural formula (II), the arylamine compound with the structural formula (V), the alkali and the first catalyst is 1:1-3:1.5-4:0.8-2.5, preferably 1:1.1-2:1.8-3:1-2.
Preferably, in step S3): the molar ratio of the N- (2-arylaminoethyl) -1, 4-benzoxazine compound with the structural general formula (III) to the second catalyst is 1:2.5-6, preferably 1:3-5.
Preferably, the step S1) specifically includes: adding 3, 4-dihydro-2H-1, 4-benzoxazine and 1, 2-dibromoethane with the structural formula (I) into a reaction container in proportion, slowly adding alkali under the condition of ice water bath stirring, adding a first solvent, uniformly stirring, reacting under an oil bath (preferably at the temperature of 90-110 ℃) for 8-24 hours, cooling and adding a saturated sodium chloride solution after the reaction is finished, extracting with ethyl acetate (preferably for 1-5 times), washing the obtained organic phase with distilled water and saturated sodium chloride solution (preferably with distilled water and saturated sodium chloride for 1-4 times), drying (preferably with anhydrous sodium sulfate), decompressing, desolventizing and separating and purifying by column chromatography to obtain N- (2-bromoethyl) -1, 4-benzoxazine with the structural formula (II).
Preferably, the step S2) specifically includes: adding N- (2-bromoethyl) -1, 4-benzoxazine with a structural formula (II) and a first catalyst into a reaction container in proportion, adding a second solvent for reaction (preferably reflux reaction, the reaction temperature is 80-85 ℃ and the reaction time is 10-60 min), cooling to room temperature after the reaction is finished, adding an arylamine compound with a structural formula (V) and alkali in proportion for reaction (preferably stirring reaction, the reaction temperature is 85-110 ℃ and the reaction time is 10-36 h), cooling to room temperature after the reaction is finished, filtering, and sequentially carrying out reduced pressure desolventizing and column chromatography separation and purification on filtrate to obtain the N- (2-arylaminoethyl) -1, 4-benzoxazine with the structural formula (III).
Preferably, the step S3) specifically includes: adding the N- (2-arylaminoethyl) -1, 4-benzoxazine compound with the structural formula (III) and a second catalyst into a reaction container according to a certain proportion, then adding a third solvent for reaction (preferably reflux reaction, the reaction temperature is 100-150 ℃ and the reaction time is 8-20 h), filtering after the reaction is finished, extracting filtrate with dichloromethane (preferably the extraction times are 1-3 times), washing the obtained organic phase with saturated sodium chloride solution (preferably 1-3 times), drying (preferably drying with anhydrous sodium sulfate), decompressing, desolventizing, separating and purifying by column chromatography to obtain the 4-aryl (methyl) -1, 4-benzoxazine imidazoline compound with the structural formula (IV).
According to a third embodiment of the present invention there is provided the use of a 4-aryl (meth) 1, 4-benzoxazinoimidazoline-based compound:
the use of 4-aryl (methyl) group-1, 4-benzoxazine-imidazoline compounds or the use of 4-aryl (methyl) group-1, 4-benzoxazine-imidazoline compounds in the first embodiment or the use of 4-aryl (methyl) group-1, 4-benzoxazine-imidazoline compounds prepared by the method in the second embodiment, wherein the 4-aryl (methyl) group-1, 4-benzoxazine-imidazoline compounds with the structural general formula (IV) are used for crop bacteriostasis. Is particularly used for inhibiting one or more of gibberella, phytophthora, rice blast, sclerotinia, botrytis and sheath blight. Preferably, the 4-aryl (methyl) -1, 4-benzoxazinoimidazoline compound with the structural formula (IV) is used for inhibiting rice blast bacteria and/or phytophthora infestans.
Preferably, the 4-aryl (methyl) -1, 4-benzoxazinoimidazoline compound with the structural formula (IV) is used for preparing a medicament for inhibiting bacteria of crops, and is particularly used for preparing a medicament for inhibiting one or more of gibberella, phytophthora, rice blast, sclerotinia, botrytis and sheath blight. Preferably, the 4-aryl (methyl) -1, 4-benzoxazinoimidazoline compound with the structural general formula (IV) is used for preparing medicines for inhibiting rice blast bacteria and/or phytophthora infestans.
In the invention, in the prior art, a plurality of scholars research and report the biological activities of benzoxazine compounds and imidazoline compounds, but the author researches find that the compounds are directly used for bacteriostasis (such as activity inhibition on red mold pathogen, phytophthora pathogen, rice blast pathogen, sclerotinia sclerotiorum pathogen, gray mold pathogen, sheath blight pathogen and other pathogens) of crops, and the integral bacteriostasis effect is relatively low and is insufficient for achieving the ideal bacteriostasis and sterilization effect. Therefore, the authors of the invention are subjected to targeted research and exploration, and the 4-aryl (methyl) -1, 4-benzoxazinoimidazoline compound containing benzoxazinoimidazoline ring structures is designed and synthesized according to the active substructure splicing principle and the drug effect superposition principle.
In the invention, the 4-aryl (methyl) group-1, 4-benzoxazine imidazoline compound with the structural general formula (IV) is prepared by the following method: first,: after adding 3, 4-dihydro-2H-1, 4-benzoxazine of formula (I), 1, 2-dibromoethane to a reaction vessel (e.g., a reaction vessel or a reaction bottle), and adding a first solvent (e.g., anhydrous DMF) and a base (e.g., naH), reacting in an oil bath at 90-110 ℃ (e.g., 100 ℃) for 8-24 hours (e.g., 12 hours) to produce N- (2-bromoethyl) -1, 4-benzoxazine of formula (II), the reaction process is as follows:
secondly: adding N- (2-bromoethyl) -1, 4-benzoxazine with a structural formula (II), an arylamine compound with a structural formula (V), a first catalyst (such as NaH), a base (such as anhydrous potassium carbonate) and a second solvent (such as acetonitrile) into a reaction vessel (such as a reaction kettle or a reaction bottle) to react for 10-36h (such as 24 h) at a temperature of 85-110 ℃ (such as 90 ℃) to generate the N- (2-arylaminoethyl) -1, 4-benzoxazine with a structural formula (III):
(wherein n is an integer of 0 to 12, and R is one or more selected from H, alkyl, alkoxy and halogen atoms).
