CN102838587A - Peptide bond containing cis nitenpyram analogue, and preparation and application thereof - Google Patents
Peptide bond containing cis nitenpyram analogue, and preparation and application thereof Download PDFInfo
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Abstract
The invention relates to the field of organic synthesis and pesticides and discloses a peptide bond containing cis nitenpyram analogue shown in the formula (I), wherein n is equal to 0, 1 or 2, R is H or alkyl, and Y is single-substituted or disubstituted, and is selected from at least one of H, CH3, F, Cl, Br, OH, OCH3 or CF3. A preparation method of the peptide bond containing cis nitenpyram analogue comprises the steps of performing reaction with substituted benzylamine to generate Boc (t-butyloxycarboryl)-protected amino acid amide by using Boc-protected amino acid as a starting material, and then using trifluoroacetic acid to remove Boc to obtain peptide bond containing hydrochloride, and then performing mannich reaction with formaldehyde and nitenpyram to synthesize a series of ectoine ring containing cis nitenpyram analogues with insecticidal activity. The peptide bond containing cis nitenpyram analogue has high insecticidal activity and can be used as insecticides; and the preparation method is simple, and has short reaction time and high yield.
Description
Technical field
The invention belongs to organic chemistry filed; Relate to the agricultural insecticide immunomodulator compounds; Be specifically related to have the cis Ti304 analogue of insecticidal activity, relate more specifically to one type of cis Ti304 analogue that contains peptide bond and preparation method thereof and the application aspect sterilant.
Background technology
The discovery of neonicotine sterilant can be considered to a milestone in the agrochemicals research in 30 years in the past.Anabasine insecticide be after organic phosphates, amino formate, pyrethroid insecticides the 4th generation sterilant.The anabasine material is as nAChR (nAChRs) agonist; Neural system (nAChRs) to insect optionally works; It has not only shown high-affinity to (nAChRs), but also has shown unionized property and medium physics-chem characteristic such as water-soluble.Because it has the unique insecticidal mechanism and the performance of high-efficiency low-toxicity, become the higher effective and lower toxic pesticide new variety that modern agriculture needs rapidly.
Ti304 is a kind of nicotimine insecticides of exploitation after Provado, is one of at present up-to-date nicotinic insecticide.It has ultra-high efficiency, wide spectrum, consumption is few, toxicity is low, lasting medicine, crop is not had poisoning, advantage such as safe in utilization, is the new variety that substitute high malicious organophosphorus pesticide.But owing to have the shortcoming of photo-labile property and hydrophobicity difference, promotion and application are restricted; Insect is more and more serious to its resistance simultaneously.
The present invention is employed on the Ti304 molecule molecular designing strategy of introducing a tetrahydropyrimidine ring, the Ti304 of transconfiguration is changed into cis-configuration, and on support arm, introduce peptide bond, has solved the shortcoming of hydrophobicity difference.Through existing patent documentation of retrieval and public publication; The present invention is a raw material with alpha substituted benzylamine, amino acid, thanomin, formaldehyde and Ti304 in the world first; Synthesize a series of cis Ti304 analogues that contain peptide bond, and measured the insecticidal activity of this compounds.Insecticidal activity tests showed that the present invention containing a cis peptide bond nitenpyram analogues on aphids and Rice planthopper highly efficient insecticidal activity can be used as new insecticides or pesticides used in one of the active ingredients, can be made into emulsions, suspension concentrates and water-water emulsions and the like.
Summary of the invention
The present invention seeks to cis Ti304 analogue with insecticidal activity in order to provide one type to contain peptide bond.
Another object of the present invention provides the above-mentioned preparation method who contains the cis Ti304 analogue with insecticidal activity of peptide bond.
The object of the invention is realized through following technical scheme.
A kind of Ti304 analogue that contains peptide bond, general formula is (I):
In the formula (I): n=0,1 or 2, R is H or alkyl, is preferably H or C1～C4 alkyl, more preferably H, methyl, sec.-propyl or isobutyl-;
Y is single the replacement or two replacements, and Y is selected from H, CH
3, F, Cl, Br, OH, OCH
3, CF
3In at least a.
