CN1785993A - Preparation method of non natural isocumarin and its 3,4-dihydro derivative and use thereof - Google Patents

Preparation method of non natural isocumarin and its 3,4-dihydro derivative and use thereof Download PDF

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CN1785993A
CN1785993A CNA200510122353XA CN200510122353A CN1785993A CN 1785993 A CN1785993 A CN 1785993A CN A200510122353X A CNA200510122353X A CN A200510122353XA CN 200510122353 A CN200510122353 A CN 200510122353A CN 1785993 A CN1785993 A CN 1785993A
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isocoumarin
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范志金
瓜勒姆﹒瓜弟尔
那斯姆﹒汗山﹒拉姆
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Nankai University
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Abstract

The present invention relates to a preparation method for synthesizing non-natural isocoumarin, its 3,4-dihydroderivative and its intermediate. Said invention provides the application of isocoumarin, its 3,4-dihydroderivative and its intermediate in the fields of agricultural pesticide and medicine. Said invention also provides their structure formulae.

Description

Non-natural Isocoumarin 〉97 and 3, the preparation of 4-dihydro derivative and purposes
Technical field
Technical scheme of the present invention relates to different coumarin derivative and the intermediate thereof that halogen replaces, and specifically relates to the intermediate ketone acid derivative and the alcohol acid analog derivative of different coumarin derivative and synthetic its product.
Background technology
Isocoumarin 〉97 (formal name used at school: be the basic structure of some natural products 1H-2-chromene-1-ketone), extensively be present in nature, its derivative has widely physiology and biological activity such as antibiotic, anti-inflammatory, anticancer, arrestin enzyme and weeding etc. and tangible antitumour activity (Li Li, Yang Jinfei, Yuan Xiangai, the study on the synthesis of Isocoumarin 〉97 compounds and new development, Nanjing Normal University's journal (engineering version), 2005,5 (2): 64-67.).Isocoumarin 〉97 and 3,4-dihydro Isocoumarin 〉97 is the secondary metabolites of fungi, liver moss, mould, bacterium, higher plant and animal, separates obtaining the species such as now mould from artemisia, aspergillus tubigensis, beak shell bacterium, the reaping hook of Mycophyta, Penicillium notatum, streptomycete.They also are high ingredients of vegetable such as Bombacaceae, composite family, pulse family, Myruca ceas, Saxifragaceae and Liliaceae.
The natural Isocoumarin 〉97 that contains halogen is very rare, fluorine-containing natural Isocoumarin 〉97 still is not found so far, the existing report of natural Isocoumarin 〉97 only chloride and bromine, (Thomas O.L.and Jens B. such as Thomas, Dichlorodiaportin, diaportinol, and diaportinic acid:Three novel isocoumarins from Penicillium nalgiovense.J.Nat.Prod.62,1182 (1999)) from the cheese culture of Penicillium notatum, separated the metabolite dichlorodiaportin (01) that obtains containing chlorine.Stalder separates from the ascomycetes culture and obtains 4-bromo-6-hydroxyl mellein (02) (Stadler, M., H.Anke ﹠amp; O.Sterner.Metabolites with nematicidal and antimicrobial activities from theascomycete Lachnum papyraceum (Karst.) Karst.III.Production of novel isocoumarin derivatives, isolation, and biological activites.J.Antibiotics 48,261-266, (1995)).The fluorine-containing Isocoumarin 〉97 of synthetic also seldom, (Chuikov I.P., Karpov V.M.and Platonov V.E. such as Chuikov; C.A.118:124161c.) reported 3,3,4,5,6,7,8-seven fluoro-4-trifluoromethyls-3,4-dihydro Isocoumarin 〉97 (03) and 3,3,4,4,5,6,7,8-octafluoro-3,4-dihydro Isocoumarin 〉97 synthetic.Synthesizing of a similar Isocoumarin 〉97 also by reports such as Karpov.Beautement (Beautement K.and Clough J.M.Tetrahedron Lett., B25,3025 (1984)) etc. has synthesized the Isocoumarin 〉97 (04) that is connected with the phenyl that fluorine replaces on 4 of Isocoumarin 〉97.Be connected with 3 of fluorophenyl on 3,4-dihydro Isocoumarin 〉97 (05) is also by Crenshaw synthetic (Crenshaw, L.; Khanapure, S.P.Siriwardane, U.; Biehl, E.R.A Stereocontrolled Synthesis ofcis-3,4-Diarylisochroman-1-one Through Diastereoselective Reaction of Benzaldehyde anda-Lithio-2-cyanodiarylmethane Intermediate.Tetrahedron Lett.1988,29,3777.).4-chloro-3-[(4-fluorophenyl) methoxyl group] Isocoumarin 〉97 (06) has been found to be effective inhibitor (Odake S., Kam C.M., the Narasimhan L. that human body Q31 particle dissolves mould A, Poe M., Blake J.T., Krahenbuhl O., Tschopp J.and Powers J.C.; Human andmurine cytotoxic substrates and inhibition of enzyme activity and cytolysis by isocoumarins.Biochemistry, 30,2217-2227,1991), muroid and human particle dissolve mould A and separate from cytotoxin T lymphocyte and obtain.This Isocoumarin 〉97 (06) can be used as serpin and treats pulmonary emphysema (Hudig D., Allison N.J., Kam C.M.and Powers J.C.; Selective isocoumarin serine protease inhibitors block RNK-16lymphocyte granule-mediated cytolysis.Mol.Immunol., 26,793-798,1989).3-fluoro-3,4-dihydro-5,8-dimethoxy Isocoumarin 〉97 (07) can suppress inflammation (Hudig D., Allison N.J., Kam C.M.and Powers J.C.; Selective isocoumarin serine protease inhibitors block RNK-16 lymphocyte granule-mediatedcytolysis.Mol.Immunol., 26,793-798,1989).3 (3 '-chloro-4 '-fluorophenyl)-3,4-dihydro Isocoumarin 〉97 (08) has antibacterium and anti-mycotic activity.6-(2-chloro-4-4-trifluoromethylphenopendant)-3,4-dihydro Isocoumarin 〉97 (09) can be used as weedicide (Clark M.T.and Gilmore I.J.; C.A, 111,19479v.), it is the growth of Kong Zhi Finger-millet, sinapsis alba and other weeds fully almost.
7-amino-4-chloro-3-(2 '-bromine oxethyl) Isocoumarin 〉97 (10) is synthesized (Kerrigan, J.E.; Oleksyszyn, J; Kam, C.-M.; Selzler, J.; Powers, J.C.Mechanism-based inhibitors for human leukocyte elastase.Effectof the 7-amino substituent and 3-alkoxy group in 7-amino-4-chloro-3-alkoxyisocoumarins oninhibitory potency, J.Med.Chem.1995,38,544-552.), and be considered to inhibitor (Kam, the C. of a kind of potential human leukocytes pancreas peptase and hemocoagulase; Kerrigan, J.E.; Plaskon, R.; Duffy, E.J.; Lollar, P.; Suddath, F.L.; Powers, J.C.Mechanism-based isocoumarin inhibitors for blood coagulation serine proteases.Effect of the 7-Substituent in 7-amino-4-chloro-3-isothiureidoalkoxyisocoumarin derivatives oninhibitory and anticoagulant potency, J.Med.Chem.1994,37,1298-1306.).7-amino-3-(2/3-bromine propoxy-)-4-chlorine Isocoumarin 〉97 can be used for treating neurodegenerative disorders, and 3-bromotrifluoromethane-6,8-hydroxyl Isocoumarin 〉97 (11a) are the intermediates of a kind of antitumor antibiotic Isocoumarin 〉97 (11b).Hussain (Hussan M.T., Nasim H.Rama ﹠amp; A Malik; Synthiesof some new 3-(Bromopheny) isocoumarins and their conversion to (dl)-3,4-dihydroisocoumarins.Indian J.Chem.Section B, 40B, 372-6,2001.) under doctor's Rama guidance, having synthesized 3-(bromophenyl) Isocoumarin 〉97 (12a-c), this material has antibacterium and anti-mycotic activity after tested.
Balasubramanian (Balasubramanian T.R.and Nagarajan A.Indian J.Chem., 27B, 380 (1988)) four kinds of Isocoumarin 〉97 (13a-d) have been prepared, these compounds are by lactonizing of 2-alkylbenzoic acid and N-succimide iodine to be positioned on 4, he has also reported simple method (the Waitz J.A.and Deuve C.G.Antifungal agents.Annu.Rep.Med.Chem. that synthesizes Isocoumarin 〉97 (14a-d) by the organic route of metal, 7,109,1972).
Figure A20051012235300061
At home and abroad many compounds have important physical activity and biological activity in the disclosed different coumarin derivative of patent documentation, coumarin kind compound has been used as agricultural chemicals such as rodenticide and weedicide and has been used, the different coumarin derivative synthetic patent of having reported at present is a lot, but the biologically active especially report of pesticide bioactivity is less relatively, and different coumarin derivative and the bioactive situation of reporting in the patent both at home and abroad thereof saw Table 1 in recent years.By table 1 as seen, in the isocumarans compound of biologically active, all mentioned in its substituting group and contained halogen atom, recently, Zahid Shafig etc. synthesized the dihalogenated different coumarin derivative of part comprise 3-(2 ', 4 '-chloro-phenyl-) Isocoumarin 〉97,3-(3 ', 4 '-chloro-phenyl-) Isocoumarin 〉97 and 3-(2 '-chloro-6 '-fluorophenyl) Isocoumarin 〉97 and 3,4-dihydro derivative (Zahid Shafig, Muhammad Arfan, NasimHasan Rama, Shahid Hameed, Ghulam Abbas, Muhammad Tabir Hussain.Synthesis of some newdihalophenyl and dihalobenzylisocoumarins and their (dl)-3,4-dihydroderivatives.Turk J Chem, 2005,29,321-325.), because the different coumarin derivative that replaces with halogen has biological activity preferably, the present invention synthesized the new 3-halogenophenyl Isocoumarin 〉97 of part and by their transform 3, the 4-dihydro derivative, and these compounds have been carried out relevant biological activity test, so that can detect their medicine such as antimycotic and bacterium and cytotoxicity isoreactivity and agricultural chemicals such as weeding, desinsection, the control of plant diseases such as sterilization is active.
The different coumarin derivative of table 1 biologically active
Figure A20051012235300081
Summary of the invention
Technical problem to be solved by this invention is: provide and carry out medicine and the Isocoumarin 〉97 analog derivative of pesticide bioactivity screening and the screening of synthetic method and medicine and pesticide bioactivity thereof.
The present invention solves this technical problem the technical scheme that is adopted: the chemical structure of general formula of Isocoumarin 〉97 analog derivative and intermediate thereof is as follows, and its concrete chemical structural formula is represented to see shown in I, II, III and the IV:
(A series), (B series),
Figure A20051012235300093
(HA series), (C series)
I. the chemical structure of synthetic Isocoumarin 〉97 analog derivative among the present invention:
Figure A20051012235300095
II. the chemical structure of synthetic ketone acid analog derivative among the present invention:
Figure A20051012235300096
III. the chemical structure of synthetic alcohol acid analog derivative among the present invention:
IV. synthetic 3 among the present invention, the chemical structure of 4-dihydro different coumarin derivative:
The synthetic method of Isocoumarin 〉97 analog derivative of the present invention is as follows:
Specifically be divided into following steps:
The fusing point of all compounds records in open kapillary with Gallenkemp fusing point instrument (not proofreading and correct) in the patent of the present invention; Infrared spectra is a Hitachi type 270-50 determination of infrared spectroscopy; 1H-NMR (400MHz), measures on the AM-400 instrument as interior mark with TMS, and EIMS measures on the MAT-112-S instrument, and used sherwood oil boiling point is 40-80 ℃.