Finally: n- (2-arylaminoethyl) -1, 4-benzoxazines of the general structural formula (III) and a second catalyst (e.g. Cu (OAc) 2 、Ag 2 CO 3 ) Adding a third solvent (such as DMF) into a reaction vessel (such as a reaction kettle or a reaction bottle) to react for 8-20h (such as 12 h) at a temperature of 100-150 ℃ (such as 120 ℃), so as to generate the 4-aryl (methyl) -1, 4-benzoxazinoimidazoline compound with the structural general formula (IV), wherein the reaction process is as follows:
in the present invention, as a preferred embodiment, the N- (2-arylaminoethyl) -1, 4-benzoxazine compound having the general structural formula (III) is selected from the group consisting of N- (2- (anilino) ethyl) -1, 4-benzoxazine, N- (2- (2-methylanilino) ethyl) -1, 4-benzoxazine, N- (2- (3-chloroanilino) ethyl) -1, 4-benzoxazine, N- (2- (4-methylanilino) ethyl) -1, 4-benzoxazine, N- (2- (2-methoxyanilino) ethyl) -1, 4-benzoxazine, N- (2- (3-methoxyanilino) ethyl) -1, 4-benzoxazine, N- (2- (2-chloroanilino) ethyl) -1, 4-benzoxazine, N- (2- (3, 4-dimethylanilino) ethyl) -1, 4-benzoxazine, N- (2- (3-ethylanilino) ethyl) -1, 4-benzoxazine, N- (2- (2-methylanilino) ethyl) -1, 4-benzoxazine, N- (2-methylanilino) ethyl) -1, 4-benzoxazine One or more of N- (2- (3-chlorobenzylamino) ethyl) -1, 4-benzoxazines. These compounds are prepared by the following method: firstly, reacting 3, 4-dihydro-2H-1, 4-benzoxazine with 1, 2-dibromoethane to obtain N- (2-bromoethyl) -1, 4-benzoxazine; then N- (2-bromoethyl) -1, 4-benzoxazine reacts with different arylamine compounds (such as one of aniline, 2-methylaniline, 3-chloroaniline, 4-methylaniline, 2-methoxyaniline, 3-methoxyaniline, 2-chloroaniline, 3, 4-dimethylaniline, 3-ethylaniline, benzylamine, 3-methylbenzylamine and 3-chlorobenzylamine) in an organic solvent to obtain corresponding N- (2-arylamine group Ethyl) -1, 4-benzoxazines. The method comprises the following steps: 3, 4-dihydro-2H-1, 4-benzoxazine and anhydrous DMF are stirred in ice water bath, naH is slowly added, 1, 2-dibromoethane is added after a period of reaction, and the mixture is stirred uniformly and then transferred into an oil bath pot for continuous reaction. After the reaction is completed, cooling, adding saturated sodium chloride solution, extracting by using ethyl acetate, washing an organic phase by using distilled water and the saturated sodium chloride solution for multiple times, drying by using anhydrous sodium sulfate, decompressing, desolventizing, and separating and purifying by using a rapid column chromatography to obtain N- (2-bromoethyl) -1, 4-benzoxazine; filling N- (2-bromoethyl) -1, 4-benzoxazine and NaI into a three-necked round bottom flask, adding acetonitrile as a solvent, cooling to room temperature after reflux reaction, and adding aromatic amine and anhydrous K 2 CO 3 The system is reacted under stirring, and the reaction is cooled to room temperature after complete reaction. Filtering out the precipitate, concentrating the filtrate under reduced pressure, and separating by column chromatography to obtain the corresponding N- (2-arylaminoethyl) -1, 4-benzoxazine compound.
In the invention, N- (2-arylaminoethyl) -1, 4-benzoxazine compound with a structural general formula (III) and a catalyst Cu (OAc) 2 、Ag 2 CO 3 The reaction is carried out in the presence of an organic solvent (such as anhydrous DMF) to obtain a mixed product containing 4-aryl (methyl) 1, 4-benzoxazinoimidazoline compounds with the structural general formula (IV). The preparation method provided by the invention has the advantages of simple process, high yield and easy separation and purification of the product.
Compared with the prior art, the beneficial technical effects of the invention are as follows:
1: the 4-aryl (methyl) group-1, 4-benzoxazine imidazoline compound with the structural formula (IV) prepared by the invention is a brand new compound, and has very good antibacterial activity on crops; particularly has obvious effect of inhibiting the activity of the pathogenic bacteria of gibberella, phytophthora, rice blast, sclerotinia sclerotiorum, botrytis cinerea or sheath blight.
2: in the preparation method of the 4-aryl (methyl) 1, 4-benzoxazine imidazoline compound with the structural formula (IV), the synthetic raw materials are cheap and easy to obtain, the synthetic method is simple, the yield is higher, and the product is easy to separate and purify.
Drawings
FIG. 1 is a diagram showing the structure of the 4-aryl (methyl) 1, 4-benzoxazine-imidazoline compound with the general structural formula (IV).
FIG. 2 is a diagram of the synthetic route of the 4-aryl (methyl) 1, 4-benzoxazine-imidazoline compound with the general structural formula (IV) in the invention.
Detailed Description
The following examples illustrate the technical aspects of the invention, and the scope of the invention claimed includes but is not limited to the following examples.
Preparation of N- (2-bromoethyl) -1, 4-benzoxazine having the structural formula (II):
Preparation example 1
3, 4-dihydro-2H-1, 4-benzoxazine (1.35 g,0.01 mol) having the structural formula (I) and 20mL of anhydrous DMF were stirred in an ice-water bath and NaH (1.6 g,0.06 mol) was slowly added thereto, 10mL of 1, 2-dibromoethane was added after 30min, and the mixture was stirred for 5min and then transferred to an oil bath at 100℃for reaction for 12H. After the reaction is completed, adding a saturated sodium chloride solution after cooling, extracting with ethyl acetate for three times, washing an organic phase with distilled water (20 mL) and a saturated sodium chloride solution (20 mL) respectively for two times, drying with anhydrous sodium sulfate, decompressing and desolventizing, and separating by using a flash column chromatography to obtain the N- (2-bromoethyl) -1, 4-benzoxazine with the structural general formula (II).
Preparation of N- (2-arylaminoethyl) -1, 4-benzoxazine compounds with a structural general formula (III):
preparation example 2
Preparation of N- (2- (anilino) ethyl) -1, 4-benzoxazine:
n- (2-bromoethyl) -1, 4-benzoxazine (0.726 g,3 mmol), naI (0.495 g,3.3 mmol) were charged into a 100mL three-necked round bottom flask, 30mL acetonitrile was added as solvent, refluxed for 20min and cooled to room temperature, aniline (0.307 g,3.3 mmol) and anhydrous were addedK 2 CO 3 (0.8238 g,6 mmol) and the system was stirred at 90℃for 24h and cooled to room temperature after completion of the reaction. Filtering out the precipitate, concentrating the filtrate under reduced pressure, and separating by column chromatography to finally obtain the N- (2- (anilino) ethyl) -1, 4-benzoxazine.
Preparation example 3
Preparation of N- (2- (2-methylanilino) ethyl) -1, 4-benzoxazine:
n- (2-bromoethyl) -1, 4-benzoxazine (0.726 g,3 mmol), naI (0.495 g,3.3 mmol) were charged into a 100mL three-necked round bottom flask, 30mL acetonitrile was added as solvent, refluxed for 20min and cooled to room temperature, 2-methylaniline (0.353 g,3.3 mmol) and anhydrous K were added 2 CO 3 (0.8238 g,6 mmol) and the system was stirred at 90℃for 24h and cooled to room temperature after completion of the reaction. Filtering out the precipitate, concentrating the filtrate under reduced pressure, and separating by column chromatography to finally obtain the N- (2- (2-methylanilino) ethyl) -1, 4-benzoxazine.
