CN101041660A - 1,2-dihydrogen pyridine derivative, carbon glycosides intermediate and preparation method and application thereof - Google Patents
1,2-dihydrogen pyridine derivative, carbon glycosides intermediate and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a making method and application of 1, 2-dihydropyridine derivant and carbointermediate with structure as formula III, wherein Y is O; R1 and R2 is H; R3, R4, R6, R7, R, R', R'' is hydroxy; the glycosyl acceptor is heterocyclic ketene amine, N, S- ketene aldolactol, enamine, enamine ketone and enamine ester; the glycosyl supplier is glycal.
Description
Technical field
The present invention relates to 1,2-dihydrogen pyridine derivative and its carbon glycosides intermediate, and their preparation method and application.
Background technology
The existing a large amount of reports of dihydropyridine compounds have synthesized the compound as shown in the formula I as people (J.Amer.Chem.Soc.1978,100,6696～6698) such as Frank W.Fowler report; A new generation's calcium ion antagonist such as nifedipine (formula II), nitrendipine, nicardipine, nisoldipine, nilvadipine, amlodipine, felodipine, Lacidipine (62, Isrodipine isanomal class medicine are dihydropyridine compounds.
Summary of the invention
The purpose of this invention is to provide a kind of 1,2-dihydrogen pyridine derivative and its carbon glycosides intermediate, and their preparation method.
Provided by the present invention 1, the 2-dihydrogen pyridine derivative, structure such as formula III,
Wherein, Y is O, S, NH, NR ', CH
2, CHR ', CR ' R ".
R
1, R
2Be hydrogen, halogen, nitro, cyano group, amido, C
1～8Alkyl, C
1～8Alkylamino radical, C
1～8Alkyloyl, aroyl, thick aroyl, aryl, thick aryl, cycloalkyl or aralkyl;
R
3, R
4, R
6, R
7, R, R ', R " and be hydroxyl, hydrogen, halogen, nitro, cyano group, amido, C
1～8Alkyl, C
1～8Alkoxyl group, C
1～8Alkylamino radical, C
1～8Alkylthio, C
1～8Alkyloyl, aroyl, thick aroyl, aryl, thick aryl, cycloalkyl or aralkyl.
Here, R
1, R
2Be preferably hydrogen, fluorine, halogen, bromine, iodine, nitro, cyano group, amido, methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, methylamino, ethylamino-, Propylamino, isopropylamine base, n-butylamine-based, isobutyl amine, TERTIARY BUTYL AMINE base, formyl radical, ethanoyl, propionyl, different propionyl, positive butyryl radicals, isobutyryl, uncle's butyryl radicals, benzoyl; By fluorine, chlorine, bromine, iodine, nitro, cyano group, amido, methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, n-butoxy, isobutoxy, tert.-butoxy, methylamino, ethylamino-, Propylamino, isopropylamine base, n-butylamine-based, isobutyl amine, the TERTIARY BUTYL AMINE base, methylthio group, ethylmercapto group, the rosickyite base, the iprotiazem base, positive butylthio, the isobutyl sulfenyl, uncle's butylthio, formyl radical, ethanoyl or propionyl are single to the full pyridyl that replaces, indyl, imidazolyl, naphthyl, benzimidazolyl-, benzothiazolyl; Benzoyl, pyridine formyl radical, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, phenmethyl, styroyl or hydrocinnamyl;
R
3, R
4, R
6, R
7R, R ', R " be preferably hydroxyl; hydrogen; fluorine; halogen; bromine; iodine, nitro, cyano group, amido, methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, n-butoxy, isobutoxy, tert.-butoxy, methylamino, ethylamino-, Propylamino, isopropylamine base, n-butylamine-based, isobutyl amine, the TERTIARY BUTYL AMINE base, methylthio group, ethylmercapto group, the rosickyite base, the iprotiazem base, positive butylthio, the isobutyl sulfenyl, uncle's butylthio, formyl radical, ethanoyl, propionyl, different propionyl, positive butyryl radicals, isobutyryl, uncle's butyryl radicals, benzoyl; By fluorine, halogen, bromine, iodine, nitro, cyano group, amido, methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, n-butoxy, isobutoxy, tert.-butoxy, methylamino, ethylamino-, Propylamino, isopropylamine base, n-butylamine-based, isobutyl amine, the TERTIARY BUTYL AMINE base, methylthio group, ethylmercapto group, the rosickyite base, the iprotiazem base, positive butylthio, the isobutyl sulfenyl, uncle's butylthio, formyl radical, ethanoyl or propionyl are single to the full pyridyl that replaces, indyl, imidazolyl, naphthyl, benzimidazolyl-, benzothiazolyl; Benzoyl, pyridine formyl radical, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, phenmethyl, styroyl or hydrocinnamyl.
Carbon glycosides intermediate provided by the present invention, its structure be suc as formula IV,
Wherein, Y=O, S, NH, NR ', CH
2, CHR ', CR ' R ";
R
1, R
2Be hydrogen, halogen, nitro, cyano group, amido, C
1～8Alkyl, C
1～8Alkylamino radical, C
1～8Alkyloyl, aroyl, thick aroyl, aryl, thick aryl, cycloalkyl or aralkyl;
R
3, R
4, R
6, R
7, R ', R " and be hydroxyl, hydrogen, halogen, nitro, cyano group, amido, C
1～8Alkyl, C
1～8Alkoxyl group, C
1～8Alkylamino radical, C
1～8Alkylthio, C
1～8Alkyloyl, aroyl, thick aroyl, aryl, thick aryl, cycloalkyl or aralkyl;
R
5Be halogen, nitro, cyano group, C
1～8Alkyl, C
1～8Alkoxyl group, C
1～8Alkylthio, aryl, thick aryl, cycloalkyl or aralkyl.
The present invention 1, and the 2-dihydrogen pyridine derivative can adopt two kinds of methods to synthesize:
First method, heterocyclic ketene semiamine, the N of first employing formula V structure, S-ketene acetal, N, O-ketene acetal, enamine ketone or enamine ester etc. react with the glycal of formula VI structure, obtain the carbon glycosides intermediate of formula (IV) structure; Formula (IV) carbon glycosides intermediate becomes ring under heating condition then, gets formula (III) dihydrogen pyridine derivative.
Second method, the heterocyclic ketene semiamine of formula V structure, N, S-ketene acetal, N, O-ketene acetal, enamine ketone or enamine ester etc. directly react with the glycal of formula VI structure, get formula (III) dihydrogen pyridine derivative.
Another object of the present invention provides the purposes of dihydrogen pyridine derivative of the present invention and carbon glycosides intermediate.
The inventor confirms that by experiment dihydrogen pyridine derivative of the present invention and carbon glycosides intermediate all have good insecticidal activity, can be used as sterilant and uses.
The present invention is with heterocyclic ketene semiamine, N, S-ketene acetal, enamine, enamine ketone, enamine ester etc. are glycosyl acceptor, with the glycal is glycosyl donor, synthesized 1 of a class formation novelty, 2-dihydropyridine compounds and carbon glycosides intermediate, synthetic route is short, the reaction conditions gentleness, the productive rate height, special suitability for industrialized production, cost is low.The compounds of this invention has a plurality of reaction site, is synthon important in the organic synthesis, can the various compound of regioselectivity composite structure.The compounds of this invention also has good insecticidal activity, has a extensive future.
Description of drawings
Fig. 1 is the high resolution mass spectrum figure of compound IV-f;
Fig. 2 is the high resolution mass spectrum figure of compound IV-p;
Fig. 3 is the single crystal structure figure of compound IV-w;
Fig. 4 is the single crystal structure figure of compound III-a;
Fig. 5 is the carbon-13 nmr spectra figure of compound III-b;
Fig. 6 is the high resolution mass spectrum figure of compound III-f.
