CN101544669B - Phenyl cyanoacrylate derivatives containing alpha-amino phosphonate ester and preparation method and application thereof - Google Patents
Phenyl cyanoacrylate derivatives containing alpha-amino phosphonate ester and preparation method and application thereof Download PDFInfo
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- CN101544669B CN101544669B CN2009101025486A CN200910102548A CN101544669B CN 101544669 B CN101544669 B CN 101544669B CN 2009101025486 A CN2009101025486 A CN 2009101025486A CN 200910102548 A CN200910102548 A CN 200910102548A CN 101544669 B CN101544669 B CN 101544669B
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- 0 *C(C(*)=O)=C(c1ccccc1)NC(c1ccccc1)P(*)(*)=O Chemical compound *C(C(*)=O)=C(c1ccccc1)NC(c1ccccc1)P(*)(*)=O 0.000 description 1
Abstract
The present invention discloses a preparation method and biological activity for compounds resisting plant virus action, namely phenyl cyanoacrylate derivatives containing alpha-amino phosphonate ester, and in particular relates to the compounds expressed by the following general formula and a preparation method thereof. The invention introduces the phenyl cyanoacrylate derivatives containing alpha-amino phosphonate ester, which is synthesized by three steps by taking various substituted aromatic aldehydes, ammonia, dialkyl phosphate, paratoluenesulfonic acid, cyanacetic ester, concentrated hydrochloric acid and potassium permanganate as raw materials and concentrated sulphuric acid, hexahydropyridine and triethylamine as catalysts. The compounds h, i, j, t and w have high effects of protecting, passivating, treating and inhibiting on tobacco mosaic virus (TMV), and show high anti-virus activity of plants.
Description
Technical field
The medicine that the present invention has the Antiphytoviral effect contains phenyl cyanacrylate derivant of amido phosphonate and preparation method thereof.
Background technology
Cyanoacrylate compound is because of its novel mechanism of action, and characteristics such as environmentally friendly became the focus of domestic and international agricultural chemicals and medical research in recent years.
Aspect synthetic, 1996, (Lars F.Jalander, Jan-Erik such as Lars F.Jalander
NUCLEOPHILIC V1NYL1C SUBSTITUTIONS OF (E)-AND (Z)-ETHYL 3-ARYL-3-CHLORO-2-CYANOPROPENOATES WITHPRIMARY AND SECONDARY AMINES, Synthetic Communi Cations, 26 (19), 3549-3557 (1996)) reported that with 2-cyano group-3-chloro-3-substituted-phenyl cyanoacrylate and various substituted-amino be raw material, at the exsiccant tetrahydrofuran (THF) is under solvent and the alkaline condition, heat 20 ℃-60 ℃ reaction 3-20h, reaction is followed the tracks of with GLC, and reaction is finished after precipitation, extraction, recrystallizations etc. obtain 2-cyano group-3-amino-3-substituted-phenyl cyanoacrylate compound.
Aspect weeding activity: (Zou Xiaomao, Yu Limin, Gao Ying such as the little Mao of Zou in 2006, execute joy, Pei Jiang, Liu Bin, Li Huifen, Hu Fangzhong, synthetic and the weeding activity of the polished .2-cyano group-3-of Yang Hua (2-fluorine pyridine-5-yl) methylamino--3-methylthio group cyanoacrylate compound, organic chemistry, 2006,26,337) fluorine atom is introduced the cyanoacrylate compound that obtains containing fluoro pyridine methylamino-in such compound structure.Active testing shows that compound has very high weeding activity, part of compounds under 1500g/ha concentration to the preventive effect of broadleaf weeds more than 90%, the group of fluorinated pyridine is introduced in the cyanoacrylate, R group in the molecule has considerable influence to activity, at 1500g/ha, when cauline leaf is handled behind the seedling, when the R group is the phenyl of phenyl, ortho position or a substd, the growth table of broad leaved plant such as rape is revealed very high inhibition activity; When the R group is contraposition when substituent phenyl is arranged, the weeding activity of target compound is lower; When the R group was ethyl, the activity of target compound was the highest.(Liu Yuxiu such as Liu Yu show in 2006, Lee's Heng, Zhao Qiqi, the people of Wangqing County, synthetic and the weeding activity research of yellow profit autumn .2-cyano group-3-substituted pyridines methylamino-3-substitutional crylic acid ethoxy ethyl ester, organic chemistry, 2006,26,1232) a series of 2-pyridyl-methanamine bases that alkoxyl group replaces that contain have been synthesized in design, the alpha-cyanoacrylate ester cpds of 3-pyridyl-methanamine base and 4-pyridyl-methanamine base, give birth to and survey result's demonstration: part of compounds shows higher weeding activity .3-pyridyl-methanamine based compound (60.4%) to rape the rape weeding activity is higher than 2-pyridyl-methanamine based compound (41.3%) and 4-pyridyl-methanamine based compound (15.8%), illustrates that very important effect is played to biological activity in the position of nitrogen in the pyridyl.In 2-alkoxyl group-3-pyridine base period base acrylic ester compound, the macoradical of the 2-position of 3-pyridyl is of value to the biological activity that improves compound.When R was sec.-propyl, compound was higher than other compounds to the activity of rape, and showing in the 3-position of acrylate has suitable substituting group that biological activity is just played important effect.(Gao, Y. such as Gao Ying in 2006; Zou, X.-M.; Yu, L.-M.; Xu, H.; Liu, B.; Zhu, Y.-Q.; Hu, F.-Z.; Yang, H.-Z.2-cyano group-3-methylthio group-3-replaces the synthetic and weeding activity of methylamino-acrylic ester compound, Chin.J.Chem.2006,24,521) 31 acrylic compound that contain 2-cyano group-3-methylthio group-3-methylamino-have been synthesized in design, test compounds is to the weeding activity of barnyard grass grass, Amaranthus retroflexus and rape, and give birth to and survey result's demonstration: part of compounds is to showing higher weeding activity.
Aspect fungicidal activity: calendar year 2001 Wang Fengyun etc. (Wang Fengyun, grain is cold, Ni Jueping, Li Jie, Guo Liqin, 2-cyano group 3-substituted phenylacrylate compounds, composition and method of making the same and the application on crop bactericide, ZL 01115993.0,2001-05-08, Chem, Abstr, 2001,138,89583) reported condensation under alkaline condition, through superchlorination with phenyl aldehyde and cyan-acetic ester; Perhaps obtain the intermediate of hydroxyl on the two keys with Benzoyl chloride and cyan-acetic ester reaction, again with phosphorus oxychloride reaction, these two kinds of approach all obtain a 2-cyano group-3-chloro-3-phenyl cyanoacrylate intermediate, this intermediate again with various substituted-aminos with inert solvent, methylene dichloride, ethylene dichloride or tetrahydrofuran (THF) are solvent, at pyridine or N, the accelerine acid binding agent exists down, at 0-70 ℃ of following stirring reaction, filter, dehydration, washing, get 2-cyano group-3-amino-3-ethyl phenylacrylate compounds, this compound is prevented and treated on the various crop by sickle-like bacteria, rest fungus, the application of multiple fungus-caused disease such as botrytis cinerea aspect and preparation and the application that contains this compound synergetic pesticide composition.(Wang Longgen such as Wang Long root in 2005, Wang Fengyun, Diao Yamei, Ni Jueping, Wei Ping, synthetic and the fungicidal activity of 2-cyano group-3-substituted-amino-3-(2-aminomethyl phenyl) ethyl propenoate, organic chemistry, 2005,25,1254) reported by the reaction of 2-methyl benzoyl chloride and ethyl cyanoacetate and obtained 2-cyano-3-hydroxy-3-(2-aminomethyl phenyl) ethyl propenoate, obtained 2-cyano group-3-chloro-3-(2-aminomethyl phenyl) ethyl propenoate, handled with triethylamine again and synthesized 11 2-cyano group-3-substituted-amino-3-(2-aminomethyl phenyl) ethyl propenoate class target compound through chlorination.With concentration 1.0g/L 7 kinds of pathogenic bacterias are carried out the general sieve of live body, the result shows that this compounds is withered to the wheat line, rape sclerotium, cucumber downy mildew and paddy rice rice blast and blinds are withered etc. all activity, especially better for rape sclerotium and the withered activity of paddy rice blinds.2007, (Liu Li such as Liu Li, horse naval, Ma Yafang, Guo Liqin, synthetic and the bioactivity research of Feng Hong plum .2-cyano group-3-substituted-amino-3-substituted phenylacrylate compounds. the 7th novel pesticide initiative exchanging meeting collection of thesis, Hangzhou, 2007, agricultural chemicals Professional Committee of Chemical Industry and Engineering Society of China) reported that by nitrobenzoyl chloride and cyan-acetic ester be starting raw material, generate 2-cyano-3-hydroxy-3-nitrophenyl acrylate under the triethylamine effect, carry out chlorination with phosphorus oxychloride again and obtain 2-cyano group-3-chloro-3-nitrophenyl propylene vinegar, last and each replacement amine reaction obtains target compound 2-cyano group-3-substituted-amino-3-substituted phenyl acrylic acid ester.Liu Li etc. are by having carried out the general sieve of fungicidal activity to institute's synthesising target compound, the result show compound 3-to nitre phenyl-3-(N-ethyl methylamino-)-2-cyanacrylate to the rice leaf spot bacteria biological activity of doing well, compound 3-(2-chloro-5-nitrophenyl)-3-(N-ethyl methylamino-)-2-cyanacrylate shows better biological activity to rhizoctonia cerealis, compound 3-(2-chloro-5-nitrophenyl)-3-methylamino--2-alpha-cyanoacrylate methoxy ethyl ester, 3-(2-chloro-5-nitrophenyl)-3-methylamino--2-Methyl 2-cyanoacrylate shows better biological activity to rice leaf spot bacteria.