Preparation example 4
Preparation of N- (2- (3-chloroanilino) ethyl) -1, 4-benzoxazine:
n- (2-bromoethyl) -1, 4-benzoxazine (0.726 g,3 mmol), naI (0.495 g,3.3 mmol) were charged into a 100mL three-necked round bottom flask, 30mL acetonitrile was added as solvent, refluxed for 20min and cooled to room temperature, and then 3-chloroaniline (0.319 g,3.3 mmol) and anhydrous K were added 2 CO 3 (0.8238 g,6 mmol) and the system was stirred at 90℃for 24h and cooled to room temperature after completion of the reaction. Filtering out the precipitate, concentrating the filtrate under reduced pressure, and separating by column chromatography to finally obtain the N- (2- (3-chloroanilino) ethyl) -1, 4-benzoxazine.
Preparation example 5
Preparation of N- (2- (4-methylanilino) ethyl) -1, 4-benzoxazine:
n- (2-bromoethyl) -1, 4-benzoxazine (0.726 g,3 mmol), naI (0.495 g,3.3 mmol) were charged into a 100mL three-necked round bottom flask, 30mL acetonitrile was added as solvent, refluxed for 20min and cooled to room temperature, and then 4-methylaniline (0.353 g,3.3 mmol) and anhydrous K were added 2 CO 3 (0.8238 g,6 mmol) and the system was stirred at 90℃for 24h and cooled to room temperature after completion of the reaction. Filtering out and depositingAnd concentrating the filtrate under reduced pressure, and separating by column chromatography to finally obtain the N- (2- (4-methylanilino) ethyl) -1, 4-benzoxazine.
Preparation example 6
Preparation of N- (2- (2-methoxyanilino) ethyl) -1, 4-benzoxazine:
n- (2-bromoethyl) -1, 4-benzoxazine (0.726 g,3 mmol), naI (0.495 g,3.3 mmol) were charged into a 100mL three-necked round bottom flask, 30mL acetonitrile was added as solvent, refluxed for 20min and cooled to room temperature, 2-methoxyaniline (0.406 g,3.3 mmol) and anhydrous K were added 2 CO 3 (0.8238 g,6 mmol) and the system was stirred at 90℃for 24h and cooled to room temperature after completion of the reaction. Filtering out the precipitate, concentrating the filtrate under reduced pressure, and separating by column chromatography to finally obtain the N- (2- (2-methoxyanilino) ethyl) -1, 4-benzoxazine.
Preparation example 7
Preparation of N- (2- (3-methoxyanilino) ethyl) -1, 4-benzoxazine:
n- (2-bromoethyl) -1, 4-benzoxazine (0.726 g,3 mmol), naI (0.495 g,3.3 mmol) were charged into a 100mL three-necked round bottom flask, 30mL acetonitrile was added as solvent, refluxed for 20min and cooled to room temperature, 3-methoxyaniline (0.406 g,3.3 mmol) and anhydrous K were added 2 CO 3 (0.8238 g,6 mmol) and the system was stirred at 90℃for 24h and cooled to room temperature after completion of the reaction. Filtering out the precipitate, concentrating the filtrate under reduced pressure, and separating by column chromatography to finally obtain the N- (2- (3-methoxyanilino) ethyl) -1, 4-benzoxazine.
Preparation example 8
Preparation of N- (2- (2-chloroanilino) ethyl) -1, 4-benzoxazine:
n- (2-bromoethyl) -1, 4-benzoxazine (0.726 g,3 mmol), naI (0.495 g,3.3 mmol) were charged into a 100mL three-necked round bottom flask, 30mL acetonitrile was added as solvent, refluxed for 20min and cooled to room temperature, 2-chloroaniline (0.319 g,3.3 mmol) and anhydrous K were added 2 CO 3 (0.8238 g,6 mmol) and the system was stirred at 90℃for 24h and cooled to room temperature after completion of the reaction. Filtering out precipitate, concentrating the filtrate under reduced pressure, separating by column chromatography to obtain N- (2- (2-chloroanilino) ethyl) -1,4-benzoxazines.
Preparation example 9
Preparation of N- (2- (3, 4-dimethylanilino) ethyl) -1, 4-benzoxazine:
n- (2-bromoethyl) -1, 4-benzoxazine (0.726 g,3 mmol), naI (0.495 g,3.3 mmol) were charged into a 100mL three-necked round bottom flask, 30mL acetonitrile was added as solvent, refluxed for 20min and cooled to room temperature, and then 3, 4-dimethylaniline (0.400 g,3.3 mmol) and anhydrous K were added 2 CO 3 (0.8238 g,6 mmol) and the system was stirred at 90℃for 24h and cooled to room temperature after completion of the reaction. Filtering out the precipitate, concentrating the filtrate under reduced pressure, and separating by column chromatography to finally obtain the N- (2- (3, 4-dimethylanilino) ethyl) -1, 4-benzoxazine.
Preparation example 10
Preparation of N- (2- (3-ethylamino) ethyl) -1, 4-benzoxazine:
n- (2-bromoethyl) -1, 4-benzoxazine (0.726 g,3 mmol), naI (0.495 g,3.3 mmol) were charged into a 100mL three-necked round bottom flask, 30mL acetonitrile was added as solvent, refluxed for 20min and cooled to room temperature, and then 3-ethylaniline (0.400 g,3.3 mmol) and anhydrous K were added 2 CO 3 (0.8238 g,6 mmol) and the system was stirred at 90℃for 24h and cooled to room temperature after completion of the reaction. Filtering out the precipitate, concentrating the filtrate under reduced pressure, and separating by column chromatography to finally obtain the N- (2- (3-ethyl anilino) ethyl) -1, 4-benzoxazine.
Preparation example 11
Preparation of N- (2- (benzylamino) ethyl) -1, 4-benzoxazine:
n- (2-bromoethyl) -1, 4-benzoxazine (0.726 g,3 mmol), naI (0.495 g,3.3 mmol) were charged into a 100mL three-necked round bottom flask, 30mL acetonitrile was added as solvent, refluxed for 20min and cooled to room temperature, and benzylamine (0.353 g,3.3 mmol) and anhydrous K were added 2 CO 3 (0.8238 g,6 mmol) and the system was stirred at 90℃for 24h and cooled to room temperature after completion of the reaction. The precipitate is filtered, the filtrate is concentrated under reduced pressure and separated by column chromatography, and finally N- (2- (benzylamino) ethyl) -1, 4-benzoxazine is obtained.
Preparation example 12
Preparation of N- (2- (3-methylbenzylamino) ethyl) -1, 4-benzoxazine:
n- (2-bromoethyl) -1, 4-benzoxazine (0.726 g,3 mmol), naI (0.495 g,3.3 mmol) were charged into a 100mL three-necked round bottom flask, 30mL acetonitrile was added as solvent, refluxed for 20min and cooled to room temperature, 3-methylbenzylamine (0.400 g,3.3 mmol) and anhydrous K were added 2 CO 3 (0.8238 g,6 mmol) and the system was stirred at 90℃for 24h and cooled to room temperature after completion of the reaction. Filtering out the precipitate, concentrating the filtrate under reduced pressure, and separating by column chromatography to finally obtain the N- (2- (3-methylbenzylamino) ethyl) -1, 4-benzoxazine.