Embodiment
Prepare of the present inventionly 1, the 2-dihydrogen pyridine derivative can adopt two kinds of methods to carry out:
First method is prepared the carbon glycosides intermediate of formula IV structure earlier, then, the carbon glycosides intermediate of formula IV structure is converted into 1 of formula III structure, the 2-dihydrogen pyridine derivative, and concrete reaction formula is as follows:
In the formula: Y=O, S, NH, NR ', CH
2, CHR ', CR ' R ";
R
1, R
2Separately respectively or be hydrogen, halogen, nitro, cyano group, amido, C simultaneously
1～8Alkyl, C
1～8Alkylamino radical, C
1～8Alkyloyl, aroyl, thick aroyl, aryl, thick aryl, cycloalkyl, aralkyl;
R
3, R
4, R
6, R
7, R ', R " and be hydroxyl, hydrogen, halogen, nitro, cyano group, amido, C
1～8Alkyl, C
1～8Alkoxyl group, C
1～8Alkylamino radical, C
1～8Alkylthio, C
1～8Alkyloyl, aroyl, thick aroyl, aryl, thick aryl, cycloalkyl or aralkyl;
R
5Be halogen, nitro, cyano group, C
1～8Alkyl, C
1～8Alkoxyl group, C
1～8Alkylthio, aryl, thick aryl, cycloalkyl or aralkyl.
The reaction conditions of formula V and formula VI reaction production IV: alkali that room temperature or alkalescence are more weak such as triethylamine are not enough so that the substituent R of difficult cancellation
5Reaction takes place to eliminate reaction, so can rest on this step of intermediate product formula IV.Reaction mechanism is as follows:
Wherein, the first step, the heterocyclic ketene semiamine of structure such as formula V, N, S-ketene acetal, enamine, enamine ketone or enamine ketone ester and structure are suc as formula the glycal (as: 3 of (VI), 4,6-three-O-benzyl-2-nitro-D-glucal, 3,4,6-three-O-benzyl-2-cyano group-D-glucal etc.) react formula (IV) carbon glycosides intermediate.
In the reaction, use solvent to be non-protonic solvent, as methylene dichloride, trichloromethane, 1,2-ethylene dichloride, acetonitrile, toluene, benzene, ether, N, dinethylformamide, 1,4-dioxane etc.; In the reaction, generally can add Lewis base, alkali commonly used is organic bases, as DBU, triethylamine, diisopropyl ethyl amine, pyridine, 4-(N, N-dimethyl amido) pyridine, 2,6-lutidine, 2,4-lutidine etc., and mineral alkali are as sodiumazide, sodium hydride, hydrolith etc.
In the reaction, for 1 mole formula V compound, formula (VI) compound amount is the 1-5 mole, and alkali is the 1-10 mole.Solvent load generally is a 1mmol formula V compound with 5～50 milliliters of solvents.
Temperature of reaction is more wide in range, often is 0-130 ℃; Reaction times can be controlled in 6-24 hour.Reaction process adopts TLC to detect and follows the tracks of, after reacting completely, and the cancellation reaction, use solvent extraction, and with the dry organic layer of siccative, decompression is removed organic solvent and is got head product, column chromatography (leacheate: petrol ether/ethyl acetate=3/1～0/1) separate formula (IV) intermediate.
The yield of above-mentioned reaction generally can be greater than 80%.
In second step, formula (IV) intermediate is in aprotic solvent, and reacting by heating just can obtain formula (III) compound under the alkali effect.
The reaction solvent for use is a non-protonic solvent, as N, and dinethylformamide, methylene dichloride, trichloromethane, 1,2-ethylene dichloride, acetonitrile, toluene, benzene, ether, 1,4-dioxane etc.Alkali is organic bases, as DBU, triethylamine, diisopropyl ethyl amine, pyridine, 4-(N, N-dimethyl amido) pyridine, 2, and 6-lutidine, 2,4-lutidine etc., and mineral alkali are as sodiumazide, sodium hydride, hydrolith etc.
In the reaction, for (IV) compound of 1 mole, alkali is the 1-10 mole.Solvent load generally is 1mmol (IV) compound with 5～50 milliliters of solvents.
Temperature of reaction can be controlled in 60-130 ℃ usually; Reaction times is 6-24 hour often.
The yield of above-mentioned second step reaction is often greater than 60%.
Second method is heterocyclic ketene semiamine, the N of structure such as formula V, and S-ketene acetal, enamine, enamine ketone or enamine ester and structure are reacted under acid or alkali effect suc as formula the glycal of (VI), directly obtain product, and reaction formula is as follows:
Wherein, Y=O, S, NH, NR ', CH
2, CHR ', CR ' R ";
R
1, R
2Separately respectively or be hydrogen, halogen, nitro, cyano group, amido, C simultaneously
1～8Alkyl, C
1～8Alkylamino radical, C
1～8Alkyloyl, aroyl, thick aroyl, aryl, thick aryl, cycloalkyl, aralkyl;
R
3, R
4, R
6, R
7, R ', R " and be hydroxyl, hydrogen, halogen, nitro, cyano group, amido, C
1～8Alkyl, C
1～8Alkoxyl group, C
1～8Alkylamino radical, C
1～8Alkylthio, C
1～8Alkyloyl, aroyl, thick aroyl, aryl, thick aryl, cycloalkyl or aralkyl;
R
5Be C
1～8Alkyloyl, aroyl, thick aroyl, trialkyl silyl.
The R here
5Be the substituting group of easily leaving away under alkaline condition, so obtain the formula III product once the step, reaction mechanism is as follows:
The reaction solvent for use is a non-protonic solvent, as methylene dichloride, trichloromethane, 1,2-ethylene dichloride, acetonitrile, toluene, benzene, ether, N, dinethylformamide, 1,4-dioxane etc.Alkali is organic bases, as DBU, triethylamine, diisopropyl ethyl amine, pyridine, 4-(N, N-dimethyl amido)-pyridine, 2, and 6-lutidine, 2,4-lutidine etc., and mineral alkali are as sodiumazide, sodium hydride, hydrolith etc.; Acid is Lewis acid, as boron trifluoride diethyl etherate, cerous compounds, TiCl
4, silver trifluoromethanesulfonate etc.
In the reaction, for 1 mole formula V compound, formula (VI) compound amount is the 1-10 mole, and alkali or acid are the 1-10 mole.Solvent load generally is a 1mmol formula V compound with 5～50 milliliters of solvents.
Temperature of reaction is controlled at 0-100 ℃, and the reaction times is 0.5-10 hour.Reaction process adopts TLC to detect, and after reacting completely, solvent extraction use in the cancellation reaction, and with siccative drying organic layer, reduce pressure to remove organic solvent and get head product, column chromatography (leacheate: petrol ether/ethyl acetate=3/1～0/1) separate product.
First part prepares embodiment
One, formula VI carbon glycosides intermediate is synthetic
In single neck bottle of 25 milliliters, add 10 milliliters of methylene dichloride; 1.2 mmole 2-(to the chlorobenzoyl methylene)-1; 3-Diazesuberane and 1.0 mmole 2-nitros-3; 4; 6-three-O-benzyl-D-glucal (tri-O-benzyl-2-nitro-D-glucal); an amount of triethylamine; react under the room temperature, after TLC showed the raw material completely dissolve, the methylene dichloride of going out under the decompression got solid; column chromatography separate product 2-[[1-to chlorobenzene formacyl-1-(2-deoxidation-2-nitro-3; 4,6-three-O-benzyl-β-D-glucopyanosyl base)] methylene radical]-[1,3]-Diazesuberane (IV-a): orange solids; productive rate 84%, its fusing point is: 69 ℃.Optically-active (chloroform is a solvent, concentration=1.0): [α]
25 D=+138.8;
Infrared spectra (KBr compressing tablet, JASCO FT/IR 480 plus instrument) v3358,1615,1553,1348,1088,1027cm
-1
Proton nmr spectra (deuterochloroform is a solvent, Bruker AM 300 instrument) is at room temperature measured: δ 11.37 (br, 1H, NH), 7.32 (m, 19H, ArH), 6.70 (br, 1H, NH), 4.87 (m, 1H, OCH
2), 4.76 (m, 2H, H1 andOCH
2), 4.55 (m, 1H, H
2), 4.50 (m, 3H, OCH
2), 4.15 (t, J=9.4Hz, 1H, H
3), 3.86 (m, 3H, H4, H6and H6 '), 3.53 (m, 1H, H5), 3.57 (m, 2H, CH
2N), 3.07 (m, 2H, CH
2N), 1.84 (m, 2H, CH
2N), 1.47 (m, 2H, CH
2N);
Carbon-13 nmr spectra (deuterochloroform is a solvent, Bruker AM 300 instrument) is at room temperature measured: δ 188.7,168.4, and 140.6,138.0,137.8,137.1,135.0,129.1,128.7,128.6,128.6,128.3,128.3,128.1,128.0,127.9,127.8,127.7,88.4,87.6,82.7,78.6,78.1,77.3,75.8,75.1,73.4,68.4,45.2,45.2,27.9,27.9;
Mass spectrum (FAB source, Bruker APEX-2) C
40H
42ClN
3O
7M/z:[M]
+=712; Ultimate analysis: theoretical value: C, 67.45; H, 5.94; N, 5.90, measured value C, 67.44; H, 6.00; N, 5.92.
