Trolamine derivatives, preparation method and application thereof
1. The tetramine acid derivative is characterized by having a structural general formula shown as a formula (I):
wherein R is selected from methyl, methoxy, n-butyl, phenyl, m-methylphenyl, cyclopropyl, cyclohexyl or 2-phenyl-ethylene; r1Selected from C1-C4 aliphatic alkyl, benzyl, phenethyl, indolylmethyl, naphthylmethyl, p-hydroxyphenylmethyl, p-fluorophenyl, p-chlorobenzyl, cyclohexylmethyl or C3-C6 naphthenic base directly connected on five-membered heterocyclic ring; r2Selected from hydrogen, carbonyl containing benzene ring, carbonyl containing aliphatic hydrocarbon or C1-C4 aliphatic hydrocarbon group.
2. The threonine derivative of claim 1, wherein R is methyl or methoxy; and/or
R2Is hydrogen; and/or
R1Is C3-C6 naphthenic base, m-methylphenyl, C1-C4 aliphatic base, benzyl, phenethyl, indolylmethyl, naphthylmethyl, p-hydroxyphenylmethyl, p-fluorophenyl, p-chlorobenzyl or cyclohexylmethyl.
3. The threonine derivative of claim 1, wherein R is methyl or methoxy; and/or
R2Is hydrogen; and/or
R1is-CH2C6H11or-CH2C6H5。
4. A process for preparing a threonine derivative as defined in any one of claims 1 to 3, wherein when R is methoxy, R is2When hydrogen, the process for the preparation of the compounds of formula (I) comprises:
1) carrying out amidation reaction on amino acid methyl ester hydrochloride and malonic acid monomethyl ester to obtain a compound 2a-2 o;
2) performing Dikoman condensation on the compound 2a-2o to obtain a compound 3a-3 o;
the reaction formula is as follows:
5. the method of claim 4, wherein the method comprises:
(1) synthesis of Compounds 2a-2o
Adding 5mmol of monomethyl malonate, 5mmol of amino acid methyl ester hydrochloride, 5mmol of triethylamine and 5mmol of DMAP into a reaction bottle, adding 25mL of dichloromethane serving as a solvent, stirring for half an hour under the ice bath condition, removing the ice bath, adding 5.25mmol of EDC & HCl, and stirring at room temperature overnight; after the reaction is finished, washing with 1mol/L hydrochloric acid, collecting an organic phase, adding a saturated sodium chloride solution for washing, and drying, filtering and concentrating the organic phase to obtain a compound 2a-2 o;
(2) synthesis of Compounds 3a-3o
Adding 10mmol of compound 2a-2o and 2.22mL of 30% sodium methoxide solution into a reaction bottle, adding 20mL of methanol as a solvent, heating and refluxing for 3-4 hours at 75 ℃, concentrating the obtained product after the reaction is finished, adding 12mL of water for dissolving, adding 20mL of dichloromethane for extraction, retaining the water phase, adding 20mL of 1mol/L hydrochloric acid, adding ethyl acetate for extraction, collecting the organic phase, washing with saturated sodium chloride solution, drying the organic phase, and carrying out suction filtration and concentration to obtain the compound 3a-3 o.
6. A process for preparing a threonine derivative as defined in any one of claims 1 to 3, wherein when R is methyl, R is2When hydrogen, the process for the preparation of the compounds of formula (I) comprises:
1) performing nucleophilic substitution reaction on isopropylidene malonate and acetyl chloride to obtain a compound 6;
2) amidating amino acid methyl ester hydrochloride and the compound 6 to obtain a compound 7a-7 o;
3) carrying out Dikoman condensation on the compounds 7a-7o to obtain compounds 8a-8 o;
the reaction formula is as follows:
7. the method of claim 6, wherein the method comprises:
(1) synthesis of Compound 6
Adding 40mmol of isopropylidene malonate and 82mmol of pyridine into 75mL of dichloromethane in a reaction bottle under the condition of ice-water bath, dissolving 48mmol of acetyl chloride into 25mL of dichloromethane, and slowly dropwise adding the solution into the solution within 1 hour under the protection of nitrogen; stirring at 0 deg.C for 1 hr, removing ice water bath, gradually returning to room temperature, and stirring overnight; after the reaction is finished, adding 50mL of dichloromethane into the brown solution to quench the reaction, washing an organic phase with 10% hydrochloric acid and water respectively, collecting the organic phase, drying, rotationally evaporating the organic phase to obtain a crude product, recrystallizing the crude product with hot ether, and performing suction filtration to obtain a compound 6;
(2) synthesis of Compounds 7a-7o
Dissolving 10mmol of amino acid methyl ester hydrochloride and 11mmol of compound 6 in 40mL of p-dioxane or toluene in a reaction bottle, dropwise adding 10mmol of triethylamine in the solution, heating and refluxing at 110 ℃, reacting for 4 hours, performing rotary evaporation, removing the solvent, dissolving the residue in 200mL of ethyl acetate, washing the organic phase once with 2mol/L hydrochloric acid and saturated sodium chloride solution respectively, collecting the organic phase, drying, performing rotary evaporation on the organic phase to obtain a crude product, and purifying the crude product by column chromatography to obtain compounds 7a-7 o;
(3) synthesis of Compounds 8a-8o
In a reaction flask, 10mmol of the compound 7a-7o is dissolved in 20mL of methanol, 2.22mL of 30% sodium methoxide solution is added, the mixture is heated under reflux at 75 ℃ for 4 hours, methanol is removed by rotary evaporation, the residue is dissolved in 12mL of water, the pH is adjusted to 2-3 with 1mol/L hydrochloric acid, extraction is carried out with diethyl ether, the organic phase is collected, dried, filtered and evaporated, and the compound 8a-8o is obtained.
8. A process for preparing a threonine derivative as defined in any one of claims 1 to 3, wherein when R is cyclopropyl or cyclohexyl, R is2When hydrogen, the process for the preparation of the compounds of formula (I) comprises:
1) performing nucleophilic substitution reaction on the isopropylidene malonate and acyl chloride to obtain compounds 5b-5 c;
2) amidating amino acid methyl ester hydrochloride and a compound 5b-5c to obtain a compound 7p-7 r;
3) performing Dikoman condensation on the compound 7p-7r to obtain a compound 8p-8 r;
the reaction formula is as follows:
9. a process for preparing a threonine derivative as defined in any one of claims 1 to 3, wherein when R is phenyl or methoxy, R is2Is COCH3The preparation method of the compound of the formula (I) comprises the following steps:
1) performing nucleophilic substitution reaction on the isopropylidene malonate and acyl chloride to obtain a compound 5d-5 f;
2) amidating 1-amino-1-cyclohexane carboxylic acid methyl ester and a compound 5d-5f to obtain a compound 9a-9 c;
3) carrying out Dikoman condensation on the compounds 9a-9c to obtain compounds 10a-10 c;
4) esterifying the compound 10a, 3e or 3m with glacial acetic acid to obtain a compound 11a-11 c;
wherein the compounds 3e, 3m are prepared by the method of claim 4 or 5;
the reaction formula is as follows:
10. use of the threonine derivative as defined in any one of claims 1 to 3 or prepared by the process as defined in any one of claims 4 to 9, for any one of the following applications:
A. is used for killing insects;
B. for the preparation of insecticides;
the insects comprise homoptera pests, preferably aphids, plant hoppers, mealybugs and whiteflies.
Background
With the increasing of the drug resistance of crop disease, pest and weed control drug varieties and the shortage of replacing traditional pesticides, the development of high-efficiency low-risk small-molecule new pesticide varieties based on active natural products is more and more widely concerned and applied. After the first tetronic acid acaricide spirodiclofen (spirodiclofen) developed by bayer corporation, a series of insecticidal and acaricidal agents such as tetramat (spirotetramat), which is a derivative of tetramat skeleton with bidirectional systemic conductivity, were developed successively, and studies on insecticidal and acaricidal activities of tetramat skeleton compounds are attracting more and more attention.
The tetramine acid is a compound with a beta-carbonyl five-membered ring lactam skeleton, is a heterocyclic pyrrole-2-ketone tetronic acid derivative, is widely present in secondary metabolites such as sponges, blue algae, bacteria, fungi and the like, and a natural product containing a tetramine acid structure has the characteristics of various biological activities such as insect killing, virus resistance, weeding and the like. Therefore, the efficient and simple synthesis method of the tetramine acid and the derivative has important significance for researching the relationship between the structure and the activity of the tetramine acid and the derivative.
Disclosure of Invention
The invention aims to provide a novel tetramine acid derivative, a preparation method and application thereof.
The invention has the following conception: on the basis of the existing tetramine acid molecular structure, the 3, 4 and 5 positions are modified, the length and steric hindrance of a chain are increased, the influence of the 3, 4 and 5 positions on the tetramine acid insecticidal activity is examined, and a high-activity tetramine acid derivative is further discovered.
In order to achieve the object of the present invention, in a first aspect, the present invention provides a tetramine acid derivative, which has a structural formula shown in formula (I):
wherein R can be selected from methyl, methoxy, n-butyl, phenyl, m-methylphenyl, cyclopropyl, cyclohexyl, 2-phenyl-ethylene and the like.
R1Can be selected from C1-C4 aliphatic alkyl, benzyl, phenethyl, indolylmethyl, naphthylmethyl, p-hydroxyphenylmethyl, p-fluorophenyl, p-chlorobenzyl, cyclohexylmethyl or C3-C6 naphthenic base directly connected with five-membered heterocyclic ring, etc.
R2Selected from hydrogen, carbonyl containing benzene ring, carbonyl containing aliphatic hydrocarbon or C1-C4 aliphatic hydrocarbon group, etc.
Preferably, R is methyl or methoxy.