Aspect antiviral activity: (Baoan Song such as Song Baoan in 2005, Huiping Zhang, Hua Wang, Song Yang, Linhong Jin, Deyu Hu, Lili Pang, Wei He.Synthesis and Antiviral Activity of Novel Chiral CyanoacrylateDerivatives.Journal Agric Food Chem., 2005,53,7885) utilize microwave catalysis to synthesize serial chirality 2-cyanoacrylate, adopt the withered spot method of half leaf to measure resisting tobacco mosaic virus (TMV) activity of gained compound, biological activity determination shows that the live body passivation and the live body result of treatment of chipal compounds (R)-3-(1-phenyl-ethyl amine base)-3-(4-nitrobenzoyl amido)-2-cyanacrylate are respectively 89.1% and 43.1%.(Lv Yinpu such as Lv Yinpu in 2007; 2-cyanoacrylate new compound activity of resisting tobacco mosaic virus and Study on mechanism; Guizhou University's Ph D dissertation; 2007) report a series of cyanoacrylates that contain phosphoryl, and measured resisting tobacco mosaic virus (TMV) activity of gained compound.Studies show that these compounds all have good therapeutic action; especially compound 3-dimethoxy phosphono-3-methylthio group-2-cyanacrylate and 3-diisopropoxy phosphono-3-methylthio group-2-cyanacrylate, inhibiting rate is respectively 60.0% and 64.2% under 500 μ g/mL.(Zhuo Chen such as Chen Zhuo in 2008; Xianyou Wang; Baoan Song; Hua Wang; Pinaki S.Bhadury; Kai Yan; Huiping Zhang; Song Yang; Linhong Jin; Deyu Hu; Wei Xue; Song Zeng and Jun Wang.Synthesis and antiviral activities of novel chiral cyanoacrylate derivativeswith (E) configuration.Bioorg.Med.Chem.16 (2008) 3076-3083) reported by 3; 3-two thiomethyl 2-cyanacrylate and Chiral Amine; at ethanol is that reflux obtains series and contains chirality amine cyanacrylate analog derivative under the solvent, and finds its protection under compound (E)-3-(4-fluorophenyl the ethylamino-)-3-benzene methanamine base-concentration of 2-cyanacrylate at 500ppm through the activity of resisting tobacco mosaic virus test; passivation; therapeutic activity is respectively 65.7%; 49.5%; 64.0%, its result of treatment is higher than 57.8% of contrast medicament Ningnanmycin.(NING LONG such as Long Ning in 2008; XUE-JIAN CAI; BAO-AN SONG; * SONG YANG; ZHUOCHEN; PINAKI S.BHADURY; DE-YU HU; LIN-HONG JIN; AND WEIXUE.Synthesis and Antiviral Activities of Cyanoacrylate DerivativesContaining an r-Aminophosphonate Moiety.J.Agric.Food Chem.2008; 56; 5242-5246) reported by 3; 3-two thiomethyl 2-cyanoacrylates (acid amides) and α-An Jilinsuan ester are that reflux obtains series and contains α-An Jilinsuan ester class cyanoacrylate (acid amides) analog derivative under the solvent at ethanol; and find that through activity of resisting tobacco mosaic virus test compound 3-methylthio group-3-(two n-butoxies phosphono-1-phenyl-methylamino-)-2-Methyl 2-cyanoacrylate has good resisting tobacco mosaic virus therapeutic activity (be 60.2%, contrast medicament Ningnanmycin is 55.8%) under 500ppm concentration.
Aspect anti-tumor activity: (Yang Song such as Yang Song in 2004, Jin Linhong, Song Baoan, the clock Huimin, Liu Gang, cyanacrylate derivant and preparation method and biological activity, ZL200410040350.7,2004-07-30) reported first with dithiocarbonic anhydride, cyan-acetic ester, methyl-sulfate, aromatic amine is a raw material, sodium hydride is a catalyzer, has synthesized the cyanoacrylate derivative that contains substituted anilinic, and biological activity result shows that part of compounds has the inhibition effect to PC3 prostate cancer cell propagation, NIN3T3 cell ERK protein phosphorylation there is proliferation inhibiting effect, shows good anti-cancer activity.(Baoan Song such as Song Baoan in 2005, SongYang, Huimin Zhong, Linhong Jin, Deyu Hu, Gang Liu.Synthesis andBioactivity of 2-Cyanacrylates containing a trifluoromethyl Moiety.JFluorine Chem., 2005,126,87) by 3, the 2-cyanoacrylate compound that contains trifluoromethyl has been synthesized in 3-diformazan sulfenyl-2-cyanacrylate and p-trifluoromethylaniline and aliphatic amide reaction, simultaneously it has been carried out antitumour activity test (MTT), biological activity determination shows that the male dependent/non-dependent prostate cancer cell in people source (PC3) and people's epidermal carcinoma cell (A431) are had higher inhibition activity.(Huiping Zhang such as Zhang Huiping in 2005, Baoan Song, Huimin Zhong, Song Yang, Linhong Jin, Deyu Hu, Wei He.Synthesis of2-Cyanoacrylates Containing Pyridinyl Moiety under UltrasoundIrradiation.J Heterocyclic Chem., 2005,42,1211) reported the synthetic of 3-methylthio group-3-substituted pyridines amino-2-cyanoacrylate compound, length consuming time with respect to the classical synthetic method of this compounds, the shortcoming that productive rate is low, utilize the ultrasonically catalyzing synthetic method, obtained higher productive rate, this method has superiority.The antitumour activity test shows, this compounds all has certain inhibition activity to PC3 and A431 cell.Ou Yanggui equality (Guiping Ouyang in 2005, Baoan Song, Huiping Zhang, Song Yang, Linhong Jin, Qianzhu Li, Deyu Hu.A Novel Synthesis of (E)-3-Methylthio-3-Substituted Arylamino-2-Cyanoacrylates underMicrowave Irradiation, Molecules, 2005,10,1351) reported by 3, the synthetic 3-methylthio group-3-of 3-diformazan sulfenyl-2-cyanacrylate replaces the microwave catalysis synthetic method of fragrant amino-2-cyanoacrylate compound, from temperature, time, factor such as power and solvent considers that the peak optimization reaction condition is sought in the design conditions test.The reaction under microwave catalysis 30min, 50 conditions of result proof obtains higher productive rate (64.0～93.5%), with respect to original method length consuming time, characteristics that productive rate is low, and the simple environmental protection of this method, mild condition and the time is short, productive rate is high.When being carried out antitumour activity test (MTT), the gained compound finds that part of compounds shows good active to the PC3 cell.
Characteristics such as cyanoacrylate compound is big owing to the substituent variation range in two key two ends, synthetic route is simple, it is synthetic generally to be obtained with corresponding ammonia effect after condensation reaction gets intermediate by the compound that contains active methylene group again, looks the nucleophilie nucleus ability and the conditions such as big or small selective solvent of reactant steric hindrance and base catalysis of amine.This compounds is used extensive day by day because of its particular structure and novel mechanism of action in the research of agricultural herbicide, sterilant and antiviral agent.Recently investigator seminar finds that at work the part cyanoacrylate compound has resisting tobacco mosaic disease (TMV) activity.
Summary of the invention
The object of the invention, be to design the phenyl cyanoacrylate derivative that contains amido phosphonate that has synthesized a series of novel structures, both contain cyanoacrylate composition, also contained the composition of phenyl cyanoacrylate, also contained the aminophosphonate compound composition; And the novel pesticide initiative of having carried out synthetic method and resisting tobacco mosaic virus (TMV) disease is studied.Its general structure (1) is as follows:
In the formula (1): as the substituting group on the phenyl ring, R
1Be hydrogen or (1) neighbour; between; contraposition is single to be replaced or polysubstituted halogen atom; (2) neighbour; between; contraposition is single to be replaced or polysubstituted itrile group; (3) neighbour; between; contraposition is single to be replaced or polysubstituted nitro; (4) neighbour; between; contraposition is single to be replaced or polysubstituted hydroxyl; (5) neighbour; between; contraposition is single to be replaced or polysubstituted sulfydryl; (6) C1-6 alkyl; C2-6 alkenyl or C2-6 alkynyl group; wherein each group all can be by at least one or a plurality of halogen atom; itrile group; nitro; hydroxyl; the sulfydryl substituting group replaces; (7) C1-6 alkoxyl group; C2-6 alkenyloxy or C2-6 chain oxy-acetylene; wherein each group all can be by at least one or a plurality of halogen atom; itrile group; nitro; hydroxyl; the sulfydryl substituting group replaces; (8) C1-6 alkylthio; C2-6 alkenyl thio or C2-6 alkynes sulfenyl; wherein each group all can be by at least one or a plurality of halogen atom; itrile group; nitro; hydroxyl; the sulfydryl substituting group replaces; (9) C1-6 alkyl sulphonyl; (10) C2-6 alkenyl alkylsulfonyl; (11) C1-6 alkyl sulphinyl; (12) formyl radical; (13) C3-8 cycloalkyl or C3-8 cycloalkenyl group; wherein each group all can be by at least one or a plurality of halogen atom; itrile group; nitro; hydroxyl; the sulfydryl substituting group replaces; (14) C3-8 cycloalkyloxy or C3-8 cyclenes oxygen base; wherein each group all can be by at least one or a plurality of halogen atom; itrile group; nitro; hydroxyl; the sulfydryl substituting group replaces; (15) single fluorine or polyfluoro replace the C1-6 alkyl; the C2-6 alkenyl; the C2-6 alkynyl group; the C3-8 cycloalkyl, (16) single fluorine or polyfluoro replace the C1-6 alkoxyl group; the C2-6 alkenyloxy; the C2-6 chain oxy-acetylene; the C3-8 cycloalkyloxy, (17) single fluorine or polyfluoro replace the C1-6 alkylthio; the C2-6 alkenyl thio; C2-6 alkynes sulfenyl.
R
2, R
3Be respectively C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl group, various aryl.