Embodiment 2: Synthetic 2-[[1-benzoyl-1-(2-deoxidation-2-nitro-3,4,6-three-O-benzyl-β-D-glucopyanosyl base)] methylene radical]-[1,3]-Diazesuberane (IV-b)
With 2-(benzoyl methylene radical)-1; the 3-Diazesuberane replaces the 2-(to the chlorobenzoyl methylene)-1 among the embodiment 1; the 3-Diazesuberane reacts; obtain 2-[[1-benzoyl-1-(2-deoxidation-2-nitro-3; 4,6-three-O-benzyl-β-D-glucopyanosyl base)] methylene radical]-[1,3]-Diazesuberane (IV-b); white solid, productive rate 85%.Its fusing point is: 127 ℃.
Embodiment 3: Synthetic 2-[[1-is to toluyl-1-(2-deoxidation-2-nitro-3,4,6-three-O-benzyl-β-D-glucopyanosyl base)] methylene radical]-[1,3]-Diazesuberane (IV-c)
With 2-(to the toluyl methylene radical)-1; the 3-Diazesuberane replaces the 2-(to the chlorobenzoyl methylene)-1 among the embodiment 1; the 3-Diazesuberane reacts; obtain 2-[[1-to toluyl-1-(2-deoxidation-2-nitro-3; 4,6-three-O-benzyl-β-D-glucopyanosyl base)] methylene radical]-[1,3]-Diazesuberane (IV-c); white solid, productive rate 85%.Its fusing point is: 113～114 ℃.
With the 2-(to the chlorobenzoyl methylene)-1 among 2-(to the chlorobenzoyl methylene) the hexahydropyrimidine replacement embodiment 1; the 3-Diazesuberane reacts; obtain 2-[[1-to chlorobenzene formacyl-1-(2-deoxidation-2-nitro-3; 4; 6-three-O-benzyl-β-D-glucopyanosyl base)] methylene radical]-hexahydropyrimidine (IV-d); white solid, productive rate 91%.Its fusing point is: 68～69 ℃.
Embodiment 5: Synthetic 2-[[1-benzoyl-1-(2-deoxidation-2-nitro-3,4,6-three-O-benzyl-β-D-glucopyanosyl base)] methylene radical]-hexahydropyrimidine (IV-e)
With the 2-(to the chlorobenzoyl methylene)-1 among 2-(benzoyl methylene radical) the hexahydropyrimidine replacement embodiment 1; the 3-Diazesuberane reacts has to 2-[[1-benzoyl-1-(2-deoxidation-2-nitro-3; 4; 6-three-O-benzyl-β-D-glucopyanosyl base)] methylene radical]-hexahydropyrimidine (IV-e); white solid, productive rate 81%.Its fusing point is: 113～115 ℃.
Embodiment 6: Synthetic 2-[[1-is to toluyl-1-(2-deoxidation-2-nitro-3,4,6-three-O-benzyl-β-D-glucopyanosyl base)] methylene radical]-hexahydropyrimidine (IV-f)
With the 2-(to the chlorobenzoyl methylene)-1 among 2-(to the toluyl methylene) the hexahydropyrimidine replacement embodiment 1; the 3-Diazesuberane reacts; obtain 2-[[1-to toluyl-1-(2-deoxidation-2-nitro-3; 4; 6-three-O-benzyl-β-D-glucopyanosyl base)] methylene radical]-hexahydropyrimidine (IV-f), scarlet oily liquids, productive rate 87%; optically-active (chloroform is a solvent, concentration=1.1): [α]
25 D=+3.8.
The high resolution mass spectrum of this compound as shown in Figure 1.
Embodiment 7: Synthetic 2-[[1-is to anisoyl-1-(2-deoxidation-2-nitro-3,4,6-three-O-benzyl-β-D-glucopyanosyl base)] methylene radical]-hexahydropyrimidine (IV-g)
With the 2-(to the chlorobenzoyl methylene)-1 among 2-(to the methoxybenzoyl methylene) the hexahydropyrimidine replacement embodiment 1, the 3-Diazesuberane reacts, obtain 2-[[1-to anisoyl-1-(2-deoxidation-2-nitro-3,4,6-three-O-benzyl-β-D-glucopyanosyl base)] methylene radical]-hexahydropyrimidine (IV-g), white solid, productive rate 31%; Its fusing point is: 181～182 ℃.
Embodiment 8: Synthetic 2-[[1-is to chlorobenzene formacyl-1-(2-deoxidation-2-nitro-3,4,6-three-O-benzyl-β-D-glucopyanosyl base)] methylene radical]-tetrahydroglyoxaline pyridine (IV-h)
With the 2-(to the chlorobenzoyl methylene)-1 among 2-(to the chlorobenzoyl methylene) the tetrahydroglyoxaline pyridine replacement embodiment 1, the 3-Diazesuberane reacts, obtain 2-[[1-to chlorobenzene formacyl-1-(2-deoxidation-2-nitro-3,4,6-three-O-benzyl-β-D-glucopyanosyl base)] methylene radical]-tetrahydroglyoxaline pyridine (IV-h), yellow solid, productive rate 82%; Its fusing point is: 78 ℃.
Embodiment 9: Synthetic 2-[[1-benzoyl-1-(2-deoxidation-2-nitro-3,4,6-three-O-benzyl-β-D-glucopyanosyl base)] methylene radical]-tetrahydroglyoxaline pyridine (IV-i)
With the 2-(to the chlorobenzoyl methylene)-1 among 2-(benzoyl methylene radical) the tetrahydroglyoxaline pyridine replacement embodiment 1, the 3-Diazesuberane reacts, obtain 2-[[1-benzoyl-1-(2-deoxidation-2-nitro-3,4,6-three-O-benzyl-β-D-glucopyanosyl base)] methylene radical]-tetrahydroglyoxaline pyridine (IV-i), white needle-like crystals, productive rate 83%; Its fusing point is: 142～143 ℃.
Embodiment 10: Synthetic 2-[[1-is to toluyl-1-(2-deoxidation-2-nitro-3,4,6-three-O-benzyl-β-D-glucopyanosyl base)] methylene radical]-tetrahydroglyoxaline pyridine (IV-j)
With the 2-(to the chlorobenzoyl methylene)-1 among 2-(to the toluyl methylene) the tetrahydroglyoxaline pyridine replacement embodiment 1, the 3-Diazesuberane reacts, obtain 2-[[1-to toluyl-1-(2-deoxidation-2-nitro-3,4,6-three-O-benzyl-β-D-glucopyanosyl base)] methylene radical]-tetrahydroglyoxaline pyridine (IV-j), yellow solid, productive rate 84%; Its fusing point is: 134～135 ℃.
Embodiment 11: Synthetic 2-[[1-is to anisoyl-1-(2-deoxidation-2-nitro-3,4,6-three-O-benzyl-β-D-glucopyanosyl base)] methylene radical]-tetrahydroglyoxaline pyridine (IV-k)
With the 2-(to the chlorobenzoyl methylene)-1 among 2-(to the anisoyl methylene radical) the tetrahydroglyoxaline pyridine replacement embodiment 1, the 3-Diazesuberane reacts, obtain 2-[[1-to anisoyl-1-(2-deoxidation-2-nitro-3,4,6-three-O-benzyl-β-D-glucopyanosyl base)] methylene radical]-tetrahydroglyoxaline pyridine (IV-k), white needle-like crystals, productive rate 86%; Its fusing point is: 113～114 ℃.
