CN102838587B - Containing cis-nitenpyram analogue and the Synthesis and applications thereof of peptide bond - Google Patents
Containing cis-nitenpyram analogue and the Synthesis and applications thereof of peptide bond Download PDFInfo
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- CN102838587B CN102838587B CN201210240330.9A CN201210240330A CN102838587B CN 102838587 B CN102838587 B CN 102838587B CN 201210240330 A CN201210240330 A CN 201210240330A CN 102838587 B CN102838587 B CN 102838587B
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- IBMOXUOBYLTGPT-UHFFFAOYSA-N CCN(Cc1ccc(C)nc1)C(N(C)CN(C1)C(C(C)C)C(NCc2ccc(C)cc2)=O)=C1[N+]([O-])=O Chemical compound CCN(Cc1ccc(C)nc1)C(N(C)CN(C1)C(C(C)C)C(NCc2ccc(C)cc2)=O)=C1[N+]([O-])=O IBMOXUOBYLTGPT-UHFFFAOYSA-N 0.000 description 1
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Abstract
The present invention relates to organic synthesis and pesticide field, disclose shown in general formula (I) containing the cis-nitenpyram analogue of peptide bond, wherein, n=0,1 or 2, R be H or alkyl; Y is monosubstituted or two replacements, and Y is selected from H, CH
3, F, Cl, Br, OH, OCH
3or CF
3in at least one.Its preparation method is; with the amino acid of Boc protection for starting raw material; Boc protected amino acid acid amides is generated through reacting with alpha substituted benzylamine; obtain the hydrochloride containing peptide bond after taking off Boc with trifluoroacetic acid again, and synthesize a series of cis-nitenpyram analogue with insecticidal activity containing tetrahydropyrimidine ring with formaldehyde, Ti304 through Manny alkene reaction.This compound has efficient insecticide activity, can make sterilant and use.Preparation method is simple, and the reaction times is short, and yield is higher.
Description
Technical field
The invention belongs to organic chemistry filed, relate to agricultural insecticide immunomodulator compounds, be specifically related to the cis-nitenpyram analogue with insecticidal activity, relate more specifically to a class and contain cis-nitenpyram analogue of peptide bond and preparation method thereof and the application in sterilant.
Background technology
The discovery of neonicotinoid insecticide can be considered to a milestone in agrochemicals research in 30 years in the past.Anabasine insecticide is the forth generation sterilant after organic phosphates, amino formate, pyrethroid insecticides.Anabasine material is as nAChR (nAChRs) agonist, the neural system (nAChRs) of insect is optionally worked, it not only shows high-affinity to (nAChRs), but also shows the physics-chem characteristic such as unionized and moderate water solubility.Because it has unique insecticidal mechanism and the performance of high-efficiency low-toxicity, become rapidly the higher effective and lower toxic pesticide new variety that modern agriculture needs.
Ti304 is a kind of nicotimine insecticides developed after Provado, is one of up-to-date at present nicotinic insecticide.It has ultra-high efficiency, wide spectrum, consumption is few, toxicity is low, lasting medicine, to crop without the advantage such as poisoning, use safety, be the new variety of alternative high-toxic organic phosphorus agricultural chemicals.But owing to having the shortcoming of photo-labile and hydrophobicity difference, promotion and application are restricted; The resistance of insect to it is more and more serious simultaneously.
The present invention adopts the molecular designing strategy introducing a tetrahydropyrimidine ring on Ti304 molecule, the Ti304 of transconfiguration is changed into cis-configuration, and introduce peptide bond on support arm, solve the shortcoming of hydrophobicity difference.Through retrieving existing patent documentation and public publication, the present invention in the world first with alpha substituted benzylamine, amino acid, thanomin, formaldehyde and Ti304 for raw material, synthesize a series of cis-nitenpyram analogue containing peptide bond, and determine the insecticidal activity of this compounds.Insecticidal activity test result shows, the present invention containing the cis-nitenpyram analogue of peptide bond to aphid with Rice plant hopper has efficient insecticide activity, can be used as one of effective constituent of novel pesticide or sterilant to use, and emulsion, aqueous suspension and aqueous emulsion etc. can be made into.
Summary of the invention
The present invention seeks to provide a class containing the cis-nitenpyram analogue with insecticidal activity of peptide bond.
Another object of the present invention is to provide the above-mentioned preparation method with the cis-nitenpyram analogue of insecticidal activity containing peptide bond.
Object of the present invention is achieved through the following technical solutions.
Containing a nitenpyram analogue for peptide bond, general formula is (I):
In formula (I): n=0,1 or 2, R be H or alkyl, be preferably H or C1 ~ C4 alkyl, be more preferably H, methyl, sec.-propyl or isobutyl-;
Y is monosubstituted or two replacements, and Y is selected from H, CH
3, F, Cl, Br, OH, OCH
3, CF
3in at least one.