R
4Be (1) C1-6 alkoxyl group; (2) amino; (3) the C1-6 alkoxyl group of C1-6 alkoxyl group replacement; (4) substituted amido; wherein the substituting group in the substituted amido can be (i) C1-6 alkyl C3-8 cycloalkyl; the C2-6 alkenyl; the C2-6 alkynyl group; (ii) benzyl; (5) heterocyclic group; comprise pyrryl; furyl; tetrahydrofuran base; thienyl; thiazolyl; isothiazolyl; imidazolyl; pyrazolyl oxazolyl isoxazolyl; triazolyl; tetrazyl; thiadiazolyl group; pyridyl; morpholinyl; piperazinyl; triazinyl; piperidyl; pyridazinyl; pyrimidyl; purine radicals; pyrazinyl; naphthyl; quinolyl; isoquinolyl; phthalazinyl; naphthyridinyl; indyl; draw the azoles base; benzofuryl; benzimidazolyl-; benzothiazolyl; benzisothiazole base benzoxazolyl; the benzoisoxazole base; the benzopyrazoles base; quinazolyl; different quinazolyl; dibenzofuran group; the dibenzothiophene base; the bisbenzimidazole base; the dibenzo pyrimidyl; the dibenzopyridine base; carbazyl; and can independently be selected from following substituent group by one or more on the above-mentioned cyclic group replaces: (i) halogen atom; (ii) itrile group; (iii) nitro; (iv) C1-6 alkyl; C2-6 alkenyl or C2-6 alkynyl group; wherein each group all can be replaced by at least one or a plurality of halogen atom substituting group; (6) C1-6 alkoxyl group; C2-6 alkenyloxy or C2-6 chain oxy-acetylene; wherein each group all can be replaced by at least one or a plurality of halogen atom substituting group; (7) C1-6 alkylthio; C2-6 alkenyl thio or C2-6 alkynes sulfenyl; wherein each group all can be replaced by at least one or a plurality of halogen atom substituting group; (8) C1-6 alkyl sulphinyl, (9) formyl radical.
R
5Be hydrogen or (1) neighbour; between; contraposition is single to be replaced or polysubstituted halogen atom; (2) neighbour; between; contraposition is single to be replaced or polysubstituted itrile group; (3) neighbour; between; contraposition is single to be replaced or polysubstituted nitro; (4) neighbour; between; contraposition is single to be replaced or polysubstituted hydroxyl; (5) neighbour; between; contraposition is single to be replaced or polysubstituted sulfydryl; (6) C1-6 alkyl; C2-6 alkenyl or C2-6 alkynyl group; wherein each group all can be by at least one or a plurality of halogen atom; itrile group; nitro; hydroxyl; the sulfydryl substituting group replaces; (7) C1-6 alkoxyl group; C2-6 alkenyloxy or C2-6 chain oxy-acetylene; wherein each group all can be by at least one or a plurality of halogen atom; itrile group; nitro; hydroxyl; the sulfydryl substituting group replaces; (8) C1-6 alkylthio; C2-6 alkenyl thio or C2-6 alkynes sulfenyl; wherein each group all can be by at least one or a plurality of halogen atom; itrile group; nitro; hydroxyl; the sulfydryl substituting group replaces; (9) C1-6 alkyl sulphonyl; (10) C2-6 alkenyl alkylsulfonyl; (11) C2-6 alkynyl group alkylsulfonyl; (12) C1-6 alkyl sulphinyl; (13) C2-6 alkenyl sulfinyl; (14) formyl radical; (15) C3-8 cycloalkyl or C3-8 cycloalkenyl group; wherein each group all can be by at least one or a plurality of halogen atom; itrile group; nitro; hydroxyl; the sulfydryl substituting group replaces; (16) C3-8 cycloalkyloxy or C3-8 cyclenes oxygen base; wherein each group all can be by at least one or a plurality of halogen atom; itrile group; nitro; hydroxyl; the sulfydryl substituting group replaces; (17) single fluorine or polyfluoro replace the C1-6 alkyl; the C2-6 alkenyl; the C2-6 alkynyl group; the C3-8 cycloalkyl; (18) single fluorine or polyfluoro replace the C1-6 alkoxyl group; the C2-6 alkenyloxy; the C2-6 chain oxy-acetylene; the C3-8 cycloalkyloxy, (19) single fluorine or polyfluoro replace the C1-6 alkylthio; the C2-6 alkenyl thio; C2-6 alkynes sulfenyl.
In the content of the present invention, the C1-6 alkyl can be methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, tert-pentyl, neo-pentyl, n-hexyl, isohexyl, uncle's hexyl, new hexyl; The C2-6 alkenyl can be vinyl, propenyl, allyl group, butenyl (two keys are 1, two or three-digit), isobutenyl (two keys are at 1 or 2), pentenyl (two keys are at 1,2,3 or 4), isopentene group (two keys are 1, two or three-digit), new pentenyl (two keys are at 1 or 2), hexenyl (two keys are at 1,2,3,4 or 5), dissident's thiazolinyl (two keys are at 1,2); The C2-6 alkynyl group can be ethynyl, proyl, propargyl, butynyl (three key is 1, two or three-digit), isobutyl alkynyl (three key is at 1 or 2), pentynyl (three key is at 1,2,3 or 4), isoamyl alkynyl (three key is 1, two or three-digit), new pentynyl (three key is at 1 or 2), hexin base (three key is at 1,2,3,4 or 5), dissident's alkynyl (three key is at 1,2,3 or 4), new hexin base (three key is 1, two or three-digit); Halogen atom can be fluorine, chlorine, bromine, iodine.
In the content of the present invention, give prominence to compounds process for production thereof is furtherd investigate, and finally definite of the present invention simple and easy, the environmental protection method; In addition, its purposes of compound is as the plant virus inhibitor.Described pharmaceutical composition, contain mixture as formula at least (I) compound of activeconstituents itself or itself and one or more pharmaceutically useful inert non-toxic vehicle or carrier, and can be used for preventing and treating plant virus, weeds, the animal pest that appears on husbandry, the forest aspect, and store the animal pest on product, material protection, the health aspect; Also can be used as activeconstituents and also can be used as defoliating agent, weedicide, anti-plant virus agent and sterilant.Particularly The compounds of this invention has good active to tobacco mosaic virus (TMV) (TMV) as anti-plant virus agent the time.
The present invention is to be raw material with various substituted aroma aldehyde, ammoniacal liquor, phosphate dialkyl ester, tosic acid, cyan-acetic ester, concentrated hydrochloric acid, potassium permanganate, with tetrahydrofuran (THF), dehydrated alcohol, toluene, ethylene dichloride is solvent, with the vitriol oil, hexahydropyridine, triethylamine is catalyzer, through following synthetic forming of three steps, synthetic route is as follows:
The first step: the preparation of alpha-amino group benzylphosphonic acid ester
Aldehyde joined in 26% the ammoniacal liquor, reflux and stirred 1 hour.In this process, the adularescent precipitation produces, with its filtering drying.Subsequently, phosphate dialkyl ester is dropped in this solid.The solid dissolving refluxed 2 hours under 80, and intermediate produces in this process.Splash into afterwards with 50mL tetrahydrofuran (THF) dissolved tosic acid to reaction system, stirred 2 hours at 0.The gained throw out is filtered, with an amount of tetrahydrofuran (THF) washing.At normal temperatures, the ammoniacal liquor toward throw out adding 10% stirred 30 minutes.Remove impurity 2 times with the ether extraction, water extracted with diethyl ether 2 times then.Be spin-dried for solvent at last, with column chromatography (sherwood oil: ethyl acetate=4: 1) obtain pure oily product alpha-amino group benzylphosphonic acid ester.
Aldehyde: ammoniacal liquor: phosphorous acid ester: tosic acid=1: 1-1.5: 1-1.5: 1-1.5 (mol ratio)
Temperature of reaction: 0-80
Reaction times: 1-25h
This step is applicable to the synthetic of all above-mentioned alpha-amino group benzylphosphonic acid esters.
Second step: 2-cyano group-3-chloro-3-phenyl acrylic acid ester product synthetic
(1) 2-cyano group-3-phenyl acrylate is synthetic
Cyan-acetic ester, replacement aromatic aldehyde and piperidines are joined in the dehydrated alcohol, heated and stirred backflow 0.1h～10h, cooling is filtered, washing, small amount of ethanol is washed, oven dry.
Cyan-acetic ester: replace aromatic aldehyde: piperidines=1: 1: 0.1-0.5 (mol ratio)
Temperature of reaction: 0-78
Reaction times: 10min-10h
(2) 2-cyano group-3-chloro-3-phenyl acrylate is synthetic
Slowly feed excessive chlorine to 2-cyano group-3-phenyl acrylate, reheat to 100～145 stirs, and adds pyridine hydrochloride again, and reaction is followed the tracks of with thin layer chromatography TLC.Finish, use dichloromethane extraction, get organic layer, washing, drying, precipitation is with column chromatography (sherwood oil: ethyl acetate=4: 1) obtain pure oily or solid 2-cyano group-3-phenyl-chlorallylene esters of gallic acid product.
2-cyano group-3-phenyl acrylate: pyridine hydrochloride=1: 0.1-0.8 (mol ratio)
Temperature of reaction: 100-145
Reaction times: 1h-15h
The 3rd step: 2-cyano group-3-(diethoxy phosphonium mesitoyl base-1-phenyl-methylamino-)-3-phenyl acrylate synthetic
2-cyano group-3-chloro-3-phenyl acrylate, α-An Jilinsuan ester and triethylamine are added in methylene dichloride or the tetrahydrofuran (THF); room temperature 0～70 stir 0.5h～20h; washing; dry; precipitation is with thin layer chromatography (sherwood oil: ethyl acetate=1: 1) obtain pure target product 2-cyano group-3-(diethoxy phosphonium mesitoyl base-1-phenyl-methylamino-)-3-phenyl acrylate.