Preferably, R2Is hydrogen.
Preferably, R1Is C3-C6 naphthenic base, m-methylphenyl, C1-C4 aliphatic base, benzyl, phenethyl, indolylmethyl, naphthylmethyl, p-hydroxyphenylmethyl, p-fluorophenyl, p-chlorobenzyl or cyclohexylmethyl.
More preferably, R1is-CH2C6H11or-CH2C6H5。
The influence of different groups at positions 3, 4 and 5 on the insecticidal activity of the tryptophan is compared through experiments, and the influence of different positions on the active compound is judged by changing the structure of any one of the positions 3, 4 and 5. The experimental data are shown in table 1:
TABLE 1
In the present invention, the threonine derivative is most preferably compound 3e, 3m, 8i or 8g (table 1).
In a second aspect, the present invention provides a process for preparing the tetramine acid derivative, wherein when R is methoxy, R is2When hydrogen, the process for the preparation of the compounds of formula (I) comprises:
1) carrying out amidation reaction on amino acid methyl ester hydrochloride and malonic acid monomethyl ester to obtain a compound 2a-2 o;
2) the compound 2a-2o is subjected to Dikoman condensation to obtain a compound 3 a-30.
The reaction formula is as follows:
further, the method comprises:
(1) synthesis of Compounds 2a-2o
Adding 5mmol of monomethyl malonate, 5mmol of amino acid methyl ester hydrochloride, 5mmol of triethylamine and 5mmol of DMAP into a reaction bottle, adding 25mL of dichloromethane serving as a solvent, stirring for half an hour under the ice bath condition, removing the ice bath, adding 5.25mmol of EDC.HCl, and stirring at room temperature overnight. After the reaction is finished, washing with 1mol/L hydrochloric acid (20mL), collecting an organic phase, adding a saturated sodium chloride solution (20mL) for washing, and drying, filtering and concentrating the organic phase to obtain a compound 2a-2 o;
(2) synthesis of Compounds 3a-3o
Adding 10mmol of compound 2a-2o and 2.22mL of 30% sodium methoxide solution into a reaction bottle, adding 20mL of methanol (analytically pure) as a solvent, heating and refluxing for 3-4 hours at 75 ℃, concentrating the obtained product after the reaction is finished, adding 12mL of water for dissolving, adding 20mL of dichloromethane for extraction, retaining the water phase, adding 20mL of 1mol/L hydrochloric acid for acidification, adding ethyl acetate (20mL) for extraction, collecting the organic phase, washing with saturated sodium chloride solution (20mL), drying and carrying out suction filtration and concentration on the organic phase to obtain the compound 3a-3 o.
When R is methyl, R2When hydrogen, the process for the preparation of the compounds of formula (I) comprises:
1) performing nucleophilic substitution reaction on isopropylidene malonate and acetyl chloride to obtain a compound 6;
2) amidating amino acid methyl ester hydrochloride and the compound 6 to obtain a compound 7a-7 o;
3) the compounds 7a-7o are subjected to Dikoman condensation to obtain compounds 8a-8 o.
The reaction formula is as follows:
further, the method comprises:
(1) synthesis of Compound 6
In a reaction flask, under the condition of ice-water bath, 40mmol of malonic acid cycloisopropyl ester and 82mmol of pyridine are added into 75mL of dichloromethane, 48mmol of acetyl chloride is dissolved into 25mL of dichloromethane, and the solution is slowly added dropwise into the solution within 1 hour under the protection of nitrogen. And kept stirring below 0 ℃ for 1 hour, after which the ice-water bath was removed, gradually returned to room temperature, and kept stirring overnight. After the reaction is finished, adding 50mL of dichloromethane into the brown solution to quench the reaction, washing the organic phase with 10% hydrochloric acid (washing 3 times, 75mL each time) and 100mL of water respectively, collecting the organic phase, drying, performing rotary evaporation on the organic phase to obtain a crude product, recrystallizing the crude product with hot ether, and performing suction filtration to obtain a compound 6;
(2) synthesis of Compounds 7a-7o
Dissolving 10mmol of amino acid methyl ester hydrochloride and 11mmol of compound 6 in 40mL of p-dioxane or toluene in a reaction bottle, dropwise adding 10mmol of triethylamine in the solution, heating and refluxing at 110 ℃, reacting for 4 hours, performing rotary evaporation, removing the solvent, dissolving the residue in 200mL of ethyl acetate, washing the organic phase once with 2mol/L hydrochloric acid (100mL) and saturated sodium chloride solution (100mL), collecting the organic phase, drying, performing rotary evaporation on the organic phase to obtain a crude product, and purifying the crude product by column chromatography to obtain compounds 7a-7 o;
(3) synthesis of Compounds 8a-8o
In a reaction flask, 10mmol of the compound 7a-7o is dissolved in 20mL of methanol, 2.22mL of 30% sodium methoxide solution is added, the mixture is heated under reflux at 75 ℃ for 4 hours, methanol is removed by rotary evaporation, the residue is dissolved in 12mL of water, the pH is adjusted to 2-3 with 1mol/L hydrochloric acid, extraction is carried out with diethyl ether, the organic phase is collected, dried, filtered and evaporated, and the compound 8a-8o is obtained.
When R is cyclopropyl or cyclohexyl, R2When hydrogen, the process for the preparation of the compounds of formula (I) comprises:
1) performing nucleophilic substitution reaction on the isopropylidene malonate and acyl chloride to obtain compounds 5b-5 c;
2) amidating amino acid methyl ester hydrochloride and a compound 5b-5c to obtain a compound 7p-7 r;
3) the compound 7p-7r is subjected to Dikoman condensation to obtain a compound 8p-8 r.
The reaction formula is as follows:
further, the method comprises:
(1) synthesis of Compounds 5b-5c
In a reaction flask, under the condition of ice-water bath, 40mmol of isopropylidene malonate and 82mmol of pyridine are added into 75mL of dichloromethane, 48mmol of acyl chloride is dissolved into 25mL of dichloromethane, and the solution is slowly added dropwise into the solution within 1 hour under the protection of nitrogen. And kept stirring below 0 ℃ for 1 hour, after which the ice-water bath was removed, gradually returned to room temperature, and kept stirring overnight. After the reaction is finished, 50mL of dichloromethane is added into the brown solution to quench the reaction, the organic phase is washed by 10% hydrochloric acid (washed for 3 times, 75mL each time) and 100mL of water respectively, the organic phase is collected, the organic phase is dried and then is subjected to rotary evaporation to obtain a crude product, the crude product is recrystallized by hot ether, and the compound 5b-5c is obtained after suction filtration.
(2) Synthesis of Compounds 7p to 7r
Synthesis of methyl 2- (3-cyclopropyl-3-oxopropanoylamino) valerate (7p)
In a 100mL eggplant-shaped bottle, norvaline methyl ester hydrochloride (1.68g, 10mmol) and 5- (cyclopropanecarbonyl) -2, 2-dimethyl-1, 3-dioxane-4, 6-dione (2.33g, 11mmol) were dissolved in 1, 4-dioxane (40mL), triethylamine (1.01g, 10mmol) was added dropwise to the solution, heating and refluxing at 110 ℃, reacting for 4 hours, rotary evaporating, removing the solvent, dissolving the residue in 200mL ethyl acetate, the organic phase was washed once with 2mol/L hydrochloric acid (100mL) and once with saturated sodium chloride solution (100mL), and placing the organic phase on anhydrous sodium sulfate for drying, filtering, performing rotary evaporation on the organic phase to obtain a crude product, and purifying the crude product by column chromatography to obtain a light yellow oily liquid, namely the compound 7 p.
Synthesis of methyl 2- (3-cyclopropyl-3-oxopropanoylamino) butanoate (7q)
Dissolving methyl (2s) -2-aminobutyric acid hydrochloride (1.54g, 10mmol) and 5- (cyclopropanecarbonyl) -2, 2-dimethyl-1, 3-dioxane-4, 6-dione (2.33g, 11mmol) in 1, 4-dioxane (40mL) in a 100mL eggplant-shaped bottle, dropwise adding triethylamine (1.01g, 10mmol) to the above solution, heating under reflux at 110 deg.C for 4 hours, rotary evaporating, removing the solvent, dissolving the residue in 200mL ethyl acetate, washing the organic phase once with 2mol/L hydrochloric acid (100mL) and saturated sodium chloride solution (100mL), drying the organic phase over anhydrous sodium sulfate, filtering, rotary evaporating the organic phase to obtain a crude product, purifying the crude product by column chromatography, a light yellow oily liquid, compound 7q, was obtained.
Synthesis of methyl 2- (3-cyclohexyl-3-oxopropanoylamino) valerate (7r)
In a 100mL eggplant-shaped bottle, norvaline methyl ester hydrochloride (1.68g, 10mmol) and 5- (cyclohexanecarbonyl) -2, 2-dimethyl-1, 3-dioxane-4, 6-dione (2.80g, 11mmol) were dissolved in p-dioxane (40N L), triethylamine (1.01g, 10mmol) was added dropwise to the solution, heating and refluxing at 110 ℃, reacting for 4 hours, rotary evaporating, removing the solvent, dissolving the residue in 200mL ethyl acetate, the organic phase was washed once with 2mol/L hydrochloric acid (100mL) and once with saturated sodium chloride solution (100mL), and placing the organic phase on anhydrous sodium sulfate for drying, filtering, performing rotary evaporation on the organic phase to obtain a crude product, and purifying the crude product by column chromatography to obtain a light yellow oily liquid, namely the compound 7 r.