I. dichlorophenyl-and preparation of difluorophenyl Isocoumarin 〉97 (31,32,33,41,42,43,44) A:
Its synthetic reaction equation is as follows:
At dihalogen acid (31,32,33,41,42,43,44) add a DMF (53.0mmol) and in the mixture of thionyl chloride (38.0mmole), refluxed 30 minutes, when regeneration gas not, the decompression remove the Arius acyl chlorides obtain dihalo acyl chlorides (50.0mmole) (31 ', 32 ', 33 ', 41 ', 42 ', 43 ', 44 '); With homophthalic acid (1) (11.3mmol) and phenyl-dihalide formyl chloride (47.0mmol) (31 ', 32 ', 33 ', 41 ', 42 ', 43 ', 44 ') mixture heating up to 200 ℃ and refluxed 4 hours, cooled reaction mixture acetic acid ethyl dissolution adds anhydrous sodium carbonate then and removes unreacted o-carboxyl phenylacetic acid, isolate organic phase, cross silica gel column chromatography with polyester ether (40-80 ℃) as eluent after concentrating and get Isocoumarin 〉97 (31,32,33,41,42,43,44) A, be further purified by recrystallizing methanol, measure fusing point and 1H NMR and other structural parameter;
The preparation of II.2-(replacement) phenylformic acid (31,32,33,41,42,43) B:
According to following reaction equation, with ethanol (50mL) dissolving Isocoumarin 〉97 (31,32,33,41,42,43) A adds potassium hydroxide (5%, 100mL), refluxed 4 hours, ethanol is removed in underpressure distillation, adds frozen water (20mL), mixture is used methylene dichloride again with hcl acidifying, and (removal of solvent under reduced pressure obtains crude product (31,32 for 3 * 20mL) extractions, anhydrous sodium sulfate drying, 33,41,42,43,44) B is with recrystallizing methanol and measure structural parameter;
Figure A20051012235300111
III. (dl)-3-(replacement)-3, the preparation of 4-dihydro Isocoumarin 〉97 analog derivative (31,32,33,41,42,43) C:
According to following reaction equation, and the usefulness potassium hydroxide solution (1%, 25mL) dissolving ketone acid (31,32,33,41,42,43) B (2.07mmol), potassium sodium borohydride (0.25g), mixture stirred under room temperature 1 hour, after the dilute hydrochloric acid acidifying, with ethyl acetate (2 * 50mL) extractions, anhydrous sodium sulfate drying, underpressure distillation remove to desolvate and obtain crude product alcohol acid HA-(31,32,33,41,42,43), with diacetyl oxide (1mL) dissolving, reflux 2 hours, reaction mixture adds entry (25mL), and mixture stirs and spends the night, the crystal that filtration obtains separating out, (2 * 20mL) extract filtrate, and methylene dichloride is used anhydrous sodium sulfate drying mutually with methylene dichloride, removal of solvent under reduced pressure gets crude product crude product dihydro Isocoumarin 〉97 (31,32,33,41,42,43) C, with sherwood oil do eluent carry out column chromatographic isolation and purification and measure fusing point and 1H NMR and other physical and chemical parameters;
Figure A20051012235300112
The bioactive screening method of diazosulfide derivative of the present invention is as follows:
I. the screening method of weeding activity: adopt the greenhouse pot culture method to carry out, cauline leaf is handled after dividing preceding soil treatment of seedling and seedling, treatment dosage is 750 gram/hectares, application method is for spraying, after dispenser, measured overground part fresh weight inhibition percentage in 15 days, measure the examination material and comprise rape (Brassica campestris), barnyard grass grass (Echinochloa crus-galli), three-coloured amaranth (Amaranthusretroflexus L.) and lady's-grass (Digitaria sanguinalis (L.) Scop);
II. the screening method of insecticidal activity: mythimna separata (Mythimna separata) is adopted leaf dipping method, impregnated in leaf of Semen Maydis in the soup of acetone preparation (500 μ g/mL), treat to insert 4 instar larvaes behind the soup, main mensuration stomach toxicity and action of contace poison, 24,96 hours check test results (observing the insect growth regulator(IGR) effect) represent the insecticidal activity height with per cent death loss.The mensuration of mosquito larvae (Culex pipiens pallens) is 4 instar larvaes to be put into the soup (water) of finite concentration (5 μ g/mL), the death condition of 24 hours inspection mosquito larvaes;
III. the screening method of fungicidal activity: adopt thalli growth rate assay method (Mycelium growth rate test), detailed process is, get the 5mg sample dissolution in an amount of dimethyl formamide, then with containing the medicament that a certain amount of polysorbas20 emulsifier aqueous solution is diluted to 500 μ g/mL, reagent agent is respectively drawn 1mL under aseptic condition inject in the culture dish, add the 9mL substratum more respectively, make 50 μ g/mL pastille flat boards after shaking up, do blank with the flat board that adds the 1mL aqua sterilisa, punch tool with diameter 4mm cuts the bacterium dish along the mycelia outer rim, move on the pastille flat board, be equilateral triangle and put, every processing repeats 3 times, culture dish is placed on cultivation in 24 ± 1 ℃ of constant incubators, " Invest, Then Investigate " was respectively handled bacterium dish expansion diameter in 48 hours, averaged, and relatively calculated relative bacteriostasis rate with blank.Comprise gibberella saubinetii (Gibberellazeae), tomato early epidemic disease (Alternaria), asparagus stem withered (Phoma asparagi solani), apple wheel line (Physalosporapiricola) and peanut foxiness (Cercospora arachidicola) for the examination pathogenic fungi;
IV. the active screening method of anti-human pathogenic fungi: adopt the agar tube dilution method to carry out (WaitzJ.A.and Deuve C.G.Antifungal agents.Annu.Rev.Med.Chem. with reference to the method for Waitz, 7,109 (1972)), anti-human body pathogen comprises trichophyton (Trichophyton longifusus), Candida albicans bacterium (Candida albicans), aflatoxin produces bacterium (Aspergillus flavus), Sabouraudites lanosus (Microsporum canis), aspergillus tubigensis (Fusarium solani) and candidiasis (Candida glaberata), n-compound is miconazole (Miconazole) and both sexes toxin B (Amphotericin B), and the mensuration concentration of each compound is 200 μ g/mL;
V. the screening method of antibacterial activity: the method with reference to Kasprzykowski is carried out (Kasprzykowski F, Schal é nC, Kasprzykowska R, Jastrzebska B, Grubb A.Synthesis and antibacterial properties of peptidylderivatives and cyclopeptides structurally based upon the Inhibitory centre of human cystatin C.Dissociation of antiproteolytic and antibacterial effects.APMIS 2000; 108:473-81), adopt the agar tube dilution method to test the antibacterial activity of synthetic compound, bacteria tested comprises: Escherichia intestinal bacteria (Escherichiacoli); Bacillus subtilus (Bacillhas subtilis); Shigellae (Shigella flexenari); Staphylococcus (Staphylococcus aureus); Pseudomonas (Pseudomonas) and salmonella typhi (Slamonella typhi), as the mark medicine, 24 hours culture comprises about 10 with imipenum 4-10 6CFU (colony forming unit), they are distributed on MHA (the Muller Hinton agar) surface, and different specimen is added in separately the aperture, cultivate 24 hours in the time of 37 ℃, measure inhibiting rate and with the contrast of mark medicine;
VI. Cytotoxic screening method: adopt the test of salt solution shrimp mortality, to the fatefulue measuring method of salt solution shrimp shrimp be with the ovum of salt solution shrimp by with Petri dish (34g sea salt/L deionized water) under the 60W head light, temperature is 24-26 ℃ and cultivates hatching, preparation mycotoxin solution in acetonitrile-water (1: 1), transfer to then in 96 orifice plates through air-dry overnight, after solvent volatilizees fully again with toxin dissolution in 100-μ L-seawater.Accurate solution concentration is by HPLC-MS test (carry out quantitatively according to isotopic dilution method, D-FB1 is as interior mark).Each comprises the cathodic control that contains 100-μ L acetonitrile-water (1: 1) and 200 μ L seawater.DAS carries out three experiments as anodic control (40 μ L in the 10 μ g/mL solution) for each toxin, six various dose, and each dosage repeats 8 times.After the 24h hatching, will not have joint meat worm and separate from its shell, packing is transferred in the fresh seawater with pipette, puts into the 100 μ L that contain the organic solution of 10-20 in each well, makes last volume for being 200 μ L.Prevent that with sealing film moisture from losing, then 24-26 ℃ of directing light irradiation, rotating speed is hatching 48 hours under the condition of 140rpm, hatch the dead borer population amount of detection in each hole after 2 days, detects the quantity of the shrimp in each hole.
The present invention will more specifically describe the synthetic and biological activity of Isocoumarin 〉97 analog derivative and intermediate thereof by specific preparation and biological activity determination embodiment, but described embodiment only is used for specific description the present invention and unrestricted the present invention, and concrete embodiment is as follows:
Embodiment 1
3, the preparation of 5-dichlorobenzoyl chloride (31 '):
In the there-necked flask of 500mL, add 3,5-dichlorobenzoic acid (31) (10.0g, 53.0mmol) and thionyl chloride (4.5ml, 38.0mmol), in mixture, add and drip DMF, refluxed 30 minutes, proved response finishes when not producing gas, decompression is removed unreacted thionyl chloride and is obtained the phenyl-dihalide formyl chloride (product need not purifying and is kept at and gets single step reaction in the moisture eliminator ready and directly use for 11g, 50.0mmol) (31 ').
Embodiment 2
The preparation of 2,3 dichloro benzoyl chloride (32 '):
In the there-necked flask of 500mL, add 2,3-dichlorobenzoic acid (32) (10.0g, 53.0mmol) and thionyl chloride (4.5ml, 38.0mmol), in mixture, add and drip DMF, refluxed 30 minutes, proved response finishes when not producing gas, decompression is removed unreacted thionyl chloride and is obtained the phenyl-dihalide formyl chloride (product need not purifying and is kept at and gets single step reaction in the moisture eliminator ready and directly use for 11g, 50.0mmol) (32 ').
Embodiment 3
2, the preparation of 5-dichlorobenzoyl chloride (33 '):
In the there-necked flask of 500mL, add 2,5-dichlorobenzoic acid (33) (10.0g, 53.0mmol) and thionyl chloride (4.5ml, 38.0mmol), in mixture, add and drip DMF, refluxed 30 minutes, proved response finishes when not producing gas, decompression is removed unreacted thionyl chloride and is obtained the phenyl-dihalide formyl chloride (product need not purifying and is kept at and gets single step reaction in the moisture eliminator ready and directly use for 11g, 50.0mmol) (33 ').
Embodiment 4
2, the preparation of 3-difluoro benzoyl chloride (41 '):
In the there-necked flask of 500mL, add 2,3-difluoro-benzoic acid (41) (10.0g, 63.3mmol) and thionyl chloride (4.5ml, 38.0mmol), in mixture, add and drip DMF, refluxed 30 minutes, proved response finishes when not producing gas, decompression is removed unreacted thionyl chloride and is obtained the phenyl-dihalide formyl chloride (product need not purifying and is kept at and gets single step reaction in the moisture eliminator ready and directly use for 11g, 62.3mmol) (41 ').
Embodiment 5
3, the preparation of 5-difluoro benzoyl chloride (42 '):
In the there-necked flask of 500mL, add 3,5-difluoro-benzoic acid (42) (10.0g, 63.0mmol) and thionyl chloride (4.5ml, 38.0mmol), in mixture, add and drip DMF, refluxed 30 minutes, proved response finishes when not producing gas, decompression is removed unreacted thionyl chloride and is obtained the phenyl-dihalide formyl chloride (product need not purifying and is kept at and gets single step reaction in the moisture eliminator ready and directly use for 11g, 62.3mmol) (42 ').