2-cyano group-3-chloro-3-phenyl acrylate: α-An Jilinsuan ester: triethylamine=1: 1: 1～3 (mol ratio)
Temperature of reaction: 0～70
Reaction times: 0.5h～20h
Embodiment
Embodiment one, 2-cyano group-3-(diethoxy phosphonium mesitoyl base-1-phenyl-methylamino-)-3-ethyl phenylacrylate synthetic (compound number is a):
(1) the aminobenzyl diethyl phosphonate is synthetic:
(1.59g 15mmol) joins 26%, in the ammoniacal liquor of 30mL, refluxes and stirs 2 hours with phenyl aldehyde.In this process, the adularescent precipitation produces, with its filtering drying.Subsequently, (1.035g 7.5mmol) drops in this solid with the phosphorous acid diethyl ester.The solid dissolving refluxed 5 hours under 80, and intermediate produces in this process.(0.86g 5mmol) to reaction system, stirred 2 hours at 0 to splash into usefulness 50mL tetrahydrofuran (THF) dissolved tosic acid afterwards.The gained throw out is filtered, with the washing of 20mL tetrahydrofuran (THF).At normal temperatures, the 30mL ammoniacal liquor toward throw out adding 10% stirred 4 hours.(impurity is removed in 2 * 50mL) extractions, and (2 * 50mL) extract water with ether then with ether.Be spin-dried for solvent at last, with column chromatography (sherwood oil: ethyl acetate=4: 1) obtain pure oily product aminobenzyl diethyl phosphonate, yield 40.5%.This step be applicable to above-mentioned alpha-amino group benzylphosphonic acid ester synthetic.
(2) 2-cyano group-3-chloro-3-ethyl phenylacrylate is synthetic:
Add in the 500mL there-necked flask with piperidines phenyl aldehyde 10.6g (100mmol), 0.2 times of equivalent 1.7g (20mmol) and 300mL dehydrated alcohol ethyl cyanacetate 11.3g (100mmol), heated and stirred backflow 3h, underpressure distillation goes out partial solvent, cooling, filter, washing, small amount of ethanol is washed, oven dry gets white crystal 2-cyano group-3-ethyl phenylacrylate; This solid is joined in the 500mL there-necked flask, slowly feed chlorine, reheat to 120 stirs, and adds pyridine hydrochloride 2.3g (20mmol) again, reaction 8h; With the system cooling, with 100mL water/100mL dichloromethane extraction, get organic layer, washing, drying, precipitation is with column chromatography (sherwood oil: ethyl acetate=4: 1) obtain pure colourless liquid 2-cyano group-3-chloro-3-ethyl phenylacrylate.Yield 72.3%.
(3) 2-cyano group-3-(diethoxy phosphonium mesitoyl base-1-phenyl-methylamino-)-3-ethyl phenylacrylate is synthetic:
2-cyano group-3-chloro-3-ethyl phenylacrylate of 0.7g (3mmol), the alpha-amino group benzylphosphonic acid diethyl ester of 0.729g (3mmol), triethylamine and the 30mL methylene dichloride of 0.909g (9mmol) are added in the 50mL single port bottle; heated and stirred backflow 15h; washing; dry; precipitation is with thin layer chromatography (sherwood oil: ethyl acetate=1: 1) obtain pure target product 2-cyano group-3-(diethoxy phosphonium mesitoyl base-1-phenyl-methylamino-)-3-ethyl phenylacrylate.Yield 51.3%.
Synthetic (compound number is b) of embodiment two, 2-cyano group-3-(two positive propoxies phosphono-1-phenyl-methylamino-)-3-ethyl phenylacrylate:
(1) the positive dipropyl of aminobenzyl phosphonic acids is synthetic:
Synthetic as embodiment one (1) method and condition, difference is to add the positive dipropyl of phosphorous acid, and (1.245g, 7.5mmol), the reaction times is 6h, yield 45.9%.
(2) 2-cyano group-3-chloro-3-ethyl phenylacrylate is synthetic:
Synthetic as embodiment one (2) method and condition.
(3) 2-cyano group-3-(two positive propoxies phosphono-1-phenyl-methylamino-)-3-ethyl phenylacrylate is synthetic
2-cyano group-3-chloro-3-ethyl phenylacrylate of 0.7g (3mmol), the alpha-amino group benzylphosphonic acid di-n-propyl ester of 0.813g (3mmol), triethylamine and the 30mL methylene dichloride of 0.909g (9mmol) are added in the 50mL single port bottle; heated and stirred backflow 10h; washing; dry; precipitation is with thin layer chromatography (sherwood oil: ethyl acetate=1: 1) obtain pure target product 2-cyano group-3-(two positive propoxies phosphono-1-phenyl-methylamino-)-3-ethyl phenylacrylate.Yield 43.5%.
Synthetic (compound number is c) of embodiment three, 2-cyano group-3-(diisopropoxy phosphono-1-phenyl-methylamino-)-3-ethyl phenylacrylate:
(1) aminobenzyl phosphonic acids diisopropyl ester is synthetic:
Synthetic as embodiment one (1) method and condition, difference is to add the phosphorous acid diisopropyl ester, and (1.245g, 7.5mmol), the reaction times is 6h, yield 50.3%.
(2) 2-cyano group-3-chloro-3-ethyl phenylacrylate is synthetic:
Synthetic as embodiment one (2) method and condition.
(3) 2-cyano group-3-(diisopropoxy phosphono-1-phenyl-methylamino-)-3-ethyl phenylacrylate is synthetic
2-cyano group-3-chloro-3-ethyl phenylacrylate of 0.7g (3mmol), the alpha-amino group benzylphosphonic acid diisopropyl ester of 0.813g (3mmol), triethylamine and the 30mL methylene dichloride of 0.909g (9mmol) are added in the 50mL single port bottle; heated and stirred backflow 10h; washing; dry; precipitation is with thin layer chromatography (sherwood oil: ethyl acetate=1: 1) obtain pure target product 2-cyano group-3-(diisopropoxy phosphono-1-phenyl-methylamino-)-3-ethyl phenylacrylate.Yield 40.6%.
Synthetic (compound number is d) of embodiment four, 2-cyano group-3-(two n-butoxies phosphono-1-phenyl-methylamino-)-3-ethyl phenylacrylate:
(1) aminobenzyl phosphonic acids di-n-butyl is synthetic:
Synthetic as embodiment one (1) method and condition, difference is to add phosphorous acid di-n-butyl ester, and (1.445g, 7.5mmol), the reaction times is 10h, yield 52.3%.
(2) 2-cyano group-3-chloro-3-ethyl phenylacrylate is synthetic:
Synthetic as embodiment one (2) method and condition.
(3) 2-cyano group-3-(two n-butoxies phosphono-1-phenyl-methylamino-)-3-ethyl phenylacrylate is synthetic
2-cyano group-3-chloro-3-ethyl phenylacrylate of 0.7g (3mmol), the alpha-amino group benzylphosphonic acid di-n-butyl of 0.897g (3mmol), triethylamine and the 30mL methylene dichloride of 0.909g (9mmol) are added in the 50mL single port bottle; heated and stirred backflow 10h; washing; dry; precipitation is with thin layer chromatography (sherwood oil: ethyl acetate=1: 1) obtain pure target product 2-cyano group-3-(two n-butoxies phosphono-1-phenyl-methylamino-)-3-ethyl phenylacrylate.Yield 41.5%.
Synthetic (compound number is e) of the adjacent fluorophenyl ethyl propenoate of embodiment five, 2-cyano group-3-(diethoxy phosphonium mesitoyl base-1-phenyl-methylamino-)-3-:
(1) the aminobenzyl diethyl phosphonate is synthetic:
Synthetic as embodiment one (1) method and condition.
(2) the adjacent fluorophenyl ethyl propenoate of 2-cyano group-3-chloro-3-is synthetic:
Add in the 500mL there-necked flask with piperidines adjacent fluorobenzaldehyde 12.4g (100mmol), 0.2 times of equivalent 1.7g (20mmol) and 300mL dehydrated alcohol cyan-acetic ester 11.3g (100mmol), heated and stirred backflow 4h, underpressure distillation goes out partial solvent, cooling, filter, washing, small amount of ethanol is washed, oven dry gets the adjacent fluorophenyl ethyl propenoate of white crystal 2-cyano group-3-; This solid is joined in the 500mL there-necked flask, slowly feed chlorine, reheat to 123 stirs, and adds pyridine hydrochloride 2.3g (2mmol) again, reaction 8h; With the system cooling, with 100mL water/100mL dichloromethane extraction, get organic layer, washing, drying, precipitation is with column chromatography (sherwood oil: ethyl acetate=4: 1) obtain the adjacent fluorophenyl ethyl propenoate of pure weak yellow liquid 2-cyano group-3-chloro-3-.Yield 79.4%.
(3) the adjacent fluorophenyl ethyl propenoate of 2-cyano group-3-(diethoxy phosphonium mesitoyl base-1-phenyl-methylamino-)-3-is synthetic
The alpha-amino group benzylphosphonic acid diethyl ester of the adjacent fluorophenyl ethyl propenoate of 2-cyano group-3-chloro-3-of 0.76g (3mmol), 0.729g (3mmol), triethylamine and the 30mL methylene dichloride of 0.909g (9mmol) are added in the 50mL single port bottle; heated and stirred backflow 18h; washing; dry; precipitation is with thin layer chromatography (sherwood oil: ethyl acetate=1: 1) obtain the adjacent fluorophenyl ethyl propenoate of pure target product 2-cyano group-3-(diethoxy phosphonium mesitoyl base-1-phenyl-methylamino-)-3-.Yield 33.4%.
Synthetic (compound number is f) of the adjacent fluorophenyl ethyl propenoate of embodiment six, 2-cyano group-3-(two positive propoxies phosphono-1-phenyl-methylamino-)-3-:
(1) the positive dipropyl of aminobenzyl phosphonic acids is synthetic:
Synthetic as embodiment one (1) method and condition, difference is to add the positive dipropyl of phosphorous acid, and (1.245g, 7.5mmol), the reaction times is 6h, yield 45.9%.