The above-mentioned preparation method who contains the cis Ti304 analogue of peptide bond comprises the steps:
(1) amino acid amide of Boc protection shown in the logical formula II of preparation:
N=0,1 or 2 in the formula II, R is H or alkyl, is preferably H or C1～C4 alkyl, more preferably H, methyl, sec.-propyl or isobutyl-H; Y is single the replacement or two replacements, and Y is selected from H, CH
3, F, Cl, Br, OH, OCH
3Or CF
3In at least a;
Amino acid and the carbonyl dimidazoles of structure suc as formula Boc shown in (III) (tertbutyloxycarbonyl) protection mixed with the exsiccant THF under the nitrogen protection condition; Maintain the temperature at 0.5～2 hour (preferred 40～60 minutes) of 55～65 ℃ (being preferably 60 ℃) reaction; After having reacted, be cooled to room temperature, add structure suc as formula the alpha substituted benzylamine shown in (IV); Reacted under the room temperature 2～3 hours, and obtained the midbody crude product of amide containing key; The mol ratio of amino acid, carbonyl dimidazoles and the alpha substituted benzylamine of Boc protection is 1:1.2:1; Preferably, crude product is crossed post (volume ratio is preferably 3:1) with volume ratio 2:1～4:1 ETHYLE ACETATE and sherwood oil mixed solution;
The n=0 of formula (III), 1 or 2, R is H or alkyl, is preferably H or C1～C4 alkyl, more preferably H, methyl, sec.-propyl or isobutyl-H; Formula (IV) be that Y is single the replacement or two alpha substituted benzylamines for benzylamine, Y is selected from H, CH
3, F, Cl, Br, OH, OCH
3Or CF
3In at least a;
Step (1) reaction formula is following:
(2) hydrochloride that contains peptide bond shown in the formula V is led in preparation:
Be dissolved in methylene dichloride to the amino acid amide of step (1) product B oc protection ,-5～0 ℃ drips trifluoroacetic acid down, reacts 8～15 hours, obtains containing shown in the logical formula V hydrochloride of peptide bond; 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 following:
(3) will lead to the solution and the solvent of hydrochloride, Ti304 and formaldehyde that compound shown in the formula V contains peptide bond; Reflux 4～6 hours; Perhaps 65～70 ℃ of following microwave reactions 20～40 minutes (being preferably 25 minutes) obtain containing shown in the general formula (I) the cis Ti304 analogue of peptide bond; Wherein Ti304 and the logical formula V compound hydrochloride that contains peptide bond is 1:1.2～1.5:1.5～2.5 with molar ratio with formaldehyde, is preferably 1:1.25:2; The concentration of formaldehyde solution is 30wt%～37wt%; Preferably, use triethylamine to be catalyzer, Ti304 and triethylamine mol ratio are 1:0.5～2, are preferably 1:1, and reaction formula is following:
THF and methylene dichloride used in step (1) and (2) are anhydrous solvent, more preferably through the THF and the methylene dichloride of overweight steaming.
The cis Ti304 analogue that contains peptide bond shown in the above-mentioned general formula (I) has the efficient insecticide activity, can be used for preparing sterilant, especially can suppress brown rice hopper and clover aphid.This compound can be used as effective constituent and prepares sterilant, and the formulation of sterilant can be formulations such as emulsion, aqueous suspension and aqueous emulsion.
The present invention is a starting raw material with the amino acid of Boc protection; Warp generates Boc protection amino acid amide with the alpha substituted benzylamine reaction; Take off the hydrochloride that obtains containing peptide bond behind the Boc with trifluoroacetic acid again, and synthesized a series of cis Ti304 analogues that contain the tetrahydropyrimidine ring through the Manny alkene reaction with insecticidal activity with formaldehyde, Ti304.The present invention has measured this and has contained the efficient insecticide activity of the cis Ti304 analogue of peptide bond, has significant practicality in modern times in the agriculture prodn.
Embodiment:
Further set forth technical characterstic of the present invention below in conjunction with specific embodiment.