The preparation method of the above-mentioned cis-nitenpyram analogue containing peptide bond, comprises the steps:
(1) amino acid amide of Boc protection shown in the logical formula II of preparation:
N=0 in formula II, 1 or 2, R be H or alkyl, be preferably H or C1 ~ C4 alkyl, be more preferably H, methyl, sec.-propyl or isobutyl-H; Y is monosubstituted or two replacements, and Y is selected from H, CH
3, F, Cl, Br, OH, OCH
3or CF
3in at least one;
By structure Boc(tertbutyloxycarbonyl as shown in the formula (III)) amino acid protected and carbonyl dimidazoles mix with the tetrahydrofuran (THF) of drying under nitrogen protection condition, maintain the temperature at 55 ~ 65 DEG C of (being preferably 60 DEG C) reactions, 0.5 ~ 2 hour (preferably 40 ~ 60 minutes), after having reacted, be cooled to room temperature, add structure such as formula the alpha substituted benzylamine shown in (IV), react 2 ~ 3 hours under room temperature, obtain the intermediate crude product of amide bond; The mol ratio of the amino acid that Boc protects, carbonyl dimidazoles and alpha substituted benzylamine is 1:1.2:1; Preferably, post (volume ratio is preferably 3:1) crossed by crude product volume ratio 2:1 ~ 4:1 ethyl acetate and sherwood oil mixed solution;
The n=0 of formula (III), 1 or 2, R be H or alkyl, be preferably H or C1 ~ C4 alkyl, be more preferably H, methyl, sec.-propyl or isobutyl-H; Formula (IV) be Y for benzylamine be monosubstituted or two alpha substituted benzylamines, Y is selected from H, CH
3, F, Cl, Br, OH, OCH
3or CF
3in at least one;
Step (1) reaction formula is as follows:
(2) hydrochloride of peptide bond is contained shown in the logical formula V of preparation:
The amino acid amide that step (1) product B oc protects is dissolved in methylene dichloride, drips trifluoroacetic acid at-5 ~ 0 DEG C, react 8 ~ 15 hours, obtain the hydrochloride containing peptide bond shown in logical formula V; The amino acid amide of Boc protection and the mol ratio of trifluoroacetic acid are 1:4 ~ 6, are preferably 1:5; Reaction formula is as follows:
(3) compound shown in logical formula V is contained solution and the solvent of the hydrochloride of peptide bond, Ti304 and formaldehyde, reflux 4 ~ 6 hours, or microwave reaction 20 ~ 40 minutes (being preferably 25 minutes), obtains the cis-nitenpyram analogue containing peptide bond shown in general formula (I) at 65 ~ 70 DEG C; Wherein Ti304 and logical formula V compound contain the hydrochloride of peptide bond is 1:1.2 ~ 1.5:1.5 ~ 2.5 with the molar ratio with formaldehyde, is preferably 1:1.25:2; The concentration of formaldehyde solution is 30wt% ~ 37wt%; Preferably, be catalyzer with triethylamine, Ti304 and triethylamine mol ratio are 1:0.5 ~ 2, and be preferably 1:1, reaction formula is as follows:
In step (1) and (2), tetrahydrofuran (THF) used and methylene dichloride are anhydrous solvent, are preferredly through the tetrahydrofuran (THF) and methylene dichloride that heavily steam.
Cis-nitenpyram analogue containing peptide bond shown in above-mentioned general formula (I) has efficient insecticide activity, can be used for preparing sterilant, especially can suppress brown planthopper and clover aphid.This compound can be used as effective constituent and prepares sterilant, and the formulation of sterilant can be the formulations such as emulsion, aqueous suspension and aqueous emulsion.
The amino acid that the present invention protects with Boc is for starting raw material; Boc protected amino acid acid amides is generated through reacting with alpha substituted benzylamine; obtain the hydrochloride containing peptide bond after taking off Boc with trifluoroacetic acid again, and synthesize a series of cis-nitenpyram analogue with insecticidal activity containing tetrahydropyrimidine ring with formaldehyde, Ti304 through Manny alkene reaction.It is active that the present invention determines this efficient insecticide containing the cis-nitenpyram analogue of peptide bond, has significant practicality in modern agricultural production.
Embodiment:
Technical characterstic of the present invention is set forth further below in conjunction with specific embodiment.
The example of the cis-nitenpyram analogue (I) containing peptide bond prepared by the present invention comprising:
(Ia): 2-[4-(N-ethyl-N-(6-chloro-3-pyridylmethyl) amino-3-methyl-5-nitro]-1,2,5,6 ,-tetrahydropyrimidine-1 base)-N-benzylacetamide;
(Ib): 2-[4-(N-ethyl-N-(6-chloro-3-pyridylmethyl) amino-3-methyl-5-nitro]-1,2,5,6 ,-tetrahydropyrimidine-1 base)-N-4-methyl-benzyl ethanamide;
(Ic): 2-[4-(N-ethyl-N-(6-chloro-3-pyridylmethyl) amino-3-methyl-5-nitro]-1,2,5,6 ,-tetrahydropyrimidine-1 base)-2-methyl-N-benzyl ethanamide;
(Id) 2-[4-(N-ethyl-N-(6-chloro-3-pyridylmethyl) amino-3-methyl-5-nitro]-1,2,5,6 ,-tetrahydropyrimidine-1 base)-N-4-bromobenzyl propionic acid amide;
(Ie) 2-[4-(N-ethyl-N-(6-chloro-3-pyridylmethyl) amino-3-methyl-5-nitro]-1,2,5,6 ,-tetrahydropyrimidine-1 base)-N-4-luorobenzyl propionic acid amide;
(If) 2-[4-(N-ethyl-N-(6-chloro-3-pyridylmethyl) amino-3-methyl-5-nitro]-1,2,5,6 ,-tetrahydropyrimidine-1 base)-2-isobutyl--N-4-bromobenzyl ethanamide;
(Ig) 2-[4-(N-ethyl-N-(6-chloro-3-pyridylmethyl) amino-3-methyl-5-nitro]-1,2,5,6 ,-tetrahydropyrimidine-1 base)-2-sec.-propyl-N-benzylacetamide;
(Ih) 2-[4-(N-ethyl-N-(6-chloro-3-pyridylmethyl) amino-3-methyl-5-nitro]-1,2,5,6 ,-tetrahydropyrimidine-1 base)-2-sec.-propyl-N-4-methyl-benzyl ethanamide;
The tetrahydrofuran (THF) used in embodiment and methylene dichloride are through the tetrahydrofuran (THF) and methylene dichloride that heavily steam, are anhydrous solvent.