Preparation example 13
Preparation of N- (2- (3-chlorobenzylamino) ethyl) -1, 4-benzoxazine:
n- (2-bromoethyl) -1, 4-benzoxazine (0.726 g,3 mmol), naI (0.495 g,3.3 mmol) were charged into a 100mL three-necked round bottom flask, 30mL acetonitrile was added as solvent, refluxed for 20min and cooled to room temperature, 3-chlorobenzylamine (0.460 g,3.3 mmol) and anhydrous K were added 2 CO 3 (0.8238 g,6 mmol) and the system was stirred at 90℃for 24h and cooled to room temperature after completion of the reaction. Filtering out the precipitate, concentrating the filtrate under reduced pressure, and separating by column chromatography to finally obtain the N- (2- (3-chlorobenzylamino) ethyl) -1, 4-benzoxazine.
Synthesis of 4-aryl (methyl) 1, 4-benzoxazinoimidazoline compounds having the general structural formula (IV):
example 1
Synthesis of 4-phenyl-1, 4-benzoxazinoimidazoline:
n- (2- (anilino) ethyl) -1, 4-benzoxazine (1.2707 g,5.0 mmol), cu (OAc) was weighed out 2 (0.5989g,3mmol)，Ag 2 CO 3 (4.1363 g,15 mmol) was added to a 250mL round bottom flask, and 20mL DMF was added as solvent and heated to reflux in an oil bath at 120deg.C for 12h (TLC plate tracking). After the reaction is completed, the mixture is filtered and extracted (the organic phase is obtained by extracting with methylene dichloride and is washed by saturated sodium chloride solutionWashing organic phase), drying with sodium sulfate, removing solvent under reduced pressure, separating by column chromatography to obtain yellowish brown solid with melting point (mp): 83.5 to 85.6, yield: 65.0%.
1 H NMR(500MHz,CDCl3)δ7.32(dd,J＝8.8,7.3Hz,2H),7.01–6.94(m,3H),6.85(ttd,J＝6.1,3.6,2.9,1.7Hz,2H),6.81–6.75(m,2H),4.72(dd,J＝9.0,2.7Hz,1H),4.66(dd,J＝10.5,2.7Hz,1H),4.02(ddd,J＝8.5,6.1,2.0Hz,1H),3.73(ddd,J＝7.6,6.3,2.0Hz,1H),3.46(tdd,J＝17.7,9.1,6.7Hz,2H),3.26(dd,J＝10.5,8.9Hz,1H).
13 C NMR(101MHz,Chloroform-d)δ146.77,145.09,134.08,129.60(2C),122.03,120.63,118.91,118.53,117.07,113.17(2C),70.56,64.07,50.17,47.08.
Example 2
Synthesis of 4- (2-methylphenyl) -1, 4-benzoxazinoimidazoline:
n- (2- (2-methylanilino) ethyl) -1, 4-benzoxazine (1.3407 g,5.0 mmol), cu (OAc) was weighed out 2 (0.5989g,3mmol)，Ag 2 CO 3 (4.1363 g,15 mmol) was added to a 250mL round bottom flask, and 20mL DMF was added as solvent and heated to reflux in an oil bath at 120deg.C for 12h (TLC plate tracking). After the reaction is completed, carrying out suction filtration and extraction (extracting with dichloromethane to obtain an organic phase, washing the organic phase with saturated sodium chloride solution), drying with sodium sulfate, carrying out reduced pressure desolventizing, carrying out column chromatography separation after reduced pressure desolventizing, and finally obtaining brown solid; melting point: 90.8-92.4; yield: 58.0%.
1 H NMR(500MHz,CDCl3)δ7.33–7.22(m,3H),7.12(td,J＝7.4,1.4Hz,1H),7.02–6.93(m,2H),6.82–6.71(m,2H),4.84(dd,J＝8.6,3.4Hz,1H),4.31(dd,J＝10.2,3.4Hz,1H),3.85(ddd,J＝8.3,6.5,3.0Hz,1H),3.64(ddd,J＝9.3,6.6,3.0Hz,1H),3.53(td,J＝8.1,6.6Hz,1H),3.34(dd,J＝10.2,8.6Hz,1H),3.20(ddd,J＝9.1,8.1,6.6Hz,1H),2.37(s,3H).
13 C NMR(125MHz,CDCl3)δ146.26,143.68,134.87,134.75,131.47,127.07,124.79,122.37,120.88,118.07,116.48,114.33,72.13,66.55,51.81,48.62,18.43.
Example 3
Synthesis of 4- (3-chlorophenyl) -1, 4-benzoxazinoimidazoline:
n- (2- (3-Chloroamino) ethyl) -1, 4-benzoxazine (1.4405 g,5.0 mmol), cu (OAc) was weighed out 2 (0.5989g,3mmol)，Ag 2 CO 3 (4.1363 g,15 mmol) was added to a 250mL round bottom flask, and 20mL DMF was added as solvent and heated to reflux in an oil bath at 120deg.C for 12h (TLC plate tracking). After the reaction is completed, the mixture is subjected to suction filtration and extraction (the organic phase is obtained by extraction with methylene dichloride, the organic phase is washed by saturated sodium chloride solution), sodium sulfate drying and reduced pressure desolventizing, and after the reduced pressure desolventizing, the mixture is separated by column chromatography, and finally light yellow solid is obtained, and the melting point is obtained: 114.3-115.7; yield: 57.8%.
1 H NMR(500MHz,CDCl3)δ7.20(t,J＝8.1Hz,1H),7.01–6.93(m,3H),6.89–6.79(m,2H),6.73(s,1H),6.62(dd,J＝8.4,2.4Hz,1H),4.69(dd,J＝9.0,2.7Hz,1H),4.58(dd,J＝10.6,2.7Hz,1H),4.06–3.99(m,1H),3.71–3.65(m,1H),3.52–3.38(m,2H),3.30–3.22(m,1H).
13 C NMR(125MHz,CDCl3)δ147.72,145.13,135.46,133.82,130.54,122.10,120.97,119.19,118.39,117.15,113.13,111.21,70.44,63.56,50.23,46.92.
Example 4
Synthesis of 4- (4-methylphenyl) -1, 4-benzoxazinoimidazoline:
n- (2- (4-methylanilino) ethyl) -1, 4-benzoxazine (1.3407 g,5.0 mmol), cu (OAc) was weighed out 2 (0.5989g,3mmol)，、Ag 2 CO 3 (4.1363 g,15 mmol) was addedIn a 250mL round bottom flask, 20mL of DMF was added as solvent and heated to reflux in an oil bath at 120℃for 12h (TLC plate tracking). After the reaction is completed, the yellow brown solid is finally obtained through suction filtration, extraction (the organic phase is obtained by extraction with methylene dichloride, the organic phase is washed by saturated sodium chloride solution), drying by sodium sulfate, decompression desolventizing, column chromatography separation after decompression desolventizing, and melting point: 112.8-114.9; yield: 68.0%.