The example of the cis Ti304 analogue (I) that contains peptide bond of the present invention's preparation comprises:
(Ia): 2-[4-(N-ethyl-N-(6-chloro-3-picolyl) amino-3-methyl-5-nitro]-1,2,5,6 ,-tetrahydropyrimidine-1 base)-N-benzyl ethanamide;
(Ib): 2-[4-(N-ethyl-N-(6-chloro-3-picolyl) 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-picolyl) 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-picolyl) 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-picolyl) 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-picolyl) 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-picolyl) amino-3-methyl-5-nitro]-1,2,5,6 ,-tetrahydropyrimidine-1 base)-2-sec.-propyl-N-benzyl ethanamide;
(Ih) 2-[4-(N-ethyl-N-(6-chloro-3-picolyl) amino-3-methyl-5-nitro]-1,2,5,6 ,-tetrahydropyrimidine-1 base)-2-sec.-propyl-N-4-methyl-benzyl ethanamide;
Employed THF and methylene dichloride are THF and the methylene dichloride through overweight steaming among the embodiment, are anhydrous solvent.
Embodiment 1
Preparation 2-[4-(N-ethyl-N-(6-chloro-3-picolyl) amino-3-methyl-5-nitro]-1,2,5,6 ,-tetrahydropyrimidine-1 base)-N-benzyl ethanamide (Ia);
Add the glycocoll of 1.086g (5mmol) Boc protection and 0.973g (6mmol) carbonyl dimidazoles in the round-bottomed flask, under the nitrogen protection effect, add 30ml exsiccant THF, maintain the temperature at 60 ℃ of reactions one hour; After having reacted, be cooled to room temperature, add the 6mmol benzylamine; Reaction is 2-3 hour under the room temperature; Obtain the midbody crude product, cross post with ETHYLE ACETATE and sherwood oil 3:1 and obtain product, productive rate is 95.24%.Splash into products therefrom to 2-4ml exsiccant methylene dichloride, dissolve fully until solid.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 ℃, the product midbody contains the hydrochloride of peptide bond.
Hydrochloride (10mmol), 1.8mL (10mmol) triethylamine and the 2.0mL mass concentration that 2.707g (10mmol) Ti304,1.934g midbody are contained peptide bond is that 37% formaldehyde solution (20mmol) is dissolved in the 30mL ethanol together; The three-necked flask that mixed reaction solution is housed is placed microwave reactor; 5 minutes internal heating to 65 ℃; And keep 65 ℃ of reactions after 20 minutes decompression steam solvent, add 10mL water dissolution and divide three extractions with 60mL ETHYLE ACETATE.Combining extraction liquid spends the night with anhydrous magnesium sulfate drying, steams solvent, obtains yellow oil.With ethanol: ETHYLE ACETATE=4:1 column chromatography gets faint yellow oily thing, and 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-picolyl) amino-3-methyl-5-nitro]-1,2,5,6 ,-tetrahydropyrimidine-1 base)-N-4-methyl-benzyl ethanamide (Ib);
Add the glycocoll of 1.086g (5mmol) Boc protection and 0.973g (6mmol) carbonyl dimidazoles in the round-bottomed flask, under the nitrogen protection effect, add 30ml exsiccant THF, maintain the temperature at 60 ℃ of reactions one hour; After having reacted, be cooled to room temperature, add 6mmol 4-methylbenzylamine; Reaction is 2-3 hour under the room temperature; Obtain 4-methylbenzylamine glycocoll acid amides crude product, cross post with ETHYLE ACETATE and sherwood oil 3:1 and obtain product, productive rate is 90.24%.Splash into products therefrom to 2-4ml exsiccant methylene dichloride, dissolve fully until solid.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 ℃, the product midbody contains the hydrochloride of peptide bond.