Embodiment 6
3, the preparation of 4-difluoro benzoyl chloride (43 '):
In the there-necked flask of 500mL, add 3,4-difluoro-benzoic acid (43) (10.0g, 63.0mmol) and thionyl chloride (4.5ml, 38.0mmol), in mixture, add and drip DMF, refluxed 30 minutes, proved response finishes when not producing gas, decompression is removed unreacted thionyl chloride and is obtained the phenyl-dihalide formyl chloride (product need not purifying and is kept at and gets single step reaction in the moisture eliminator ready and directly use for 11g, 62.3mmol) (43 ').
Embodiment 7
The preparation of 2,4 difluorobenzene formyl chloride (44 '):
In the there-necked flask of 500mL, add 2,4-difluoro-benzoic acid (44) (10.0g, 63.0mmol) and thionyl chloride (4.5ml, 38.0mmol), in mixture, add and drip DMF, refluxed 30 minutes, proved response finishes when not producing gas, decompression is removed unreacted thionyl chloride and is obtained the phenyl-dihalide formyl chloride (product need not purifying and is kept at and gets single step reaction in the moisture eliminator ready and directly use for 11g, 62.3mmol) (44 ').
Embodiment 8
3-(3 ', 5 '-chloro-phenyl-) the synthetic and structure of Isocoumarin 〉97 (31A) identifies:
In the there-necked flask of 100mL, add o-carboxyl phenylacetic acid (1) (2.5g, 13mmol) with 3,5-dichlorobenzoyl chloride (11g, 52.5mmol) (31 ') mixture heating up to 200 ℃ refluxed 4 hours, mixture is dissolved in the ethyl acetate, add anhydrous sodium carbonate and remove unreacted o-carboxyl phenylacetic acid, tell organic phase, concentrate the back with polyester ether (40-80 ℃) as eluent cross silica gel column chromatography obtain 3-(3 ', 5 '-chloro-phenyl-) Isocoumarin 〉97 (31A), by recrystallizing methanol be further purified pure product 8.9g, 30.7mmol, measure fusing point and 1H NMR, its chemical structural formula and physical and chemical parameter see Table 2 and table 3, by table 2 and table 3 as seen, and this compound 1H NMR shows and the corresponding chemical shift of its structure that the number of H and its structure are coincide, and MS measures and corresponding M occurs +The m/z peak, corresponding skeleton absorption peak appears in IR.
Embodiment 9
3-(2 ', 3 '-dichlorophenyl) the synthetic and structure of Isocoumarin 〉97 (32A) identifies:
(2.5g, 13mmol) with 3, (11g, 52.5mmol) ℃ backflow of (32 ') mixture heating up to 200 is 4 hours for the 5-dichlorobenzoyl chloride to add o-carboxyl phenylacetic acid (1) in the there-necked flask of 100mL.Mixture is dissolved in the ethyl acetate, adds anhydrous sodium carbonate and removes unreacted o-carboxyl phenylacetic acid.Tell organic phase, concentrate the back with polyester ether (40-80 ℃) as eluent cross silica gel column chromatography obtain 3-(2 ', 3 '-chloro-phenyl-) Isocoumarin 〉97 (32A), by recrystallizing methanol be further purified pure product 8.8g, 30.3mmol, the mensuration fusing point with 1H NMR, its chemical structural formula and physical and chemical parameter see Table 2 and table 3, by table 2 and table 3 as seen, and this compound 1H NMR shows and the corresponding chemical shift of its structure that the number of H and its structure are coincide, and MS measures and corresponding M occurs +The m/z peak, corresponding skeleton absorption peak appears in IR.
Embodiment 10
3-(2 ', 5 '-dichlorophenyl) the synthetic and structure of Isocoumarin 〉97 (33A) identifies:
(2.5g, 13mmol) with 2, (11g, 52.5mmol) ℃ backflow of (33 ') mixture heating up to 200 is 4 hours for the 5-dichlorobenzoyl chloride to add o-carboxyl phenylacetic acid (1) in the there-necked flask of 100mL.Mixture is dissolved in the ethyl acetate, adds anhydrous sodium carbonate and removes unreacted o-carboxyl phenylacetic acid.Tell organic phase, concentrate the back with polyester ether (40-80 ℃) as eluent cross silica gel column chromatography obtain 3-(2 ', 5 '-chloro-phenyl-) Isocoumarin 〉97 (33A), by recrystallizing methanol be further purified pure product 8.9g, 30.7mmol), the mensuration fusing point with 1H NMR, its chemical structural formula and physical and chemical parameter see Table 2 and table 3, by table 2 and table 3 as seen, and this compound 1H NMR shows and the corresponding chemical shift of its structure that the number of H and its structure are coincide, and MS measures and corresponding M occurs +The m/z peak, corresponding skeleton absorption peak appears in IR.
Embodiment 11
3-(2 ', 3 '-difluorophenyl) the synthetic and structure of Isocoumarin 〉97 (41A) identifies:
In the there-necked flask of 100mL, add o-carboxyl phenylacetic acid (1) (2.5g, 13mmol) and 2,3 dichloro benzoyl chloride (11g, 62.3mmol) (41 ') mixture heating up to 200 ℃ refluxed 4 hours.Mixture is dissolved in the ethyl acetate, adds anhydrous sodium carbonate and removes unreacted o-carboxyl phenylacetic acid.Tell organic phase, concentrate the back with polyester ether (40-80 ℃) as eluent cross silica gel column chromatography obtain 3-(2 ', 3 '-fluorophenyl) Isocoumarin 〉97 (41A), by recrystallizing methanol be further purified pure product 8.5g, 32.8mmol, the mensuration fusing point with 1H NMR, its chemical structural formula and physical and chemical parameter see Table 2 and table 3, by table 2 and table 3 as seen, and this compound 1H NMR shows and the corresponding chemical shift of its structure that the number of H and its structure are coincide, and MS measures and corresponding M occurs +The m/z peak, corresponding skeleton absorption peak appears in IR.
Embodiment 12
3-(3 ', 5 '-difluorophenyl) the synthetic and structure of Isocoumarin 〉97 (42A) identifies:
(2.5g, 13mmol) with 3, (11g, 62.3mmol) ℃ backflow of (42 ') mixture heating up to 200 is 4 hours for the 5-difluoro benzoyl chloride to add o-carboxyl phenylacetic acid (1) in the there-necked flask of 100mL.Mixture is dissolved in the ethyl acetate, adds anhydrous sodium carbonate and removes unreacted o-carboxyl phenylacetic acid.Tell organic phase, concentrate the back with polyester ether (40-80 ℃) as eluent cross silica gel column chromatography obtain 3-(3 ', 5 '-fluorophenyl) Isocoumarin 〉97 (42A), by recrystallizing methanol be further purified pure product 8.7g, 33.7mmol, the mensuration fusing point with 1H NMR, its chemical structural formula and physical and chemical parameter see Table 2 and table 3, by table 2 and table 3 as seen, and this compound 1H NMR shows and the corresponding chemical shift of its structure that the number of H and its structure are coincide, and MS measures and corresponding M occurs +The m/z peak, corresponding skeleton absorption peak appears in IR.
Embodiment 13
3-(3 ', 4 '-difluorophenyl) the synthetic and structure of Isocoumarin 〉97 (43A) identifies:
(2.5g, 13mmol) with 3, (11g, 62.3mmol) ℃ backflow of (43 ') mixture heating up to 200 is 4 hours for the 4-difluoro benzoyl chloride to add o-carboxyl phenylacetic acid (1) in the there-necked flask of 100mL.Mixture is dissolved in the ethyl acetate, adds anhydrous sodium carbonate and removes unreacted o-carboxyl phenylacetic acid.Tell organic phase, concentrate the back with polyester ether (40-80 ℃) as eluent cross silica gel column chromatography obtain 3-(2 ', 3 '-chloro-phenyl-) Isocoumarin 〉97 (32A), by recrystallizing methanol be further purified pure product 8.7g, 33.7mmol, the mensuration fusing point with 1H NMR, its chemical structural formula and physical and chemical parameter see Table 2 and table 3, by table 2 and table 3 as seen, and this compound 1H NMR shows and the corresponding chemical shift of its structure that the number of H and its structure are coincide, and MS measures and corresponding M occurs +The m/z peak, corresponding skeleton absorption peak appears in IR.
Embodiment 14
3-(2 ', 4 '-difluorophenyl) the synthetic and structure of Isocoumarin 〉97 (44A) identifies:
In the there-necked flask of 100mL, add o-carboxyl phenylacetic acid (1) (2.5g, 13mmol) and 2,4 dichlorobenzyl chloride (11g, 62.3mmol) (44 ') mixture heating up to 200 ℃ refluxed 4 hours.Mixture is dissolved in the ethyl acetate, adds anhydrous sodium carbonate and removes unreacted o-carboxyl phenylacetic acid.Tell organic phase, concentrate the back with polyester ether (40-80 ℃) as eluent cross silica gel column chromatography obtain 3-(2 ', 4 '-difluorophenyl) Isocoumarin 〉97 (44A), by recrystallizing methanol be further purified pure product 8.6g, 33.3mmol, the mensuration fusing point with 1H NMR, its chemical structural formula and physical and chemical parameter see Table 2 and table 3, by table 2 and table 3 as seen, and this compound 1H NMR shows and the corresponding chemical shift of its structure that the number of H and its structure are coincide, and MS measures and corresponding M occurs +The m/z peak, corresponding skeleton absorption peak appears in IR.
Embodiment 15
2-(3 ', 5 '-phenacyl) benzoic (31B) synthetic and structure evaluation:
In the there-necked flask of 100mL in the there-necked flask of 100mL with ethanol (50mL) and potassium hydroxide (5%, 100mL) dissolving 3-(3 ', 5 '-dichlorophenyl) (9.0g, 30mmol) (31A's Isocoumarin 〉97) refluxed 4 hours, after the cooling, reduced pressure and removed ethanol.In reaction mixture, add cold water (20mL), use the dilute hydrochloric acid acidifying, with methylene dichloride (3 * 20mL) extractions, anhydrous sodium sulfate drying, underpressure distillation removes to desolvate and obtains crude product, with recrystallizing methanol obtain 2-(3 ', 5 '-the dichloro-benzoyl methyl) the pure product 6.5g of phenylformic acid (31B), 21.1mmol, measure fusing point and 1H NMR, its chemical structural formula and physical and chemical parameter see Table 2 and table 3, by table 2 and table 3 as seen, and this compound 1H NMR shows and the corresponding chemical shift of its structure that the number of H and its structure are coincide, and MS measures and corresponding M occurs +The m/z peak, corresponding skeleton absorption peak appears in IR.
Embodiment 16
2-(2 ', 3 '-the dichloro-benzoyl methyl) the synthetic and structure of phenylformic acid (32B) identifies:
In the there-necked flask of 100mL with ethanol (50mL) and potassium hydroxide (5%, 100mL) dissolving 3-(2 ', 3 '-dichlorophenyl) (8.8g, 30mmol) (32A's Isocoumarin 〉97) refluxed 4 hours, after the cooling, reduced pressure and removed ethanol.In reaction mixture, add cold water (20mL), use the dilute hydrochloric acid acidifying, with methylene dichloride (3 * 20mL) extractions, anhydrous sodium sulfate drying, underpressure distillation removes to desolvate and obtains crude product, with recrystallizing methanol obtain 2-(2 ', 3 '-the dichloro-benzoyl methyl) the pure product 6.8g of phenylformic acid (32B), 22.0mmol, measure fusing point and 1H NMR, its chemical structural formula and physical and chemical parameter see Table 2 and table 3, by table 2 and table 3 as seen, and this compound 1H NMR shows and the corresponding chemical shift of its structure that the number of H and its structure are coincide, and MS measures and corresponding M occurs +The m/z peak, corresponding skeleton absorption peak appears in IR.