Embodiment 1
Preparation 2-[4-(N-ethyl-N-(6-chloro-3-pyridylmethyl) amino-3-methyl-5-nitro]-1,2,5,6 ,-tetrahydropyrimidine-1 base)-N-benzylacetamide (Ia);
The glycine that 1.086g (5mmol) Boc is protected and 0.973g(6mmol) carbonyl dimidazoles adds in round-bottomed flask; the tetrahydrofuran (THF) of 30ml drying is added under nitrogen protection effect; maintain the temperature at 60 DEG C of reactions one hour; after having reacted, be cooled to room temperature, add 6mmol benzylamine; 2-3 hour is reacted under room temperature; obtain intermediate crude product, cross post obtain product with ethyl acetate and sherwood oil 3:1, productive rate is 95.24%.The methylene dichloride of 2-4ml drying instillation products therefrom, until solid dissolves completely.Under condition of ice bath, drip the trifluoroacetic acid (15mmol) of 2.5ml, reaction is spent the night.Add product with methyl alcohol and spin off solvent in 65 DEG C, obtain the hydrochloride of product Intermediate containing peptide bond.
By 2.707g(10mmol) Ti304,1.934g intermediate is containing hydrochloride (10mmol), the 1.8mL(10mmol of peptide bond) triethylamine and 2.0mL mass concentration be 37% formaldehyde solution (20mmol) be dissolved in 30mL ethanol together, the three-necked flask that mixed reaction solution is housed is placed in microwave reactor, 65 DEG C are heated in 5 minutes, and keep 65 DEG C to react decompression after 20 minutes steaming solvent, add 10mL water dissolution and divide three extractions by 60mL ethyl acetate.Combining extraction liquid anhydrous magnesium sulfate drying spends the night, and steams solvent, obtains yellow oil.With ethanol: ethyl acetate=4:1 column chromatography obtains pale yellow oil, productive rate is 82.12%.
Ultimate analysis: measured value C%57.58 H%5.93 N%13.81
Calculated value C%57.54 H%5.91 N%13.80
IR(KBr,cm-1）vmax 2950，1674（C=O）,1546(NO2),720.
1H NMR(400MHz,DMSO)δ8.43(t,J=6.1Hz,1H),8.38(d,J=2.3Hz,1H),7.82(dd,J=8.2,2.4Hz,1H),7.50(d,J=8.2Hz,1H),7.35-7.21(m,5H),4.47(d,J=14.9Hz,1H),4.33(t,J=28.2Hz,4H),3.90(s,2H),3.62(d,J=13.9Hz,1H),3.22(d,J=21.5Hz,2H),3.00(s,3H),1.11(t,J=7.1Hz,3H).
Embodiment 2
Preparation 2-[4-(N-ethyl-N-(6-chloro-3-pyridylmethyl) amino-3-methyl-5-nitro]-1,2,5,6 ,-tetrahydropyrimidine-1 base)-N-4-methyl-benzyl ethanamide (Ib);
1.086g(5mmol) glycine of Boc protection and 0.973g(6mmol) carbonyl dimidazoles adds in round-bottomed flask; the tetrahydrofuran (THF) of 30ml drying is added under nitrogen protection effect; maintain the temperature at 60 DEG C of reactions one hour; after having reacted, be cooled to room temperature, add 6mmol 4-methylbenzylamine; 2-3 hour is reacted under room temperature; obtain 4-methylbenzylamine Glycine amide crude product, cross post obtain product with ethyl acetate and sherwood oil 3:1, productive rate is 90.24%.The methylene dichloride of 2-4ml drying instillation products therefrom, until solid dissolves completely.Under condition of ice bath, drip the trifluoroacetic acid (15mmol) of 2.5ml, reaction is spent the night.Add product with methyl alcohol and spin off solvent in 65 DEG C, obtain the hydrochloride of product Intermediate containing peptide bond.