1 H NMR(500MHz,CDCl 3 )δ7.09(d,J＝8.1Hz,2H),6.97–6.91(m,3H),6.83–6.78(m,1H),6.67(d,J＝8.5Hz,2H),4.63(dd,J＝16.3,9.6Hz,2H),3.97(t,J＝6.9Hz,1H),3.69(t,J＝6.9Hz,1H),3.46–3.34(m,2H),3.26–3.18(m,1H),2.28(s,3H).
13 C NMR(125MHz,CDCl3)δ144.95,144.69,134.13,130.05(2C),127.86,122.00,120.36,118.55,116.98,113.36(2C),70.75,64.40,49.98,47.45,20.44.
Example 5
Synthesis of 4- (2-methoxyphenyl) -1, 4-benzoxazinoimidazoline:
n- (2- (2-Methoxyanilino) ethyl) -1, 4-benzoxazine (1.4207 g,5.0 mmol), cu (OAc) was weighed out 2 (0.5989g,3mmol)，、Ag 2 CO 3 (4.1363 g,15 mmol) was added to a 250mL round bottom flask, and 20mL DMF was added as solvent and heated to reflux in an oil bath at 120deg.C for 12h (TLC plate tracking). After the reaction is completed, carrying out suction filtration and extraction (the organic phase is obtained by extracting with dichloromethane, and is washed by saturated sodium chloride solution), drying by sodium sulfate, desolventizing under reduced pressure, separating by column chromatography after desolventizing under reduced pressure, and finally obtaining yellow brown oily substance; yield: 53.2%.
1 H NMR(500MHz,CDCl 3 )δ7.07–7.00(m,2H),6.98–6.85(m,4H),6.79–6.68(m,2H),4.93(dd,J＝8.6,3.2Hz,1H),4.44(dd,J＝10.1,3.1Hz,1H),4.05–3.92(m,1H),3.89(s,3H),3.80(dtd,J＝8.6,4.1,2.5Hz,1H),3.59–3.48(m,1H),3.36–3.23(m,2H).
13 C NMR(125MHz,CDCl 3 )δ152.25,143.75,136.27,134.44,123.07,122.23,121.32,118.44,118.20,116.37,114.77,112.05,77.44,70.32,65.86,55.61,49.19,48.30.
Example 6
Synthesis of 4- (3-methoxyphenyl) -1, 4-benzoxazinoimidazoline:
n- (2- (3-Methoxyanilino) ethyl) -1, 4-benzoxazine (1.4207 g,5.0 mmol), cu (OAc) was weighed out 2 (0.5989g,3mmol)，、Ag 2 CO 3 (4.1363 g,15 mmol) was added to a 250mL round bottom flask, and 20mL DMF was added as solvent and heated to reflux in an oil bath at 120deg.C for 12h (TLC plate tracking). After the reaction is completed, carrying out suction filtration and extraction (extracting with dichloromethane to obtain an organic phase, washing the organic phase with saturated sodium chloride solution), drying with sodium sulfate, carrying out reduced pressure desolventizing, carrying out column chromatography separation after reduced pressure desolventizing, and finally obtaining yellow brown solid; melting point: 80.6-84.3; yield: 52.4%.
1 H NMR(500MHz,CDCl 3 )δ7.05–7.01(m,2H),6.98–6.90(m,4H),6.78–6.70(m,2H),4.93(dd,J＝8.6,3.2Hz,1H),4.46(dd,J＝10.2,3.2Hz,1H),3.98(ddd,J＝9.1,6.9,4.1Hz,1H),3.89(s,3H),3.83–3.76(m,2H),3.55(dt,J＝8.5,7.1Hz,1H),3.36–3.26(m,2H).
13 C NMR(125MHz,CDCl 3 )δ152.24,143.74,136.26,134.43,123.07,122.24,121.31,118.43,118.19,116.37,114.77,112.04,70.31,65.86,55.62,49.19,48.30.
Example 7
Synthesis of 4- (2-chlorophenyl) -1, 4-benzoxazinoimidazoline:
n- (2- (2-Chloroanilino) ethyl) -1, 4-benzoxazine (1.4405 g,5.0 mmol) was weighed out)，Cu(OAc) 2 (0.5989g,3mmol)，、Ag 2 CO 3 (4.1363 g,15 mmol) was added to a 250mL round bottom flask, and 20mL DMF was added as solvent and heated to reflux in an oil bath at 120deg.C for 12h (TLC plate tracking). After the reaction is completed, carrying out suction filtration and extraction (extracting with dichloromethane to obtain an organic phase, washing the organic phase with saturated sodium chloride solution), drying with sodium sulfate, carrying out reduced pressure desolventizing, carrying out column chromatography separation after reduced pressure desolventizing, and finally obtaining brown oily matter; yield: 44.0%.
1 H NMR(500MHz,CDCl 3 )δ7.32(dd,J＝8.7,7.3Hz,2H),6.99–6.96(m,2H),6.87(tdd,J＝5.9,4.4,2.4Hz,2H),6.80–6.76(m,2H),4.72(dd,J＝8.9,2.7Hz,1H),4.65(dd,J＝10.5,2.7Hz,1H),4.02(ddd,J＝8.5,6.1,2.0Hz,1H),3.75(ddd,J＝7.7,6.3,2.1Hz,1H),3.54–3.39(m,2H),3.28(dd,J＝10.5,9.0Hz,1H).
13 C NMR(125MHz,CDCl 3 )δ146.77,145.09,134.08,129.60(2C),122.03,120.64,118.92,118.53,117.07,113.17(2C),70.56,64.07,50.17,47.08.
Example 8
Synthesis of 4- (3, 4-dimethylphenyl) -1, 4-benzoxazinoimidazoline:
n- (2- (3, 4-dimethylanilino) ethyl) -1, 4-benzoxazine (1.4108 g,5.0 mmol), cu (OAc) was weighed out 2 (0.5989g,3mmol)，、Ag 2 CO 3 (4.1363 g,15 mmol) was added to a 250mL round bottom flask, and 20mL DMF was added as solvent and heated to reflux in an oil bath at 120deg.C for 12h (TLC plate tracking). After the reaction is completed, carrying out suction filtration and extraction (the organic phase is obtained by extracting with dichloromethane, and is washed by saturated sodium chloride solution), drying by sodium sulfate, carrying out reduced pressure desolventizing, carrying out column chromatography separation after the reduced pressure desolventizing, and finally obtaining yellow brown solid with the melting point of 121.4-122.8; yield: 66.4%.
1 H NMR(500MHz,CDCl3)δ7.08(d,J＝8.2Hz,1H),7.02–6.93(m,3H),6.88–6.80(m,1H),6.64–6.52(m,2H),4.72–4.63(m,2H),4.05–3.96(m,1H),3.73(d,J＝6.0Hz,1H),3.50–3.38(m,2H),3.31–3.21(m,1H),2.29(s,3H),2.22(s,3H).
13 C NMR(125MHz,CDCl3)δ145.16,144.98,137.71,134.23,130.61,126.78,122.04,120.29,118.44,116.98,115.03,110.95,70.72,64.58,49.94,47.53,20.37,18.79.