With the 2-(to the chlorobenzoyl methylene)-1 among 2-(cyano group methylene radical) the tetrahydroglyoxaline pyridine replacement embodiment 1, the 3-Diazesuberane reacts, obtain 2-[[1-cyano group-1-(2-deoxidation-2-nitro-3,4,6-three-O-benzyl-β-D-glucopyanosyl base)] methylene radical]-tetrahydroglyoxaline pyridine (IV-1), white solid, productive rate 56%; Its fusing point is: 67 ℃.
With the 2-(to the chlorobenzoyl methylene)-1 among 2-(cyano group methylene radical) the tetrahydroglyoxaline pyridine replacement embodiment 1, the 3-Diazesuberane reacts, obtain 2-[[1-cyano group-1-(2-deoxidation-2-nitro-3,4,6-three-O-benzyl-β-D-pyran-mannose glycosylation)] methylene radical]-tetrahydroglyoxaline pyridine (IV-m): yellow oily liquid, productive rate 30%; This compound is the isomers of IV-1;
Optically-active (chloroform is a solvent, concentration=1.1): [α]
25 D=+19.0;
Mass spectrum (FAB source, Bruker APEX-2) C
32H
34N
4O
6M/z:[M+H]
+=571;
High resolution mass spectrum (FAB source, Bruker APEX-2) measured value 571.2544, theoretical value C
32H
34N
4O
6[M+H]
+571.2551.
Embodiment 14: Synthetic 2-[[1-ethanoyl-1-(2-deoxidation-2-nitro-3,4,6-three-O-benzyl-β-D-glucopyanosyl base)] methylene radical]-tetrahydroglyoxaline pyridine (IV-n)
With the 2-(to the chlorobenzoyl methylene)-1 among 2-(ethanoyl methylene radical) the tetrahydroglyoxaline pyridine replacement embodiment 1; the 3-Diazesuberane reacts; obtain 2-[[1-ethanoyl-1-(2-deoxidation-2-nitro-3; 4; 6-three-O-benzyl-β-D-glucopyanosyl base)] methylene radical]-tetrahydroglyoxaline pyridine (IV-n); the scarlet oily liquids, productive rate 90%.
Embodiment 15: Synthetic 2-[[1-ethoxycarbonyl-1-(2-deoxidation-2-nitro-3,4,6-three-O-benzyl-β-D-glucopyanosyl base)] methylene radical]-tetrahydroglyoxaline pyridine (IV-o)
With the 2-(to the chlorobenzoyl methylene)-1 among 2-(ethoxycarbonyl methylene radical) the tetrahydroglyoxaline pyridine replacement embodiment 1; the 3-Diazesuberane reacts; obtain 2-[[1-ethoxycarbonyl-1-(2-deoxidation-2-nitro-3; 4; 6-three-O-benzyl-β-D-glucopyanosyl base)] methylene radical]-tetrahydroglyoxaline pyridine (IV-o); the yellowish red color oily liquids, productive rate 65%.
In single neck bottle of 25 milliliters, add 10 ml methanol; 1 mmole 2-[[1-is to chlorobenzene formacyl-1-(2-deoxidation-2-nitro-3; 4; 6-three-O-benzyl-β-D-glucopyanosyl base)] methylene radical]-hexahydropyrimidine (IV-d); an amount of ammonium chloride; an amount of zinc powder; react after several hours; after TLC shows the raw material completely dissolve; aftertreatment gets product: 2-[[1-is to chlorobenzene formacyl-1-(2-deoxidation-2-amido-3; 4,6-three-O-benzyl-β-D-glucopyanosyl base)] methylene radical]-hexahydropyrimidine (IV-p): white solid, productive rate 78%.Its fusing point is: 204～205 ℃; High resolution mass spectrum (FAB source, Bruker APEX-2) measured value 668.2882, theoretical value C
39H
42C1N
3O
5[M+H]
+668.2886.
The high resolution mass spectrum of this compound as shown in Figure 2.
Embodiment 17: Synthetic 2-[[1-is to toluyl-1-(2-deoxidation-2-amido-3,4,6-three-O-benzyl-β-D-glucopyanosyl base)] methylene radical]-tetrahydroglyoxaline pyridine (IV-q)
With 2-[[1-to toluyl-1-(2-deoxidation-2-nitro-3,4,6-three-O-benzyl-β-D-glucopyanosyl base)] methylene radical]-tetrahydroglyoxaline pyridine (IV-j) replaces 2-[[1-among the embodiment 16 to chlorobenzene formacyl-1-(2-deoxidation-2-nitro-3,4,6-three-O-benzyl-β-D-glucopyanosyl base)] methylene radical]-hexahydropyrimidine (IV-d) reacts and has to 2-[[1-to toluyl-1-(2-deoxidation-2-amido-3,4,6-three-O-benzyl-β-D-glucopyanosyl base)] methylene radical]-the tetrahydroglyoxaline pyridine, white solid, productive rate 87%;
High resolution mass spectrum (FAB source, Bruker APEX-2) measured value 634.3273, theoretical value C
39H
43N
3O
5[M+H]
+634.3275.
Embodiment 18: Synthetic 2-[[1-is to anisoyl-1-(2-deoxidation-2-amido-3,4,6-three-O-benzyl-β-D-glucopyanosyl base)] methylene radical]-tetrahydroglyoxaline pyridine (IV-r)
With 2-[[1-to anisoyl-1-(2-deoxidation-2-nitro-3; 4; 6-three-O-benzyl-β-D-glucopyanosyl base)] methylene radical]-tetrahydroglyoxaline pyridine (IV-k) replaces 2-[[1-among the embodiment 16 to chlorobenzene formacyl-1-(2-deoxidation-2-nitro-3; 4; 6-three-O-benzyl-β-D-glucopyanosyl base)] methylene radical]-hexahydropyrimidine (IV-d) reacts; obtain 2-[[1-to anisoyl-1-(2-deoxidation-2-amido-3; 4; 6-three-O-benzyl-β-D-glucopyanosyl base)] methylene radical]-tetrahydroglyoxaline pyridine (IV-r); white solid, productive rate 80%.
In single neck bottle of 25 milliliters, add 50 milligrams of 2-[[1-to chlorobenzene formacyl-1-(2-deoxidation-2-amido-3; 4; 6-three-O-benzyl-β-D-glucopyanosyl base)] methylene radical]-hexahydropyrimidine (IV-p); 2 milliliters of acetic anhydride; an amount of pyridine; room temperature reaction; after TLC shows the raw material completely dissolve; aftertreatment gets product 1-ethanoyl-2-[[1-to chlorobenzene formacyl-1-(2-deoxidation-2-acetamido-3; 4; 6-three-O-benzyl-β-D-glucopyanosyl base)] methylene radical]-hexahydropyrimidine (IV-s), white solid, productive rate 70%.Its fusing point is: 101～103 ℃.
Embodiment 20: Synthetic 2-[[1-is to toluyl-1-(2-deoxidation-2-acetamido-3,4,6-three-O-benzyl-β-D-glucopyanosyl base)] methylene radical]-tetrahydroglyoxaline pyridine (IV-t)
In single neck bottle of 25 milliliters, add 10 methylene dichloride; 200 milligrams of 2-[[1-are to toluyl-1-(2-deoxidation-2-amido-3; 4; 6-three-O-benzyl-β-D-glucopyanosyl base)] methylene radical]-tetrahydroglyoxaline pyridine (IV-q); stir the back and add 54 milligrams of acetic acid; add an amount of TBTU (O-(Benzotriazol-1-yl)-N again; N; N '; N '-tetra methyluroniumtetrafluoroborate); after room temperature reaction several hours, TLC showed that raw material disappears, aftertreatment got product 2-[[1-to toluyl-1-(2-deoxidation-2-acetamido-3; 4; 6-three-O-benzyl-β-D-glucopyanosyl base)] methylene radical]-tetrahydroglyoxaline pyridine (IV-t), white solid, productive rate 70%.Its fusing point is: 101～103 ℃;
High resolution mass spectrum (FAB source, Bruker APEX-2) measured value 752.3091, theoretical value C
43H
46ClN
3O
7[M+H]
+752.3101.