By 2.707g(10mmol) Ti304,1.904g intermediate is containing hydrochloride (10mmol), the 1.8mL(10mmol of peptide bond) triethylamine and 2.0mL mass concentration be 37% formaldehyde solution (20mmol) be dissolved in 30mL ethanol together, the three-necked flask that mixed reaction solution is housed is placed in microwave reactor, 65 DEG C are heated in 5 minutes, and keep 65 DEG C to react decompression after 20 minutes steaming solvent, add 10mL water dissolution and divide three extractions by 60mL ethyl acetate.Combining extraction liquid anhydrous magnesium sulfate drying spends the night, and steams solvent, obtains yellow oil.With ethanol: ethyl acetate=4:1 column chromatography obtains pale yellow oil, productive rate is 80.22%.
Ultimate analysis: measured value C%58.41 H%6.88 N%17.77
Calculated value C%58.42 H%6.86 N%17.71
IR(KBr,cm
-1）v
max2950，1674（C=O）,1545(NO
2),720.
1H NMR(400MHz,DMSO)δ8.28(d,J=2.3Hz,1H),8.28(d,J=2.3Hz,1H),7.66(dd,J=8.2,2.5Hz,1H),7.66(dd,J=8.2,2.5Hz,1H),7.31(d,J=8.2Hz,1H),7.31(d,J=8.2Hz,1H),7.17(t,J=5.8Hz,1H),6.91-6.64(m,3H),4.43(t,J=5.9Hz,3H),4.43(t,J=5.9Hz,2H),3.87(d,J=3.9Hz,6H),3.73(dt,J=12.1,8.3Hz,5H),3.24(d,J=7.7Hz,3H),2.98-2.23(m,7H),1.17(t,J=7.1Hz,3H),1.17(t,J=7.1Hz,4H).
Embodiment 3
Preparation 2-[4-(N-ethyl-N-(6-chloro-3-pyridylmethyl) amino-3-methyl-5-nitro]-1,2,5,6 ,-tetrahydropyrimidine-1 base)-2-methyl-N-benzyl ethanamide (Ic)
The ALANINE that 0.94g (5mmol) Boc is protected and 0.973g(6mmol) carbonyl dimidazoles adds in round-bottomed flask; the tetrahydrofuran (THF) of 30ml drying is added under nitrogen protection effect; maintain the temperature at 60 DEG C of reactions one hour; after having reacted, be cooled to room temperature, add 6mmol benzylamine; 2-3 hour is reacted under room temperature; obtain intermediate crude product, cross post obtain product with ethyl acetate and sherwood oil 3:1, productive rate is 86.24%.The methylene dichloride of 2-4ml drying instillation products therefrom, until solid dissolves completely.Under condition of ice bath, drip the trifluoroacetic acid (15mmol) of 2.5ml, reaction is spent the night.Add product with methyl alcohol and spin off solvent in 65 DEG C, obtain the hydrochloride of product Intermediate containing peptide bond.
By 2.707g(10mmol) Ti304,1.876g intermediate is containing hydrochloride (10mmol), the 1.8mL(10mmol of peptide bond) triethylamine and 2.0mL mass concentration be 37% formaldehyde solution (20mmol) be dissolved in 30mL ethanol together, the three-necked flask that mixed reaction solution is housed is placed in microwave reactor, 65 DEG C are heated in 5 minutes, and keep 65 DEG C to react decompression after 20 minutes steaming solvent, add 10mL water dissolution and divide three extractions by 60mL ethyl acetate.Combining extraction liquid anhydrous magnesium sulfate drying spends the night, and steams solvent, obtains yellow oil.With ethanol: ethyl acetate=4:1 column chromatography obtains pale yellow oil, productive rate is 80.12%.
Ultimate analysis: measured value C%58.41 H%6.18 N%17.77
Calculated value C%58.43 H%6.23 N%17.72
IR(KBr,cm-1）vmax 2950，1674（C=O）,1545(NO2),720.
1H NMR(400MHz,DMSO)δ8.26(s,0H),7.66(dd,J=19.4,8.2Hz,0H),7.39-7.26(m,2H),7.12-7.02(m,0H),4.46(dd,J=15.1,5.6Hz,1H),4.15(d,J=6.4Hz,0H),4.08(d,J=8.4Hz,0H),3.85-3.72(m,0H),3.76-3.55(m,1H),3.23-3.15(m,0H),2.87(dd,J=13.8,6.9Hz,0H),2.69(d,J=15.0Hz,1H),1.26(t,J=7.1Hz,3H).
Embodiment 4
Preparation 2-[4-(N-ethyl-N-(6-chloro-3-pyridylmethyl) amino-3-methyl-5-nitro]-1,2,5,6 ,-tetrahydropyrimidine-1 base)-N-4-bromobenzyl propionic acid amide (Id);
The Beta-alanine that 1.14g (5mmol) Boc is protected and 0.973g(6mmol) carbonyl dimidazoles adds in round-bottomed flask; the tetrahydrofuran (THF) of 30ml drying is added under nitrogen protection effect; maintain the temperature at 60 DEG C of reactions one hour; after having reacted, be cooled to room temperature, add 6mmol to bretylium; 2-3 hour is reacted under room temperature; obtain intermediate crude product, cross post obtain product with ethyl acetate and sherwood oil 3:1, productive rate is 85.24%.The methylene dichloride of 2-4ml drying instillation products therefrom, until solid dissolves completely.Under condition of ice bath, drip the trifluoroacetic acid (15mmol) of 2.5ml, reaction is spent the night.Add product with methyl alcohol and spin off solvent in 65 DEG C, obtain the hydrochloride of product Intermediate containing peptide bond.