Hydrochloride (10mmol), 1.8mL (10mmol) triethylamine and the 2.0mL mass concentration that 2.707g (10mmol) Ti304,1.904g midbody are contained peptide bond is that 37% formaldehyde solution (20mmol) is dissolved in the 30mL ethanol together; The three-necked flask that mixed reaction solution is housed is placed microwave reactor; 5 minutes internal heating to 65 ℃; And keep 65 ℃ of reactions after 20 minutes decompression steam solvent, add 10mL water dissolution and divide three extractions with 60mL ETHYLE ACETATE.Combining extraction liquid spends the night with anhydrous magnesium sulfate drying, steams solvent, obtains yellow oil.With ethanol: ETHYLE ACETATE=4:1 column chromatography gets faint yellow oily thing, and 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
max?2950，1674（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-picolyl) amino-3-methyl-5-nitro]-1,2,5,6 ,-tetrahydropyrimidine-1 base)-2-methyl-N-benzyl ethanamide (Ic)
Add the L-L-Ala of 0.94g (5mmol) Boc protection and 0.973g (6mmol) carbonyl dimidazoles in the round-bottomed flask, under the nitrogen protection effect, add 30ml exsiccant THF, maintain the temperature at 60 ℃ of reactions one hour; After having reacted, be cooled to room temperature, add the 6mmol benzylamine; Reaction is 2-3 hour under the room temperature; Obtain the midbody crude product, cross post with ETHYLE ACETATE and sherwood oil 3:1 and obtain product, productive rate is 86.24%.Splash into products therefrom to 2-4ml exsiccant methylene dichloride, dissolve fully until solid.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 ℃, the product midbody contains the hydrochloride of peptide bond.
Hydrochloride (10mmol), 1.8mL (10mmol) triethylamine and the 2.0mL mass concentration that 2.707g (10mmol) Ti304,1.876g midbody are contained peptide bond is that 37% formaldehyde solution (20mmol) is dissolved in the 30mL ethanol together; The three-necked flask that mixed reaction solution is housed is placed microwave reactor; 5 minutes internal heating to 65 ℃; And keep 65 ℃ of reactions after 20 minutes decompression steam solvent, add 10mL water dissolution and divide three extractions with 60mL ETHYLE ACETATE.Combining extraction liquid spends the night with anhydrous magnesium sulfate drying, steams solvent, obtains yellow oil.With ethanol: ETHYLE ACETATE=4:1 column chromatography gets faint yellow oily thing, and 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-picolyl) amino-3-methyl-5-nitro]-1,2,5,6 ,-tetrahydropyrimidine-1 base)-N-4-bromobenzyl propionic acid amide (Id);
Add the Beta-alanine of 1.14g (5mmol) Boc protection and 0.973g (6mmol) carbonyl dimidazoles in the round-bottomed flask, under the nitrogen protection effect, add 30ml exsiccant THF, maintain the temperature at 60 ℃ of reactions one hour; After having reacted, be cooled to room temperature, add 6mmol bretylium; Reaction is 2-3 hour under the room temperature; Obtain the midbody crude product, cross post with ETHYLE ACETATE and sherwood oil 3:1 and obtain product, productive rate is 85.24%.Splash into products therefrom to 2-4ml exsiccant methylene dichloride, dissolve fully until solid.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 ℃, the product midbody contains the hydrochloride of peptide bond.
Hydrochloride (10mmol), 1.8mL (10mmol) triethylamine and the 2.0mL mass concentration that 2.707g (10mmol) Ti304,1.876g midbody are contained peptide bond is that 37% formaldehyde solution (20mmol) is dissolved in the 30mL ethanol together; The three-necked flask that mixed reaction solution is housed is placed microwave reactor; 5 minutes internal heating to 65 ℃; And keep 65 ℃ of reactions after 20 minutes decompression steam solvent, add 10mL water dissolution and divide three extractions with 60mL ETHYLE ACETATE.Combining extraction liquid spends the night with anhydrous magnesium sulfate drying, steams solvent, obtains yellow oil.With ethanol: ETHYLE ACETATE=4:1 column chromatography gets faint yellow oily thing, and 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-picolyl) amino-3-methyl-5-nitro]-1,2,5,6 ,-tetrahydropyrimidine-1 base)-N-4-luorobenzyl propionic acid amide (Ie);
Add the Beta-alanine of 1.14g (5mmol) Boc protection and 0.973g (6mmol) carbonyl dimidazoles in the round-bottomed flask, under the nitrogen protection effect, add 30ml exsiccant THF, maintain the temperature at 60 ℃ of reactions one hour; After having reacted, be cooled to room temperature, add the 6mmol NSC 158269; Reaction is 2-3 hour under the room temperature; Obtain the midbody crude product, cross post with ETHYLE ACETATE and sherwood oil 3:1 and obtain product, productive rate is 92.24%.Splash into products therefrom to 2-4ml exsiccant methylene dichloride, dissolve fully until solid.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 ℃, the product midbody contains the hydrochloride of peptide bond.