Embodiment 17
2-(2 ', 5 '-the dichloro-benzoyl methyl) the synthetic and structure of phenylformic acid (33B) identifies:
In the there-necked flask of 100mL with ethanol (50mL) and potassium hydroxide (5%, 100mL) dissolving 3-(2 ', 3 '-dichlorophenyl) (9.0g, 30mmol) (32A's Isocoumarin 〉97) refluxed 4 hours, after the cooling, reduced pressure and removed ethanol.In reaction mixture, add cold water (20mL), use the dilute hydrochloric acid acidifying, with methylene dichloride (3 * 20mL) extractions, anhydrous sodium sulfate drying, underpressure distillation removes to desolvate and obtains crude product, with recrystallizing methanol obtain 2-(2 ', 5 '-the dichloro-benzoyl methyl) the pure product 6.3g of phenylformic acid (33B), 20.5mmol, measure fusing point and 1H NMR, its chemical structural formula and physical and chemical parameter see Table 2 and table 3, by table 2 and table 3 as seen, and this compound 1H NMR shows and the corresponding chemical shift of its structure that the number of H and its structure are coincide, and MS measures and corresponding M occurs +The m/z peak, corresponding skeleton absorption peak appears in IR.
Embodiment 18
2-(2 ', 3 '-the difluoro phenacyl) the synthetic and structure of phenylformic acid (41B) identifies:
In the there-necked flask of 100mL with ethanol (50mL) and potassium hydroxide (5%, 100mL) dissolving 3-(2 ', 3 '-difluorophenyl) (8.5g, 30mmol) (41A's Isocoumarin 〉97) refluxed 4 hours, after the cooling, reduced pressure and removed ethanol.In reaction mixture, add cold water (20mL), use the dilute hydrochloric acid acidifying, with methylene dichloride (3 * 20mL) extractions, anhydrous sodium sulfate drying, underpressure distillation removes to desolvate and obtains crude product, with recrystallizing methanol obtain 2-(2 ', 3 '-the difluoro phenacyl) the pure product 5.9g of phenylformic acid (41B), 21.5mmol, measure fusing point and 1H NMR, its chemical structural formula and physical and chemical parameter see Table 2 and table 3, by table 2 and table 3 as seen, and this compound 1H NMR shows and the corresponding chemical shift of its structure that the number of H and its structure are coincide, and MS measures and corresponding M occurs +The m/z peak, corresponding skeleton absorption peak appears in IR.
Embodiment 19
2-(3 ', 5 '-the dichloro-benzoyl methyl) the synthetic and structure of phenylformic acid (42B) identifies:
In the there-necked flask of 100mL with ethanol (50mL) and potassium hydroxide (5%, 100mL) dissolving 3-(2 ', 3 '-dichlorophenyl) (8.7g, 30mmol) (42A's Isocoumarin 〉97) refluxed 4 hours, after the cooling, reduced pressure and removed ethanol.In reaction mixture, add cold water (20mL), use the dilute hydrochloric acid acidifying, with methylene dichloride (3 * 20mL) extractions, anhydrous sodium sulfate drying, underpressure distillation removes to desolvate and obtains crude product, with recrystallizing methanol obtain 2-(3 ', 5 '-the dichloro-benzoyl methyl) the pure product 7.0g of phenylformic acid (42B), 25.2mmol, measure fusing point and 1H NMR, its chemical structural formula and physical and chemical parameter see Table 2 and table 3, by table 2 and table 3 as seen, and this compound 1H NMR shows and the corresponding chemical shift of its structure that the number of H and its structure are coincide, and MS measures and corresponding M occurs +The m/z peak, corresponding skeleton absorption peak appears in IR.
Embodiment 20
2-(3 ', 4 '-the difluoro phenacyl) the synthetic and structure of phenylformic acid (43B) identifies:
In the there-necked flask of 100mL, use ethanol (50mL) and potassium hydroxide (5%; 100mL) dissolving 3-(3 ', 4 '-difluorophenyl) (8.69g, 30mmol) (43A's Isocoumarin 〉97) refluxed 4 hours, after the cooling, reduced pressure and to remove ethanol.In reaction mixture, add cold water (20mL), use the dilute hydrochloric acid acidifying, with methylene dichloride (3 * 20mL) extractions, anhydrous sodium sulfate drying, underpressure distillation removes to desolvate and obtains crude product, with recrystallizing methanol obtain 2-(3 ', 4 '-the difluoro phenacyl) the pure product 6.0g of phenylformic acid (43B), 21.7mmol, measure fusing point and 1H NMR, its chemical structural formula and physical and chemical parameter see Table 2 and table 3, by table 2 and table 3 as seen, and this compound 1H NMR shows and the corresponding chemical shift of its structure that the number of H and its structure are coincide, and MS measures and corresponding M occurs +The m/z peak, corresponding skeleton absorption peak appears in IR.
Embodiment 21
Synthetic and the structure of 2-[2 '-hydroxyl-2 '-(3 ", 5 " dichlorophenyl) ethyl benzoate (HA-31) is identified:
In the there-necked flask of 100mL with potassium hydroxide solution (1%, 25mL) dissolving 2-(3 ', 5 '-the dichloro-benzoyl methyl) (6.6g 0.02mol), adds potassium sodium borohydride (0.25g) to phenylformic acid (31B), and mixture stirred under room temperature 1 hour.After the dilute hydrochloric acid acidifying, with ethyl acetate (2 * 50mL) extractions, anhydrous sodium sulfate drying, underpressure distillation remove desolvate obtain crude product 2-[2 '-hydroxyl-2 '-(3 "; 5 "-dichlorophenyl) ethyl benzoate (HA-31), make eluent with sherwood oil and carry out column chromatographic isolation and purification and get pure product 5.0g, 16.1mmol, measure fusing point and 1H NMR, its chemical structural formula and physical and chemical parameter see Table 2 and table 3, by table 2 and table 3 as seen, and this compound 1H NMR shows and the corresponding chemical shift of its structure that the number of H and its structure are coincide, and MS measures and corresponding M occurs +The m/z peak, corresponding skeleton absorption peak appears in IR.
Embodiment 22
Synthetic and the structure of 2-[2 '-hydroxyl-2 '-(2 ", 3 " dichlorophenyl) ethyl benzoate (HA-32) is identified:
In the there-necked flask of 100mL with potassium hydroxide solution (1%, 25mL) dissolving 2-(2 ', 3 '-the dichloro-benzoyl methyl) (6.7g 0.02mol), adds potassium sodium borohydride (0.25g) to phenylformic acid (32B), and mixture stirred under room temperature 1 hour.After the dilute hydrochloric acid acidifying, with ethyl acetate (2 * 50mL) extractions, anhydrous sodium sulfate drying, underpressure distillation remove desolvate obtain crude product 2-[2 '-hydroxyl-2 '-(2 "; 3 "-dichlorophenyl) ethyl benzoate (HA-32), make eluent with sherwood oil and carry out column chromatographic isolation and purification and get pure product 4.7g, 15.1mmol, measure fusing point and 1H NMR, its chemical structural formula and physical and chemical parameter see Table 2 and table 3, by table 2 and table 3 as seen, and this compound 1H NMR shows and the corresponding chemical shift of its structure that the number of H and its structure are coincide, and MS measures and corresponding M occurs +The m/z peak, corresponding skeleton absorption peak appears in IR.
Embodiment 23
Synthetic and the structure of 2-[2 '-hydroxyl-2 '-(2 ", 5 " dichlorophenyl) ethyl benzoate (HA-33) is identified:
In the there-necked flask of 100mL with potassium hydroxide solution (1%, 25mL) dissolving 2-(2 ', 5 '-the dichloro-benzoyl methyl) (6.4g 0.02mol), adds potassium sodium borohydride (0.25g) to phenylformic acid (33B), and mixture stirred under room temperature 1 hour.After the dilute hydrochloric acid acidifying, with ethyl acetate (2 * 50mL) extractions, anhydrous sodium sulfate drying, underpressure distillation remove desolvate obtain crude product 2-[2 '-hydroxyl-2 '-(2 "; 5 "-dichlorophenyl) ethyl benzoate (HA-33), make eluent with sherwood oil and carry out column chromatographic isolation and purification and get pure product 4.5g, 14.6mmol, measure fusing point and 1H NMR, its chemical structural formula and physical and chemical parameter see Table 2 and table 3, by table 2 and table 3 as seen, and this compound 1H NMR shows and the corresponding chemical shift of its structure that the number of H and its structure are coincide, and MS measures and corresponding M occurs +The m/z peak, corresponding skeleton absorption peak appears in IR.
Embodiment 24
(dl)-3-(3 ', 5 '-dichlorophenyl)-3, the synthetic and structure of 4-dihydro Isocoumarin 〉97 (31C) is identified:
Usefulness diacetyl oxide (1mL) dissolving 2-[2 '-hydroxyl-2 in the there-necked flask of 250mL '-(3 "; 5 "-dichlorophenyl) ethyl benzoate (HA-31) (5.0g, 10mmol), reflux 2 hours, after the reaction mixture cooling, add entry (25mL), stirred overnight at room temperature filters out precipitation, (2 * 20mL) extract filtrate with methylene dichloride, methylene dichloride is used anhydrous sodium sulfate drying mutually, removal of solvent under reduced pressure get crude product (dl)-3-(3 ', 5 '-dichlorophenyl)-3,4-dihydro Isocoumarin 〉97 (31C), make eluent with sherwood oil and carry out column chromatographic isolation and purification and get pure product 3.65g, 12.5mmol, measure fusing point and 1H NMR, its chemical structural formula and physical and chemical parameter see Table 2 and table 3, by table 2 and table 3 as seen, and this compound 1H NMR shows and the corresponding chemical shift of its structure that the number of H and its structure are coincide, and MS measures and corresponding M occurs +The m/z peak, corresponding skeleton absorption peak appears in IR.
Embodiment 25
(dl)-3-(2 ', 3 '-dichlorophenyl)-3, the synthetic and structure of 4-dihydro Isocoumarin 〉97 (32C) is identified:
Usefulness diacetyl oxide (1mL) dissolving 2-[2 '-hydroxyl-2 in the there-necked flask of 250mL '-(2 "; 3 "-dichlorophenyl) ethyl benzoate (HA-32) (4.6g, 10mmol), reflux 2 hours, after the reaction mixture cooling, add entry (25mL), stirred overnight at room temperature filters out precipitation, (2 * 20mL) extract filtrate with methylene dichloride, methylene dichloride is used anhydrous sodium sulfate drying mutually, removal of solvent under reduced pressure get crude product (dl)-3-(2 ', 3 '-dichlorophenyl)-3,4-dihydro Isocoumarin 〉97 (32C), make eluent with sherwood oil and carry out column chromatographic isolation and purification and get pure product 3.6g, 12.3mmol, measure fusing point and 1H NMR, its chemical structural formula and physical and chemical parameter see Table 2 and table 3, by table 2 and table 3 as seen, and this compound 1H NMR shows and the corresponding chemical shift of its structure that the number of H and its structure are coincide, and MS measures and corresponding M occurs +The m/z peak, corresponding skeleton absorption peak appears in IR.
Embodiment 26
(dl)-3-(2 ', 5 '-dichlorophenyl)-3, the synthetic and structure of 4-dihydro Isocoumarin 〉97 (33C) is identified:
Usefulness diacetyl oxide (1mL) dissolving 2-[2 '-hydroxyl-2 in the there-necked flask of 250mL '-(2 "; 5 "-dichlorophenyl) ethyl benzoate (HA-33) (4.6g, 10mmol), reflux 2 hours, after the reaction mixture cooling, add entry (25mL), stirred overnight at room temperature filters out precipitation, (2 * 20mL) extract filtrate with methylene dichloride, methylene dichloride is used anhydrous sodium sulfate drying mutually, removal of solvent under reduced pressure get crude product (dl)-3-(2 ', 5 '-dichlorophenyl)-3,4-dihydro Isocoumarin 〉97 (33C), make eluent with sherwood oil and carry out column chromatographic isolation and purification and get pure product 3.5g, 11.8mmol, measure fusing point and 1H NMR, its chemical structural formula and physical and chemical parameter see Table 2 and table 3, by table 2 and table 3 as seen, and this compound 1H NMR shows and the corresponding chemical shift of its structure that the number of H and its structure are coincide, and MS measures and corresponding M occurs +The m/z peak, corresponding skeleton absorption peak appears in IR.