(3) Synthesis of Compounds 8p to 8r
Synthesis of 3- (cyclopropanecarbonyl) -4-hydroxy-5-propyl-2, 5-dihydro-pyrrol-2-one (8p)
Dissolving methyl 2- (3-cyclopropyl-3-oxopropanoylamino) valerate (2.41g, 10mmol) in a methanol (20mL) solution in a 100mL eggplant-shaped bottle, adding 30% sodium methoxide (2.22mL, 12mmol), heating and refluxing at 75 ℃ for 4 hours, rotary evaporating to remove methanol, dissolving the residue in pure water (12mL), adjusting the pH to about 2-3 with 1mol/L hydrochloric acid, extracting with diethyl ether, drying the organic phase over anhydrous sodium sulfate, filtering, and evaporating the organic phase to obtain a light yellow solid, namely the compound 8 p.
Synthesis of 3- (cyclopropanecarbonyl) -4-hydroxy-5-ethyl-2, 5-dihydro-pyrrol-2-one (8q)
Dissolving methyl 2- (3-cyclopropyl-3-oxopropanamido) butyrate (2.27g, 10mmol) in a methanol (20mL) solution in a 100mL eggplant-shaped bottle, adding 30% sodium methoxide (2.22mL, 12mmol), heating and refluxing for 4 hours at 75 ℃, removing methanol by rotary evaporation, dissolving the residue in pure water (12mL), adjusting the pH to about 2-3 with 1mol/L hydrochloric acid, extracting with diethyl ether, drying the organic phase on anhydrous sodium sulfate, filtering and evaporating the organic phase to obtain a white solid, namely the compound 8 q.
Synthesis of 3- (cyclohexanecarbonyl) -4-hydroxy-5-propyl-2, 5-dihydro-pyrrol-2-one (8r)
Dissolving methyl 2- (3-cyclohexyl-3-oxopropanoylamino) valerate (2.83g, 10mmo1) in a methanol (20mL) solution in a 100mL eggplant-shaped bottle, adding 30% sodium methoxide (2.22mL, 12mmol), heating and refluxing at 75 ℃ for 4 hours, rotary evaporating to remove methanol, dissolving the residue in pure water (12mL), adjusting pH to about 2-3 with 1mol/L hydrochloric acid, extracting with diethyl ether, drying the organic phase over anhydrous sodium sulfate, filtering, and evaporating the organic phase to obtain a yellow solid, namely the compound 8 r.
When R is phenyl or methoxy, R2Is COCH3The preparation process of the compound of formula (I) comprises：
1) Performing nucleophilic substitution reaction on the isopropylidene malonate and acyl chloride to obtain a compound 5d-5 f;
2) amidating 1-amino-1-cyclohexane carboxylic acid methyl ester and a compound 5d-5f to obtain a compound 9a-9 c;
3) carrying out Dikoman condensation on the compounds 9a-9c to obtain compounds 10a-10 c;
4) esterifying the compound 10a, 3e or 3m with glacial acetic acid to obtain a compound 11a-11 c;
wherein, the compounds 3e and 3m are prepared by the method.
The reaction formula is as follows:
further, the method comprises:
(1) synthesis of Compounds 5d-5f
In a reaction flask, under the condition of ice-water bath, 40mmol of isopropylidene malonate and 82mmol of pyridine are added into 75mL of dichloromethane, 48mmol of acyl chloride is dissolved into 25mL of dichloromethane, and the solution is slowly added dropwise into the solution within 1 hour under the protection of nitrogen. And kept stirring below 0 ℃ for 1 hour, after which the ice-water bath was removed, gradually returned to room temperature, and kept stirring overnight. After the reaction is finished, 50mL of dichloromethane is added into the brown solution to quench the reaction, the organic phase is washed by 10% hydrochloric acid (washed for 3 times, 75mL each time) and 100mL of water respectively, the organic phase is collected, the organic phase is dried and then is subjected to rotary evaporation to obtain a crude product, the crude product is recrystallized by hot ether, and the compound 5d-5f is obtained after suction filtration.
(2) Synthesis of Compounds 9a-9c
Synthesis of methyl 1- (3-oxo-3-phenylpropionamido) cyclohexane-1-carboxylate (9a)
Dissolving 1-aminocyclohexanecarboxylic acid methyl ester hydrochloride (1.57g, 10mmol) and the compound 5d-5f (11mmol) in p-dioxane (40mL), dropwise adding triethylamine (1.01g, 10mmol) to the solution, reacting under heating and refluxing conditions for 4 hours, performing rotary evaporation to remove the solvent, dissolving the residue in 200mL ethyl acetate, washing the organic phase once with 2mol/L hydrochloric acid (100mL) and saturated sodium chloride solution (100mL), respectively, drying the organic phase over anhydrous sodium sulfate, filtering, performing rotary evaporation to the organic phase to obtain a crude product, and purifying the crude product by column chromatography to obtain the compounds 9a-9 c.
(3) Synthesis of Compounds 10a-10c
Dissolving 9a-9c (10mmol) in methanol (20mL), adding 30% sodium methoxide (2.22mL, 12mmol), reacting under heating reflux for 4 hours, rotary evaporating to remove methanol, dissolving the residue in pure water (12mL), adjusting pH to about 2-3 with 1mol/L hydrochloric acid, extracting with diethyl ether, drying the organic phase over anhydrous sodium sulfate, filtering and evaporating the organic phase to obtain compounds 10a-10 c.
(4) Synthesis of Compounds 11a-11c
Synthesis of 3-benzoyl-2-oxo-1-azaspiro [4.5] dec-3-en-4-yl acetate (11a)
Glacial acetic acid (0.87g, 7.5mmol), DMAP (0.92g, 7.5mmol) and EDC & HCl (1.44g, 7.5mmol) were dissolved in an anhydrous dichloromethane solution (20mL) in a 100mL eggplant-shaped bottle, and after stirring at room temperature for 30 minutes, a 10a (2.71g, 5mmol) dichloromethane solution was added dropwise to the mixed solution. The reaction was carried out at room temperature for 16 hours and TLC followed until the starting material had reacted completely. After the reaction is finished, filtering is carried out, 20mL of dichloromethane is added into filtrate for dilution, and organic phase 5% NaHCO is added3The solution (30 mL each), 1mol/L hydrochloric acid (30 mL each), pure water (30 mL each) washed three times. The dichloromethane phase was dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (ethyl acetate: petroleum ether 3: 1, vol.) to give compound 11a as a white solid.
Synthesis of 4-acetoxy-5-benzyl-2-oxo-2, 5-dihydro-1H-pyrrole-3-carboxylic acid methyl ester (11b)
In a 100mL eggplant-shaped bottle, glacial acetic acid (0.87g, 7.5mmol), DMAP (0.92g, 7.5mmol) and EDC & HCl (1.44g, 7.5mmol 1) were dissolved in anhydrous dichloromethane solution (20mL), and after stirring at room temperature for 30 minutes, a 3e (1.23g, 5mmol) dichloromethane solution was added dropwise to the mixed solution. The reaction was carried out at room temperature for 16 hours and followed by TLCUntil the raw materials are completely reacted. After the reaction is complete, filtration is carried out, the filtrate is diluted with 20mL of dichloromethane and the organic phase is diluted with 5% NaHCO3The solution (30 mL each), 1mol/L hydrochloric acid (30 mL each), pure water (30 mL each) washed three times. The dichloromethane phase was dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (ethyl acetate: petroleum ether 3: 1, vol.) to give compound 11b as a white solid.
Synthesis of methyl 4-acetoxy-5- (cyclohexylmethyl) -2-oxo-2, 5-dihydro-1H-pyrrole-3-carboxylate (11c)
Glacial acetic acid (0.87g, 7.5mmol), DMAP (0.92g, 7.5mmol) and EDC & HCl (1.44g, 7.5mmol) were dissolved in an anhydrous dichloromethane solution (20mL) in a 100mL eggplant-shaped bottle, and after stirring at room temperature for 30 minutes, a 3m (1.26, 5mmol) dichloromethane solution was added dropwise to the mixed solution. The reaction was carried out at room temperature for 16 hours and TLC followed until the starting material had reacted completely. After the reaction is complete, filtration is carried out, the filtrate is diluted with 20mL of dichloromethane and the organic phase is diluted with 5% NaHCO3The solution (30 mL each), 1mol/L hydrochloric acid (30 mL each), pure water (30 mL each) washed three times. The dichloromethane phase was dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (ethyl acetate: petroleum ether 3: 1, vol.) to give compound 11c as a white solid.
In a third aspect, the present invention provides any one of the following uses of the tetramine acid derivative or the tetramine acid derivative prepared according to the above method:
A. is used for killing insects;
B. for the preparation of insecticides;
such insects include, but are not limited to, homoptera pests such as aphids, plant hoppers, mealybugs, whiteflies, and the like.
Experiments show that the 3-position R of the compound of the formula (I) is-OCH3When the compound has certain enhancing effect on the activity of the compound, R is at the 4-position2is-COCH3In the meantime, the insecticidal activity against aphids and plant hoppers is reduced, and the differently substituted compounds in position 5 show a certain structural and activity relationship. Therefore, a compound with certain activity at the 5-position is found, and a compound with better insecticidal activity effect is easily found by modifying the 3-position.
By the technical scheme, the invention at least has the following advantages and beneficial effects:
compared with the reported compounds, the tetramine acid derivative provided by the invention has the advantages that the lead compound is modified and structurally optimized by using the natural amino acid methyl ester, the screened compound basically has no influence on the growth of crops, various pests can be effectively killed, the residual amount is small, the residual compound is easy to remove, the environmental pollution is small, the structure is novel, the raw materials are cheap and easy to obtain, the synthetic method is simple and efficient, the social benefit and the economic benefit are obvious, and the tetramine acid derivative is suitable for industrial production.