Hydrochloride (10mmol), 1.8m (10mmol) L triethylamine and the 2.0mL mass concentration that 2.707g (10mmol) Ti304,1.704g midbody are contained peptide bond is that 37% formaldehyde solution (20mmol) is dissolved in the 30mL ethanol together; The three-necked flask that mixed reaction solution is housed is placed microwave reactor; 5 minutes internal heating to 65 ℃; And keep 65 ℃ of reactions after 20 minutes decompression steam solvent, add 10mL water dissolution and divide three extractions with 60mL ETHYLE ACETATE.Combining extraction liquid spends the night with anhydrous magnesium sulfate drying, steams solvent, obtains yellow oil.With ethanol: ETHYLE ACETATE=4:1 column chromatography gets faint yellow oily thing, and 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-picolyl) amino-3-methyl-5-nitro]-1,2,5,6 ,-tetrahydropyrimidine-1 base)-2-isobutyl--N-4-bromobenzyl ethanamide (If);
Add the leucine of 1.210g (5mmol) Boc protection and 0.973g (6mmol) carbonyl dimidazoles in the round-bottomed flask, under the nitrogen protection effect, add 30ml exsiccant THF, maintain the temperature at 60 ℃ of reactions one hour; After having reacted, be cooled to room temperature, add 6mmol bretylium; Reaction is 2-3 hour under the room temperature; Obtain the midbody crude product, cross post with ETHYLE ACETATE and sherwood oil 3:1 and obtain product, productive rate is 95.24%.Splash into products therefrom to 2-4ml exsiccant methylene dichloride, dissolve fully until solid.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 ℃, the product midbody contains the hydrochloride of peptide bond.
Hydrochloride (10mmol), 1.8mL (10mmol) triethylamine and the 2.0mL mass concentration that 2.707g (10mmol) Ti304,1.764g midbody are contained peptide bond is that 37% formaldehyde solution (20mmol) is dissolved in the 30mL ethanol together; The three-necked flask that mixed reaction solution is housed is placed microwave reactor; 5 minutes internal heating to 65 ℃; And keep 65 ℃ of reactions after 20 minutes decompression steam solvent, add 10mL water dissolution and divide three extractions with 60mL ETHYLE ACETATE.Combining extraction liquid spends the night with anhydrous magnesium sulfate drying, steams solvent, obtains yellow oil.With ethanol: ETHYLE ACETATE=4:1 column chromatography gets faint yellow oily thing, and 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-picolyl) amino-3-methyl-5-nitro]-1,2,5,6 ,-tetrahydropyrimidine-1 base)-2-sec.-propyl-N-benzyl ethanamide (Ig);
Add the Xie Ansuan of 1.190g (5mmol) Boc protection and 0.973g (6mmol) carbonyl dimidazoles in the round-bottomed flask, under the nitrogen protection effect, add 30ml exsiccant THF, maintain the temperature at 60 ℃ of reactions one hour; After having reacted, be cooled to room temperature, add the 6mmol benzylamine; Reaction is 2-3 hour under the room temperature; Obtain the midbody crude product, cross post with ETHYLE ACETATE and sherwood oil 3:1 and obtain product, productive rate is 95.24%.Splash into products therefrom to 2-4ml exsiccant methylene dichloride, dissolve fully until solid.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 ℃, the product midbody contains the hydrochloride of peptide bond.
With contain peptide bond hydrochloride (10mmol), 1.8mL (10mmol) triethylamine and the 2.0mL concentration of 2.707g (10mmol) Ti304,1.934g midbody is that the formaldehyde solution (20mmol) of 37wt% is dissolved in the 30mL ethanol together; The three-necked flask that mixed reaction solution is housed is placed microwave reactor; 5 minutes internal heating to 65 ℃; And keep 65 ℃ of reactions after 20 minutes decompression steam solvent, add 10mL water dissolution and divide three extractions with 60mL ETHYLE ACETATE.Combining extraction liquid spends the night with anhydrous magnesium sulfate drying, steams solvent, obtains yellow oil.With ethanol: ETHYLE ACETATE=4:1 column chromatography gets faint yellow oily thing, and 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
System 2-[4-(N-ethyl-N-(6-chloro-3-picolyl) amino-3-methyl-5-nitro]-1,2,5,6 ,-tetrahydropyrimidine-1 base)-2-sec.-propyl-N-4-methyl-benzyl ethanamide (Ih);
Add the Xie Ansuan of 1.190g (5mmol) Boc protection and 0.973g (6mmol) carbonyl dimidazoles in the round-bottomed flask, under the nitrogen protection effect, add 30ml exsiccant THF, maintain the temperature at 60 ℃ of reactions one hour; After having reacted, be cooled to room temperature, add 6mmol methylbenzylamine; Reaction is 2-3 hour under the room temperature; Obtain the midbody crude product, cross post with ETHYLE ACETATE and sherwood oil 3:1 and obtain product, productive rate is 95.24%.Splash into products therefrom to 2-4ml exsiccant methylene dichloride, dissolve fully until solid.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 ℃, the product midbody contains the hydrochloride of peptide bond.