Embodiment 27
(dl)-3-(2 ', 3 '-difluorophenyl)-3, the synthetic and structure of 4-dihydro Isocoumarin 〉97 (41C) is identified:
Usefulness diacetyl oxide (1mL) dissolving 2-[2 '-hydroxyl-2 in the there-necked flask of 250mL '-(2 "; 3 "-difluorophenyl) ethyl benzoate (41B) (5.9g, 21.5mmol), reflux 2 hours, after the reaction mixture cooling, add entry (25mL), stirred overnight at room temperature filters out precipitation, (2 * 20mL) extract filtrate with methylene dichloride, methylene dichloride is used anhydrous sodium sulfate drying mutually, removal of solvent under reduced pressure get crude product (dl)-3-(2 ', 3 '-difluorophenyl)-3,4-dihydro Isocoumarin 〉97 (41C), make eluent with sherwood oil and carry out column chromatographic isolation and purification and get pure product 4.7g, 18.2mmol, measure fusing point and 1H NMR, its chemical structural formula and physical and chemical parameter see Table 2 and table 3, by table 2 and table 3 as seen, and this compound 1H NMR shows and the corresponding chemical shift of its structure that the number of H and its structure are coincide, and MS measures and corresponding M occurs +The m/z peak, corresponding skeleton absorption peak appears in IR.
Embodiment 28
(dl)-3-(3 ', 5 '-difluorophenyl)-3, the synthetic and structure of 4-dihydro Isocoumarin 〉97 (42C) is identified:
Usefulness diacetyl oxide (1mL) dissolving 2-[2 '-hydroxyl-2 in the there-necked flask of 250mL '-(3 "; 5 "-difluorophenyl) ethyl benzoate (42B) (7.0g, 25.2mmol), reflux 2 hours, after the reaction mixture cooling, add entry (25mL), stirred overnight at room temperature filters out precipitation, (2 * 20mL) extract filtrate with methylene dichloride, methylene dichloride is used anhydrous sodium sulfate drying mutually, removal of solvent under reduced pressure get crude product (dl)-3-(3 ', 5 '-difluorophenyl)-3,4-dihydro Isocoumarin 〉97 (42C), make eluent with sherwood oil and carry out column chromatographic isolation and purification and get pure product 4.8g, 18.6mmol, measure fusing point and 1H NMR, its chemical structural formula and physical and chemical parameter see Table 2 and table 3, by table 2 and table 3 as seen, and this compound 1H NMR shows and the corresponding chemical shift of its structure that the number of H and its structure are coincide, and MS measures and corresponding M occurs +The m/z peak, corresponding skeleton absorption peak appears in IR.
Embodiment 29
(dl)-3-(3 ', 4 '-difluorophenyl)-3, the synthetic and structure of 4-dihydro Isocoumarin 〉97 (43C) is identified:
Usefulness diacetyl oxide (1mL) dissolving 2-[2 '-hydroxyl-2 in the there-necked flask of 250mL '-(3 "; 4 "-difluorophenyl) ethyl benzoate (43B) (6.0g, 21.7mmol), reflux 2 hours, after the reaction mixture cooling, add entry (25mL), stirred overnight at room temperature filters out precipitation, (2 * 20mL) extract filtrate with methylene dichloride, methylene dichloride is used anhydrous sodium sulfate drying mutually, removal of solvent under reduced pressure get crude product (dl)-3-(3 ', 4 '-dichlorophenyl)-3,4-dihydro Isocoumarin 〉97 (43C), make eluent with sherwood oil and carry out column chromatographic isolation and purification and get pure product 4.5g, 17.3mmol, measure fusing point and 1H NMR, its chemical structural formula and physical and chemical parameter see Table 2 and table 3, by table 2 and table 3 as seen, and this compound 1H NMR shows and the corresponding chemical shift of its structure that the number of H and its structure are coincide, and MS measures and corresponding M occurs +The m/z peak, corresponding skeleton absorption peak appears in IR.
Embodiment 30
The mensuration of synthetic new compound fungicidal activity among the present invention:
Adopt thalli growth rate assay method (Mycelium growth rate test), detailed process is, get the 5mg sample dissolution in an amount of dimethyl formamide, then with containing the medicament that a certain amount of polysorbas20 emulsifier aqueous solution is diluted to 500 μ g/mL, reagent agent is respectively drawn 1mL under aseptic condition inject in the culture dish, add the 9mL substratum more respectively, make 50 μ g/mL pastille flat boards after shaking up, do blank with the flat board that adds the 1mL aqua sterilisa, punch tool with diameter 4mm cuts the bacterium dish along the mycelia outer rim, move on the pastille flat board, be equilateral triangle and put, every processing repeats 3 times, culture dish is placed on cultivation in 24 ± 1 ℃ of constant incubators, " Invest, Then Investigate " was respectively handled bacterium dish expansion diameter in 48 hours, averaged, and relatively calculated relative bacteriostasis rate with blank.Comprise gibberella saubinetii (Gibberella zeae), tomato early epidemic disease (Alternaria), asparagus stem withered (Phoma asparagi solani), apple wheel line (Physalospora piricola) and peanut foxiness (Cercosporaarachidicola) for the examination pathogenic fungi.Measurement result sees Table 4, and table 4 shows that compound 33C when 50 μ g/mL apple is taken turns line (Physalosporapiricola) and peanut foxiness (Cercospora arachidicola) shows certain inhibition growth effect.
Embodiment 31
The mensuration of synthetic new compound insecticidal activity among the present invention:
Compound of the present invention adopts leaf dipping method to the mensuration of the insecticidal activity of mythimna separata, impregnated in leaf of Semen Maydis in the soup of acetone preparation (500 μ g/mL), treat to insert 4 instar larvaes behind the soup, main mensuration stomach toxicity and action of contace poison, 24,96 hours check test results (observing the insect growth regulator(IGR) effect) represent the insecticidal activity height with per cent death loss.Compound of the present invention adopts immersion method to measure to the insecticidal activity of mosquito larvae, 4 instar larvaes is put into the soup (water) of finite concentration (5 μ g/mL).Mosquito larvae was checked the death condition of mosquito larvae in 24 hours.Measurement result sees Table 5, and table 5 shows that the compound of mensuration does not have any insecticidal activity.The normal decortication of mythimna separata became for 5 ages after 4 days, did not also find the insect growth regulator(IGR) effect.
Embodiment 32
The mensuration of synthetic new compound weeding activity among the present invention:
Adopt the greenhouse pot culture method to carry out, cauline leaf is handled after dividing preceding soil treatment of seedling and seedling, treatment dosage is 750 gram/hectares, application method is for spraying, after dispenser, measured overground part fresh weight inhibition percentage in 15 days, measure the examination material and comprise rape (Brassicacampestris), barnyard grass grass (Echinochloa crus-galli), three-coloured amaranth (Amaranthus retroflexus L.) and lady's-grass (Digitariasanguinalis (L.) Scop).Measurement result sees Table 6, and table 6 shows that 32A, 44A, 32B and HA-31 have growth-inhibiting effect preferably to rape.
Embodiment 33
The active mensuration of synthetic new compound human pathogenic fungi among the present invention:
The mensuration of the anti-medical fungi effect of synthetic compound is carried out (Waitz J.A.and Deuve C.G.Antifungal agents.Annu.Rev.Med.Chem. by the agar tube dilution method with reference to the method for Waitz among the present invention, 7,109 (1972)), anti-human body pathogen comprises trichophyton, the Candida albicans bacterium, aflatoxin produces bacterium, Sabouraudites lanosus, aspergillus tubigensis and candidiasis, n-compound is miconazole and both sexes toxin B, the mensuration concentration of each compound is 200 μ g/mL, measurement result sees Table 7, table 7 is the result show, 32B and 43A are active suitable substantially with the standard medicament to trichophytic inhibition.
Embodiment 34
The mensuration of synthetic new compound antibacterial activity among the present invention:
Carry out (Kasprzykowski F with reference to the Kasprzykowski reported method, Schal é n C, Kasprzykowska R, Jastrzebska B, Grubb A.Synthesis and antibacterial properties of peptidyl derivatives andcyclopeptides structurally based upon the Inhibitory centre of human cystatin C.Dissociation ofantiproteolytic and antibacterial effects.APMIS 2000; 108:473-81.), adopt the agar tube dilution method to test the antibacterial activity of synthetic compound, bacteria tested comprises: the Escherichia intestinal bacteria; Bacillus subtilus; Shigellae; Staphylococcus; Pseudomonas; Salmonella typhi, as the mark medicine, 24 hours culture comprises about 10 with imipenum 4-10 6CFU, they are distributed on the agar surface, different specimen is added in separately the aperture, experiment was cultivated 24 hours in the time of 37 ℃, measure inhibiting rate and with the contrast of mark medicine, measurement result sees Table 8, table 8 shows, most compound nonreactive bacterium living beings activity, but part of compounds shows antibacterial activity preferably, as 32B to the restraining effect of staphylococcus be imipenum 3-4 doubly.
Embodiment 35
The toxic mensuration of synthetic new compound anti-cell among the present invention:
Adopt the test of salt solution shrimp mortality, to the fatefulue measuring method of salt solution shrimp shrimp be with the ovum of salt solution shrimp by with Petri dish (34g sea salt/L deionized water) under the 60W head light, temperature is 24-26 ℃ and cultivates hatching, preparation mycotoxin solution in acetonitrile-water (1: 1), transfer to then in 96 orifice plates through air-dry overnight, after solvent volatilizees fully again with toxin dissolution in 100-μ L-seawater.Accurate solution concentration is by HPLC-MS test (carry out quantitatively according to isotopic dilution method, D-FB1 is as interior mark).Each comprises the cathodic control that contains 100-μ L acetonitrile-water (1: 1) and 200 μ L seawater.DAS carries out three experiments as anodic control (40 μ L in the 10 μ g/mL solution) for each toxin, six various dose, and each dosage repeats 8 times.After the 24h hatching, will not have joint meat worm and separate from its shell, packing is transferred in the fresh seawater with pipette, puts into the 100 μ L that contain the organic solution of 10-20 in each well, makes last volume for being 200 μ L.Prevent that with sealing film moisture from losing, then 24-26 ℃ of directing light irradiation, rotating speed is hatching 48 hours under the condition of 140rpm, hatch the dead borer population amount of detection in each hole after 2 days, detects the quantity of the shrimp in each hole.Measurement result sees Table 9, and table 9 shows, compound nonreactive cytotoxicity of the present invention.