Detailed Description
The invention provides a tetramine acid derivative with insecticidal activity, and a preparation method thereof comprises the following steps:
1. amino acid methyl ester hydrochloride and monomethyl malonate are used as raw materials, dichloromethane is used as a solvent, and a compound 2a-2o is obtained through amidation reaction;
2. performing Dikoman condensation on the compound 2a-2o to obtain a compound 3a-3 o;
3. performing nucleophilic substitution reaction on raw materials of isopropylidene malonate, pyridine and acyl chloride and dichloromethane serving as a solvent to obtain compounds 5a-5 f;
4. amino acid methyl ester hydrochloride, 5-acetyl-2, 2-dimethyl-1, 3-dioxane-4, 6-diketone and triethylamine are used as raw materials, dioxane is used as a solvent, and a compound 7a-7o is obtained through amidation;
5. carrying out Dikoman condensation on the compounds 7a-7o to obtain compounds 8a-8 o;
6. amidating a compound 5b or 5c, isoleucine methyl ester hydrochloride or 2-aminobutyric acid methyl ester hydrochloride and triethylamine serving as raw materials and 1, 4-dioxane serving as a solvent to obtain a compound 7p-7 r;
7. performing Dikoman condensation on the compound 7p-7r to obtain a compound 8p-8 r;
8. amidating 1-amino-1-cyclohexane carboxylic acid methyl ester, DMAP, EDC.HCl, benzoyl chloride, m-methyl benzoyl chloride and valeryl chloride which are used as raw materials and anhydrous dichloromethane which is used as a raw material to obtain compounds 9a-9 c;
9. carrying out Dieckmann condensation on the compounds 9a-9c to obtain compounds 10a-10 c;
10. glacial acetic acid, EDC.HCl, DMAP and compounds 10a, 3e and 3m are used as raw materials, and anhydrous dichloromethane is used as a solvent, and the compounds 11a-11c are obtained through esterification.
The specific synthetic route is as follows:
the information on the above synthesized compounds is shown in table 2:
TABLE 2
The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention. Unless otherwise specified, the technical means used in the examples are conventional means well known to those skilled in the art, and the raw materials used are commercially available products.
EXAMPLE 1 preparation of the amino acid derivatives
1. Synthesis of Compound (2a-2o)
To a 100mL eggplant-shaped bottle, monomethyl malonate (0.59g, 5mmol), various amino acid methyl ester hydrochlorides (5mmol), triethylamine (0.5g, 5mmol) and DMAP (0.03g, 5mmol) were added, 25mL of methylene chloride was added as a solvent, the mixture was cooled in an ice bath under ambient conditions, and after stirring for half an hour, the ice bath was removed, EDC & HCl (1.0g, 5.25mmol) was added, and the mixture was stirred at room temperature overnight. After the reaction is finished, washing the remained organic phase by 1mol/L hydrochloric acid (20mL), adding sodium chloride solution (20mL) to wash the remained organic phase, finally drying by anhydrous sodium sulfate, filtering and concentrating to obtain the intermediate 2a-2o of the target compound.
2. Synthesis of Compounds 3a-3o
The intermediate 2a-2o (10mmol) and 30% sodium methoxide (2.22mL, 10mmol) were added to a 100mL eggplant-shaped bottle, and methanol (20mL, analytical grade) was added as a solvent, and the mixture was heated under reflux at 75 ℃ for 3 to 4 hours and followed by TLC until the reaction was completed. After the reaction is finished, the obtained product is concentrated, water (12mL) is added for dissolving, dichloromethane (20mL) is added for extracting to leave a water phase, 1mol/L hydrochloric acid (20mL) is added for acidification, ethyl acetate (20mL) is added for extracting to leave an organic phase, then a saturated sodium chloride solution (20mL) is used for washing, and finally the organic phase is placed on anhydrous sodium sulfate for drying, and is filtered and concentrated to obtain the target compound.
Compound 3 a: white solid, melting point 95-97 ℃. The yield was 76%.1H NMR(600MHz，CDCl3)δ6.46(s，1H)，3.89(s，3H)，1.83(t，J＝11.2Hz，3H)，1.72(d，J＝12.0Hz，1H)，1.55(d，J＝12.1Hz，2H)，1.41(d，J＝13.6Hz，2H)，1.37-1.27(m，1H).HRMS[ESI-]for C11H15NO4[(M-H)-]，m/z Calcd：224.0923；Found：226.0923。
Compound 3 b: pale yellow solid, melting point 112-. The yield was 77%.1H NMR(600MHz，CDCl3)δ6.20(s，1H)，4.15(d，J＝2.5Hz，1H)，3.91(s，3H)，1.93(s，1H)，1.49-1.36(m，1H)，1.34-1.26(m，1H)，0.98(d，J＝6.9Hz，3H)，0.92(t，J＝7.4Hz，3H).HRMS[ESI-]for C10H15NO4[(M-H)-]，m/z Calcd：212.0923；Found：210.0923。
Compound 3 c: pale yellow solid, melting point 174-. The yield was 80%.1H NMR(600MHz，DMSO)δ8.14(d，J＝8.4Hz，1H)，7.90(d，J＝8.0Hz，1H)，7.79(d，J＝7.8Hz，1H)，7.52(dt，J＝14.7，7.1Hz，2H)，7.43-7.30(m，2H)，4.33(s，1H)，3.63(d，J＝4.1Hz，1H)，3.62(d，J＝9.5Hz，3H)，3.08(dd，J＝14.3，8.2Hz，1H).HRMS[ESI-]for C17H15NO4[(M-H)-]，m/z Calcd：296.0923；Found：298.0923。
Compound 3 d: pale pink solid, melting point 150-. The yield was 75%.1H NMR(600MHz，CDCl3)δ7.29(t，J＝6.7Hz，1H)，7.22-7.13(m，2H)，6.37(s，1H)，4.17(s，1H)，3.92(s，2H)，2.74(s，1H)，2.21(s，1H)，1.98(s，1H).HRMS[ESI-]for C14H15NO4[(M-H)-]，m/z Calcd：260.0923；Found：262.0923。
Compound 3 e: white solid, melting point 155-. The yield was 81%.1H NMR(600MHz，CDCl3)δ7.29(t，J＝6.7Hz，1H)，7.22-7.13(m，2H)，6.37(s，1H)，4.17(s，1H)，3.92(s，2H)，2.74(s，1H)，2.21(s，1H)，1.98(s，1H).HRMS[ESI-]for C13H18NO4[(M-H)-]，m/z Calcd：252.1236；Found：254.1236。
Compound 3 f: yellow solid, melting point 150-. The yield was 79%.1HNMR(600MHz，CD3OD)δ7.57(d，J＝7.9Hz，1H)，7.29(d，J＝8.1Hz，1H)，7.05(dd，J＝14.9，7.0Hz，2H)，6.99(d，J＝7.8Hz，1H)，4.43-4.26(m，1H)，3.70(s，2H)，3.52-3.41(m，1H)，3.34(dd，J＝14.3，3.9Hz，1H)，3.09(dd，J＝14.7，6.5Hz，1H).HRMS[ESI-]for C15H14N2O4[(M-H)-]，m/z Calcd：285.0875；Found：283.0875。
Compound 3 g: white solid, melting point 161-. The yield was 83%.1H NMR(600MHz，CDCl3) δ 6.33(s, 1H), 4.16(s, 1H), 3.91(s, 2H), 1.97-1.77(m, 1H), 1.65(tdd, where 13.6, 8.8, 4.7Hz, 1H), 1.46-1.24(m, 3H), 0.90(t, J, 7.1Hz, 2H), HRMS [ ESI ]-]for C10H15NO4[(M-H)-]，m/z Calcd：212.0923；Found：214.0923。
Compound 3h: pale pink solid, melting point 115-. The yield was 77%.1H NMR(600MHz，DMSO)δ3.90(s，1H)，3.62(s，3H)，1.73(ddd，J＝13.7，7.4，4.1Hz，1H)，1.55-1.30(m，1H)，0.79(t，J＝7.4Hz，3H).HRMS[ESI-]for C8H11NO4[(M-H)-]，m/z Calcd：184.0610；Found：186.0610。
Compound 3 i: white solid, melting point 117-. The yield was 78%.1H NMR(600MHz，CDCl3)δ6.18(s，1H)，4.26-4.08(m，1H)，3.92(s，2H)，1.92-1.72(m，1H)，1.71-1.52(m，1H)，1.42(ddd，J＝16.6，13.6，6.4Hz，2H)，0.96(t，J＝7.3Hz，3H).HRMS[ESI-]for C9H13NO4[(M-H)-]，m/z Calcd：198.0766；Found：196.0766。
Compound 3 j: white solid, melting point 133-. The yield was 76%.1H NMR(600MHz，DMSO)δ9.14(s，1H)，7.77(s，1H)，6.92(s，2H)，6.58(s，2H)，4.14(s，1H)，3.57(d，J＝7.1Hz，3H)，2.86(s，1H)，2.76(s，1H).HRMS[ESI-]for C13H13NO5[(M-H)-]，m/z Calcd：262.0715；Found：264.0715。
Compound 3 k: white solid, melting point 198-. The yield was 80%.1H NMR(600MHz，CDCl3))δ6.45(s，1H)，3.89(d，J＝16.7Hz，3H)，1.03(s，7H).HRMS[ESI-]for C10H15NO4[(M-H)-]，m/z Calcd：213.10；Found：213.23。
Compound 31: white solid, melting point 101-. The yield was 81%.1H NMR(600MHz，CDCl3)δ6.70(s，1H)，4.34(s，1H)，3.91(s，2H)，2.82-2.43(m，2H)，2.19(d，J＝5.3Hz，1H)，2.10(d，J＝9.5Hz，2H)，1.90(dd，J＝14.2，7.0Hz，1H).HRMS[ESI-]for C9H13NO4S[(M-H)-]，m/z Calcd：231.06；Found：231.27。