(2) the adjacent fluorophenyl ethyl propenoate of 2-cyano group-3-chloro-3-is synthetic:
Synthetic as embodiment five (2) methods and condition.
(3) the adjacent fluorophenyl ethyl propenoate of 2-cyano group-3-(two positive propoxies phosphono-1-phenyl-methylamino-)-3-is synthetic:
The alpha-amino group benzylphosphonic acid di-n-propyl ester of the adjacent fluorophenyl ethyl propenoate of 2-cyano group-3-chloro-3-of 0.76g (3mmol), 0.813g (3mmol), triethylamine and the 30mL methylene dichloride of 0.909g (9mmol) are added in the 50mL single port bottle; heated and stirred backflow 18h; washing; dry; precipitation is with thin layer chromatography (sherwood oil: ethyl acetate=1: 1) obtain the adjacent fluorophenyl ethyl propenoate of pure target product 2-cyano group-3-(two positive propoxies phosphono-1-phenyl-methylamino-)-3-.Yield 31.8%.
Synthetic (compound number is g) of the adjacent fluorophenyl ethyl propenoate of embodiment seven, 2-cyano group-3-(diisopropoxy phosphono-1-phenyl-methylamino-)-3-:
(1) aminobenzyl phosphonic acids diisopropyl ester is synthetic:
Synthetic as embodiment one (1) method and condition, difference is to add the phosphorous acid diisopropyl ester, and (1.245g, 7.5mmol), the reaction times is 6h, yield 50.3%.
(2) the adjacent fluorophenyl ethyl propenoate of 2-cyano group-3-chloro-3-is synthetic:
Synthetic as embodiment five (2) methods and condition.
(3) the adjacent fluorophenyl ethyl propenoate of 2-cyano group-3-(diisopropoxy phosphono-1-phenyl-methylamino-)-3-is synthetic:
The alpha-amino group benzylphosphonic acid diisopropyl ester of the adjacent fluorophenyl ethyl propenoate of 2-cyano group-3-chloro-3-of 0.76g (3mmol), 0.813g (3mmol), triethylamine and the 30mL methylene dichloride of 0.909g (9mmol) are added in the 50mL single port bottle; heated and stirred backflow 18h; washing; dry; precipitation is with thin layer chromatography (sherwood oil: ethyl acetate=1: 1) obtain the adjacent fluorophenyl ethyl propenoate of pure target product 2-cyano group-3-(diisopropoxy phosphono-1-phenyl-methylamino-)-3-.Yield 32.7%.
Synthetic (compound number is h) of the adjacent fluorophenyl ethyl propenoate of embodiment eight, 2-cyano group-3-(two n-butoxies phosphono-1-phenyl-methylamino-)-3-:
(1) aminobenzyl phosphonic acids di-n-butyl is synthetic:
Synthetic as embodiment one (1) method and condition, difference is to add phosphorous acid di-n-butyl ester, and (1.445g, 7.5mmol), the reaction times is 10h, yield 52.3%.
(2) the adjacent fluorophenyl ethyl propenoate of 2-cyano group-3-chloro-3-is synthetic:
Synthetic as embodiment five (2) methods and condition.
(3) the adjacent fluorophenyl ethyl propenoate of 2-cyano group-3-(two n-butoxies phosphono-1-phenyl-methylamino-)-3-is synthetic:
The alpha-amino group benzylphosphonic acid di-n-butyl of the adjacent fluorophenyl ethyl propenoate of 2-cyano group-3-chloro-3-of 0.76g (3mmol), 0.897g (3mmol), triethylamine and the 30mL methylene dichloride of 0.909g (9mmol) are added in the 50mL single port bottle; heated and stirred backflow 18h; washing; dry; precipitation is with thin layer chromatography (sherwood oil: ethyl acetate=1: 1) obtain the adjacent fluorophenyl ethyl propenoate of pure target product 2-cyano group-3-(two n-butoxies phosphono-1-phenyl-methylamino-)-3-.Yield 31.2%%.
Between embodiment nine, 2-cyano group-3-(diethoxy phosphonium mesitoyl base-1-phenyl-methylamino-)-3-synthetic (compound number is i) of nitre ethyl phenylacrylate:
(1) the aminobenzyl diethyl phosphonate is synthetic:
Synthetic as embodiment one (1) method and condition.
(2) nitre ethyl phenylacrylate synthetic between 2-cyano group-3-chloro-3-:
Add in the 500mL there-necked flask with piperidines m-nitrobenzaldehyde 15.3g (100mmol), 0.2 times of equivalent 1.7g (20mmol) and 300mL dehydrated alcohol cyan-acetic ester 11.3g (100mmol), heated and stirred backflow 30min, underpressure distillation goes out partial solvent, cooling, filter, washing, small amount of ethanol is washed, oven dry gets nitre ethyl phenylacrylate between clear crystal 2-cyano group-3-; This solid is joined in the 500mL there-necked flask, slowly feed chlorine, reheat to 125 stirs, and adds pyridine hydrochloride 2.3g (20mmol) again, reaction 8h; With the system cooling, with 100mL water/100mL dichloromethane extraction, get organic layer, washing, drying, precipitation is with column chromatography (sherwood oil: ethyl acetate=4: 1) obtain nitre ethyl phenylacrylate between pure khaki look solid 2-cyano group-3-chloro-3-.Yield 67.7%.
(3) nitre ethyl phenylacrylate synthetic between 2-cyano group-3-(diethoxy phosphonium mesitoyl base-1-phenyl-methylamino-)-3-:
The alpha-amino group benzylphosphonic acid diethyl ester of nitre ethyl phenylacrylate, 0.729g (3mmol) between 2-cyano group-3-chloro-3-of 0.84g (3mmol), triethylamine and the 30mL methylene dichloride of 0.909g (9mmol) are added in the 50mL single port bottle; heated and stirred backflow 5h; washing; dry; precipitation is with thin layer chromatography (sherwood oil: ethyl acetate=1: 1) obtain nitre ethyl phenylacrylate between pure target product 2-cyano group-3-(diethoxy phosphonium mesitoyl base-1-phenyl-methylamino-)-3-.Yield 57.9%.
Between embodiment ten, 2-cyano group-3-(two positive propoxies phosphono-1-phenyl-methylamino-)-3-synthetic (compound number is j) of nitre ethyl phenylacrylate:
(1) the positive dipropyl of aminobenzyl phosphonic acids is synthetic:
Synthetic as embodiment one (1) method and condition, difference is to add the positive dipropyl of phosphorous acid, and (1.245g, 7.5mmol), the reaction times is 6h, yield 45.9%.
(2) nitre ethyl phenylacrylate synthetic between 2-cyano group-3-chloro-3-:
Synthetic as embodiment nine (2) methods and condition.
(3) nitre ethyl phenylacrylate synthetic between 2-cyano group-3-(two positive propoxies phosphono-1-phenyl-methylamino-)-3-:
The alpha-amino group benzylphosphonic acid di-n-propyl ester of nitre ethyl phenylacrylate, 0.813g (3mmol) between 2-cyano group-3-chloro-3-of 0.84g (3mmol), triethylamine and the 30mL methylene dichloride of 0.909g (9mmol) are added in the 50mL single port bottle; heated and stirred backflow 15h; washing; dry; precipitation is with thin layer chromatography (sherwood oil: ethyl acetate=1: 1) obtain nitre ethyl phenylacrylate between pure target product 2-cyano group-3-(two positive propoxies phosphono-1-phenyl-methylamino-)-3-.Yield 55.9%.
Between embodiment 11,2-cyano group-3-(diisopropoxy phosphono-1-phenyl-methylamino-)-3-synthetic (compound number is k) of nitre ethyl phenylacrylate:
(1) aminobenzyl phosphonic acids diisopropyl ester is synthetic:
Synthetic as embodiment one (1) method and condition, difference is to add the phosphorous acid diisopropyl ester, and (1.245g, 7.5mmol), the reaction times is 6h, yield 50.3%.
(2) nitre ethyl phenylacrylate synthetic between 2-cyano group-3-chloro-3-:
Synthetic as embodiment nine (2) methods and condition.
(3) nitre ethyl phenylacrylate synthetic between 2-cyano group-3-(diisopropoxy phosphono-1-phenyl-methylamino-)-3-:
The alpha-amino group benzylphosphonic acid diisopropyl ester of nitre ethyl phenylacrylate, 0.813g (3mmol) between 2-cyano group-3-chloro-3-of 0.84g (3mmol), triethylamine and the 30mL methylene dichloride of 0.909g (9mmol) are added in the 50mL single port bottle; heated and stirred backflow 15h; washing; dry; precipitation is with thin layer chromatography (sherwood oil: ethyl acetate=1: 1) obtain nitre ethyl phenylacrylate between pure target product 2-cyano group-3-(diisopropoxy phosphono-1-phenyl-methylamino-)-3-.Yield 51.6%.
Between embodiment 12,2-cyano group-3-(two n-butoxies phosphono-1-phenyl-methylamino-)-3-synthetic (compound number is l) of nitre ethyl phenylacrylate:
(1) aminobenzyl phosphonic acids di-n-butyl is synthetic:
Synthetic as embodiment one (1) method and condition, difference is to add phosphorous acid di-n-butyl ester, and (1.445g, 7.5mmol), the reaction times is 10h, yield 52.3%.
(2) nitre ethyl phenylacrylate synthetic between 2-cyano group-3-chloro-3-:
Synthetic as embodiment nine (2) methods and condition.
(3) nitre ethyl phenylacrylate synthetic between 2-cyano group-3-(two n-butoxies phosphono-1-phenyl-methylamino-)-3-:
The alpha-amino group benzylphosphonic acid di-n-butyl of nitre ethyl phenylacrylate, 0.897g (3mmol) between 2-cyano group-3-chloro-3-of 0.84g (3mmol), triethylamine and the 30mL methylene dichloride of 0.909g (9mmol) are added in the 50mL single port bottle; heated and stirred backflow 15h; washing; dry; precipitation is with thin layer chromatography (sherwood oil: ethyl acetate=1: 1) obtain nitre ethyl phenylacrylate between pure target product 2-cyano group-3-(two n-butoxies phosphono-1-phenyl-methylamino-)-3-.Yield 54.7%.