By 2.707g(10mmol) Ti304,1.876g intermediate is containing hydrochloride (10mmol), the 1.8mL(10mmol of peptide bond) triethylamine and 2.0mL mass concentration be 37% formaldehyde solution (20mmol) be dissolved in 30mL ethanol together, the three-necked flask that mixed reaction solution is housed is placed in microwave reactor, 65 DEG C are heated in 5 minutes, and keep 65 DEG C to react decompression after 20 minutes steaming solvent, add 10mL water dissolution and divide three extractions by 60mL ethyl acetate.Combining extraction liquid anhydrous magnesium sulfate drying spends the night, and steams solvent, obtains yellow oil.With ethanol: ethyl acetate=4:1 column chromatography obtains pale yellow oil, productive rate is 70.12%.
Ultimate analysis: measured value C%50.06 H%5.11 N%15.23
Calculated value C%50.03 H%5.13 N%15.22
IR(KBr,cm-1）vmax 2950，1674（C=O）,1545(NO2),720.
1H NMR(400MHz,DMSO)δ8.25(d,J=2.2Hz,0H),7.62(dd,J=8.2,2.5Hz,0H),7.41(d,J=8.4Hz,1H),7.24(dd,J=53.0,8.3Hz,1H),4.44(s,0H),4.15(s,0H),3.64(dd,J=31.3,15.7Hz,1H),3.63-3.44(m,1H),3.22(dt,J=14.2,4.6Hz,0H),2.96-2.91(m,0H),2.89(s,3H),2.50(d,J=6.5Hz,1H),1.17(t,J=7.2Hz,1H).
Embodiment 5
Preparation 2-[4-(N-ethyl-N-(6-chloro-3-pyridylmethyl) amino-3-methyl-5-nitro]-1,2,5,6 ,-tetrahydropyrimidine-1 base)-N-4-luorobenzyl propionic acid amide (Ie);
The Beta-alanine that 1.14g (5mmol) Boc is protected and 0.973g(6mmol) carbonyl dimidazoles adds in round-bottomed flask; the tetrahydrofuran (THF) of 30ml drying is added under nitrogen protection effect; maintain the temperature at 60 DEG C of reactions one hour; after having reacted, be cooled to room temperature, add 6mmol NSC 158269; 2-3 hour is reacted under room temperature; obtain intermediate crude product, cross post obtain product with ethyl acetate and sherwood oil 3:1, productive rate is 92.24%.The methylene dichloride of 2-4ml drying instillation products therefrom, until solid dissolves completely.Under condition of ice bath, drip the trifluoroacetic acid (15mmol) of 2.5ml, reaction is spent the night.Add product with methyl alcohol and spin off solvent in 65 DEG C, obtain the hydrochloride of product Intermediate containing peptide bond.
By 2.707g(10mmol) Ti304,1.704g intermediate is containing hydrochloride (10mmol), the 1.8m(10mmol of peptide bond) L triethylamine and 2.0mL mass concentration be 37% formaldehyde solution (20mmol) be dissolved in 30mL ethanol together, the three-necked flask that mixed reaction solution is housed is placed in microwave reactor, 65 DEG C are heated in 5 minutes, and keep 65 DEG C to react decompression after 20 minutes steaming solvent, add 10mL water dissolution and divide three extractions by 60mL ethyl acetate.Combining extraction liquid anhydrous magnesium sulfate drying spends the night, and steams solvent, obtains yellow oil.With ethanol: ethyl acetate=4:1 column chromatography obtains pale yellow oil, productive rate is 76.22%.
Ultimate analysis: measured value C%56.27 H%5.75 N%17.12
Calculated value C%56.28 H%5.77 N%17.10
IR(KBr,cm-1）vmax 2950，1674（C=O）,1545(NO2),720.
1H NMR(400MHz,DMSO)δ8.25(d,J=2.4Hz,0H),7.63(dd,J=8.2,2.5Hz,0H),7.37-7.17(m,2H),4.45(q,J=4.6Hz,1H),4.13(dd,J=11.0,7.4Hz,0H),3.71-3.51(m,1H),3.48(s,1H),3.22(dd,J=14.1,7.1Hz,0H),2.90(t,J=5.7Hz,0H),2.82(s,3H),2.50(t,J=6.4Hz,1H),1.16(t,J=7.1Hz,1H).
Embodiment 6
Preparation 2-[4-(N-ethyl-N-(6-chloro-3-pyridylmethyl) amino-3-methyl-5-nitro]-1,2,5,6 ,-tetrahydropyrimidine-1 base)-2-isobutyl--N-4-bromobenzyl ethanamide (If);
The leucine that 1.210g (5mmol) Boc is protected and 0.973g(6mmol) carbonyl dimidazoles adds in round-bottomed flask; the tetrahydrofuran (THF) of 30ml drying is added under nitrogen protection effect; maintain the temperature at 60 DEG C of reactions one hour; after having reacted, be cooled to room temperature, add 6mmol to bretylium; 2-3 hour is reacted under room temperature; obtain intermediate crude product, cross post obtain product with ethyl acetate and sherwood oil 3:1, productive rate is 95.24%.The methylene dichloride of 2-4ml drying instillation products therefrom, until solid dissolves completely.Under condition of ice bath, drip the trifluoroacetic acid (15mmol) of 2.5ml, reaction is spent the night.Add product with methyl alcohol and spin off solvent in 65 DEG C, obtain the hydrochloride of product Intermediate containing peptide bond.