Compound 3 m: white solid, melting point 115-116 ℃. The yield was 80%.1H NMR(600MHz，DMSO)δ7.85(s，1H)，7.21(d，J＝7.4Hz，2H)，7.15(d，J＝7.1Hz，3H)，4.23(d，J＝4.7Hz，1H)，3.57(s，3H)，2.99(dd，J＝13.9，4.5Hz，1H)，2.93-2.75(m，1H).HRMS[ESI-]for C13H13NO4[(M-H)-]，m/z Calcd：247.08；Found：247.25。
Compound 3 n: white solid, melting point 145-147 ℃. The yield was 85%.1H NMR(600MHz，DMSO)δ7.84(s，1H)，7.28(d，J＝8.3Hz，2H)，7.16(d，J＝8.3Hz，2H)，4.24(t，J＝4.7Hz，1H)，3.57(s，3H)，2.98(dd，J＝14.0，4.5Hz，1H)，2.86(dd，J＝14.0，5.6Hz，1H).HRMS[ESI-]for C13H12ClNO4[(M-H)-]，m/z Calcd：281.05；Found：281.69。
Compound 3 o: white solid, melting point 161-. The yield was 80%.1H NMR(600MHz，DMSO)δ8.37(s，1H)，7.28(dd，J＝8.2，5.7Hz，1H)，7.18(t，J＝8.8Hz，1H)，5.06(s，1H)，3.64(s，2H)..HRMS[ESI-]for C12H10FNO4[(M-H)-]，m/z Calcd：251.06；Found：251.21。
The specific synthesis method of the compounds 3e and 3m with better activity is as follows:
synthesis of methyl 3-cyclohexyl-2- (3-methoxy-3-oxopropanamido) propionate (2e)
To a 100mL eggplant-shaped bottle, monomethyl malonate (0.59g, 5mmol), (S) - (-) -cyclohexylpropylamine acid methyl ester hydrochloride (1.1g, 5mmol), triethylamine (0.5g, 5mmol) and DMAP (0.03g, 5mmol) were added, and then 25mL of dichloromethane was added as a solvent, and the mixture was stirred in an ice bath under ambient conditions for half an hour, then the ice bath was removed, EDC & HCl (1.0g, 5.25mmol) was added, and the mixture was stirred at room temperature overnight. After the reaction, the remaining organic phase was washed with 1mol/L hydrochloric acid (20mL), washed with sodium chloride solution (20mL), dried over anhydrous sodium sulfate, and concentrated by suction filtration to give a pale yellow oily liquid, Compound 2 e. Yield, 74%.1H NMR(600MHz，CDCl3)δ7.37(d，J＝6.8Hz，1H)，4.64(d，J＝5.3Hz，1H)，3.75(s，1H)，3.72(s，1H)，3.34(s，1H)，1.77(d，J＝12.6Hz，1H)，1.68(d，J＝13.2Hz，2H)，1.64-1.51(m，1H)，1.32(dd，J＝8.0，5.5Hz，1H)，1.25-1.07(m，1H)，1.00-0.80(m，1H).HRMS[ESI-]for C14H23NO5[(M-H)-]，m/z Calcd：284.1498；Found：286.1498。
Synthesis of methyl 5- (cyclohexylmethyl) -4-hydroxy-2-oxo-2, 5-dihydro-1H-pyrrole-3-carboxylate (3e)
Compound 2e (2.85g, 10mmol) and 30% sodium methoxide (2.22mL, 10mmol) were added to a 100mL eggplant-shaped bottle, and methanol (20mL, analytical grade) was added as a solvent, and the mixture was refluxed at 75 ℃ for 3 to 4 hours and followed by TLC until the reaction was completed. After the reaction is finished, the obtained product is concentrated, water (12mL) is added for dissolving, dichloromethane (20mL) is added for extraction to leave a water phase, 1mol/L hydrochloric acid (20mL) is added for acidification, ethyl acetate (20mL) is added for extraction to leave an organic phase, then a saturated sodium chloride solution (20mL) is used for washing, finally, the organic phase is placed on anhydrous sodium sulfate for drying, and suction filtration and concentration are carried out to obtain a white solid, namely a compound 3 e. Melting point 155-. The yield was 81%.1H NMR(600MHz，CDCl3)δ7.29(t，J＝6.7Hz，1H)，7.22-7.13(m，2H)，6.37(s，1H)，4.17(s，1H)，3.92(s，2H)，2.74(s，1H)，2.21(s，1H)，1.98(s，1H).HRMS[ESI-]for C13H18NO4[(M-H)-]，m/z Calcd：252.1236；Found：254.1236。
Synthesis of methyl 3- ((1-methoxy-1-oxo-3-phenylpropan-2-yl) amino) -3-oxopropanoate (2m)
To a 100mL eggplant-shaped bottle, monomethyl malonate (0.59g, 5mmol), L-phenylalanine methyl ester hydrochloride (0.89g, 5mmol), triethylamine (0.5g, 5mmol) and DMAP (0.03g, 5mmol) were added, and then 25mL of dichloromethane was added as a solvent, and the mixture was stirred in an ice bath under ambient conditions for half an hour, then the ice bath was removed, EDC & HCl (1.0g, 5.25mmol) was added, and the mixture was stirred at room temperature overnight. After the reaction, the remaining organic phase was washed with 1mol/L hydrochloric acid (20mL), and then with sodium chloride solution (20mL), and finally dried over anhydrous sodium sulfate, followed by suction filtration and concentration to obtain a pale yellow oily liquid, i.e., Compound 2 m. The yield was 85%.1H NMR(600MHz，DMSO)δ8.56(d，J＝7.6Hz，1H)，7.26(t，J＝7.3Hz，2H)，7.23-7.13(m，3H)，4.46(td，J＝8.3，5.7Hz，1H)，3.58(s，2H)，3.55(d，J＝3.0Hz，2H)，3.23(s，2H)，3.00(dd，J＝13.8，5.7Hz，1H)，2.89(dd，J＝13.8，8.7Hz，1H).HRMS[ESI-]for C14H17NO5[(M-H)-]，m/z Calcd：279.11；Found：279.29。
Synthesis of 5-benzyl-4-hydroxy-2-oxo-2, 5-dihydro-1H-pyrrole-3-carboxylic acid methyl ester (3m)
In a 100mL eggplant-shaped bottle, 2m (2.47g, 10mmol) of the compound and 30% sodium methoxide (2.22mL, 10mmol) were added, and methanol (20mL, analytical grade) was added as a solvent, and the mixture was refluxed at 75 ℃ for 3 to 4 hours and followed by TLC until the reaction was completed. After the reaction is finished, the obtained product is concentrated, water (12mL) is added for dissolving, dichloromethane (20mL) is added for extraction to leave a water phase, 1mol/L hydrochloric acid (20mL) is added for acidification, ethyl acetate (20mL) is added for extraction to leave an organic phase, a saturated sodium chloride solution (20mL) is used for washing, finally, the organic phase is placed on anhydrous sodium sulfate for drying, and suction filtration and concentration are carried out to obtain a white solid, namely a compound 3 m. Melting point 115 ℃ and 116 ℃. The yield was 80%.1H NMR(600MHz，DMSO)δ7.85(s，1H)，7.21(d，J＝7.4Hz，2H)，7.15(d，J＝7.1Hz，3H)，4.23(d，J＝4.7Hz，1H)，3.57(s，3H)，2.99(dd，J＝13.9，4.5Hz，1H)，2.93-2.75(m，1H).HRMS[ESI-]for C13H13NO4[(M-H)-]，m/z Calcd：247.08；Found：247.25。
3. Synthesis of Compounds 5a-5f
In a 100mL eggplant-shaped bottle, under the ice-water bath condition, the isopropylidene malonate (5.8g, 40mmol) and the pyridine (6.5g, 82mmol) are added into a dichloromethane (75mL) solution, the acyl chloride 4a-4f (48mmol) is dissolved in a dichloromethane (25mL) solution, and the solution is slowly dropped into the solution within 1 hour under the protection of nitrogen. And kept stirring for one hour below 0c, after which the ice-water bath was removed, gradually returned to room temperature, and kept stirring overnight. After the reaction is finished, 50mL of dichloromethane is added into the brown solution to quench the reaction, the organic phase is washed by 10% hydrochloric acid (washing 3 times, 75mL each time) and 100mL of pure water respectively, the organic phase is collected and placed on anhydrous sodium sulfate to be dried, the sodium sulfate is removed by filtration, the organic phase is subjected to rotary evaporation to obtain a crude product, the crude product is recrystallized by hot ether, and the target compound is obtained finally by suction filtration.
Compound 5 a: brown solid, yield, 83%.1H NMR(600MHz，CDCl3)δ1.75(s，6H)，2.69(s，3H)，15.13(s，1H).HRMS[ESI-]for C8H10O5[(M-H)-]，m/z Calcd：185.0450；Found：185.0451.
Compound 5 b: pale yellow solid, yield, 82%.1H NMR(600MHz，CDCl3)δ1.25(d，IH，J＝6.9Hz)，1.74(s，6H)，4.10(t，6H，J＝6.9Hz)，15.50(s，1H).HRMS[ESI-]for C10H12O5[(M-H)-]，m/z Calcd：211.0606；Found：211.0609.
Compound 5 c: yellowish brown solid, yield, 85%.1H NMR(600MHz，CDCl3)δ1.20-1.90(m，10H)，1.74(s，6H)，3.74-3.85(m，1H)，15.51(s，1H).HRMS[ESI-]for C13H18O5[(M-H)-]，m/z Calcd：235.1076；Found：235.1077.