Example 9
Synthesis of 4- (3-ethylphenyl) -1, 4-benzoxazinoimidazoline:
n- (2- (3-ethylamino) ethyl) -1, 4-benzoxazine (1.4108 g,5.0 mmol), cu (OAc) was weighed out 2 (0.5989g,3mmol)，、Ag 2 CO 3 (4.1363 g,15 mmol) was added to a 250mL round bottom flask, and 20mL DMF was added as solvent and heated to reflux in an oil bath at 120deg.C for 12h (TLC plate tracking). After the reaction is completed, carrying out suction filtration and extraction (extracting with dichloromethane to obtain an organic phase, washing the organic phase with saturated sodium chloride solution), drying with sodium sulfate, carrying out reduced pressure desolventizing, carrying out column chromatography separation after reduced pressure desolventizing, and finally obtaining yellow brown solid; a melting point; 105.3-108.8; melting point: 66.7%.
1 H NMR(500MHz,CDCl 3 )δ7.21(dd,J＝9.0,7.2Hz,1H),6.98–6.92(m,3H),6.84(ddd,J＝8.3,5.7,3.3Hz,1H),6.70(d,J＝7.5Hz,1H),6.59(d,J＝6.8Hz,2H),4.70(dd,J＝9.0,2.7Hz,1H),4.64(dd,J＝10.5,2.7Hz,1H),4.01(ddd,J＝8.5,6.5,2.0Hz,1H),3.72(td,J＝6.4,3.1Hz,1H),3.50–3.44(m,1H),3.43–3.37(m,1H),3.25(dd,J＝10.5,9.0Hz,1H),2.63(q,J＝7.6Hz,2H),1.26(d,J＝7.5Hz,3H).
13 C NMR(125MHz,CDCl 3 )δ146.87,145.88,145.05,134.15,129.54,122.04,120.53,118.81,118.24,117.03,112.83,110.66,70.54,64.22,50.10,47.15,29.40,15.87.
Example 10
Synthesis of 4-benzyl-1, 4-benzoxazinoimidazoline:
n- (2- (benzylamino) ethyl) -1, 4-benzoxazine (1.3407 g,5.0 mmol), cu (OAc) was weighed out 2 (0.5989g,3mmol)，、Ag 2 CO 3 (4.1363 g,15 mmol) was added to a 250mL round bottom flask, and 20mL DMF was added as solvent and heated to reflux in an oil bath at 120deg.C for 12h (TLC plate tracking). After the reaction is completed, carrying out suction filtration and extraction (extracting with dichloromethane to obtain an organic phase, washing the organic phase with saturated sodium chloride solution), drying with sodium sulfate, carrying out reduced pressure desolventizing, carrying out column chromatography separation after reduced pressure desolventizing, and finally obtaining brown solid; melting point: 73.3-75.1; yield: 40.0%.
1 H NMR(500MHz,CDCl 3 )δ7.40–7.27(m,5H),6.94–6.85(m,2H),6.66(t,J＝7.5Hz,2H),4.01(dd,J＝10.0,3.5Hz,1H),3.94(dd,J＝8.6,3.5Hz,1H),3.80(q,J＝12.9Hz,2H),3.69(t,J＝6.9Hz,1H),3.31–3.23(m,2H),3.18(dd,J＝10.0,8.6Hz,1H),2.82–2.72(m,1H).
13 C NMR(125MHz,CDCl 3 )δ143.37,138.35,134.49,128.95(2C),128.63(2C),127.71,122.37,117.51,116.24,113.37,74.74,67.42,58.66,52.26,47.47.
Example 11
Synthesis of 4- (3-methylbenzyl) -1, 4-benzoxazinoimidazoline:
n- (2- (3-methylbenzylamino) ethyl) -1, 4-benzoxazine (1.4108 g,5.0 mmol), cu (OAc) was weighed out 2 (0.5989g,3mmol)，、Ag 2 CO 3 (4.1363 g,15 mmol) was added to a 250mL round bottom flask, and 20mL DMF was added as solvent and heated to reflux in an oil bath at 120deg.C for 12h (TLC plate tracking). After the reaction is completed, the organic phase is obtained by suction filtration and extraction (the organic phase is washed by using methylene dichloride solution), dried by sodium sulfate and desolventized under reduced pressure, and separated by column chromatography after desolventized under reduced pressureFinally, brown solid is obtained; melting point: 69.6-71.8; yield is improved; 47.1%.
1 H NMR(500MHz,CDCl 3 )δ7.29–7.22(m,1H),7.18(dd,J＝23.7,6.7Hz,3H),6.97–6.87(m,2H),6.68(t,J＝7.6Hz,2H),4.03(dd,J＝10.1,3.4Hz,1H),3.95(dd,J＝8.7,3.5Hz,1H),3.85–3.66(m,3H),3.35–3.26(m,2H),3.22–3.15(m,1H),2.79(h,J＝6.6,5.9Hz,1H),2.39(s,3H).
13 C NMR(125MHz,CDCl 3 )δ143.37,138.29,138.25,134.52,129.68,128.51,128.45,126.03,122.37,117.48,116.23,113.32,74.77,67.47,58.68,52.31,47.44,21.53.
Example 12
Synthesis of 4- (3-chlorobenzyl) -1, 4-benzoxazinoimidazoline:
n- (2- (3-chlorobenzylamino) ethyl) -1, 4-benzoxazine (1.5106 g,5.0 mmol), cu (OAc) was weighed out 2 (0.5989g,3mmol)，、Ag 2 CO 3 (4.1363 g,15 mmol) was added to a 250mL round bottom flask, and 20mL DMF was added as solvent and heated to reflux in an oil bath at 120deg.C for 12h (TLC plate tracking). After the reaction is completed, carrying out suction filtration and extraction (extracting with dichloromethane to obtain an organic phase, washing the organic phase with saturated sodium chloride solution), drying with sodium sulfate, carrying out reduced pressure desolventizing, carrying out column chromatography separation after the reduced pressure desolventizing, and finally obtaining a white solid; melting point: 61.4-63.5; yield: 54.6%.
1 H NMR(500MHz,CDCl 3 )δ7.40(s,1H),7.34–7.24(m,3H),6.93(ddd,J＝16.1,8.0,1.4Hz,2H),6.69(tt,J＝7.9,1.5Hz,2H),4.08(dd,J＝10.1,3.5Hz,1H),3.96(dd,J＝8.7,3.5Hz,1H),3.86(d,J＝13.2Hz,1H),3.73(dd,J＝13.6,5.5Hz,2H),3.34–3.17(m,3H),2.82–2.71(m,1H).
13 C NMR(125MHz,CDCl 3 )δ143.35,140.57,134.53,134.40,129.89,128.87,127.87,126.91,122.45,117.68,116.31,113.49,74.72,67.34,57.96,52.16,47.55.