By 2.707g(10mmol) Ti304,1.764g intermediate is containing hydrochloride (10mmol), the 1.8mL(10mmol of peptide bond) triethylamine and 2.0mL mass concentration be 37% formaldehyde solution (20mmol) be dissolved in 30mL ethanol together, the three-necked flask that mixed reaction solution is housed is placed in microwave reactor, 65 DEG C are heated in 5 minutes, and keep 65 DEG C to react decompression after 20 minutes steaming solvent, add 10mL water dissolution and divide three extractions by 60mL ethyl acetate.Combining extraction liquid anhydrous magnesium sulfate drying spends the night, and steams solvent, obtains yellow oil.With ethanol: ethyl acetate=4:1 column chromatography obtains pale yellow oil, productive rate is 92.62%.
Ultimate analysis: measured value C%52.58 H%5.77 N%14.15
Calculated value C%52.57 H%5.79 N%14.11
IR(KBr,cm-1）vmax 2950，1674（C=O）,1545(NO2),720.
1H NMR(400MHz,DMSO)δ8.24(s,1H),7.74(d,J=10.5Hz,1H),7.59(d,J=8.2Hz,1H),7.29(d,J=8.2Hz,4H),4.48(d,J=14.6Hz,1H),4.15(d,J=15.0Hz,1H),3.76(d,J=15.4Hz,4H),3.61(s,1H),3.32(d,J=9.8Hz,2H),3.12(d,J=14.2Hz,1H),2.87(s,1H),2.83(s,3H),1.60(s,1H),1.21(d,J=9.6Hz,6H),1.11(d,J=7.1Hz,3H).
Embodiment 7
Preparation 2-[4-(N-ethyl-N-(6-chloro-3-pyridylmethyl) amino-3-methyl-5-nitro]-1,2,5,6 ,-tetrahydropyrimidine-1 base)-2-sec.-propyl-N-benzylacetamide (Ig);
The α-amino-isovaleric acid that 1.190g (5mmol) Boc is protected and 0.973g(6mmol) carbonyl dimidazoles adds in round-bottomed flask; the tetrahydrofuran (THF) of 30ml drying is added under nitrogen protection effect; maintain the temperature at 60 DEG C of reactions one hour; after having reacted, be cooled to room temperature, add 6mmol benzylamine; 2-3 hour is reacted under room temperature; obtain intermediate crude product, cross post obtain product with ethyl acetate and sherwood oil 3:1, productive rate is 95.24%.The methylene dichloride of 2-4ml drying instillation products therefrom, until solid dissolves completely.Under condition of ice bath, drip the trifluoroacetic acid (15mmol) of 2.5ml, reaction is spent the night.Add product with methyl alcohol and spin off solvent in 65 DEG C, obtain the hydrochloride of product Intermediate containing peptide bond.
By 2.707g(10mmol) Ti304,1.934g intermediate containing peptide bond hydrochloride (10mmol), 1.8mL(10mmol) triethylamine and 2.0mL concentration is that the formaldehyde solution (20mmol) of 37wt% is dissolved in 30mL ethanol together, the three-necked flask that mixed reaction solution is housed is placed in microwave reactor, 65 DEG C are heated in 5 minutes, and keep 65 DEG C to react decompression after 20 minutes steaming solvent, add 10mL water dissolution and divide three extractions by 60mL ethyl acetate.Combining extraction liquid anhydrous magnesium sulfate drying spends the night, and steams solvent, obtains yellow oil.With ethanol: ethyl acetate=4:1 column chromatography obtains pale yellow oil, productive rate is 95.62%.
Ultimate analysis: measured value C%59.93 H%6.64 N%16.77
Calculated value C%59.96 H%6.65 N%16.76
IR(KBr,cm-1）vmax 2950，1674（C=O）,1545(NO2),720.
1H NMR(400MHz,DMSO)δ8.29-8.26(m,2H),7.82(dd,J=8.3,2.3Hz,1H),7.57(dd,J=8.2,2.4Hz,1H),7.31(d,J=1.7Hz,5H),4.48(dd,J=15.0,5.3Hz,2H),4.21(d,J=15.0Hz,1H),3.78(d,J=12.9Hz,1H),3.69(d,J=4.5Hz,1H),3.64(dd,J=11.7,8.0Hz,4H),3.28(dd,J=13.9,7.1Hz,1H),3.17(dd,J=14.2,7.1Hz,1H),2.13(d,J=7.5Hz,1H),1.13(t,J=7.1Hz,3H),1.07(d,J=6.6Hz,6H).