Compound 5 d: yellowish brown solid, yield, 85%.1H NMR(600MHz，CDCl3)δ7.75-7.40(m，1H)，1.83(d，J＝1.5Hz，1H).HRMS[ESI-]for C13H12O5[(M-H)-]，m/z Calcd：248.07；Found：248.23.
Compound 5 e: yellowish brown solid, yield, 78%.1H NMR(600MHz，CDCl3)δ7.66-7.27(m，1H)，2.40(s，0H)，1.83(d，J＝1.5Hz，1H).HRMS[ESI-]for C14H14O5[(M-H)-]，m/z Calcd：262.08；Found：262.26.
Compound 5 f: yellowish brown solid, yield, 80%.1H NMR(600MHz，CDCl3)δ3.06-2.99(m，1H)，1.70(d，J＝1.1Hz，2H)，1.66(t，J＝7.5Hz，1H)，1.41(q，J＝7.5Hz，1H)，0.96-0.88(m，1H).HRMS[ESI-]for C11H16O5[(M-H)-]，m/z Calcd：228.10；Found：228.24.
4. Synthesis of Compounds 7a to 7o
Dissolving amino acid methyl ester hydrochloride (10mmol) and compound 6(2.09g, 11mmol) in p-dioxane (40mL) in a 100mL eggplant-shaped bottle, dropwise adding triethylamine (1.01g, 10mmol) to the solution, heating and refluxing at 110 ℃, reacting for 4 hours, performing rotary evaporation, removing the solvent, dissolving the residue in 200mL ethyl acetate, washing the organic phase once with 2mol/L hydrochloric acid (100mL) and saturated sodium chloride solution (100mL), respectively, placing the organic phase on anhydrous sodium sulfate, drying, filtering, performing rotary evaporation on the organic phase to obtain a crude product, and purifying the crude product by column chromatography to obtain intermediates 7a-7o of the target compound.
5. Synthesis of Compounds 8a to 8o
Dissolving 7a-7o (10mmol) in methanol (20mL) in a 100mL eggplant-shaped bottle, adding 30% sodium methoxide (2.22mL, 12mmol), heating and refluxing at 75 ℃ for 4 hours, removing methanol by rotary evaporation, dissolving the residue in pure water (12mL), adjusting the pH to about 2-3 with 1mol/L hydrochloric acid, extracting with diethyl ether, drying the organic phase over anhydrous sodium sulfate, filtering, and evaporating the organic phase to obtain the target compounds 8a-8 o.
Compound 8 a: light yellow solid, melting point 115-116 ℃. Yield, 85%.1H NMR(600MHz，CDCl3)δ2.22(s，3H)，3.03(dd，J＝14.0，6.7Hz，1H)，3.13(dd，J＝14.0，5.6Hz，1H)，3.38(s，2H)，3.72(d，J＝6.1Hz，3H)，4.84(dd，J＝13.5，6.8Hz，1H)，7.07(d，J＝8.2Hz，2H)，7.25(d，J＝8.2Hz，2H).HRMS[ESI-]for C13H12ClNO3[(M-H)-]，m/z Calcd：264.0427；Found：264.0428.
Compound 8 b: white solid, melting point 117-. Yield, 83%.1H NMR(600MHz，CDCl3)δ2.46(d，J＝8.1Hz，3H)，2.69(dd，J＝14.0，9.8Hz，1H)，3.23(dt，J＝12.1，6.0Hz，1H)，4.00(dd，J＝9.5，3.2Hz，1H)，6.32(s，1H)，6.94-7.05(m，2H)，7.19-7.12(m，2H).HRMS[ESI-]for C13H12FNO3[(M-H)-]，m/z Calcd：248.0723；Found：248.0722.
Compound 8 c: yellow solid, melting point 141-. Yield, 88%.1H NMR(600MHz，DMSO)δ0.82(t，J＝7.4Hz，3H)，1.43-1.52(m，1H)，1.61-1.71(m，1H)，2.47(s，3H)，3.78(s，1H)，8.93(s，1H).HRMS[ESI-]for C8H11NO3[(M-H)-]，m/z Calcd：168.0661；Found：168.0660.
Compound 8 d: pale yellow solid, melting point 174-. Yield, 81%.1H NMR(600MHz，CDCl3)δ0.92-0.97(m，3H)，1.41(dt，J＝10.0，7.6Hz，2H)，1.58(dd，J＝13.8，5.6Hz，1H)，1.78-1.85(m，1H)，2.47(d，J＝33.4Hz，3H)，3.82(dd，J＝7.8，4.1Hz，1H)，6.64(d，J＝17.6Hz，1H).HRMS[ESI-]for C9H13NO3[(M-H)-]，m/z Calcd：182.0817；Found：182.0818.
Compound 8 e: white solid, melting point 150-. Yield, 83%.1H NMR(600MHz，CDCl3)δ0.90(t，J＝7.0Hz，3H)，1.28-1.42(m，4H)，1.55-1.66(m，1H)，1.79-1.88(m，1H)，2.48(d，J＝32.7Hz，3H)，3.82(dd，J＝7.9，4.3Hz，1H).HRMS[ESI-]for C10H15NO3[(M-H)-]，m/z Calcd：196.0974；Found：196.0972.
Compound 8 f: yellow solid, melting point 152-. Yield, 78%.1H NMR(600MHz，CDCl3)δ0.85(t，J＝6.2Hz，3H)，1.31(ddd，J＝24.2，14.9，8.5Hz，8H)，1.58(dd，J＝11.9，7.1Hz，1H)，1.82(dd，J＝11.1，7.2Hz，1H)，2.39-2.51(m，3H)，3.80(dd，J＝7.8，4.2Hz，1H)，6.81(s，1H).HRMS[ESI-]for C12H19NO3[(M-H)-]，m/z Calcd：224.1287；Found：224.1286.
Compound 8 g: pale yellow solid, melting point 142-. Yield, 80％。1H NMR(600MHz，CD3OD)δ2.09(s，2H)，2.97(dt，J＝17.9，8.9Hz，1H)，3.16(dd，J＝14.0，5.5Hz，1H)，3.68(d，J＝10.4Hz，3H)，4.70(dd，J＝16.1，10.0Hz，1H)，7.16-7.25(m，3H)，7.27(t，J＝7.1Hz，2H).HRMS[ESI-]for C13H13N03[(M-H)-]，m/z Calcd：230.0817；Found：230.0818.
Compound 8 h: white solid, melting point 123-. Yield, 81%.1H NMR(600MHz，CDCl3)δ1.89-1.80(m，1H)，2.10(s，3H)，2.14-2.23(m，1H)，2.48(d，J＝33.3Hz，3H)，2.58-2.69(m，2H)，3.95(dd，J＝8.4，3.8Hz，1H)，6.88(s，1H).HRMS[ESI-]for C9H13NO3S[(M-H)-]，m/z Calcd：214.0538；Found：214.0537.
Compound 8 i: yellow solid, melting point 141-. Yield, 89%.1H NMR(600MHz，CDCl3)δ0.84-1.04(m，2H)，1.28-1.09(m，3H)，1.35-1.49(m，2H)，1.62-1.79(m，6H)，2.47(d，J＝34.5Hz，3H)，3.88(dd，J＝9.8，3.8Hz，1H)，6.80(s，1H).HRMS[ESI-]for C13H19NO3[(M-H)-]，m/z Calcd：236.1287；Found：236.1288.
Compound 8 j: pale yellow solid, melting point 105-. Yield, 81%.1H NMR(600MHz，CDCl3)δ1.37(dd，J＝16.9，6.9Hz，3H)，2.47(d，J＝34.9Hz，3H)，3.94(dt，J＝20.7，6.9Hz，1H)，6.43(s，1H).HRMS[ESI-]for C7H9NO3[(M-H)-]，m/z Calcd：154.0504；Found：154.0503.
Compound 8 k: white solid, melting point 144-. Yield, 88%.1H NMR(600MHz，CD3OD)δ1.02(d，J＝11.4Hz，9H)，2.21(s，2H)，4.28(d，J＝17.0Hz，1H).HRMS[ESI-]for C10H15NO3[(M-H)-]，m/z Calcd：196.0974；Found：196.0975.
Compound 81: yellow solid, melting point 140-.Yield, 81%.1H NMR(600MHz，CDCl3)δ1.92(dt，J＝14.9，8.0Hz，1H)，2.19(dd，J＝19.7，13.8Hz，1H)，2.38-2.52(m，3H)，2.72(dt，J＝14.0，7.3Hz，2H)，3.81(dd，J＝7.5，4.3Hz，1H)，7.19(dd，J＝14.5，7.2Hz，4H)，7.27(dd，J＝16.1，8.7Hz，2H).HRMS[ESI-]for C14H15NO3[(M-H)-]，m/z Calcd：244.0974；Found：244.0975.
Compound 8 m: light yellow solid, melting point 145-146 ℃. Yield, 85%.1H NMR(600MHz，CD3OD)δ2.33(s，3H)，2.86(dd，J＝14.1，6.0Hz，1H)，2.98(dd，J＝14.2，4.2Hz，1H)，4.08(s，1H)，6.67(dd，J＝19.1，8.4Hz，2H)，6.97(d，J＝8.4Hz，2H).HRMS[ESI-]for C13H13NO4[(M-H)-]，m/z Calcd：246.0766；Found：246.0767.
Compound 8 n: white solid, melting point 139-142 ℃. Yield, 84%.1H NMR(600MHz，DMSO)δ2.25(s，3H)，2.96-3.04(m，1H)，3.08(dt，J＝21.4，10.7Hz，1H)，4.15(s，1H)，6.94(t，J＝7.4Hz，1H)，7.02(t，J＝7.5Hz，1H)，7.46(dd，J＝47.2，8.2Hz，1H)，7.30(t，J＝10.2Hz，1H)，8.87(s，1H)，10.71-10.94(m，1H).HRMS[ESI-]for C15H14N2O3[(M-H)-]，m/z Calcd：269.0926；Found：269.0927.