With 2-[[1-to anisoyl-1-(2-deoxidation-2-amido-3; 4; 6-three-O-benzyl-β-D-glucopyanosyl base)] methylene radical]-tetrahydroglyoxaline pyridine (IV-r) replaces 2-[[1-among the embodiment 19 to chlorobenzene formacyl-1-(2-deoxidation-2-amido-3; 4; 6-three-O-benzyl-β-D-glucopyanosyl base)] methylene radical]-hexahydropyrimidine (IV-p) reacts; obtain 2-[[1-to anisoyl-1-(2-deoxidation-2-acetamido-3; 4; 6-three-O-benzyl-β-D-glucopyanosyl base)] methylene radical]-tetrahydroglyoxaline pyridine (IV-u); white solid, productive rate 87%.
Embodiment 22: Synthetic 2-[[1-is to anisoyl-1-(2-deoxidation-2-(the sweet amine amide base of N-fluorenylmethyloxycarbonyl)-3,4,6-three-O-benzyl-β-D-glucopyanosyl base)] methylene radical]-tetrahydroglyoxaline pyridine (IV-v)
Replace acetic acid among the embodiment 19 to react with N-fluorenylmethyloxycarbonyl glycine and have to 2-[[1-anisoyl-1-(2-deoxidation-2-(the sweet amine amide base of N-fluorenylmethyloxycarbonyl)-3; 4; 6-three-O-benzyl-β-D-glucopyanosyl base)] methylene radical]-tetrahydroglyoxaline pyridine (IV-v); white solid, productive rate 78%.Mass spectrum (FAB source, Bruker APEX-2) C
56H
56N
4O
9M/z:[M+H]
+=929.
Embodiment 23, synthetic (2S, 3R, 4S, 5S)-acetate-[2-ethanoyl-3,5-two-[2-(1-cyano group methylene radical) tetrahydroglyoxaline pyridine base]-4-nitro-THP trtrahydropyranyl] methyl alcohol ester (IV-w)
Replace 2-(to the chlorobenzoyl methylene) hexahydropyrimidine among the embodiment 1 to react with 2-(cyano group methylene radical) tetrahydroglyoxaline pyridine; obtain (2S; 3R; 4S; 5S)-acetate-[2-ethanoyl-3; 5-two-[2-(1-cyano group methylene radical) tetrahydroglyoxaline pyridine base]-4-nitro-THP trtrahydropyranyl] methyl alcohol ester (IV-w), yellow solid, productive rate 61%.Its fusing point is: 134～135 ℃.
The single crystal structure figure of this compound as shown in Figure 3.
Embodiment 24: synthetic (3S, 4R, 5S, 6S)-and 1-methylol-2-hydroxyl-3,5-two-[2-(1-cyano group methylene radical) tetrahydroglyoxaline pyridine base]-4-nitro-tetrahydropyrans (IV-x)
In single neck bottle of 25 milliliters, add 10 ml methanol; add 15 milligrams in sodium; treat to add (2S after sodium disappears; 3R; 4S, 5S)-acetate-[2-ethanoyl-3,5-two-[2-(1-cyano group methylene radical) tetrahydroglyoxaline pyridine base]-4-nitro-THP trtrahydropyranyl] methyl alcohol ester (IV-w) milligram; react to the raw material disappearance; the decompression under remove part methyl alcohol, column chromatography separate product (3S, 4R; 5S; 6S)-and 1-methylol-2-hydroxyl-3,5-two-[2-(1-cyano group methylene radical) tetrahydroglyoxaline pyridine base]-4-nitro-tetrahydropyrans (IV-x), yellow solid; productive rate 87%, its fusing point is: 160～161 ℃.
Above institute synthetic carbon glycosides intermediate, structure is as shown in table 1:
Table 1 part carbon glycosides intermediate structure formula
Two, formula III 1,2-dihydrogen pyridine derivative synthetic
Embodiment 25, synthetic (4R)-4-[(1R, 2S)-(1,3-benzyloxy-2-hydroxyl) propyl group]-5-nitro-7-is to anisoyl-2,3,3a, 4-tetrahydrochysene-3a-azaindole (III-a)
In single neck bottle of 25 milliliters, add 10 milliliters of N; dinethylformamide; add 136 milligrams of 2-[[1-to anisoyl-1-(2-deoxidation-2-nitro-3; 4; 6-three-O-benzyl-β-D-glucopyanosyl base)] methylene radical]-tetrahydroglyoxaline pyridine (IV-k); 26 milligrams of sodiumazide; after the reacting by heating several hours, treat that raw material disappears after, cool to room temperature; aftertreatment gets product (4R)-4-[(1R; 2S)-(1,3-benzyloxy-2-hydroxyl) propyl group]-5-nitro-7-is to anisoyl-2,3; 3a, 4-tetrahydrochysene-3a-azaindole (III-a).
Yellow solid, productive rate 68%.Its fusing point is: 54～56 ℃; High resolution mass spectrum (FAB source, Bruker APEX-2) measured value 572.2395, theoretical value C
32H
33N
3O
7[M+H]
+572.2392.
Embodiment 26: synthetic (5R)-5-[(1R, 2S)-(1,3-O-diacetyl-1,2,3-trihydroxy-) propyl group]-6-nitro-8-is to chlorobenzene formacyl-1,2,3,4,4a, 5-six hydrogen-4a-azepine quinoline (III-b)
In single neck bottle of 100 milliliters, add 40 milliliters of methylene dichloride; 1 mmole 2-nitro-3; 4,6-three-O-ethanoyl-D-glucal (tri-O-acetyl-2-nitro-D-glucal) drips 0.2～0.5 milliliter of triethylamine; add 236 milligrams of 2-(to the chlorobenzoyl methylene) hexahydropyrimidine; react to the completely dissolve of TLC demonstration raw material, cancellation is reacted and is got product (5R)-5-[(1R through aftertreatment, 2S)-(1; 3-O-diacetyl-1; 2,3-trihydroxy-) propyl group]-6-nitro-8-is to chlorobenzene formacyl-1,2; 3; 4,4a, 5-six hydrogen-4a-azepine quinoline (III-b); yellow solid, productive rate 26%.Its fusing point is: 189～190 ℃;
Optically-active (chloroform is a solvent, concentration=0.96): [α]
25 D=+654.2;
Infrared spectra (KBr compressing tablet, JASCO FT/IR 480 plus instrument) v3451,1743,1614,1325,1225,1048cm
-1
Mass spectrum (ESI source, Bruker APEX-2) C
22H
24ClN
3O
8M/z:[M+Na]
+=516;
Ultimate analysis: theoretical value: C, 53.50; H, 4.90; N, 8.51. measured value C, 53.10; H, 5.14; N, 8.17.
The single crystal structure figure of this compound as shown in Figure 4.
Embodiment 27: synthetic (5R)-5-[(1R, 2S)-(1,3-O-diacetyl-1,2,3-trihydroxy-) propyl group]-6-nitro-8-benzoyl-1,2,3,4,4a, 5-six hydrogen-4a-azepine quinoline (III-c)
Replace 2-(to the chlorobenzoyl methylene) hexahydropyrimidine among the embodiment 26 to react with 2-(benzoyl methylene radical) hexahydropyrimidine, obtain (5R)-5-[(1R, 2S)-(1; 3-O-diacetyl-1; 2, the 3-trihydroxy-) propyl group]-6-nitro-8-benzoyl-1,2; 3; 4,4a, 5-six hydrogen-4a-azepine quinoline (III-c); yellow solid, productive rate 27%.Its fusing point is: 210～212 ℃.
The carbon-13 nmr spectra of this compound as shown in Figure 5.