Synthetic (compound number is m) of embodiment 13,2-cyano group-3-(diethoxy phosphonium mesitoyl base-1-phenyl-methylamino-)-3-phenylacrylic acid methyl esters:
(1) the aminobenzyl diethyl phosphonate is synthetic:
Synthetic as embodiment one (1) method and condition.
(2) 2-cyano group-3-chloro-3-phenylacrylic acid methyl esters is synthetic:
In exsiccant 50mL is connected to the there-necked flask of water segregator capable, add cyanoacetic acid (12.7g, 119mmol), methyl alcohol 5g (158mmol), (0.9g 0.9mmol) and toluene (20mL), is back under magnetic agitation and no longer includes water generates anhydrous slufuric acid.Filter, filtrate is washed with 10% sodium bicarbonate, and anhydrous magnesium sulfate drying is spin-dried for toluene, and underpressure distillation obtains the colourless liquid methyl-cyanacetate; Add in the 500mL there-necked flask with piperidines phenyl aldehyde 10.6g (100mmol), 0.2 times of equivalent 1.7g (20mmol) and 300mL dehydrated alcohol methyl-cyanacetate 8.7g (100mmol) again, heated and stirred backflow 3h, underpressure distillation goes out partial solvent, cooling, filter, washing, small amount of ethanol is washed, oven dry gets the adjacent fluorophenyl methyl acrylate of white crystal 2-cyano group-3-; This solid is joined in the 500mL there-necked flask, slowly feed chlorine, reheat to 120 stirs, and adds pyridine hydrochloride 2.3g (20mmol) again, reaction 8h; With the system cooling, with 100mL water/100mL dichloromethane extraction, get organic layer, washing, drying, precipitation is with column chromatography (sherwood oil: ethyl acetate=4: 1) obtain pure weak yellow liquid 2-cyano group-3-chloro-3-phenylacrylic acid methyl esters.Yield 81.5%.
(3) 2-cyano group-3-(diethoxy phosphonium mesitoyl base-1-phenyl-methylamino-)-3-phenylacrylic acid methyl esters is synthetic:
2-cyano group-3-chloro-3-phenylacrylic acid methyl esters of 0.665g (3mmol), the alpha-amino group benzylphosphonic acid diethyl ester of 0.729g (3mmol), triethylamine and the 30mL methylene dichloride of 0.909g (9mmol) are added in the 50mL single port bottle; heated and stirred backflow 15h; washing; dry; precipitation is with thin layer chromatography (sherwood oil: ethyl acetate=1: 1) obtain pure target product 2-cyano group-3-(diethoxy phosphonium mesitoyl base-1-phenyl-methylamino-)-3-phenylacrylic acid methyl esters.Yield 45.2%.
Synthetic (compound number is n) of embodiment 14,2-cyano group-3-(two positive propoxies phosphono-1-phenyl-methylamino-)-3-phenylacrylic acid methyl esters:
(1) the positive dipropyl of aminobenzyl phosphonic acids is synthetic:
Synthetic as embodiment one (1) method and condition, difference is to add the positive dipropyl of phosphorous acid, and (1.245g, 7.5mmol), the reaction times is 6h, yield 45.9%.
(2) 2-cyano group-3-chloro-3-phenylacrylic acid methyl esters is synthetic:
Synthetic as embodiment ten three (2) methods and condition.
(3) 2-cyano group-3-(two positive propoxies phosphono-1-phenyl-methylamino-)-3-phenylacrylic acid methyl esters is synthetic:
2-cyano group-3-chloro-3-phenylacrylic acid methyl esters of 0.665g (3mmol), the alpha-amino group benzylphosphonic acid di-n-propyl ester of 0.813g (3mmol), triethylamine and the 30mL methylene dichloride of 0.909g (9mmol) are added in the 50mL single port bottle; heated and stirred backflow 15h; washing; dry; precipitation is with thin layer chromatography (sherwood oil: ethyl acetate=1: 1) obtain pure target product 2-cyano group-3-(two positive propoxies phosphono-1-phenyl-methylamino-)-3-phenylacrylic acid methyl esters.Yield 44.7%.
Synthetic (compound number is o) of embodiment 15,2-cyano group-3-(diisopropoxy phosphono-1-phenyl-methylamino-)-3-phenylacrylic acid methyl esters:
(1) aminobenzyl phosphonic acids diisopropyl ester is synthetic:
Synthetic as embodiment one (1) method and condition, difference is to add the phosphorous acid diisopropyl ester, and (1.245g, 7.5mmol), the reaction times is 6h, yield 50.3%.
(2) 2-cyano group-3-chloro-3-phenylacrylic acid methyl esters is synthetic:
Synthetic as embodiment ten three (2) methods and condition.
(3) 2-cyano group-3-(diisopropoxy phosphono-1-phenyl-methylamino-)-3-phenylacrylic acid methyl esters is synthetic:
2-cyano group-3-chloro-3-phenylacrylic acid methyl esters of 0.665g (3mmol), the alpha-amino group benzylphosphonic acid diisopropyl ester of 0.813g (3mmol), triethylamine and the 30mL methylene dichloride of 0.909g (9mmol) are added in the 50mL single port bottle; heated and stirred backflow 15h; washing; dry; precipitation is with thin layer chromatography (sherwood oil: ethyl acetate=1: 1) obtain pure target product 2-cyano group-3-(diisopropoxy phosphono-1-phenyl-methylamino-)-3-phenylacrylic acid methyl esters.Yield 41.5%.
Synthetic (compound number is p) of embodiment 16,2-cyano group-3-(two n-butoxies phosphono-1-phenyl-methylamino-)-3-phenylacrylic acid methyl esters:
(1) aminobenzyl phosphonic acids di-n-butyl is synthetic:
Synthetic as embodiment one (1) method and condition, difference is to add phosphorous acid di-n-butyl ester, and (1.445g, 7.5mmol), the reaction times is 10h, yield 52.3%.
(2) 2-cyano group-3-chloro-3-phenylacrylic acid methyl esters is synthetic:
Synthetic as embodiment ten three (2) methods and condition.
(3) 2-cyano group-3-(two n-butoxies phosphono-1-phenyl-methylamino-)-3-phenylacrylic acid methyl esters is synthetic:
2-cyano group-3-chloro-3-phenylacrylic acid methyl esters of 0.665g (3mmol), the alpha-amino group benzylphosphonic acid di-n-butyl of 0.897g (3mmol), triethylamine and the 30mL methylene dichloride of 0.909g (9mmol) are added in the 50mL single port bottle; heated and stirred backflow 15h; washing; dry; precipitation is with thin layer chromatography (sherwood oil: ethyl acetate=1: 1) obtain pure target product 2-cyano group-3-(two n-butoxies phosphono-1-phenyl-methylamino-)-3-phenylacrylic acid methyl esters.Yield 38.3%.
Synthetic (compound number is q) of the adjacent fluorophenyl methyl acrylate of embodiment 17,2-cyano group-3-(diethoxy phosphonium mesitoyl base-1-phenyl-methylamino-)-3-:
(1) the aminobenzyl diethyl phosphonate is synthetic:
Synthetic as embodiment one (1) method and condition.
(2) the adjacent fluorophenyl methyl acrylate of 2-cyano group-3-chloro-3-is synthetic:
In exsiccant 50mL is connected to the there-necked flask of water segregator capable, add cyanoacetic acid (12.7g, 119mmol), methyl alcohol 5g (158mmol), (0.9g 0.9mmol) and toluene (20mL), is back under magnetic agitation and no longer includes water generates anhydrous slufuric acid.Filter, filtrate is washed with 10% sodium bicarbonate, and anhydrous magnesium sulfate drying is spin-dried for toluene, and underpressure distillation obtains the colourless liquid methyl-cyanacetate; Add in the 500mL there-necked flask with piperidines adjacent fluorobenzaldehyde 12.4g (100mmol), 0.2 times of equivalent 1.7g (20mmol) and 300mL dehydrated alcohol methyl-cyanacetate 8.7g (100mmol) again, heated and stirred backflow 3h, underpressure distillation goes out partial solvent, cooling, filter, washing, small amount of ethanol is washed, oven dry gets the adjacent fluorophenyl methyl acrylate of white crystal 2-cyano group-3-; This solid is joined in the 500mL there-necked flask, slowly feed chlorine, reheat to 120 stirs, and adds pyridine hydrochloride 2.3g (20mmol) again, reaction 8h; With the system cooling, with 100mL water/100mL dichloromethane extraction, get organic layer, washing, drying, precipitation is with column chromatography (sherwood oil: ethyl acetate=4: 1) obtain the adjacent fluorophenyl methyl acrylate of pure weak yellow liquid 2-cyano group-3-chloro-3-.Yield 79.0%.
(3) the adjacent fluorophenyl methyl acrylate of 2-cyano group-3-(diethoxy phosphonium mesitoyl base-1-phenyl-methylamino-)-3-is synthetic:
The alpha-amino group benzylphosphonic acid diethyl ester of the adjacent fluorophenyl methyl acrylate of 2-cyano group-3-chloro-3-of 0.719g (3mmol), 0.729g (3mmol), triethylamine and the 30mL methylene dichloride of 0.909g (9mmol) are added in the 50mL single port bottle; heated and stirred backflow 15h; washing; dry; precipitation is with thin layer chromatography (sherwood oil: ethyl acetate=1: 1) obtain the adjacent fluorophenyl methyl acrylate of pure target product 2-cyano group-3-(diethoxy phosphonium mesitoyl base-1-phenyl-methylamino-)-3-.Yield 42.7%.