Embodiment 8
2-processed [4-(N-ethyl-N-(6-chloro-3-pyridylmethyl) amino-3-methyl-5-nitro]-1,2,5,6 ,-tetrahydropyrimidine-1 base)-2-sec.-propyl-N-4-methyl-benzyl ethanamide (Ih);
The α-amino-isovaleric acid that 1.190g (5mmol) Boc is protected and 0.973g(6mmol) carbonyl dimidazoles adds in round-bottomed flask; the tetrahydrofuran (THF) of 30ml drying is added under nitrogen protection effect; maintain the temperature at 60 DEG C of reactions one hour; after having reacted, be cooled to room temperature, add 6mmol to methylbenzylamine; 2-3 hour is reacted under room temperature; obtain intermediate crude product, cross post obtain product with ethyl acetate and sherwood oil 3:1, productive rate is 95.24%.The methylene dichloride of 2-4ml drying instillation products therefrom, until solid dissolves completely.Under condition of ice bath, drip the trifluoroacetic acid (15mmol) of 2.5ml, reaction is spent the night.Add product with methyl alcohol and spin off solvent in 65 DEG C, obtain the hydrochloride of product Intermediate containing peptide bond.
By 2.707g(10mmol) Ti304,1.863g intermediate is containing hydrochloride (10mmol), the 1.8mL(10mmol of peptide bond) triethylamine and 2.0mL mass concentration be 37% formaldehyde solution (20mmol) be dissolved in 30mL ethanol together, the three-necked flask that mixed reaction solution is housed is placed in microwave reactor, 65 DEG C are heated in 5 minutes, and keep 65 DEG C to react decompression after 20 minutes steaming solvent, add 10mL water dissolution and divide three extractions by 60mL ethyl acetate.Combining extraction liquid anhydrous magnesium sulfate drying spends the night, and steams solvent, obtains yellow oil.With ethanol: ethyl acetate=4:1 column chromatography obtains pale yellow oil, productive rate is 93.62%.
Ultimate analysis: measured value C%60.63 H%6.85 N%16.32
Calculated value C%60.62 H%6.87 N%16.38
IR(KBr,cm-1）vmax 2950，1750（C=O）,1546(NO2),720.
1H NMR(400MHz,DMSO)δ8.29(dd,J=5.9,2.3Hz,1H),7.84(dd,J=8.4,2.3Hz,1H),7.58(dd,J=8.2,2.4Hz,1H),7.35-7.21(m,4H),4.50(dd,J=15.2,4.0Hz,2H),4.23(d,J=15.0Hz,1H),4.13(d,J=7.2Hz,1H),3.79(d,J=12.9Hz,1H),3.68(dd,J=8.9,4.0Hz,4H),3.30(dd,J=14.0,7.1Hz,1H),3.19(dd,J=14.2,7.1Hz,1H),2.83(s,3H),2.76-2.74(m,1H),2.06(s,3H),1.15(t,J=7.2Hz,3H),1.08(d,J=6.6Hz,6H).
The insecticidal activity test of experimental example 9 general formula (I) compound
Test target: aphis craccivora (Aphis medicaginis), Brown Planthopper (Nilaparvata legen).
Plant and instrument: culture dish, electronic analytical balance, Potter spray tower, liquid-transfering gun, writing brush etc.
Chemicals treatment: the medicament taking a certain amount of target compound with analytical balance (0.0001g), adds the solvent (as acetone or chloroform) containing 0.1% tween-80, is mixed with 1 ~ 5%wt preparation.Take the preparation of certain mass, adding distil water dilution is mixed with the liquid measuring desired concn.General sieve concentration is generally 500mg/L.
Test method:
A. aphis craccivora screening---pickling process
Broad Bean Leaves is broken into leaf dish, the back side is placed on fritter cotton upward, is placed in plastic culture dish, adds a small amount of water, if connect aphis craccivora aphid mixed population.After examination worm is stable on blade, after blade is fully infiltrated 10s in liquid, be again placed on cotton, naturally dry to be placed on and observe indoor feeding and observation.Check result after 48h.With 0.1% tween water for blank.
B. brown paddy plant hopper screening---spray method
Adopt Potter spray method.Rice seedling (being about 3 ~ 4cm) by 4 ~ 62 leaf 1 hearts is fixed in the culture dish of Φ 7cm with white quartz sand, Brown Planthopper 3 nymph in mid-term in age is with after CO2 anesthesia, every ware connects 30 ~ 40, under being placed in Potter spray tower, (pressure is 5Ib/iW2 in quantitative (2.5mL) spraying process, sinkability is 4.35mg/cm2), test sets tween water containing the organic solvent of maximum concentration as blank, cover with transparent plastics cup after spraying, be placed in 27 DEG C, the observation indoor cultivation of 14h illumination, 3d " Invest, Then Investigate " result.Touch polypide with writing brush, be reactionlessly considered as dead worm.
Test statistics and enter sieve standard:
Add up the dead borer population of each process and borer population of living, calculating mortality ratio (Abbott ' s formula).
Embodiment chemical compounds I a ~ I h desinsection test result:
Target compound I a ~ I h is to the insecticidal activity of aphis craccivora (Aphis medicaginis), Brown Planthopper (Nilaparvata legen), and contrast with Ti304 (Nitenpyram), activity data is in table 1.