Embodiment 28: synthetic (5R)-5-[(1R, 2S)-(1,3-O-diacetyl-1,2,3-trihydroxy-) propyl group]-6-nitro-8-is to methyl benzoyl-1,2,3,4,4a, 5-six hydrogen-4a-azepine quinoline (III-d)
Replace 2-(to the chlorobenzoyl methylene) hexahydropyrimidine among the embodiment 26 to react with 2-(to the toluyl methylene) hexahydropyrimidine, obtain (5R)-5-[(1R, 2S)-(1; 3-O-diacetyl-1; 2,3-trihydroxy-) propyl group]-6-nitro-8-is to methyl benzoyl-1,2; 3; 4,4a, 5-six hydrogen-4a-azepine quinoline (III-d); red solid, productive rate 30%.Its fusing point is: 201～202 ℃.
Embodiment 29, synthetic (5R)-5-[(1R, 2S)-(1,3-O-diacetyl-1,2,3-trihydroxy-) propyl group]-6-nitro-8-is to anisoyl-1,2,3,4,4a, 5-six hydrogen-4a-azepine quinoline (III-e)
Replace 2-(to the chlorobenzoyl methylene) hexahydropyrimidine among the embodiment 26 to react with 2-(to the anisoyl methylene radical) hexahydropyrimidine, obtain (5R)-5-[(1R, 2S)-(1; 3-O-diacetyl-1; 2,3-trihydroxy-) propyl group]-6-nitro-8-is to anisoyl-1,2; 3; 4,4a, 5-six hydrogen-4a-azepine quinoline (III-e); red solid, productive rate 30%.Its fusing point is: 79～81 ℃.
Embodiment 30, synthetic (2R)-3-nitro-4-ethoxycarbonyl-5-oxyethyl group-2-[(1R, 2S)-(1,3-O-diacetyl-2-hydroxyl) propyl group]-1,2-dihydropyridine (III-f)
In single neck bottle of 100 milliliters, add 35 milliliters of methylene dichloride; 159 milligrams of 2-cyano group EAs and 380 milligrams of 2-nitros-3; 4; 6-three-O-ethanoyl-D-glucal (tri-O-acetyl-2-nitro-D-glucal); an amount of triethylamine; after reaction shows the raw material completely dissolve to TLC approximately under the room temperature; cancellation is reacted and is got product (2R)-3-nitro-4-ethoxycarbonyl-5-oxyethyl group-2-[(1R through aftertreatment; 2S)-(1; 3-O-diacetyl-2-hydroxyl) propyl group]-1; 2-dihydropyridine (III-f): yellow solid, productive rate 59%.Its fusing point is: 173～174 ℃;
Optically-active (chloroform is a solvent, concentration=0.60) [α]
25 D=+303.2;
Infrared spectra (KBr compressing tablet, JASCO FT/IR 480 plus instrument) v3551,3494,1741,1579,1365,1237,1044cm
-1
Mass spectrum (ESI source, Bruker APEX-2) C
17H
24N
2O
10M/z:[M+H]
+=417;
High resolution mass spectrum (FAB source, Bruker APEX-2) measured value 417.1293, theoretical value C
17H
24N
2O
10[M+H]
+417.1331.
Embodiment 31, synthetic (5R)-5-[(1R, 2S)-(1,2, the 3-trihydroxy-) propyl group]-6-nitro-8-benzoyl-1,2,3,4,4a, 5-six hydrogen-4a-azepine quinoline (III-g)
Add 5 ml methanol in single neck bottle of 25 milliliters, add 20 milligrams in sodium, the back adds (5R)-5-[(1R; 2S)-(1,3-O-diacetyl-1,2; the 3-trihydroxy-) propyl group]-6-nitro-8-benzoyl-1,2,3; 4,4a, 5-six hydrogen-4a-azepine quinoline (III-c) milligram; react to the raw material disappearance; get product (5R)-5-[(1R through aftertreatment, 2S)-(1,2; the 3-trihydroxy-) propyl group]-6-nitro-8-benzoyl-1; 2,3,4; 4a; 5-six hydrogen-4a-azepine quinoline (III-g), yellow solid, productive rate 92%.Its fusing point is: 121～125 ℃.
The high resolution mass spectrum of this compound as shown in Figure 6.
Embodiment 32, synthetic (4R)-4-[(1R, 2S)-(1,3-O-diacetyl-2-hydroxyl) propyl group]-5-nitro-7-ethoxycarbonyl-2,3,3a, 4-tetrahydrochysene-3a-azaindole (III-h)
With 2-[[1-ethoxycarbonyl-1-(2-deoxidation-2-nitro-3,4,6-three-O-benzyl-β-D-glucopyanosyl base)] methylene radical]-tetrahydroglyoxaline pyridine (IV-o) replaces 2-[[1-among the embodiment 25 to anisoyl-1-(2-deoxidation-2-nitro-3,4,6-three-O-benzyl-β-D-glucopyanosyl base)] methylene radical]-tetrahydroglyoxaline pyridine (IV-k) reacts, obtain (4R)-4-[(1R, 2S)-(1,3-O-diacetyl-2-hydroxyl) propyl group]-5-nitro-7-ethoxycarbonyl-2,3,3a, 4-tetrahydrochysene-3a-azaindole (III-h), orange oily liquids, productive rate 13%;
Optically-active (chloroform is a solvent, concentration=1.4): [α]
25 D=+250.4;
Infrared spectra (KBr compressing tablet, JASCO FT/IR 480 plus instrument) v3363,1667,1614,1569,1520,1379,1294cm
-1
Proton nmr spectra (deuterochloroform is a solvent, Bruker AM 300 instrument) is at room temperature measured: δ 8.48 (s, 1H, H1), 7.29 (m, 10H, ArH), 5.35 (s, 1H, H3), 4.52 (m, 4H, OCH
2, OCH
2), 4.20 (q, J=7.1Hz, 2H, OCH
2CH
3), 3.99 (m, 2H, CH
2N), 3.73 (m, 1H, H4), 3.68 (m, 1H, H5), 3.55～3.63 (m, 4H, NCH
2, H6 and H6 '), 1.33 (t, J=7.1Hz, 3H, OCH
2CH
3);
Carbon-13 nmr spectra (deuterochloroform is a solvent, Bruker AM 300 instrument) is at room temperature measured: δ 166.1,160.4, and 139.0,137.7,137.6,128.5,128.4,128.4,128.3,128.3,128.0,83.3,78.7,73.5,73.2,71.0,70.2,60.0,57.2,48.2,43.1,14.5;
Mass spectrum (FAB source, Bruker APEX-2) C
27H
31N
3O
7M/z:[M+H]
+=510;
High resolution mass spectrum (FAB source, Bruker APEX-2) measured value 510.2214, theoretical value C
27H
31N
3O
7[M+H]
+510.2235.
Above-mentioned institute synthetic formula III 1, the structural formula of 2-dihydrogen pyridine derivative is as shown in table 2:
Table 2 part 1, the structural formula of 2-dihydrogen pyridine derivative
The insecticidal effect of second section The compounds of this invention
One, formula IV carbon glycosides intermediate is to the prevention effect of carmine spider mite
Embodiment 33, IV-c are to the prevention effect of carmine spider mite
With IV-c:2-[[1-to toluyl-1-(2-deoxidation-2-nitro-3,4,6-three-O-benzyl-β-D-glucopyanosyl base)] methylene radical]-[1,3]-Diazesuberane becomes the solution of 250ppm concentration with acetone solution.The quantitative spray method of POTTER tower: well-grown broad bean blade is broken into the leaf dish of diameter 2cm, and the back side is placed on the fritter cotton up, place in the 9cm plastic culture dish, add less water, connect carmine spider mite and become 10/ware of mite, be placed on 27 ± 1 ℃, the observation indoor cultivation of 14h illumination is laid eggs.After 24 hours, remove into mite, improving room temp is 29 ± 1 ℃, continues to be cultured to pieces of an egg and hatches fully, standby.Water in the culture dish is fallen to do, place spraying (pressure 5Ib/in under the POTTER spray tower
2, sinkability 4.35mg/cm
2), add a cover (hole that there is Φ 2cm the center) after the spraying, be put in 27 ± 1 ℃ behind the mark, in the observation ward of 14h illumination.Check result behind the 72h.With pyridaben, hexythiazox and blank CK is contrast.Drug effect result shows: intermediate (IV-c) 250ppm to carmine spider mite (Tetranychus cinnabarnus) children (if) mortality ratio of mite is 100%.