Hydrochloride (10mmol), 1.8mL (10mmol) triethylamine and the 2.0mL mass concentration that 2.707g (10mmol) Ti304,1.863g midbody are contained peptide bond is that 37% formaldehyde solution (20mmol) is dissolved in the 30mL ethanol together; The three-necked flask that mixed reaction solution is housed is placed microwave reactor; 5 minutes internal heating to 65 ℃; And keep 65 ℃ of reactions after 20 minutes decompression steam solvent, add 10mL water dissolution and divide three extractions with 60mL ETHYLE ACETATE.Combining extraction liquid spends the night with anhydrous magnesium sulfate drying, steams solvent, obtains yellow oil.With ethanol: ETHYLE ACETATE=4:1 column chromatography gets faint yellow oily thing, and 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 formulas (I) compound
Test target: aphis craccivora (Aphis medicaginis), paddy rice brown paddy plant hopper (Nilaparvata legen).
Plant and instrument: petridish, electronic analytical balance, Potter spray tower, liquid-transfering gun, writing brush etc.
Chemicals treatment: take by weighing the medicament of a certain amount of target compound with analytical balance (0.0001g), add the solvent (like acetone or chloroform) that contains 0.1% tween-80, be mixed with 1～5%wt preparation.Take by weighing the preparation of certain mass, the adding distil water dilution is mixed with the soup of measuring desired concn.General sieve concentration is generally 500mg/L.
TP:
A. aphis craccivora screening---pickling process
If the broad bean blade is broken into the leaf dish, and the back side is placed on the fritter cotton up, places in the plastic culture dish, adds less water, connects aphis craccivora the aphid mixed population.Wait to try worm after stablizing on the blade, blade behind the abundant infiltration 10s, is placed on the cotton in soup again, dry naturally to be placed on and observe indoor feeding and observation.Check result behind the 48h.With 0.1% tween water is blank.
B. brown paddy plant hopper screening---spray method
Adopt the Potter spray method.(being about 3～4cm) is fixed in the petridish of Φ 7cm with white quartz sand to be about to the rice seedling of 4～6 2 leaf 1 hearts; Paddy rice brown paddy plant hopper nymph in 3 mid-term in age is with after the CO2 anesthesia, and every ware connects 30～40, and (pressure is 5Ib/iW2 to place the Potter spray tower under quantitatively (2.5mL) spraying processing; Sinkability is 4.35mg/cm2); The tween water that the organic solvent that contains maximum concentration is established in test is blank, and the spraying back covers with the transparent plastics cup, places 27 ℃; The observation indoor cultivation of 14h illumination, 3d " Invest, Then Investigate " result.Touch polypide with writing brush, reactionlessly be regarded as dead worm.
Test statistics with advance the sieve standard:
Add up the dead borer population and the borer population of living of each processing, the calculating mortality ratio (Abbott ' the 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), paddy rice brown paddy plant hopper (Nilaparvata legen), and (Nitenpyram) does contrast with Ti304, and activity data is seen table 1.
Table 1 embodiment compound (I a-I h) and Ti304 are to the lethality rate of paddy rice brown paddy plant hopper and aphis craccivora
The above is merely the preferred embodiments of the present invention, is not limited to the present invention, and for a person skilled in the art, the present invention can have change and change.All within spirit of the present invention and principle, any modification of being done, improvement etc. all should be included within protection scope of the present invention.