Table 1 embodiment compound (I a-I h) and Ti304 to the lethality rate of Brown Planthopper and aphis craccivora
The foregoing is only the preferred embodiments of the present invention, be not limited to the present invention, for a person skilled in the art, the present invention can have change and change.Within the spirit and principles in the present invention all, any amendment, improvement etc. done, all should be included within protection scope of the present invention.
Claims (7)
1., containing the cis-nitenpyram analogue of peptide bond, it is characterized in that, structure as shown in general formula (I),
Wherein, n=0;
R＝H，Y＝H。
2. contain the preparation method of the cis-nitenpyram analogue of peptide bond shown in general formula described in claim 1 (I), it is characterized in that comprising the steps:
(1) amino acid amide of Boc protection shown in the logical formula II of preparation:
The amino acid protect Boc and carbonyl dimidazoles add dry tetrahydrofuran (THF) under nitrogen or protection of inert gas effect, when reacting 0.5 ~ 2 at 55 ~ 65 DEG C; After having reacted, be cooled to room temperature, add alpha substituted benzylamine, continue reaction under room temperature 2 ~ 3 hours, obtain the intermediate crude product of amide bond shown in logical formula II,
The amino acid structure of described Boc protection such as formula shown in (III), n=0 in formula (III); R is H; The structure of described alpha substituted benzylamine is such as formula (IV), and wherein Y is selected from H;
(2) the amino acid amide hydrochloride of peptide bond is contained shown in the logical formula V of preparation:
The amino acid amide (II) of Boc protection step (1) prepared is dissolved in methylene dichloride, trifluoroacetic acid is dripped at-5 ~ 0 DEG C, react 8 ~ 15 hours, obtain the amino acid amide hydrochloride containing peptide bond shown in logical formula V; The amino acid amide (II) of Boc protection is 1:4 ~ 6 with the mol ratio of trifluoroacetic acid;
(3) by shown in logical formula V containing the solution of the amino acid amide hydrochloride of peptide bond and Ti304, formaldehyde and ethanol reflux 4 ~ 6 hours at 60 ~ 80 DEG C, or microwave reaction 20 ~ 40 minutes at 65 ~ 70 DEG C, obtain the cis-nitenpyram analogue containing peptide bond shown in general formula (I), wherein Ti304: the amino acid amide hydrochloride of peptide bond: the molar ratio of formaldehyde is 1:1.2 ~ 1.5:1.5 ~ 2.5.
3. preparation method as claimed in claim 2, is characterized in that, the mol ratio of amino acid, carbonyl dimidazoles and alpha substituted benzylamine that the described Boc of step (1) protects is 1:1.2:1; Be that the ethyl acetate of 2:1 ~ 4:1 and sherwood oil mixed solution are crossed post and obtained product by the intermediate crude product volume ratio of amide bond shown in logical formula II in step (1).
4. preparation method as claimed in claim 2, is characterized in that, the described amino acid amide of Boc protection of step (2) and the mol ratio of trifluoroacetic acid are 1:5.
5. preparation method as claimed in claim 2, is characterized in that, Ti304 in step (3), containing peptide bond hydrochloride with and the molar ratio of formaldehyde be 1:1.25:2; Microwave reaction temperature is 65 DEG C, and the reaction times is 25 minutes; The concentration of formaldehyde solution is 30wt% ~ 37wt%.
6. the cis-nitenpyram analogue containing peptide bond shown in general formula described in claim 1 (I) is preparing the application in sterilant, and described sterilant suppresses brown planthopper and clover aphid.
7. apply as claimed in claim 6, it is characterized in that, the formulation of described sterilant is emulsion or aqueous suspension.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101558758A (en) * | 2009-05-26 | 2009-10-21 | 上海师范大学 | L-alpha-amino acid ester contained Z-configuration anabasine pesticide and preparation method thereof |
| CN102067838A (en) * | 2010-12-22 | 2011-05-25 | 上海师范大学 | Amide fragment-containing (Z) type nitenpyram analogue pesticide and preparation method thereof |
| CN102304122A (en) * | 2011-06-29 | 2012-01-04 | 上海师范大学 | Cis-nitenpyram compound containing amino-acid ester as well as preparation method and application thereof |
| CN102344446A (en) * | 2011-08-19 | 2012-02-08 | 上海师范大学 | Cis-nitenpyram analog containing carboxylic acid-substituted methyl ester and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101558758A (en) * | 2009-05-26 | 2009-10-21 | 上海师范大学 | L-alpha-amino acid ester contained Z-configuration anabasine pesticide and preparation method thereof |
| CN102067838A (en) * | 2010-12-22 | 2011-05-25 | 上海师范大学 | Amide fragment-containing (Z) type nitenpyram analogue pesticide and preparation method thereof |
| CN102304122A (en) * | 2011-06-29 | 2012-01-04 | 上海师范大学 | Cis-nitenpyram compound containing amino-acid ester as well as preparation method and application thereof |
| CN102344446A (en) * | 2011-08-19 | 2012-02-08 | 上海师范大学 | Cis-nitenpyram analog containing carboxylic acid-substituted methyl ester and preparation method and application thereof |
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