Embodiment 34:IV-d is to the prevention effect of carmine spider mite
With IV-d:2-[[1-to chlorobenzene formacyl-1-(2-deoxidation-2-nitro-3,4,6-three-O-benzyl-β-D-glucopyanosyl base)] methylene radical]-hexahydropyrimidine (IV-d) replaces that IV-c carries out identical insecticidal test among the embodiment 33.Drug effect result shows: intermediate (IV-d) 250ppm to carmine spider mite (Tetranychus cinnabarnus) children (if) mortality ratio of mite is 100%.
Embodiment 35, IV-h are to the prevention effect of carmine spider mite
With IV-h:2-[[1-to chlorobenzene formacyl-1-(2-deoxidation-2-nitro-3,4,6-three-O-benzyl-β-D-glucopyanosyl base)] methylene radical]-the tetrahydroglyoxaline pyridine replaces that IV-c carries out identical insecticidal test among the embodiment 33.Drug effect result shows: intermediate (IV-h) 250ppm to carmine spider mite (Tetranychus cinnabarnus) children (if) mortality ratio of mite is 100%.
Two, formula III 1, the insecticidal effect of 2-dihydrogen pyridine derivative
Embodiment 36, III-e are to the prevention effect of carmine spider mite
With III-e:(5R)-5-[(1R, 2S)-(1,3-O-diacetyl-1,2,3-trihydroxy-) propyl group]-6-nitro-8-is to anisoyl-1,2,3,4,4a, and 5-six hydrogen-4a-azepine quinoline becomes the solution of 250ppm concentration with acetone solution.The quantitative spray method of POTTER tower: well-grown broad bean blade is broken into the leaf dish of diameter 2cm, and the back side is placed on the fritter cotton up, place in the 9cm plastic culture dish, add less water, connect carmine spider mite and become 10/ware of mite, be placed on 27 ± 1 ℃, the observation indoor cultivation of 14h illumination is laid eggs.After 24 hours, remove into mite, improving room temp is 29 ± 1 ℃, continues to be cultured to pieces of an egg and hatches fully, standby.Water in the culture dish is fallen to do, place spraying (pressure 5Ib/in under the POTTER spray tower
2, sinkability 4.35mg/cm
2), add a cover (hole that there is Φ 2cm the center) after the spraying, be put in 27 ± 1 ℃ behind the mark, in the observation ward of 14h illumination.Check result behind the 72h.With pyridaben, hexythiazox and blank CK is contrast.Drug effect result shows: 1,2-dihydropyridine compounds (III-e) 250ppm to carmine spider mite (Tetranychus cinnabarnus) children (if) mortality ratio of mite is 100%.
Claims (17)
1,1 of structure such as formula III, the 2-dihydrogen pyridine derivative,
Y is O, S, NH, NR ', CH
2, CHR ', CR ' R ";
R
1, R
2Be hydrogen, halogen, nitro, cyano group, amido, C
1～8Alkyl, C
1～8Alkylamino radical, C
1～8Alkyloyl, aroyl, thick aroyl, aryl, thick aryl, cycloalkyl or aralkyl;
R
3, R
4, R
6, R
7, R, R ', R " and be hydroxyl, hydrogen, halogen, nitro, cyano group, amido, C
1～8Alkyl, C
1～8Alkoxyl group, C
1～8Alkylamino radical, C
1～8Alkylthio, C
1～8Alkyloyl, aroyl, thick aroyl, aryl, thick aryl, cycloalkyl or aralkyl.
2, according to claim 11, the 2-dihydrogen pyridine derivative is characterized in that: R
1, R
2Be hydrogen, fluorine, halogen, bromine, iodine, nitro, cyano group, amido, methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, methylamino, ethylamino-, Propylamino, isopropylamine base, n-butylamine-based, isobutyl amine, TERTIARY BUTYL AMINE base, formyl radical, ethanoyl, propionyl, different propionyl, positive butyryl radicals, isobutyryl, uncle's butyryl radicals, benzoyl; By fluorine, chlorine, bromine, iodine, nitro, cyano group, amido, methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, n-butoxy, isobutoxy, tert.-butoxy, methylamino, ethylamino-, Propylamino, isopropylamine base, n-butylamine-based, isobutyl amine, the TERTIARY BUTYL AMINE base, methylthio group, ethylmercapto group, the rosickyite base, the iprotiazem base, positive butylthio, the isobutyl sulfenyl, uncle's butylthio, formyl radical, ethanoyl or propionyl are single to the full pyridyl that replaces, indyl, imidazolyl, naphthyl, benzimidazolyl-, benzothiazolyl; Benzoyl, pyridine formyl radical, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, phenmethyl, styroyl or hydrocinnamyl;
R
3, R
4, R
6, R
7R, R ', R " be hydroxyl; hydrogen; fluorine; halogen; bromine; iodine, nitro, cyano group, amido, methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, n-butoxy, isobutoxy, tert.-butoxy, methylamino, ethylamino-, Propylamino, isopropylamine base, n-butylamine-based, isobutyl amine, the TERTIARY BUTYL AMINE base, methylthio group, ethylmercapto group, the rosickyite base, the iprotiazem base, positive butylthio, the isobutyl sulfenyl, uncle's butylthio, formyl radical, ethanoyl, propionyl, different propionyl, positive butyryl radicals, isobutyryl, uncle's butyryl radicals, benzoyl; By fluorine, halogen, bromine, iodine, nitro, cyano group, amido, methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, n-butoxy, isobutoxy, tert.-butoxy, methylamino, ethylamino-, Propylamino, isopropylamine base, n-butylamine-based, isobutyl amine, the TERTIARY BUTYL AMINE base, methylthio group, ethylmercapto group, the rosickyite base, the iprotiazem base, positive butylthio, the isobutyl sulfenyl, uncle's butylthio, formyl radical, ethanoyl or propionyl are single to the full pyridyl that replaces, indyl, imidazolyl, naphthyl, benzimidazolyl-, benzothiazolyl; Benzoyl, pyridine formyl radical, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, phenmethyl, styroyl or hydrocinnamyl.
3, according to claim 11, the 2-dihydrogen pyridine derivative is characterized in that: described 1, the 2-dihydrogen pyridine derivative is following compound:
4, the carbon glycosides intermediate of formula IV structure,
Wherein, Y=O, S, NH, NR ', CH
2, CHR ', CR ' R ";
R
1, R
2Be hydrogen, halogen, nitro, cyano group, amido, C
1～8Alkyl, C
1～8Alkylamino radical, C
1～8Alkyloyl, aroyl, thick aroyl, aryl, thick aryl, cycloalkyl or aralkyl;
R
3, R
4, R
6, R
7, R ', R " and be hydroxyl, hydrogen, halogen, nitro, cyano group, amido, C
1～8Alkyl, C
1～8Alkoxyl group, C
1～8Alkylamino radical, C
1～8Alkylthio, C
1～8Alkyloyl, aroyl, thick aroyl, aryl, thick aryl, cycloalkyl or aralkyl;
R
5Be halogen, nitro, cyano group, benzyloxy, substituted benzyloxy, C
1～8Alkyl, C
1～8Alkoxyl group, C
1～8Alkylthio, aryl, thick aryl, cycloalkyl or aralkyl.