The physical and chemical parameter of table 2 The compounds of this invention
Compound Outward appearance Molecular formula m.p./℃ Productive rate % Ultimate analysis (experimental value/theoretical value) Cl/F
C H O
31A White powder C 15H 8Cl 2O 2 208-210 81.0 61.83/62.07 2.76/2.76 11.08/10.69 24.33/24.48
32A White powder C 15H 8Cl 2O 2 180-182 80.0 61.83/62.07 2.76/2.76 11.08/10.69 24.33/24.48
33A White powder C 15H 8Cl 2O 2 187-189 81.0 61.83/62.07 2.76/2.76 11.08/10.69 24.33/24.48
41A White powder C 15H 8F 2O 2 156-158 77.0 69.73/69.77 3.10/3.10 12.44/12.40 14.73/14.73
42A White powder C 15H 8F 2O 2 149-151 79.0 69.73/69.77 3.10/3.10 12.44/12.40 14.73/14.73
43A White powder C 15H 8F 2O 2 156-159 79.0 69.73/69.77 3.10/3.10 12.44/12.40 14.73/14.73
44A White powder C 15H 8F 2O 2 131-133 78.0 69.73/69.77 3.10/3.10 12.44/12.40 14.73/14.73
31B Clear crystal C 15H 10Cl 2O 3 172-173 73.0 58.23/58.44 3.28/3.25 15.60/15.26 22.89/23.05
32B Clear crystal C 15H 10C l2O 3 160-162 77.0 58.23/58.44 3.28/3.25 15.60/15.26 22.89/23.05
33B White powder C 15H 10Cl 2O 3 140-142 71.0 58.23/58.44 3.28/3.25 15.60/15.26 22.89/23.05
41B Clear crystal C 15H 10F 2O 3 151-154 70.0 65.24/65.22 3.66/3.62 17.34/17.39 13.76/13.77
42B White powder C 15H 10F 2O 3 124-126 80.0 65.24/65.22 3.66/3.62 17.34/17.39 13.76/13.77
43B White powder C 15H 10F 2O 3 132-135 69.0 65.24/65.22 3.66/3.62 17.34/17.39 13.76/13.77
HA-31 Clear crystal C 15H 12Cl 2O 3 138-140 77.0 57.91/58.06 3.88/3.87 15.41/15.17 22.80/22.90
HA-32 Clear crystal C 15H 12Cl 2O 3 150-152 69.0 57.91/58.06 3.88/3.87 15.41/15.17 22.80/22.90
HA-33 Clear crystal C 15H 12Cl 2O 3 172-174 72.0 57.91/58.06 3.88/3.87 15.41/15.17 22.80/22.90
31C White powder C 15H 9Cl 2O 2 184-186 73.0 61.44/61.64 3.44/3.08 10.95/10.96 24.17/24.32
32C White powder C 15H 9Cl 2O 2 236-238 77.0 61.44/61.64 3.44/3.08 10.95/10.96 24.17/24.32
33C White powder C 15H 9Cl 2O 2 121-124 77.0 61.44/61.64 3.44/3.08 10.95/10.96 24.17/24.32
41C White powder C 15H 8F 2O 2 118-121 80.0 69.25/69.23 3.85/3.08 12.31/13.07 14.59/14.62
42C White powder C 15H 8F 2O 2 121-122 69.0 69.25/69.23 3.85/3.08 12.31/13.07 14.59/14.62
43C White powder C 15H 8F 2O 2 96-98 75.0 69.25/69.23 3.85/3.08 12.31/13.07 14.59/14.62
Table 3 The compounds of this invention 1H NMR and MS and IR data
Numbering MSm/z 1H NMR δ (solvent) IR cm -1
31A 290.00(100％)(M +) 292.00(67.5％)(M+2) 294.00(13％)(M+4) 6.95(1H，s，H-4)，7.39(1H s，H-4′)，7.50(1H，d，J＝8.14Hz，H-7)，7.53(1H，d，J＝9.24Hz， H-6)，7.55(1H，d，J＝7.60Hz，H-5)，7.75(2H，d，J＝1.24Hz，H-2’，6’)，8.31(1H，d，J＝7.88 Hz，H-8)(CDCl 3). 2935，1708，1567， 1245，1099
32A 290.10(28％)(M +) 292.00(17.5％)(M+2) 294.10(3.7％)(M+4) 6.89(1H，s，H-4)，7.29(1H，dd，J＝7.9Hz，H-3′)，7.50(2H，d，J＝7.8Hz，H-2’，4’)，7.54(1H，d， J＝8.9Hz，H-7)，7.56(1H，d，J＝8.0Hz，H-5)，7.74(1H，m，J＝0.98，8.28Hz，H-6)，8.33(1H，d， J＝7.90Hz，H-8)(CDCl 3). 2920，1704，1563， 1249，1096
33A 289.96(100％)(M +) 291.97(69.6％)(M+2) 293.96(12.1％)(M+4) 7.01(1H，s，H-4)，7.32(1H，dd J＝2.47，8.56Hz，H-4′)，7.41(1H，d，J＝8.56Hz，H-3’)，7.50 (1H，d，J＝7.80Hz，H-5)，7.56(1H，m，J＝1.2，7.82Hz，H-7)，7.72(1H，dd，J＝2.02Hz，H-6’)， 7.75(1H，m，J＝2.02，8.26Hz，H-6)，8.32(1H，d，J＝7.9Hz，H-8)(CDCl 3). 2923，1703，1563， 1244，1080
41A 258.10(100％)(M +) 7.19(1H，s，H-4)，7.36(1H，m，J＝1.98，4.6，8.08Hz，H-4’)，7.44(1H，m，J＝1.14，1.2，9.5Hz， H-5’)，7.54(1H，dd，J＝8.2Hz，H-7)，7.68(1H，d，J＝7.36Hz，H-5)，7.74(1H，m， J＝1.7，7.44Hz，H-6’)，7.92(1H，m，J＝1.2，6.84Hz，H-6)，8.31(1H，d，J＝7.90Hz，H-8) (CDCl 3). 2935，1707，1566， 1242，1141
42A 258.10(100％)(M +) 6.86(1H，m，H-4’)，6.94(1H，s，H-4)，7.40(2H，dd，J＝1.98，8.30Hz，H-2′，6’)，7.50(1H，dd， J＝7.88Hz，H-7)，7.54(1H，d，J＝7.40，Hz，H-5)，7.74(1H，m，J＝1.04，7.76Hz，H-6)，8.31 (1H，d，J＝7.92Hz，H-8)(CDCl 3). 2920，1704，1569， 1241，1142
43A 258.00(100％)(M +) 6.88(1H，s，H-4)，7.23(1H，m，J＝1.1，8.6Hz，H-7)，7.51(1H，m，J＝3.36，4.8，15.3Hz，H-2’)， 7.53(1H，dd，J＝1.0，7.8Hz，H-5)，7.72(1H，m，J＝1.2，8.5，10.1Hz，H-5’)，7.74(1H，m， J＝1.04，7.76Hz，H-6)，7.75(1H，d，J＝1.24，7.8，11.2Hz，H-6’)，8.30(1H，dd，J＝8.0.0.6Hz， H-8)(CDCl 3). 2923，1703，1565， 1247，1189
44A 258.00(83.22％)(M +) 6.93(1H，m，J＝2.4，8,6，11.6Hz，H-4’)，6.99(1H，m，J＝2.3，9.1，11.4Hz，H-5’)，7.12(1H，s，H-4)， 7.50(1H，dd，J＝3.0，7.8Hz，H-7)，7.53(1H，d，J＝7.56Hz，H-5)，7.73(1H，m，J＝1.04，7.76Hz， H-6)，7.99(1H，m，J＝2.3，6.4，8.8Hz，H-6’)，8.30(1H，d，J＝7.89Hz，H-8)(CDCl 3) 2927，1709，1562， 1248，1141
31B 308.00(M+) 310.00(M+2) 312.00(M+4) 4.62(1H，s，H-1’)，7.24(1H，d，J＝7.9Hz，H-3)，7.26(1H，dd，J＝8.9Hz，H-5)，7.58(1H，dd， J＝1.0，7.54Hz，H-4，4”)，7.94(2H，d，J＝1.76Hz，H-2”，6”)，8.15(1H，dd，J＝7.9Hz， H-6)(D 2O). 3300-3250，2935，2733， 1708，1470，1099
32B 308.10(M+) 310.10(M+2) 312.00(M+4) 4.64(1H，s，H-1’)，7.06(1H，dd，J＝7.9Hz，H-5”)，7.27(2H，dd，J＝7.86Hz，H-3，5)，7.42(1H， d，J＝8.17Hz，H-4”)，7.63(1H，m，J＝1.3，7.9Hz，H-4)，7.81(1H，d，J＝1.43，7.78Hz，H-6”)， 8.02(1H，dd，J＝8.01Hz，H-6)(D 2O). 3300-3250，2920，2732， 1704，1471，1096
33B 308.00(M+) 310.00(M+2) 312.10(M+4) 4.63(1H，s，H-1’)，7.32(1H，d，J＝7.55Hz，H-3)，7.34(1H，d，J＝7.9Hz，H-5)，7.41(1H，d， J＝8.9Hz，H-3”)，7.44(1H，d，J＝8.8Hz，H-4”)，7.58(1H，dd，J＝1.0，7.54Hz，H-4)，7.97(1H，d， J＝1.78Hz，H-6”)，8.17(1H，dd，J＝7.9Hz，H-6)(D 2O). 3300-3250，2923，2733， 1703，1473，1080
41B 276.00(M +) 4.69(1H，s，H-1’)，7.15(2H，m，J＝3.12，8.34Hz，H-4”，5”)，7.18(1H，m，J＝1.37，7.49Hz，H-3， 5)，7.39(1H，m，J＝1.42，7.76，9.45Hz，H-4)，7.77(1H，m，J＝1.5，6.2，8.8Hz，H-6”)，8.09(1H， dd，J＝7.62Hz，H-6)(D 2O). 3300-3250，2935，2735， 1707，1470，1141
42B 276.20(M +) 4.61(1H，s，H-1’)，6.98(1H，dd，J＝8.25，16.6Hz，H-4”)，7.23(1H，d，J＝7.4Hz，H-3)， 7.37(1H，dd，J＝7.6Hz，H-4)，7.51(2H，m，J＝1.0，11.8Hz，H-2”，6”)，7.77(m，J＝1.6，7.90Hz， H-4)，8.08(1H，dd，J＝7.23Hz，H-6)(D 2O). 3300-3250，2920，2733， 1704，1470，1142
43B 276(M +) 4.63(1H，s，H-1’)，6.98(1H，dd，J＝8.34Hz，H-5”)，7.23(1H，d，J＝5.8Hz，H-3)，7.37(1H，m， J＝3.0，7.5Hz，H-7)，7.52(1H，m，J＝1.0，7.49Hz，H-4)，7.75(1H，dd，J＝1.68，11.8Hz，H-2”)， 7.79(1H，d，J＝8.8Hz，H-6”)，8.09(1H，dd，J＝7.62Hz，H-6)(D 2O). 3300-3250，2923，2737， 1703，1475，1189
HA-31 310.10(M+) 312.10(M+2) 314.00(M+4) 2.25(1H，dd，J＝8.22，15.6Hz，H-1’b)，2.60(1H，dd，J＝6.24，15.6Hz，H-1’a)，4.10(1H，dd， J＝7.12，14.20Hz，H-2’)，7.57(1H，dd，J＝1.58，7.9Hz，H-3)，7.73(1H，dd，J＝8.9Hz，H-5)， 7.78(1H，dd，J＝7.54Hz，H-4)，7.95(3H，d，J＝1.76Hz，H-2”，4”，6”)，8.16(1H，dd，J＝7.9 Hz，H-6)(D 2O). 3350-3200，1384，2935， 2731，1708，1473，1099
HA-32 310.00(M+) 312.10(M+2) 314.00(M+4) 2.25(1H，dd，J＝8.22，15.6Hz，H-1’b)，2.60(1H，dd，J＝6.24，15.6Hz，H-1’a)，4.10(1H，dd， J＝7.12，14.20Hz，H-2’)，7.55(1H，dd，J＝1.76，8.1Hz，H-4”)，7.59(1H，dd，J＝7.72Hz， H-5”)，7.63(1H，dd，J＝1.76，7.78Hz，H-6”)，7.57(1H，dd，J＝1.58，7.9Hz，H-3)，7.73(1H， dd，J＝8.9Hz，H-5)，7.78(1H，dd，J＝7.54Hz，H-4)，8.13(1H，dd，J＝7.9Hz，H-6)(D 2O). 3350-3200，1384，2920， 2733，1704，1471，1096
HA-33 310.00(M+) 312.00(M+2) 314.00(M+4) 2.25(1H，dd，J＝8.22，15.6Hz，H-1’b)，2.60(1H，dd，J＝6.24，15.6Hz，H-1’a)，4.10(1H，dd， J＝7.12，14.20Hz，H-2’)，7.23(1H，d，J＝8.9Hz，H-3”)，7.24(1H，dd，J＝1.56，7.8Hz，H-4”)， 7.27(1H，dd，J＝1.0Hz，H-6”)，7.42(1H，dd，J＝1.58，7.9Hz，H-3)，7.73(1H，dd，J＝8.9Hz， H-5)，7.78(1H，dd，J＝7.54Hz，H-4)，8.15(1H，dd，J＝7.79Hz，H-6)(D 2O). 3350-3200，1385，2923， 2732，1703，1476，1080
31C 292.20(11.3％)(M +) 294.00(92％)(M+2) 296.00(3％)(M+4) 3.09(1H，dd，J＝12.10，16.25Hz，H-4b)，3.29(1H，dd，J＝2.90，16.36Hz，H-4a)，5.93(1H，dd， J＝2.90，12.03Hz，H-3)，7.30(2H，dd，J＝2.6Hz，H-2′，6’)，7.44(1H，dd，J＝2.3Hz，H-4’)，7.48 (1H，m，J＝2.46，9.24Hz，H-7)，7.58(1H，m，J＝2.24，7.60Hz，H-6)，7.66(1H，dd， J＝1.24，7.78Hz，H-5)，8.15(1H，d，J＝7.6Hz，H-8)(CDCl 3). 2935，1708，1246，1099
32C 292.10(11.3％)(M +) 294.00(9.2％)(M+2) 296.00(3％)(M+4) 3.10(1H，dd，J＝12.11，16.20Hz，H-4b)，3.27(1H，dd，J＝2.90，16.38Hz，H-4a)，5.93(1H，dd， J＝2.86，12.02Hz，H-3)，7.29(1H，dd，J＝2.6，7.4Hz，H-4’)，7.30(1H，dd，J＝5.1Hz，H-5’)， 7.32(1H，d，J＝7.9Hz，H-6’)，7.45(1H，m，J＝1.08，9.04Hz，H-7)，7.58(1H，m，J＝0.6，7.6Hz， H-6)，7.66(1H，d，J＝7.73Hz，H-5)，8.15(1H，d，J＝7.61Hz，H-8)(CDCl 3). 2920，1704，1245，1096
33C 292.00(11.3％)(M +) 294.00(92％)(M+2) 296.00(3％)(M+4) 3.10(1H，dd，J＝12.22，16.3Hz，H-4b)，3.26(1H，dd，J＝30，16.36Hz，H-4a)，5.60(1H，dd， J＝3.0，12.17Hz，H-3)，7.26(1H，d，J＝2.4Hz，H-6’)，7.28(1H，d，J＝2.2Hz，H-3’)，7.31(1H， dd，J＝2.01，8.5Hz，H-4’)，7.44(1H，dd，J＝7.64Hz，H-7)，7.58(1H，m，J＝1.1，7.48z，H-6)， 7.75(1H，d，J＝7.73Hz，H-5)，8.16(1H，d，J＝7.59Hz，H-8)(CDCl 3). 2923，1703，1243，1080
41C 261.20(51％)(M+1) 3.09(1H，dd，J＝2.92，16.37Hz，H-4b)，3.31(1H，dd，J＝4.09，16.31Hz，H-4a)，5.76(1H，dd， J＝2.94，12.16Hz，H-3)，6.61(1H，m，H-4’)，6.71(m，J＝2.3，8.54Hz，H-6’)，7.46(1H，m， J＝5.0，8.6Hz，H-5’)，754(1H，dd，J＝2.24，7.90Hz，H-7)，7.62(1H，dd，J＝2.5，7.57Hz，H-5)， 7.68(1H，dd，J＝3.20，5.72Hz，H-6)，8.13(1H，d，J＝7.27Hz，H-8)(CDCl 3).. 2935，1707，1244，1141
42C 261.20(4％)(M+1) 3.46(1H，dd，J＝2.92，16.37Hz，H-4b)，3.81(1H，dd，J＝4.09，13.04Hz，H-4a)，5.92(1H，dd， J＝2.95，13.10Hz，H-3)，6.90(1H，m，H-4’)，7.12(1H，m，J＝2.3，9.54Hz，H-2’，6’)，7.28(1H， m，J＝1.76，6.72Hz，H-7)，7.51(1H，dd，J＝2.15，7.68Hz，H-5)；7.67(1H，dd，J＝3.37，5.67Hz， H-6)，8.14(1H，d，J＝7.58Hz，H-8)(CDCl 3). 2920，1704，1244，1142
43C 260.00(4.5％)(M +) 3.08(1H，dd，J＝3.10，16.39Hz，H-4b)，3.29(1H，dd，J＝4.4，16.38Hz，H-4a)，5.46(1H，dd， J＝3.09，11.91Hz，H-3)，7.15(2H，m，J＝7.8，11.3Hz，H-2’，5’)，7.21(1H，m，J＝3.8，5.1，8.2Hz， H-6’)，7.41(1H，m，J＝1.1，8.6Hz，H-7)，7.55(1H，dd，J＝1.22，7.48Hz，H-5)，7.88(1H，m， J＝1.8，6.90Hz，H-6)，8.13(1H，d，J＝7.79Hz，H-8)(CDCl 3). 2923，1703，1243，1189