Claims (10)
1. a cis Ti304 analogue that contains peptide bond is characterized in that, structure shown in general formula (I),
Wherein, n=0,1 or 2, R are H or alkyl;
Y is single the replacement or two replacements, and Y is selected from H, CH
3, F, Cl, Br, OH, OCH
3Or CF
3In at least a.
2. contain the cis Ti304 analogue of peptide bond shown in the claim 1, it is characterized in that, described R is H or C1～C4 alkyl.
3. contain the cis Ti304 analogue of peptide bond shown in the claim 1, it is characterized in that, described R is H, methyl, sec.-propyl or isobutyl-.
4. contain the preparation method of the cis Ti304 analogue of peptide bond shown in each said general formula (I) of claim 1～4, 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 and the carbonyl dimidazoles of Boc protection are added the exsiccant THF under nitrogen or protection of inert gas effect, reacted 0.5～2 o'clock down at 55～65 ℃; After having reacted, be cooled to room temperature, add alpha substituted benzylamine, continue reaction 2～3 hours under the room temperature, obtain the midbody crude product of amide containing key;
The amino acid structure of said Boc protection is suc as formula shown in (III), n=0,1 or 2 in the formula (III), and R is H or C1～C4 alkyl;
Said alpha substituted benzylamine is a replacement or a dibasic benzylamine, and structure is suc as formula (IV), and wherein Y is selected from H, CH
3, F, Cl, Br, OH, OCH
3Or CF
3In at least a;
The amino acid amide of Boc protection shown in the logical formula II, n=0,1 or 2, R are H or C1～C4 alkyl; Y is single the replacement or two replacements, and Y is selected from H, CH
3, F, Cl, Br, OH, OCH
3Or CF
3In at least a;
(2) hydrochloride that contains peptide bond shown in the formula V is led in preparation:
The amino acid amide that the Boc that step (1) is prepared protects is dissolved in the methylene dichloride, and-5～0 ℃ drips trifluoroacetic acid down, reacts 8～15 hours, obtains containing shown in the logical formula V hydrochloride of peptide bond; The amino acid amide of Boc protection and the mol ratio of trifluoroacetic acid are 1:4～6;
Be dissolved in product (II) in the methylene dichloride by stoichiometric ratio down, 1:5 drips trifluoroacetic acid in molar ratio under condition of ice bath, reacts 8～15 hours, obtains containing shown in the logical formula V hydrochloride of peptide bond.
Solution and the ethanol of hydrochloride and Ti304, formaldehyde that (3) will contain peptide bond is 60～80 ℃ of following reflux 4～6 hours, and perhaps 65～70 ℃ of following microwave reactions are 20～40 minutes; Wherein Ti304 contain the hydrochloride of peptide bond and the molar ratio of formaldehyde is 1:1.2～1.5:1.5～2.5, obtain containing shown in the general formula (I) the cis Ti304 analogue of peptide bond.
5. preparation method as claimed in claim 4 is characterized in that, the mol ratio of amino acid, carbonyl dimidazoles and the alpha substituted benzylamine of the said Boc protection of step (1) is 1:1.2:1; Use volume ratio to cross post the midbody crude product of amide containing key in the step (1) and obtain product as the ETHYLE ACETATE of 2:1～4:1 and sherwood oil mixed solution.
6. preparation method as claimed in claim 4 is characterized in that, the amino acid amide of the said Boc protection of step (2) and the mol ratio of trifluoroacetic acid are 1:5.
7. preparation method as claimed in claim 4 is characterized in that, in the step (3) Ti304 contain, the hydrochloride of peptide bond with and the molar ratio of formaldehyde be 1:1.25:2; The microwave reaction temperature is 65 ℃, and the reaction times is 25 minutes; The concentration of formaldehyde solution is 30wt%～37wt%.
8. contain the application of cis Ti304 analogue aspect the preparation sterilant of peptide bond shown in the said general formula of claim 1 (I).
9. application as claimed in claim 8 is characterized in that, said sterilant suppresses brown rice hopper and clover aphid.
10. application as claimed in claim 8 is characterized in that, the formulation of said sterilant is emulsion, aqueous suspension or aqueous emulsion.
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Citations (4)
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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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| 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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