5, carbon glycosides intermediate according to claim 4 is characterized in that:
R
1, R
2Be hydrogen, fluorine, halogen, bromine, iodine, nitro, cyano group, amido, methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, methylamino, ethylamino-, Propylamino, isopropylamine base, n-butylamine-based, isobutyl amine, TERTIARY BUTYL AMINE base, formyl radical, ethanoyl, propionyl, different propionyl, positive butyryl radicals, isobutyryl, uncle's butyryl radicals, benzoyl; By fluorine, chlorine, bromine, iodine, nitro, cyano group, amido, methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, n-butoxy, isobutoxy, tert.-butoxy, methylamino, ethylamino-, Propylamino, isopropylamine base, n-butylamine-based, isobutyl amine, the TERTIARY BUTYL AMINE base, methylthio group, ethylmercapto group, the rosickyite base, the iprotiazem base, positive butylthio, the isobutyl sulfenyl, uncle's butylthio, formyl radical, ethanoyl or propionyl are single to the full pyridyl that replaces, indyl, imidazolyl, naphthyl, benzimidazolyl-, benzothiazolyl; Benzoyl, pyridine formyl radical, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, phenmethyl, styroyl or hydrocinnamyl;
R
3, R
4, R
6, R
7R ', R " be hydroxyl; hydrogen; fluorine; halogen; bromine; iodine, nitro, cyano group, amido, methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, n-butoxy, isobutoxy, tert.-butoxy, methylamino, ethylamino-, Propylamino, isopropylamine base, n-butylamine-based, isobutyl amine, the TERTIARY BUTYL AMINE base, methylthio group, ethylmercapto group, the rosickyite base, the iprotiazem base, positive butylthio, the isobutyl sulfenyl, uncle's butylthio, formyl radical, ethanoyl, propionyl, different propionyl, positive butyryl radicals, isobutyryl, uncle's butyryl radicals, benzoyl; By fluorine, halogen, bromine, iodine, nitro, cyano group, amido, methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, n-butoxy, isobutoxy, tert.-butoxy, methylamino, ethylamino-, Propylamino, isopropylamine base, n-butylamine-based, isobutyl amine, the TERTIARY BUTYL AMINE base, methylthio group, ethylmercapto group, the rosickyite base, the iprotiazem base, positive butylthio, the isobutyl sulfenyl, uncle's butylthio, formyl radical, ethanoyl or propionyl are single to the full pyridyl that replaces, indyl, imidazolyl, naphthyl, benzimidazolyl-, benzothiazolyl; Benzoyl, pyridine formyl radical, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, phenmethyl, styroyl or hydrocinnamyl;
R
5Be halogen, nitro, cyano group, benzyloxy, substituted benzyloxy, C
1～8Alkyl, C
1～8Alkoxyl group, C
1～8Alkylthio, aryl, thick aryl, cycloalkyl or aralkyl.
6, carbon glycosides intermediate according to claim 4, it is characterized in that: described glucosides intermediate is following compound:
7, the described carbon glycosides of claim 4 intermediates preparation is that formula V compound and formula VI compound are reacted, and obtains formula IV structural carbon glycosides intermediate;
(formula V) (formula VI)
Wherein, Y is O, S, NH, NR ', CH
2, CHR ', CR ' R ";
R
1, R
2Be hydrogen, halogen, nitro, cyano group, amido, C
1～8Alkyl, C
1～8Alkylamino radical, C
1～8Alkyloyl, aroyl, thick aroyl, aryl, thick aryl, cycloalkyl, aralkyl;
R
3, R
4, R
6, R
7, R ', R " and be hydroxyl, hydrogen, halogen, nitro, cyano group, amido, C
1～8Alkyl, C
1～8Alkoxyl group, C
1～8Alkylamino radical, C
1～8Alkylthio, C
1～8Alkyloyl, aroyl, thick aroyl, aryl, thick aryl, cycloalkyl, aralkyl;
R
5Be halogen, nitro, cyano group, benzyloxy, substituted benzyloxy, C
1～8Alkyl, C
1～8Alkoxyl group, C
1～8Alkylthio, aryl, thick aryl, cycloalkyl or aralkyl.
8, preparation method according to claim 7, it is characterized in that: also add Lewis base in the reaction, described Lewis base is selected from DBU, triethylamine, diisopropyl ethyl amine, pyridine, 4-(N, the N-dimethyl amido) pyridine, 2,6-lutidine, 2,4-lutidine, sodiumazide, sodium hydride and hydrolith; Reaction solvent is selected from methylene dichloride, trichloromethane, 1,2-ethylene dichloride, acetonitrile, toluene, benzene, ether, N, dinethylformamide and 1,4-dioxane.
9, preparation method according to claim 8 is characterized in that: formula V compound: formula VI compound: the mol ratio of Lewis base is 1: 1-5: 1-10; Temperature of reaction is 0-50 ℃; Reaction times is 12-24 hour.
10, claim 1 is described 1, the preparation method of 2-dihydrogen pyridine derivative, be with formula IV structural carbon glycosides intermediate under the Lewis base effect 40-130 ℃ down reaction obtain 1 of formula III structure, 2-dihydrogen pyridine derivative.
11, preparation method according to claim 10, it is characterized in that: described Lewis base is selected from DBU, triethylamine, diisopropyl ethyl amine, pyridine, 4-(N, the N-dimethyl amido) pyridine, 2,6-lutidine, 2,4-lutidine, sodiumazide, sodium hydride and hydrolith; Reaction solvent is selected from methylene dichloride, trichloromethane, 1,2-ethylene dichloride, acetonitrile, toluene, benzene, ether, N, dinethylformamide and 1,4-dioxane.
12, preparation method according to claim 10 is characterized in that: formula IV structural carbon glycosides intermediate: the mol ratio of Lewis base is 1: 1-10; Reaction times is 12-24 hour.
13, claim 1 is described 1, and the preparation method of 2-dihydrogen pyridine derivative is that formula V compound and formula VI compound are reacted, and obtains 1 of formula I structure, the 2-dihydrogen pyridine derivative;
(formula V) (formula VI)
Wherein, Y is O, S, NH, NR ', CH
2, CHR ', CR ' R ";
R
1, R
2Be hydrogen, halogen, nitro, cyano group, amido, C
1～8Alkyl, C
1～8Alkylamino radical, C
1～8Alkyloyl, aroyl, thick aroyl, aryl, thick aryl, cycloalkyl, aralkyl;
R
3, R
4, R
6, R
7, R ', R " and be hydroxyl, hydrogen, halogen, nitro, cyano group, amido, C
1～8Alkyl, C
1～8Alkoxyl group, C
1～8Alkylamino radical, C
1～8Alkylthio, C
1～8Alkyloyl, aroyl, thick aroyl, aryl, thick aryl, cycloalkyl, aralkyl;
R
5Be halogen, nitro, cyano group, benzyloxy, substituted benzyloxy, C
1～8Alkyl, C
1～8Alkoxyl group, C
1～8Alkylthio, aryl, thick aryl, cycloalkyl or aralkyl, C
1～8Alkyloyl, aroyl, thick aroyl, trialkyl silyl.
14, preparation method according to claim 13, it is characterized in that: also add Lewis base in the reaction, described Lewis base is selected from DBU, triethylamine, diisopropyl ethyl amine, pyridine, 4-(N, the N-dimethyl amido) pyridine, 2,6-lutidine, 2,4-lutidine, sodiumazide, sodium hydride, hydrolith; Reaction solvent is selected from methylene dichloride, trichloromethane, 1,2-ethylene dichloride, acetonitrile, toluene, benzene, ether, N, dinethylformamide, 1,4-dioxane.
15, preparation method according to claim 14 is characterized in that: formula V compound: formula VI compound: the mol ratio of Lewis base is 1: 1-10: 1-10; Temperature of reaction is 0-100 ℃; Reaction times is 1-24 hour.
16, claim 1 is described 1, and the 2-dihydrogen pyridine derivative is as the application of sterilant.
17, the described carbon glycosides of claim 4 intermediate is as the application of sterilant.
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| US10287282B2 (en) | 2014-12-31 | 2019-05-14 | Angion Biomedica Corp. | Methods and agents for treating disease |
| US11459319B2 (en) | 2014-08-11 | 2022-10-04 | Angion Biomedica Corp. | Cytochrome P450 inhibitors and uses thereof |
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| US11459319B2 (en) | 2014-08-11 | 2022-10-04 | Angion Biomedica Corp. | Cytochrome P450 inhibitors and uses thereof |
| US10287282B2 (en) | 2014-12-31 | 2019-05-14 | Angion Biomedica Corp. | Methods and agents for treating disease |
| US10851095B2 (en) | 2014-12-31 | 2020-12-01 | Angion Biomedica Corp. | Methods and agents for treating disease |
| US11434234B2 (en) | 2014-12-31 | 2022-09-06 | Angion Biomedica Corp. | Methods and agents for treating disease |
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