The chemical reagent sources or structural formulas used in the various embodiments of the present invention are as follows:
activity effect test
The bactericidal activity was tested using an ex vivo method on 4-phenyl-1, 4-benzoxazinoimidazoline, 4- (2-methylphenyl) -1, 4-benzoxazinoimidazoline, 4- (3-chlorophenyl) -1, 4-benzoxazinoimidazoline, 4- (4-methylphenyl) -1, 4-benzoxazinoimidazoline, 4- (2-methoxyphenyl) -1, 4-benzoxazinoimidazoline, 4- (3-methoxyphenyl) -1, 4-benzoxazinoimidazoline, 4- (2-chlorophenyl) -1, 4-benzoxazinoimidazoline, 4- (3, 4-dimethylphenyl) -1, 4-benzoxazinoimidazoline, 4- (3-ethylphenyl) -1, 4-benzoxazinoimidazoline, 4-benzyl-1, 4-benzoxazinoimidazoline, 4- (3-methylbenzyl) -1, 4-benzoxazinoimidazoline, 4- (3-chlorobenzyl) -1, 4-benzoxazinoimidazoline.
The test materials for testing the bactericidal activity are selected from gibberella, phytophthora, rice blast, sclerotinia, botrytis or sheath blight, the test reagents are dissolved in acetone, and then 200g/mL of sorrel-144 emulsifying agent is used for diluting into 500g/mL of liquid medicine. Under aseptic operating conditions, 1mL of the compound solution was pipetted into a sterilized dish, and then 9mL of sterilized PDA culture-based dish was pipetted into the dish, and mixed well to prepare a drug-containing plate of the corresponding concentration. And (3) cutting bacterial cakes from the edges of bacterial colonies by using a sterilization puncher with the diameter of 4mm under the aseptic condition, inoculating the bacterial cakes to the center of a medicine-containing flat plate by using an inoculator after the culture medium is solidified, and culturing in an incubator with proper temperature. Blank control was made with no drug added. The individual treatments were incubated in an incubator at 24.+ -. 1 ℃ and after 72 hours the colony diameters were observed and measured, and the diameters were measured vertically once for each colony by the crisscross method, and the average value was obtained.
Growth inhibition (%) = (control colony diameter-treated colony diameter) ×100/(control colony diameter-4 mm).
The drug concentration was 50. Mu.g/mL. The results of the bactericidal activity test are shown in the following table.
Table antibacterial Activity results (inhibition ratio/%) of 4-aryl (methyl) 1, 4-benzoxazinoimidazoline compounds
As can be seen from Table I, the target compounds have moderate to good inhibitory activity against the test pathogens. Wherein, the inhibition rate of 4- (4-methylphenyl) -1, 4-benzoxazine-imidazoline to rice blast germ is up to 93.9 percent, and the inhibition rate of 4-benzyl-1, 4-benzoxazine-imidazoline is up to 91.8 percent; the inhibition rate of 4- (2-methylphenyl) -1, 4-benzoxazinoimidazoline to phytophthora bacteria is up to 90.3%, the inhibition rate of 4- (3, 4-dimethylphenyl) -1, 4-benzoxazinoimidazoline is up to 83.8%, the inhibition rate of 4- (3-chlorophenyl) -1, 4-benzoxazinoimidazoline is 78.9%, the inhibition rate of 4- (4-methylphenyl) -1, 4-benzoxazinoimidazoline is 77.4%, the inhibition rate of 4- (3-methoxyphenyl) -1, 4-benzoxazinoimidazoline is 76.7%, and the inhibition rate of 4- (3-ethylphenyl) -1, 4-benzoxazinoimidazoline is 70.0%; the inhibition rate of the 4-phenyl-1, 4-benzoxazinoimidazoline to sclerotinia sclerotiorum is up to 81.4 percent, and the inhibition rate of the 4- (2-methoxyphenyl) -1, 4-benzoxazinoimidazoline is 77.9 percent; the inhibition ratio of 4-phenyl-1, 4-benzoxazine-imidazoline to botrytis cinerea is up to 82.4%, the inhibition ratio of 4- (2-methoxyphenyl) -1, 4-benzoxazine-imidazoline is 71.8%, the inhibition ratio of 4- (2-chlorophenyl) -1, 4-benzoxazine-imidazoline is 75.8%, the inhibition ratio of 4- (3-ethylphenyl) -1, 4-benzoxazine-imidazoline is 78.4%, the inhibition ratio of 4-benzyl-1, 4-benzoxazine-imidazoline is 74.5%, the inhibition ratio of 4- (3-methylbenzyl) -1, 4-benzoxazine-imidazoline is 70.5%, and the inhibition ratio of 4- (3-chlorobenzyl) -1, 4-benzoxazine-imidazoline is 75.8%.
Claims (10)
1. A 4-aryl (methyl) group-1, 4-benzoxazine imidazoline compound, which is characterized in that: the compound is shown in the following structural general formula (IV):
in the formula (IV), n is an integer of 0-12, and R is one or more selected from H, alkyl, alkoxy and halogen atoms.
2. A compound according to claim 1, characterized in that: the n is an integer of 0 to 6, and the R is H, C 1 -C 8 Alkyl, C of (2) 1 -C 8 One or more of alkoxy groups, halogen atoms.
3. A compound according to claim 1 or 2, characterized in that: and n is 0 or 1, wherein:
when n=0, the R is H, C 1 -C 4 Alkyl, C of (2) 1 -C 4 Preferably R is H, 2-CH 3 、3-Cl、4-CH 3 、2-OCH 3 、3-OCH 3 、2-Cl、3,4-(CH 3 ) 2 、3-CH 2 CH 3 One of the following;
when n=1, the R is H, C 1 -C 2 Preferably, R is H, 3-CH 3 One of 3-Cl.
4. A compound according to any one of claims 1 to 3, characterized in that: the 4-aryl (methyl) group-1, 4-benzoxazine imidazoline compound with the structural general formula (IV) is selected from one or more of the following compounds:
4-phenyl-1, 4-benzoxazinoimidazoline:
4- (2-methylphenyl) -1, 4-benzoxazinoimidazoline:
4- (3-chlorophenyl) -1, 4-benzoxazinoimidazoline:
4- (4-methylphenyl) -1, 4-benzoxazinoimidazoline:
4- (2-methoxyphenyl) -1, 4-benzoxazinoimidazoline:
4- (3-methoxyphenyl) -1, 4-benzoxazinoimidazoline:
4- (2-chlorophenyl) -1, 4-benzoxazinoimidazoline:
4- (3, 4-dimethylphenyl) -1, 4-benzoxazinoimidazoline:
4- (3-ethylphenyl) -1, 4-benzoxazinoimidazoline:
4-benzyl-1, 4-benzoxazinoimidazoline:
4- (3-methylbenzyl) -1, 4-benzoxazinoimidazoline:
4- (3-chlorobenzyl) -1, 4-benzoxazinoimidazoline:
5. a process for preparing 4-aryl (meth) 1, 4-benzoxazinoimidazolins of the general structural formula (IV) or a process for preparing 4-aryl (meth) 1, 4-benzoxazinoimidazolins of the general structural formula (IV) as claimed in any of claims 1 to 4: the method is characterized in that: the method specifically comprises the following steps:
s1) reacting 3, 4-dihydro-2H-1, 4-benzoxazine having the structural formula (I) with 1, 2-dibromoethane in the presence of a base in a first solvent to obtain N- (2-bromoethyl) -1, 4-benzoxazine having the structural formula (II):
s2) reacting N- (2-bromoethyl) -1, 4-benzoxazine with a structural formula (II) with an arylamine compound with a structural formula (V) in the presence of alkali and a first catalyst in a second solvent to obtain the N- (2-arylaminoethyl) -1, 4-benzoxazine compound with a structural formula (III):
S3) reacting the N- (2-arylaminoethyl) -1, 4-benzoxazine compound with the structural formula (III) in the presence of a second catalyst in a third solvent to obtain the 4-aryl (methyl) group-1, 4-benzoxazine-imidazoline compound with the structural formula (IV):
wherein: n is an integer of 0-12, and R is one or more selected from H, alkyl, alkoxy and halogen atoms; preferably, n is an integer of 0 to 6, and R is H, C 1 -C 8 Alkyl, C of (2) 1 -C 8 One or more of alkoxy groups, halogen atoms.