Synthetic (compound number is r) of the adjacent fluorophenyl methyl acrylate of embodiment 18,2-cyano group-3-(two positive propoxies phosphono-1-phenyl-methylamino-)-3-:
(1) the positive dipropyl of aminobenzyl phosphonic acids is synthetic:
Synthetic as embodiment one (1) method and condition, difference is to add the positive dipropyl of phosphorous acid, and (1.245g, 7.5mmol), the reaction times is 6h, yield 45.9%.
(2) the adjacent fluorophenyl methyl acrylate of 2-cyano group-3-chloro-3-is synthetic:
Synthetic as embodiment ten seven (2) methods and condition.
(3) the adjacent fluorophenyl methyl acrylate of 2-cyano group-3-(two positive propoxies phosphono-1-phenyl-methylamino-)-3-is synthetic:
The alpha-amino group benzylphosphonic acid di-n-propyl ester of the adjacent fluorophenyl methyl acrylate of 2-cyano group-3-chloro-3-of 0.719g (3mmol), 0.813g (3mmol), triethylamine and the 30mL methylene dichloride of 0.909g (9mmol) are added in the 50mL single port bottle; heated and stirred backflow 15h; washing; dry; precipitation is with thin layer chromatography (sherwood oil: ethyl acetate=1: 1) obtain the adjacent fluorophenyl methyl acrylate of pure target product 2-cyano group-3-(two positive propoxies phosphono-1-phenyl-methylamino-)-3-.Yield 34.5%.
Synthetic (compound number is s) of the adjacent fluorophenyl methyl acrylate of embodiment 19,2-cyano group-3-(diisopropoxy phosphono-1-phenyl-methylamino-)-3-:
(1) aminobenzyl phosphonic acids diisopropyl ester is synthetic:
Synthetic as embodiment one (1) method and condition, difference is to add the phosphorous acid diisopropyl ester, and (1.245g, 7.5mmol), the reaction times is 6h, yield 50.3%.
(2) the adjacent fluorophenyl methyl acrylate of 2-cyano group-3-chloro-3-is synthetic:
Synthetic as embodiment ten seven (2) methods and condition.
(3) the adjacent fluorophenyl methyl acrylate of 2-cyano group-3-(diisopropoxy phosphono-1-phenyl-methylamino-)-3-is synthetic:
The alpha-amino group benzylphosphonic acid diisopropyl ester of the adjacent fluorophenyl methyl acrylate of 2-cyano group-3-chloro-3-of 0.719g (3mmol), 0.813g (3mmol), triethylamine and the 30mL methylene dichloride of 0.909g (9mmol) are added in the 50mL single port bottle; heated and stirred backflow 15h; washing; dry; precipitation is with thin layer chromatography (sherwood oil: ethyl acetate=1: 1) obtain the adjacent fluorophenyl methyl acrylate of pure target product 2-cyano group-3-(diisopropoxy phosphono-1-phenyl-methylamino-)-3-.Yield 33.1%.
Synthetic (compound number is t) of the adjacent fluorophenyl methyl acrylate of embodiment 20,2-cyano group-3-(two n-butoxies phosphono-1-phenyl-methylamino-)-3-:
(1) aminobenzyl phosphonic acids di-n-butyl is synthetic:
Synthetic as embodiment one (1) method and condition, difference is to add phosphorous acid di-n-butyl ester, and (1.445g, 7.5mmol), the reaction times is 10h, yield 52.3%.
(2) the adjacent fluorophenyl methyl acrylate of 2-cyano group-3-chloro-3-is synthetic:
Synthetic as embodiment ten seven (2) methods and condition.
(3) the adjacent fluorophenyl methyl acrylate of 2-cyano group-3-(two n-butoxies phosphono-1-phenyl-methylamino-)-3-is synthetic:
The alpha-amino group benzylphosphonic acid di-n-butyl of the adjacent fluorophenyl methyl acrylate of 2-cyano group-3-chloro-3-of 0.719g (3mmol), 0.897g (3mmol), triethylamine and the 30mL methylene dichloride of 0.909g (9mmol) are added in the 50mL single port bottle; heated and stirred backflow 15h; washing; dry; precipitation is with thin layer chromatography (sherwood oil: ethyl acetate=1: 1) obtain the adjacent fluorophenyl methyl acrylate of pure target product 2-cyano group-3-(two n-butoxies phosphono-1-phenyl-methylamino-)-3-.Yield 32.4%.
Between embodiment 21,2-cyano group-3-(diethoxy phosphonium mesitoyl base-1-phenyl-methylamino-)-3-synthetic (compound number is u) of nitre phenylacrylic acid methyl esters:
(1) the aminobenzyl diethyl phosphonate is synthetic:
Synthetic as embodiment one (1) method and condition.
(2) nitre phenylacrylic acid methyl esters synthetic between 2-cyano group-3-chloro-3-:
In exsiccant 50mL is connected to the there-necked flask of water segregator capable, add cyanoacetic acid (12.7g, 119mmol), methyl alcohol 5g (158mmol), (0.9g 0.9mmol) and toluene (20mL), is back under magnetic agitation and no longer includes water generates anhydrous slufuric acid.Filter, filtrate is washed with 10% sodium bicarbonate, and anhydrous magnesium sulfate drying is spin-dried for toluene, and underpressure distillation obtains the colourless liquid methyl-cyanacetate; Again with methyl-cyanacetate 8.7g's (100mmol) with in the piperidines of a nitre phenyl aldehyde 15.3g (100mmol), 0.2 times of equivalent 1.7g (20mmol) and the 300mL dehydrated alcohol adding 500mL there-necked flask, heated and stirred backflow 30min, underpressure distillation goes out partial solvent, cooling, filter, washing, small amount of ethanol is washed, oven dry gets nitre phenylacrylic acid methyl esters between white crystal 2-cyano group-3-; This solid is joined in the 500mL there-necked flask, slowly feed chlorine, reheat to 125 stirs, and adds pyridine hydrochloride 2.3g (20mmol) again, reaction 8h; With the system cooling, with 100mL water/100mL dichloromethane extraction, get organic layer, washing, drying, precipitation is with column chromatography (sherwood oil: ethyl acetate=4: 1) obtain nitre phenylacrylic acid methyl esters between pure khaki solid 2-cyano group-3-chloro-3-.Yield 67.7%.
(3) nitre phenylacrylic acid methyl esters synthetic between 2-cyano group-3-(diethoxy phosphonium mesitoyl base-1-phenyl-methylamino-)-3-:
The alpha-amino group benzylphosphonic acid diethyl ester of nitre phenylacrylic acid methyl esters, 0.729g (3mmol) between 2-cyano group-3-chloro-3-of 0.80g (3mmol), triethylamine and the 30mL methylene dichloride of 0.909g (9mmol) are added in the 50mL single port bottle; heated and stirred backflow 15h; washing; dry; precipitation is with thin layer chromatography (sherwood oil: ethyl acetate=1: 1) obtain nitre phenylacrylic acid methyl esters between pure target product 2-cyano group-3-(diethoxy phosphonium mesitoyl base-1-phenyl-methylamino-)-3-.Yield 56.3%.
Between embodiment 22,2-cyano group-3-(two positive propoxies phosphono-1-phenyl-methylamino-)-3-nitre phenylacrylic acid methyl esters synthetic (compound number is for v):
(1) the positive dipropyl of aminobenzyl phosphonic acids is synthetic:
Synthetic as embodiment one (1) method and condition, difference is to add the positive dipropyl of phosphorous acid, and (1.245g, 7.5mmol), the reaction times is 6h, yield 45.9%.
(2) nitre phenylacrylic acid methyl esters synthetic between 2-cyano group-3-chloro-3-:
Synthetic as embodiment 21 (2) methods and condition.
(3) nitre phenylacrylic acid methyl esters synthetic between 2-cyano group-3-(two positive propoxies phosphono-1-phenyl-methylamino-)-3-:
The alpha-amino group benzylphosphonic acid di-n-propyl ester of nitre phenylacrylic acid methyl esters, 0.813g (3mmol) between 2-cyano group-3-chloro-3-of 0.80g (3mmol), triethylamine and the 30mL methylene dichloride of 0.909g (9mmol) are added in the 50mL single port bottle; heated and stirred backflow 15h; washing; dry; precipitation is with thin layer chromatography (sherwood oil: ethyl acetate=1: 1) obtain nitre phenylacrylic acid methyl esters between pure target product 2-cyano group-3-(two positive propoxies phosphono-1-phenyl-methylamino-)-3-.Yield 52.4%.
Between embodiment 23,2-cyano group-3-(diisopropoxy phosphono-1-phenyl-methylamino-)-3-synthetic (compound number is w) of nitre phenylacrylic acid methyl esters:
(1) aminobenzyl phosphonic acids diisopropyl ester is synthetic:
Synthetic as embodiment one (1) method and condition, difference is to add the phosphorous acid diisopropyl ester, and (1.245g, 7.5mmol), the reaction times is 6h, yield 50.3%.
(2) nitre phenylacrylic acid methyl esters synthetic between 2-cyano group-3-chloro-3-:
Synthetic as embodiment 21 (2) methods and condition.
(3) nitre phenylacrylic acid methyl esters synthetic between 2-cyano group-3-(diisopropoxy phosphono-1-phenyl-methylamino-)-3-:
The alpha-amino group benzylphosphonic acid diisopropyl ester of nitre phenylacrylic acid methyl esters, 0.813g (3mmol) between 2-cyano group-3-chloro-3-of 0.80g (3mmol), triethylamine and the 30mL methylene dichloride of 0.909g (9mmol) are added in the 50mL single port bottle; heated and stirred backflow 15h; washing; dry; precipitation is with thin layer chromatography (sherwood oil: ethyl acetate=1: 1) obtain nitre phenylacrylic acid methyl esters between pure target product 2-cyano group-3-(diisopropoxy phosphono-1-phenyl-methylamino-)-3-.Yield 54.2%.