Compound 8 o: yellow solid, melting point 145-147 ℃. Yield, 89%.1H NMR(600MHz，CDCl3)δ2.48(d，J＝30.2Hz，3H)，3.80(brs，1H)，3.93(brs，1H)，6.47(s，1H).HRMS[ESI-]for C6H7NO3[(M-H)-]，m/z Calcd：140.0348；Found：140.0349.
The specific synthesis method of the compounds 8g and 8i with better activity is as follows:
synthesis of methyl (3-oxobutanoyl) phenylalanine (7g)
In a 100mL eggplant-shaped flask, L-phenylalanine methyl ester hydrochloride (2.15g, 10mmol) and 5-acetyl-2, 2-Dimethyl-1, 3-dioxane-4, 6-dione (2.09g, 11mmol) is dissolved in p-dioxane (40mL), triethylamine (1.01g, 10mmol) is dropwise added to the solution, heating reflux is carried out at 110 ℃, reaction is carried out for 4 hours, rotary evaporation is carried out to remove the solvent, the residue is dissolved in 200mL ethyl acetate, the organic phase is washed once with 2mol/L hydrochloric acid (100mL) and saturated sodium chloride solution (100mL), the organic phase is dried over anhydrous sodium sulfate, filtration is carried out, the organic phase is rotationally evaporated to obtain a crude product, and the crude product is purified by column chromatography to obtain a light yellow oily liquid, namely the compound 7g, the yield is 78%.1H NMR(600MHz，CDCl3)δ2.19(s，3H)，2.99-3.10(m，1H)，3.10-3.18(m，1H)，3.35(s，2H)，3.69(d，J＝10.5Hz，3H)，4.79-4.89(m，1H)，7.11(t，J＝10.8Hz，2H)，7.23(t，J＝7.1Hz，2H)，7.24-7.30(m，2H).HRMS[ESI-]for C14H17NO4[(M-H)-]，m/z Calcd：262.1079；Found：262.1077.
Synthesis of 3-acetyl-4-hydroxy-5-benzyl-2, 5-dihydro-pyrrol-2-one (8g)
In a 100mL eggplant-shaped bottle, (3-oxobutanoyl) phenylalanine methyl ester (2.63g, 10mmol) was dissolved in methanol (20mL), 30% sodium methoxide (2.22mL, 12mmol) was added, the mixture was heated under reflux at 75 ℃ for 4 hours, methanol was removed by rotary evaporation, the residue was dissolved in pure water (12mL), pH was adjusted to about 2 to 3 with 1mol/L hydrochloric acid, extraction was performed with diethyl ether, and the organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to obtain a pale yellow solid, i.e., 8g of the compound. Melting point 142-. Yield, 80%.1H NMR(600MHz，CD3OD)δ2.09(s，2H)，2.97(dt，J＝17.9，8.9Hz，1H)，3.16(dd，J＝14.0，5.5Hz，1H)，3.68(d，J＝10.4Hz，3H)，4.70(dd，J＝16.1，10.0Hz，1H)，7.16-7.25(m，3H)，7.27(t，J＝7.1Hz，2H).HRMS[ESI-]for C13H13NO3[(M-H)-]，m/z Calcd：230.0817；Found：230.0818.
Synthesis of methyl 3-cyclohexyl-2- (3-oxobutanamide) propionate (7i)
Dissolving (S) - (-) cyclohexylalanine methyl ester hydrochloride (2.21g, 10mmol) and 5-acetyl-2, 2-dimethyl-1, 3-dioxane-4, 6-dione (2.09g, 11mmol) in p-dioxane (40mL) in a 100mL eggplant-shaped bottle, dropwise adding triethylamine (1.01g, 10mmol) to the solution, heating under reflux at 110 deg.C, reacting for 4 hours, rotary evaporating, removing the solvent, dissolving the residue in 200mL ethyl acetate, washing the organic phase once with 2mol/L hydrochloric acid (100mL) and saturated sodium chloride solution (100mL), drying the organic phase over anhydrous sodium sulfate, filtering, rotary evaporating the organic phase to obtain a crude product, purifying the crude product by a column chromatography to obtain a light yellow oil, this was compound 7i, yield 82%.1H NMR(600MHz，CDCl3)δ0.82-0.98(m，3H)，1.06-1.26(m，5H)，1.26-1.36(m，1H)，1.52-1.59(m，1H)，1.62(d，J＝12.2Hz，1H)，1.67(dd，J＝9.5，3.5Hz，5H)，1.74(t，J＝16.9Hz，2H)，2.26(s，3H)，3.44(s，2H)，3.71(s，3H)，4.61(td，J＝8.8，5.3Hz，1H).HRMS[ESI-]for C14H23NO4[(M-H)-]，m/z Calcd：268.1549；Found：268.1546.
Synthesis of 3-acetyl-4-hydroxy-5- (cyclohexylmethyl) -2, 5-dihydropyrrol-2-one (8i)
In a 100mL eggplant-shaped bottle, methyl 3-cyclohexyl-2- (3-oxavaleramido) propionate (2.69g, 10mmol) was dissolved in methanol (20mL), 30% sodium methoxide (2.22mL, 12mmol) was added, the mixture was heated under reflux at 75 ℃ for 4 hours, methanol was removed by rotary evaporation, the residue was dissolved in pure water (12mL), the pH was adjusted to about 2 to 3 with 1mol/L hydrochloric acid, extraction was performed with diethyl ether, the organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to obtain a yellow solid, i.e., Compound 8 i. Melting point 141-. Yield, 89%.1H NMR(600MHz，CDCl3)δ0.84-1.04(m，2H)，1.28-1.09(m，3H)，1.35-1.49(m，2H)，1.62-1.79(m，6H)，2.47(d，J＝34.5Hz，3H)，3.88(dd，J＝9.8，3.8Hz，1H)，6.80(s，1H).HRMS[ESI-]for C13H19NO3[(M-H)-]，m/z Calcd：236.1287；Found：236.1288.
6. Synthesis of Compounds 7p to 7r
Synthesis of methyl 2- (3-cyclopropyl-3-oxopropanoylamino) valerate (7p)
Dissolving norvaline methyl ester hydrochloride (1.68g, 10mmol) and 5- (cyclopropanecarbonyl) -2, 2-dimethyl-1, 3-dioxane-4, 6-diketone (2.33g, 11mmol) in 1, 4-dioxane (40mL) in a 100mL eggplant-shaped bottle, dropwise adding triethylamine (1.01g, 10mmol) to the solution, heating and refluxing at 110 ℃, reacting for 4 hours, rotary evaporating, removing the solvent, dissolving the residue in 200mL ethyl acetate, washing the organic phase once with 2mol/L hydrochloric acid (100mL) and saturated sodium chloride solution (100mL), drying the organic phase over anhydrous sodium sulfate, filtering, rotary evaporating the organic phase to obtain a crude product, purifying the crude product by a column chromatography to obtain a light yellow oily liquid, namely compound 7p, yield, 86%.1H NMR(600MHz，CDCl3)δ0.89(t，J＝7.4Hz，3H)，0.97(dd，J＝7.8，3.3Hz，2H)，1.11(td，J＝4.5，2.1Hz，2H)，1.27-1.39(m，2H)，1.65(d，J＝9.3Hz，1H)，1.78(s，1H)，1.99(t，J＝4.4Hz，1H)，3.55(s，2H)，3.70(s，3H)，4.56(dd，J＝7.5，2.1Hz，1H)，7.55(t，J＝22.2Hz，1H).HRMS[ESI-]for C12H19NO4[(M-H)-]，m/z Calcd：240.1236；Found：240.1237.
Synthesis of methyl 2- (3-cyclopropyl-3-oxopropanoylamino) butanoate (7q)
Dissolving methyl (2s) -2-aminobutyric acid hydrochloride (1.54g, 10mmol) and 5- (cyclopropanecarbonyl) -2, 2-dimethyl-1, 3-dioxane-4, 6-dione (2.33g, 11mmol) in 1, 4-dioxane (40mL) in a 100mL eggplant-shaped bottle, dropwise adding triethylamine (1.01g, 10mmol) to the solution, heating and refluxing at 110 deg.C for 4 hours, rotary evaporating, removing the solvent, dissolving the residue in 200mL ethyl acetate, washing the organic phase once with 2mol/L hydrochloric acid (100mL) and saturated sodium chloride solution (100mL), drying the organic phase over anhydrous sodium sulfate, filtering, rotary evaporating the organic phase to obtain a crude product, and introducing the crude product into a 100mL bottlePurifying by column chromatography to obtain yellowish oily liquid, i.e. compound 7q, with yield of 90%.1H NMR(600MHz，CDCl3)δ0.90(t，J＝7.5Hz，3H)，0.94-1.00(m，2H)，1.08-1.14(m，2H)，1.72(dt，J＝21.5，7.3Hz，1H)，1.82-1.92(m，1H)，1.96-2.03(m，1H)，3.55(t，J＝9.0Hz，2H)，3.71(s，3H)，4.54(dt，J＝13.0，6.4Hz，1H)，7.61(d，J＝5.8Hz，1H).HRMS[ESI-]for C11H17NO4[(M-H)-]，m/z Calcd：226.1079；Found：226.1078.