6. The method according to claim 5, wherein: and n is 0 or 1, wherein:
when n=0, the R is H, C 1 -C 4 Alkyl, C of (2) 1 -C 4 Preferably R is H, 2-CH 3 、3-Cl、4-CH 3 、2-OCH 3 、3-OCH 3 、2-Cl、3,4-(CH 3 ) 2 、3-CH 2 CH 3 One of the following;
when n=1, the R is H, C 1 -C 2 Preferably, R is H, 3-CH 3 One of 3-Cl.
7. The method according to claim 5 or 6, characterized in that: in step S1): the first solvent is an organic solvent, preferably the organic solvent is N, N-Dimethylformamide (DMF); the alkali is NaH; and/or
In step S2): the second solvent is an organic solvent, preferably acetonitrile; the alkali is Na 2 CO 3 、K 2 CO 3 And one or both, preferably K 2 CO 3 The method comprises the steps of carrying out a first treatment on the surface of the The first catalyst is one or two of KI and NaI, preferably NaI; and/or
In step S3): the third solvent is an organic solvent, preferably the organic solvent is N, N-Dimethylformamide (DMF); the second catalyst is Cu (OAc) 2 、Ag 2 CO 3 One or both of them, preferably Cu (OAc) 2 And Ag 2 CO 3 Is a mixture of (a) and (b).
8. The method according to any one of claims 5-7, characterized in that: in step S1): the molar ratio of the 3, 4-dihydro-2H-1, 4-benzoxazine with the structural formula (I), the 1, 2-dibromoethane and the alkali is 1:8-20:4-12, preferably 1:10-15:6-10; and/or
In step S2): the molar ratio of the N- (2-bromoethyl) -1, 4-benzoxazine with the structural formula (II), the arylamine compound with the structural formula (V), the alkali and the first catalyst is 1:1-3:1.5-4:0.8-2.5, preferably 1:1.1-2:1.8-3:1-2; and/or
In step S3): the molar ratio of the N- (2-arylaminoethyl) -1, 4-benzoxazine compound with the structural general formula (III) to the second catalyst is 1:2.5-6, preferably 1:3-5.
9. The method according to claim 8, wherein: the step S1) is specifically as follows: adding 3, 4-dihydro-2H-1, 4-benzoxazine and 1, 2-dibromoethane with the structural formula (I) into a reaction container in proportion, slowly adding alkali under the condition of ice water bath stirring, adding a first solvent, uniformly stirring, reacting under an oil bath (preferably at the temperature of 90-110 ℃) for 8-24 hours, cooling and adding a saturated sodium chloride solution after the reaction is finished, extracting with ethyl acetate (preferably for 1-5 times), washing the obtained organic phase with distilled water and saturated sodium chloride solution (preferably with distilled water and saturated sodium chloride for 1-4 times), drying (preferably with anhydrous sodium sulfate), decompressing, desolventizing and separating and purifying by column chromatography to obtain N- (2-bromoethyl) -1, 4-benzoxazine with the structural formula (II); and/or
The step S2) is specifically as follows: adding N- (2-bromoethyl) -1, 4-benzoxazine with a structural formula (II) and a first catalyst into a reaction container in proportion, adding a second solvent for reaction (preferably reflux reaction, wherein the reaction temperature is 80-85 ℃ and the reaction time is 10-60 min), cooling to room temperature after the reaction is finished, adding an arylamine compound with a structural formula (V) and alkali in proportion for reaction (preferably stirring reaction, the reaction temperature is 85-110 ℃ and the reaction time is 10-36 h), cooling to room temperature after the reaction is finished, filtering, and sequentially carrying out reduced pressure desolventizing and column chromatography separation and purification on filtrate to obtain the N- (2-arylaminoethyl) -1, 4-benzoxazine with the structural formula (III); and/or
The step S3) is specifically as follows: adding the N- (2-arylaminoethyl) -1, 4-benzoxazine compound with the structural formula (III) and a second catalyst into a reaction container according to a certain proportion, then adding a third solvent for reaction (preferably reflux reaction, the reaction temperature is 100-150 ℃ and the reaction time is 8-20 h), filtering after the reaction is finished, extracting filtrate with dichloromethane (preferably the extraction times are 1-3 times), washing the obtained organic phase with saturated sodium chloride solution (preferably 1-3 times), drying (preferably drying with anhydrous sodium sulfate), decompressing, desolventizing, separating and purifying by column chromatography to obtain the 4-aryl (methyl) -1, 4-benzoxazine imidazoline compound with the structural formula (IV).
10. Use of a 4-aryl (meth) 1, 4-benzoxazinoimidazoline compound of the general structural formula (IV) or a 4-aryl (meth) 1, 4-benzoxazinoimidazoline compound of the general structural formula (IV) according to any one of claims 1 to 4 or a 4-aryl (meth) 1, 4-benzoxazinoimidazoline compound of the general structural formula (IV) prepared by the method according to any one of claims 5 to 9, characterized in that: the 4-aryl (methyl) -1, 4-benzoxazine imidazoline compound with the structural formula (IV) is used for bacteriostasis of crops; is particularly used for inhibiting one or more of gibberella, phytophthora, rice blast, sclerotinia, botrytis and sheath blight; preferably, the 4-aryl (methyl) -1, 4-benzoxazinoimidazoline compound with the structural formula (IV) is used for inhibiting rice blast bacteria and/or phytophthora infestans;
preferably, the 4-aryl (methyl) -1, 4-benzoxazinoimidazoline compound with the structural formula (IV) is used for preparing a medicament for inhibiting bacteria of crops, and is particularly used for preparing a medicament for inhibiting one or more pathogens of gibberella, phytophthora, rice blast, sclerotinia, botrytis and sheath blight; preferably, the 4-aryl (methyl) -1, 4-benzoxazinoimidazoline compound with the structural general formula (IV) is used for preparing medicines for inhibiting rice blast bacteria and/or phytophthora infestans.
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| CN101679454A (en) * | 2007-03-02 | 2010-03-24 | 盟科医药有限公司 | Antimicrobial heterocyclic compounds for treatment of bacterial infections |
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