Between embodiment 24,2-cyano group-3-(two n-butoxies phosphono-1-phenyl-methylamino-)-3-synthetic (compound number is x) of nitre phenylacrylic acid methyl esters:
(1) aminobenzyl phosphonic acids di-n-butyl is synthetic:
Synthetic as embodiment one (1) method and condition, difference is to add phosphorous acid di-n-butyl ester, and (1.445g, 7.5mmol), the reaction times is 10h, yield 52.3%.
(2) nitre phenylacrylic acid methyl esters synthetic between 2-cyano group-3-chloro-3-:
Synthetic as embodiment 21 (2) methods and condition.
(3) nitre phenylacrylic acid methyl esters synthetic between 2-cyano group-3-(two n-butoxies phosphono-1-phenyl-methylamino-)-3-:
The alpha-amino group benzylphosphonic acid di-n-butyl of nitre phenylacrylic acid methyl esters, 0.897g (3mmol) between 2-cyano group-3-chloro-3-of 0.80g (3mmol), triethylamine and the 30mL methylene dichloride of 0.909g (9mmol) are added in the 50mL single port bottle; heated and stirred backflow 15h; washing; dry; precipitation is with thin layer chromatography (sherwood oil: ethyl acetate=1: 1) obtain nitre phenylacrylic acid methyl esters between pure target product 2-cyano group-3-(two n-butoxies phosphono-1-phenyl-methylamino-)-3-.Yield 51.8%.
Utilize similar synthetic method, select different phosphinates for use in the first step, second step was selected different cyan-acetic esters and substituted-phenyl for use, and it is as shown in table 1 to select for use different the first step product and second to go on foot product synthetic phenyl cyanoacrylate derivative in the 3rd step.The phenyl cyanoacrylate compound proton nmr spectra of partial synthesis (
1H NMR) data are as shown in table 1, and physico-chemical property and ultimate analysis data are as shown in table 2, and infrared spectra (IR) data are as shown in table 3, carbon-13 nmr spectra (
13C NMR) data are as shown in table 4.
The proton nmr spectra data of table 1 compound
The physico-chemical property of table 2 compound and ultimate analysis
The IR data of table 3 compound
Table 4 compound
13C NMR data
The inhibition activity test test method that embodiment 25, compound h are sick to tobacco mosaic virus (TMV) (TMV)
1.1 virus is purified
Adopt Gooding method (Gooding G V jr, Hebert T T.A simple techniquefor purification of tobacco mosaic virus in large quantities[J] .Phytopathology, 1967,57,1285.), choose more than 3 weeks of inoculation, TMV systemic infection host Nicotiana tabacum.L plant upper blade, homogenate in phosphoric acid buffer, double gauze filters, and 1000g is centrifugal, handle through 2 polyoxyethylene glycol, centrifugal again, precipitation suspends with phosphoric acid buffer, promptly obtains the crude extract body of TMV.Whole experiment under 4 ℃, carry out (see deeply along one, last China fir Kang Yan (day), Japanese plum just, the king is sincere withered, Jiao Shumei translates. an agricultural chemicals laboratory method sterilant piece of writing [M] Beijing: agriculture press, 1991,93-94.).Absorbance with ultraviolet spectrophotometer mensuration 260nm wavelength calculates virus concentration according to formula.
Virus concentration (mg/mL)=(A
260* extension rate)/E
0.1% 1cm 260nm
Wherein E represents optical extinction coefficient, and promptly during wavelength 260nm, concentration is the suspension of 0.1% (1mg/mL), the photoabsorption when light path is 1cm (optical density(OD)) value.The E of TMV
0.1% 1cm 260nmBe 3.1.
1.2 the live body provide protection that medicament infects TMV
Select the Nicotiana glutinosa of growing way unanimity, spread medicament at Zuo Banye gently with writing brush, right half leaf spreads aqua sterilisa and compares, 12 hours, treat that blade is done after, virus inoculation.Dip in writing brush and to get viral juice, concentration is 6 * 10
-3Mg/mL, artificial frictional inoculation are on the blade that spreads silicon carbide, and (full leaf) wiped 1～2 time gently along its offshoot direction on the blade face.The blade below is supported with palm or multilayer filter paper.The blade that the inoculation back connects with flowing water (or wash bottle) flushing.Promptly occur scab after 3～4 days, when scab is counted easily, add up.
1.3 medicament is to the live body passivation of TMV
With medicament and isopyknic viral juice mixing passivation 30min, a frictional inoculation Nicotiana glutinosa left side half leaf, right half leaf of aqua sterilisa and viral juice combined inoculation.Write down withered spot number after 3～4 days.
1.4 the live body therapeutic action that medicament infects TMV
Select the Nicotiana glutinosa of growing way unanimity, dip in writing brush earlier and get viral juice, full leaf virus inoculation, the water flushing of inoculation back.After treating that blade is done, spread medicament at Zuo Banye, right half leaf spreads aqua sterilisa and compares.Write down withered spot number after 3～4 days.
Wherein, the average withered spot number that does not spread the average withered spot number of medicament half leaf and spread medicament half leaf all adopts and respectively organizes multiple mean number three times.
(2) test-results
After tested, compound h drug concentration is that 500 μ g/mL passivations are 53.42%, and the live body treatment inhibiting rate that TMV is infected is 47.37%, is 51.53% to the live body provide protection, shows certain anti-phytoviral activity.
The embodiment of the invention is aided with explanation technical scheme of the present invention, but the content of embodiment is not limited thereto.
Table 5 is pressed the method for embodiment 25, and compound is to protection, passivation and the therapeutic activity of tobacco mosaic virus (TMV)
All?results?are?expressed?as?mean±SD；n＝3?for?all?groups；*P＜0.05，**P＜0.01.
Claims (4)
1. a phenyl cyanoacrylate derivative that is used for Antiphytoviral is characterized in that this compounds 3-position contains the aminophosphonic acid ester group and the 3-position contains the substituted aroma cyclic group, and by the compound of following general formula:
R wherein
1Be hydrogen or neighbour,, the single halogen atom that replaces of contraposition,
R
2, R
3Be the C1-6 alkyl,
R
4Be the C1-6 alkoxyl group,
R
5Be hydrogen or (1) neighbour,, the single halogen atom that replaces of contraposition, (2) neighbour,, the single nitro that replaces of contraposition.
2. compound according to claim 1, C1-6 alkyl are methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, tert-pentyl, neo-pentyl, n-hexyl, isohexyl, uncle's hexyl, new hexyl; Halogen atom is fluorine, chlorine, bromine, iodine.
3. compound according to claim 1 is characterized in that compound is as follows:
A.2-cyano group-3-(diethoxy phosphonium mesitoyl base-1-phenyl-methylamino-)-3-ethyl phenylacrylate
B.2-cyano group-3-(two positive propoxies phosphono-1-phenyl-methylamino-)-3-ethyl phenylacrylate
C.2-cyano group-3-(diisopropoxy phosphono-1-phenyl-methylamino-)-3-ethyl phenylacrylate
D.2-cyano group-3-(two n-butoxies phosphono-1-phenyl-methylamino-)-3-ethyl phenylacrylate
E.2-the adjacent fluorophenyl ethyl propenoate of cyano group-3-(diethoxy phosphonium mesitoyl base-1-phenyl-methylamino-)-3-
F.2-the adjacent fluorophenyl ethyl propenoate of cyano group-3-(two positive propoxies phosphono-1-phenyl-methylamino-)-3-
G.2-the adjacent fluorophenyl ethyl propenoate of cyano group-3-(diisopropoxy phosphono-1-phenyl-methylamino-)-3-
H.2-the adjacent fluorophenyl ethyl propenoate of cyano group-3-(two n-butoxies phosphono-1-phenyl-methylamino-)-3-
I.2-nitre ethyl phenylacrylate between cyano group-3-(diethoxy phosphonium mesitoyl base-1-phenyl-methylamino-)-3-
J.2-nitre ethyl phenylacrylate between cyano group-3-(two positive propoxies phosphono-1-phenyl-methylamino-)-3-
K.2-nitre ethyl phenylacrylate between cyano group-3-(diisopropoxy phosphono-1-phenyl-methylamino-)-3-
L.2-nitre ethyl phenylacrylate between cyano group-3-(two n-butoxies phosphono-1-phenyl-methylamino-)-3-
M.2-cyano group-3-(diethoxy phosphonium mesitoyl base-1-phenyl-methylamino-)-3-phenylacrylic acid methyl esters
N.2-cyano group-3-(two positive propoxies phosphono-1-phenyl-methylamino-)-3-phenylacrylic acid methyl esters
O.2-cyano group-3-(diisopropoxy phosphono-1-phenyl-methylamino-)-3-phenylacrylic acid methyl esters
P.2-cyano group-3-(two n-butoxies phosphono-1-phenyl-methylamino-)-3-phenylacrylic acid methyl esters
Q.2-the adjacent fluorophenyl methyl acrylate of cyano group-3-(diethoxy phosphonium mesitoyl base-1-phenyl-methylamino-)-3-
R.2-the adjacent fluorophenyl methyl acrylate of cyano group-3-(two positive propoxies phosphono-1-phenyl-methylamino-)-3-
S.2-the adjacent fluorophenyl methyl acrylate of cyano group-3-(diisopropoxy phosphono-1-phenyl-methylamino-)-3-
T.2-the adjacent fluorophenyl methyl acrylate of cyano group-3-(two n-butoxies phosphono-1-phenyl-methylamino-)-3-
U.2-nitre phenylacrylic acid methyl esters between cyano group-3-(diethoxy phosphonium mesitoyl base-1-phenyl-methylamino-)-3-
V.2-nitre phenylacrylic acid methyl esters between cyano group-3-(two positive propoxies phosphono-1-phenyl-methylamino-)-3-
W.2-nitre phenylacrylic acid methyl esters between cyano group-3-(diisopropoxy phosphono-1-phenyl-methylamino-)-3-
X.2-nitre phenylacrylic acid methyl esters between cyano group-3-(two n-butoxies phosphono-1-phenyl-methylamino-)-3-.
4. be used for medicine according to any described compound among the claim 1-3 as anti-plant virus agent.
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