The measurement result of the part of compounds fungicidal activity among table 4 the present invention (average results of 3 experiments)
Numbering Concentration (μ g/mL) Gibberella saubinetii Gibberella zeae Tomato is epidemic disease Alternaria solani early The withered Phoma asparagi of asparagus stem Apple wheel line Physalospora piricola Peanut foxiness Cercospora arachidicola
31B 32A 32B 33A 33B 33C HA-32 41A 43A 43B 50 50 50 50 50 50 50 50 50 50 26.5 0 0 0 0 11.8 0 17.6 14.7 0 24.2 9.1 6.1 27.3 18.2 21.2 9.1 33.3 45.5 9.1 23.5 23.5 0 0 0 35.3 0 35.3 35.3 11.8 23.1 38.5 28.9 19.2 26.9 53.9 21.2 36.5 38.5 34.6 20.0 10.0 0 10.0 10.0 60.0 10.0 35.0 20.0 0
The measurement result of the part of compounds insecticidal activity among table 5 the present invention (average results of 3 experiments)
Compound number Mythimna separata mortality ratio (%) Mosquito larvae mortality ratio (%) Remarks
Concentration (μ g/mL) 24h/96h Concentration (μ g/mL) 24h/96h
31A 31B 32A 32B 33A 33B 33C HA-33 41A 43A 43B contrast 500 500 500 500 500 500 500 500 500 500 500 acetone 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 55555555550 acetone 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 The mythimna separata mythimna separata mythimna separata mythimna separata mythimna separata mythimna separata mythimna separata mythimna separata mythimna separata mythimna separata mythimna separata mythimna separata of normally peeling of normally peeling of normally peeling of normally peeling of normally peeling of normally peeling of normally peeling of normally peeling of normally peeling of normally peeling of normally peeling is normally peeled
The measurement result of the compound weeding activity among table 6 the present invention (average results of 3 experiments)
Numbering Concentration gram/hectare Three-coloured amaranth Amaranthus retroflexus L Rape Brassica campestris Barnyard grass grass Echinochloa crus-galli Lady's-grass Digitaria sanguinalis (L.) Scop
Soil treatment Cauline leaf is handled Soil treatment Cauline leaf is handled Soil treatment Cauline leaf is handled Soil treatment Cauline leaf is handled
31A 32A 32A 32A 32A 33A 41A 42A 43A 44A 31B 32B 33B 41B 42B 43B 31C 32C 33C 41C 42C 43C HA-31 HA-32 HA-33 750 750 375 188 94 750 750 750 750 750 750 750 750 750 750 750 750 750 750 750 750 750 750 750 750 0 15.94 10.14 00 undetermineds, 00 undetermined undetermined undetermined undetermined undetermined undetermined undetermined undetermineds, 00 undetermineds, 0 13.04 13.04 13.04 1.45 undetermineds 0 15.12 000 undetermineds, 00 undetermined undetermined undetermined undetermined undetermined undetermined undetermined undetermineds, 00 undetermineds, 00000 undetermineds 0 94.94 73.03 33.71 1.69 1.52 21.35 0 10.68 0 23.28 88.55 67.94 0 0 39.31 0 0 19.84 0 1.12 0 94.38 79.78 78.24 26.55 47.95 30.44 19.74 1.74 8.82 6.60 2.96 51.96 91.18 2.94 88.24 33.33 91.18 2.96 0 19.49 52.81 0 0 16.09 0 35.55 33.11 35.29 0 undetermined undetermined undetermined undetermined 5.74 0 2.43 6.15 4.10 18.44 20.90 19.67 4.10 2.43 8.20 5.67 0 7.79 0 3.35 0 23.70 19.08 0 20.60 undetermined undetermined undetermined undetermined 10.33 422 0 2.36 2.36 17.93 10.33 0.46 2.36 0 9.95 00 14.51 16.63 000 14.14 10.71 0 undetermined undetermined undetermined undetermined undetermined, 00 undetermined undetermined undetermined undetermined undetermined undetermined undetermined undetermineds, 1.32 0 undetermineds, 000 11.19 15.14 undetermineds 0 undetermined undetermined undetermined undetermined undetermined, 00 undetermined undetermined undetermined undetermined undetermined undetermined undetermined undetermineds, 0 21.13 undetermineds, 000 22.77 0 undetermineds
The anti-mycotic activity (average results of 3 experiments) of table 7 compound of the present invention when 200 μ g/mL
Pathogenic fungi Inhibiting rate (%)
32A 32B 33A 33B 33C 43A 43B 43C 44A Miconazole
Trichophyton Candida albicans bacterium aflatoxin produces bacterium Sabouraudites lanosus aspergillus tubigensis candidiasis 50 non-activity non-activity non-activity non-activity non-activities 85 non-activity non-activities, 85 non-activity non-activities Non-activity non-activity non-activity 60 non-activity non-activities 65 non-activity non-activities, 70 15 non-activities 50 non-activities, 40 40 non-activity non-activities 70 non-activity non-activities, 65 non-activity non-activities 65 non-activity non-activities, 75 non-activity non-activities 65 non-activity non-activities, 80 non-activity non-activities Non-activity non-activity non-activity non-activity non-activity non-activity 70 110.8 20 * 98.4 73.25 110.8
*: standard specimen is both sexes toxin B
The antibacterial activity (average results of 3 experiments) of table 8 compound of the present invention when 200 μ g/mL
Pathogenic fungi Inhibiting rate (%)
32A 32B 33A 33B 33C 43A 43B 43C 44A Imipenum
Escherichia intestinal bacteria Bacillus subtilus Shigellae staphylococcus pseudomonas salmonella typhi Non-activity non-activity 12 10 non-activity non-activities Non-activity non-activity non-activity 9 non-activities 20 Non-activity non-activity non-activity non-activity non-activity non-activity Non-activity non-activity 12 14 non-activities 17 Non-activity 14 13 12 non-activities 20 Non-activity non-activity non-activity non-activity non-activity non-activity 15 10 17 non-activities 16 12 Non-activity non-activity 11 20 non-activities 13 Non-activity non-activity 14 10 non-activities 15 30 33 27 33 24 25
The cytotoxicity of table 9 compound of the present invention (average results of 3 experiments)
Numbering Dosage (μ g/mL) The shrimp sum The survival number LD 50(μg/mL) Remarks
32A 32B 33A 33B 33C 43A 43B 43C 44A Etoposide 100 10 1 100 10 1 100 10 1 100 10 1 100 10 1 100 10 1 100 10 1 100 10 1 100 10 1 - 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 - 28 30 30 22 28 30 27 30 30 324 30 30 30 30 30 30 30 30 24 30 30 0 17 30 1 19 29 - Undetermined undetermined undetermined undetermined undetermined undetermined undetermined 11.444 13.127 7.4625 No cytotoxicity no cytotoxicity no cytotoxicity no cytotoxicity no cytotoxicity no cytotoxicity no cytotoxicity no cytotoxicity no cytotoxicity

Claims (4)

1. Isocoumarin 〉97 analog derivative, intermediate ketone acid derivative and alcohol acid analog derivative and 3,4-dihydro different coumarin derivative is characterized in that: have following chemical structural formula
Figure A2005101223530002C1
2. the synthetic method of the described Isocoumarin 〉97 analog derivative of claim 1 is characterized in that total synthetic route is:
Figure A2005101223530002C2
Specifically be divided into following steps:
A. dichlorophenyl-and preparation of difluorophenyl Isocoumarin 〉97 (31,32,33,41,42,43,44) A:
At dihalogen acid (31,32,33,41,42,43,44) add a DMF (53.0mmol) and in the mixture of thionyl chloride (38.0mmole), refluxed 30 minutes, when regeneration gas not, the decompression remove the Arius acyl chlorides obtain dihalo acyl chlorides (50.0mmole) (31 ', 32 ', 33 ', 41 ', 42 ', 43 ', 44 '); With homophthalic acid (1) (11.3mmol) and phenyl-dihalide formyl chloride (47.0mmol) (31 ', 32 ', 33 ', 41 ', 42 ', 43 ', 44 ') mixture heating up to 200 ℃ and refluxed 4 hours, cooled reaction mixture acetic acid ethyl dissolution adds anhydrous sodium carbonate then and removes unreacted o-carboxyl phenylacetic acid, isolate organic phase, cross silica gel column chromatography with polyester ether (40-80 ℃) as eluent after concentrating and get Isocoumarin 〉97 (31,32,33,41,42,43,44) A, by the recrystallizing methanol purifying, the consumption of above-claimed cpd can or dwindle by corresponding proportion expansion;
B.2-the preparation of (replacement) phenylformic acid (31,32,33,41,42,43) B:
According to following reaction equation, with ethanol (50mL) dissolving Isocoumarin 〉97 (31,32,33,41,42,43) A adds potassium hydroxide (5%, 100mL), refluxed 4 hours, ethanol is removed in underpressure distillation, with frozen water 20mL, mixture is used methylene dichloride again with hcl acidifying, and (removal of solvent under reduced pressure obtains crude product (31,32 for 3 * 20mL) extractions, anhydrous sodium sulfate drying, 33,41,42,43,44) B uses the recrystallizing methanol purifying, and the consumption of above-claimed cpd can or dwindle by corresponding proportion expansion;
C. (dl)-3-(replacement)-3, the preparation of 4-dihydro Isocoumarin 〉97 analog derivative (31,32,33,41,42,43) C:
(1%, 25mL) dissolving ketone acid (31,32 with potassium hydroxide solution, 33,41,42,43) B (2.07mmol) adds sodium borohydride (0.25g), and mixture stirred under room temperature 1 hour, after the dilute hydrochloric acid acidifying, with ethyl acetate (2 * 50mL) extractions, anhydrous sodium sulfate drying, underpressure distillation removes to desolvate and obtains crude product alcohol acid HA-(31,32,33,41,42,43), dissolve with diacetyl oxide (1mL), reflux 2 hours, reaction mixture adds entry (25mL), mixture stirs and spends the night, the crystal that filtration obtains separating out, (2 * 20mL) extract filtrate, and methylene dichloride is used anhydrous sodium sulfate drying mutually with methylene dichloride, removal of solvent under reduced pressure gets crude product crude product dihydro Isocoumarin 〉97 (31,32,33,41,42,43) C makees eluent with sherwood oil and carries out column chromatographic isolation and purification, and the consumption of above-claimed cpd can or dwindle by corresponding proportion expansion.
3. the described Isocoumarin 〉97 analog derivative of claim 1, intermediate ketone acid derivative and alcohol acid analog derivative and 3,4-dihydro different coumarin derivative is used for the agricultural disease Chinese caterpillar fungus and medicine is antimycotic and the biological activity of bacterium, and its corresponding screening method is as follows:
I. the screening method of weeding activity: adopt the greenhouse pot culture method to carry out, cauline leaf is handled after dividing preceding soil treatment of seedling and seedling, treatment dosage is 750 gram/hectares, application method is for spraying, after dispenser, measured overground part fresh weight inhibition percentage in 15 days, measure the examination material and comprise rape (Brassica campestris), barnyard grass grass (Echinochloa crus-galli), three-coloured amaranth (Amaranthusretroflexus L.) and lady's-grass (Digitaria sanguinalis (L.) Scop);
II. the screening method of insecticidal activity: mythimna separata (Mythimna separata) is adopted leaf dipping method, impregnated in leaf of Semen Maydis in the soup of acetone preparation (500 μ g/mL), treat to insert 4 instar larvaes behind the soup, main mensuration stomach toxicity and action of contace poison, 24,96 hours check test results (observing the insect growth regulator(IGR) effect) represent the insecticidal activity height with per cent death loss; The mensuration of mosquito larvae (Culex pipiens pallens) is 4 instar larvaes to be put into the soup (water) of finite concentration (5 μ g/mL), the death condition of 24 hours inspection mosquito larvaes;
III. the screening method of fungicidal activity: adopt thalli growth rate assay method (Mycelium growth rate test), detailed process is, get the 5mg sample dissolution in an amount of dimethyl formamide, then with containing the medicament that a certain amount of polysorbas20 emulsifier aqueous solution is diluted to 500 μ g/mL, reagent agent is respectively drawn 1mL under aseptic condition inject in the culture dish, add the 9mL substratum more respectively, make 50 μ g/mL pastille flat boards after shaking up, do blank with the flat board that adds the 1mL aqua sterilisa, punch tool with diameter 4mm cuts the bacterium dish along the mycelia outer rim, move on the pastille flat board, be equilateral triangle and put, every processing repeats 3 times, culture dish is placed on cultivation in 24 ± 1 ℃ of constant incubators, " Invest, Then Investigate " was respectively handled bacterium dish expansion diameter in 48 hours, averaged, and relatively calculated relative bacteriostasis rate with blank; Comprise gibberella saubinetii (Gibberellazeae), tomato early epidemic disease (Alternaria), asparagus stem withered (Phoma asparagi solani), apple wheel line (Physalosporapiricola) and peanut foxiness (Cercospora arachidicola) for the examination pathogenic fungi;
IV. the active screening method of anti-human pathogenic fungi: adopt the agar tube dilution method to carry out (WaitzJ.A.and Deuve C.G.Antifungal agents.Annu.Rev.Med.Chem. with reference to the method for Waitz, 7,109 (1972)), anti-human body pathogen comprises trichophyton (Trichophyton longifusus), Candida albicans bacterium (Candida albicans) Huang Mandatory toxin produces bacterium (Aspergillus flavus), Sabouraudites lanosus (Microsporum canis), aspergillus tubigensis (Fusarium solani) and candidiasis (Candida glaberata), n-compound is miconazole (Miconazole) and both sexes toxin B (Amphotericin B), and the mensuration concentration of each compound is 200 μ g/mL;
V. the screening method of antibacterial activity: the method with reference to Kasprzykowski is carried out (Kasprzykowski F, Schal é nC, Kasprzykowska R, Jastrzebska B, Grubb A.Synthesis and antibacterial properties of peptidylderivatives and cyclopeptides structurally based upon the Inhibitory centre of human cystatin C.Dissociation of antiproteolytic and antibacterial effects.APMIS 2000; 108:473-81), adopt the agar tube dilution method to test the antibacterial activity of synthetic compound, bacteria tested comprises: Escherichia intestinal bacteria (Escherichiacoli); Bacillus subtilus (Bacillhas subtilis); Shigellae (Shigella flexenari); Staphylococcus (Staphylococcus aureus); Pseudomonas (Pseudomonas) and salmonella typhi (Slamonella typhi), with imipenum as the mark medicine, 24 hours culture comprises about 104-106CFU (colony forming unit), they are distributed on MHA (the Muller Hinton agar) surface, different specimen is added in separately the aperture, experiment was cultivated 24 hours in the time of 37 ℃, measured inhibiting rate;
VI. Cytotoxic screening method: adopt the test of salt solution shrimp mortality, to the fatefulue measuring method of salt solution shrimp shrimp be with the ovum of salt solution shrimp by with Petri dish (34g sea salt/L deionized water) under the 60W head light, temperature is 24-26 ℃ and cultivates hatching, preparation mycotoxin solution in acetonitrile-water (1: 1), transfer to then in 96 orifice plates through air-dry overnight, after solvent volatilizees fully again with toxin dissolution in 100-μ L-seawater.Accurate solution concentration is by HPLC-MS test (carry out quantitatively according to isotopic dilution method, D-FB1 is as interior mark).Each comprises the cathodic control that contains 100-μ L acetonitrile-water (1: 1) and 200 μ L seawater.DAS carries out three experiments as anodic control (40 μ L in the 10 μ g/mL solution) for each toxin, six various dose, and each dosage repeats 8 times.After the 24h hatching, will not have joint meat worm and separate from its shell, packing is transferred in the fresh seawater with pipette, puts into the 100 μ L that contain the organic solution of 10-20 in each well, makes last volume for being 200 μ L.Prevent that with sealing film moisture from losing, then 24-26 ℃ of directing light irradiation, rotating speed is hatching 48 hours under the condition of 140rpm, hatch the dead borer population amount of detection in each hole after 2 days, detects the quantity of the shrimp in each hole.
4. the described Isocoumarin 〉97 analog derivative of claim 1, intermediate ketone acid derivative and alcohol acid analog derivative and 3, biological activity and the practical application thereof of the antimycotic and bacterium of anti-agricultural disease Chinese caterpillar fungus of 4-dihydro different coumarin derivative and medicine.
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CN102218057A (en) * 2011-04-24 2011-10-19 吉林大学 Application of 3,4-dichloroisocoumarin in preparation coccidiosis-resistant medicaments
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CN102218057A (en) * 2011-04-24 2011-10-19 吉林大学 Application of 3,4-dichloroisocoumarin in preparation coccidiosis-resistant medicaments
CN102838481A (en) * 2011-06-23 2012-12-26 徐州师范大学 Synthesis of 3,5-dichlorobenzoyl chloride
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CN106588852A (en) * 2016-12-09 2017-04-26 西北农林科技大学 3-hydrocarbyl-3,4-dihydroisocoumarin compound, and preparation method and purpose thereof
CN110483467A (en) * 2019-07-11 2019-11-22 宁波大学 Dihydroiso-coumarin analog derivative and its preparation method and application
CN110483467B (en) * 2019-07-11 2023-01-03 宁波大学 Dihydroisomerin derivative and preparation method and application thereof
CN110746353A (en) * 2019-11-01 2020-02-04 四川大学 Aromatic compound and preparation method and application thereof
CN110746353B (en) * 2019-11-01 2021-08-27 四川大学 Aromatic compound and preparation method and application thereof
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CN114195753A (en) * 2021-12-23 2022-03-18 大连大学 Preparation method for preparing 3, 4-diphenyl isocoumarin derivative by ruthenium catalysis one-pot method
CN114195753B (en) * 2021-12-23 2023-07-28 大连大学 Preparation method of 3, 4-diphenyl isocoumarin derivative by ruthenium catalysis one-pot method

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