Synthesis of methyl 2- (3-cyclohexyl-3-oxopropanoylamino) valerate (7r)
Dissolving norvaline methyl ester hydrochloride (1.68g, 10mmol) and 5- (cyclohexanecarbonyl) -2, 2-dimethyl-1, 3-dioxane-4, 6-diketone (2.80g, 11mmol) in p-dioxane (40mL) in a 100mL eggplant-shaped bottle, dropwise adding triethylamine (1.01g, 10mmol) to the solution, heating and refluxing at 110 ℃, reacting for 4 hours, rotary evaporating, removing the solvent, dissolving the residue in 200mL ethyl acetate, washing the organic phase once with 2mol/L hydrochloric acid (100mL) and saturated sodium chloride solution (100mL), drying the organic phase over anhydrous sodium sulfate, filtering, rotary evaporating the organic phase to obtain a crude product, purifying the crude product by column chromatography to obtain a light yellow oily liquid, namely compound 7r, yield, 83%.1H NMR(600MHz，CDCl3)δ0.90(t，J＝7.3Hz，3H)，1.13-1.38(m，8H)，1.67(ddd，J＝15.2，10.9，7.0Hz，2H)，1.79(ddd，J＝12.8，9.8，4.4Hz，3H)，1.85(d，J＝12.8Hz，2H)，2.37-2.44(m，1H)，3.38-3.48(m，2H)，3.68-3.75(m，3H)，4.56(dd，J＝13.2，7.5Hz，1H)，7.45(d，J＝6.8Hz，1H).HRMS[ESI-]for C15H24NO4[(M-H)-]，m/z Calcd：282.1705；Found：282.1704.
7. Synthesis of Compounds 8p to 8r
Synthesis of 3- (cyclopropanecarbonyl) -4-hydroxy-5-propyl-2, 5-dihydro-pyrrol-2-one (8p)
In a 100mL eggplant-shaped bottle, 2- (3-cyclopropyl-3-oxopropanoylamino) pentane was addedMethyl acid (2.41g, 10mmol) was dissolved in methanol (20mL) solution, 30% sodium methoxide (2.22mL, 12mmol) was added, heated under reflux at 75 ℃ for 4 hours, methanol was removed by rotary evaporation, and the residue was dissolved in pure water (12mL), pH was adjusted to about 2-3 with 1mol/L hydrochloric acid, extracted with ether, and the organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to give a pale yellow solid, compound 8 p. Melting point 134-. Yield, 85%.1H NMR(600MHz，CDCl3)δ0.97(td，J＝7.4，4.0Hz，3H)，1.13-1.22(m，2H)，1.31-1.38(m，2H)，1.67(dt，J＝14.4，7.3Hz，1H)，1.82-1.92(m，1H)，2.95-3.03(m，1H)，3.78(dd，J＝7.3，4.4Hz，1H)，6.91(s，1H).HRMS[ESI-]for C11H13NO3[(M-H)-]，m/z Calcd：208.0974；Found：208.0973.
Synthesis of 3- (cyclopropanecarbonyl) -4-hydroxy-5-ethyl-2, 5-dihydro-pyrrol-2-one (8q)
In a 100mL eggplant-shaped bottle, methyl 2- (3-cyclopropyl-3-oxopropanoylamino) butyrate (2.27g, 10mmol) was dissolved in a methanol (20mL) solution, 30% sodium methoxide (2.22mL, 12mmol) was added, the mixture was heated under reflux at 75 ℃ for 4 hours, methanol was removed by rotary evaporation, the residue was dissolved in pure water (12mL), the pH was adjusted to about 2 to 3 with 1mol/L hydrochloric acid, extraction was performed with diethyl ether, the organic phase was dried over anhydrous sodium sulfate, filtered and the organic phase was evaporated to give a white solid, i.e., compound 8 q. Melting point 112-. Yield, 88%.1H NMR(600MHz，DMSO)δ0.85(t，J＝7.4Hz，3H)，1.13(q，J＝4.1Hz，4H)，1.44(tt，J＝14.7，7.0Hz，1H)，1.38-1.28(m，2H)，1.64(tdd，J＝9.6，7.6，4.4Hz，1H)，2.84(s，1H)，3.82(s，1H).HRMS[ESI-]for C10H13NO3[(M-H)-]，m/z Calcd：194.0817；Found：194.0818.
Synthesis of 3- (cyclohexanecarbonyl) -4-hydroxy-5-propyl-2, 5-dihydro-pyrrol-2-one (8r)
In a 100mL round bottom flask, methyl 2- (3-cyclohexyl-3-oxopropanoylamino) valerate (2.83g, 10mmol) was dissolved in a methanol (20mL) solution and added30% sodium methoxide (2.22mL, 12mmol), heated at 75 ℃ under reflux for 4 hours, rotary evaporation to remove methanol, and the residue dissolved in pure water (12mL), with 1mol/L hydrochloric acid to pH 2-3, ether extraction, and the organic phase placed in anhydrous sodium sulfate drying, filtration and evaporation of organic phase, yellow solid, compound 8 r. Melting point 115 ℃ and 116 ℃. Yield, 92%.1HNMR(600M HZ，CDCl3)δ0.90-0.97(m，3H)，1.16-1.27(m，1H)，1.32-1.45(m，4H)，1.45-1.53(m，2H)，1.53-1.65(m，1H)，1.71(d，J＝12.8Hz，1H)，1.73-1.86(m，5H)，3.35-3.49(m，1H)，3.79(dd，J＝7.9，4.3Hz，1H)，6.79(s，1H).HRMS[ESI-]for C14H21NO3[(M-H)-]，m/z Calcd：250.1443；Found：250.1444.
8. Synthesis of Compounds 9a to 9c
Synthesis of methyl 1- (3-oxo-3-phenylpropionamido) cyclohexane-1-carboxylate (9a)
Dissolving 1-aminocyclohexanecarboxylic acid methyl ester hydrochloride (1.57g, 10mmol) and 5d-5f (11mmol) in p-dioxane (40mL), dropwise adding triethylamine (1.01g, 10mmol) to the solution, reacting for 4 hours under heating and refluxing conditions, performing rotary evaporation to remove the solvent, dissolving the residue in 200mL ethyl acetate, washing the organic phase once with 2mol/L hydrochloric acid (100mL) and saturated sodium chloride solution (100mL), respectively, placing the organic phase on anhydrous sodium sulfate, drying, filtering, performing rotary evaporation to the organic phase to obtain a crude product, and purifying the crude product by column chromatography to obtain the target compound.
Compound 9 a: pale yellow oily liquid, yield, 78%.1H NMR(600MHz，CDCl3)δ7.97(dd，J＝8.2，1.6Hz，1H)，7.66-7.42(m，2H)，3.95(d，J＝1.5Hz，1H)，3.62(d，J＝1.6Hz，1H)，2.12-1.97(m，1H)，1.81(td，J＝13.7，13.1，3.7Hz，1H)，1.63(dt，J＝14.4，4.4Hz，2H)，1.52-1.41(m，1H)，1.28(dt，J＝12.5，3.7Hz，1H).HRMS[ESI-]for C17H21NO4[(M-H)-]，m/z Calcd：303.15；Found：303.36.
Chemical combinationAn object 9 b: pale yellow oily liquid, yield, 85%.1H NMR(600MHz，CDCl3)δ7.86-7.74(m，1H)，7.61(s，1H)，7.49-7.35(m，1H)，3.93(s，1H)，3.64(s，2H)，2.40(s，2H)，2.06(dd，J＝13.5，4.3Hz，1H)，1.81(td，J＝13.6，13.1，3.7Hz，1H)，1.63(td，J＝9.3，8.3，4.3Hz，2H)，1.44(ddq，J＝15.3，8.3，3.8Hz，1H)，1.35-1.22(m，1H).HRMS[ESI-]for C18H23NO4[(M-H)-]，m/z Calcd：317.16；Found：317.39.
Compound 9 c: pale yellow oily liquid, yield, 80%.1H NMR(600MHz，CDCl3)δ7.45(s，1H)，3.67(d，J＝1.5Hz，3H)，3.39(d，J＝1.4Hz，2H)，2.51(t，J＝7.4Hz，2H)，2.09-1.96(m，2H)，1.80(dd，J＝12.6，3.5Hz，2H)，1.67-1.60(m，4H)，1.56(td，J＝7.5，1.5Hz，2H)，1.42(dt，J＝15.4，11.4Hz，2H)，1.35-1.22(m，3H)，0.89(td，J＝7.3，1.5Hz，3H).HRMS[ESI-]for C15H25NO4[(M-H)-]，m/z Calcd：283.18；Found：283.37.
9. Synthesis of Compounds 10a to 10c
Dissolving 9a-9c (10mmol) in methanol (20mL), adding 30% sodium methoxide (2.22mL, 12mmol), reacting under heating and refluxing conditions for 4 hours, rotary evaporating to remove methanol, dissolving the residue in pure water (12mL), adjusting pH to about 2-3 with 1mol/L hydrochloric acid, extracting with diethyl ether, drying the organic phase over anhydrous sodium sulfate, filtering, and evaporating the organic phase to obtain the target compounds 10a-10c
Compound 10 a: white solid, melting point 121-.1H NMR(600MHz，CDCl3)δ8.26-8.14(m，1H)，7.72(s，1H)，7.62-7.53(m，1H)，7.51-7.44(m，1H)，1.93-1.69(m，4H)，1.58(d，J＝12.2Hz，1H)，1.50-1.26(m，2H).HRMS[ESI-]for C16H17NO3[(M-H)-]，m/z Calcd：271.12；Found：271.32.
Compound 10 b: white solid, melting point 115 ℃ and 116 ℃, yield 85%.1H NMR(600MHz，CDCl3)δ8.02(d，J＝7.7Hz，1H)，7.75(s，0H)，7.48-7.33(m，1H)，2.42(s，2H)，1.78(dt，J＝44.5，13.0Hz，3H)，1.57(d，J＝13.3Hz，1H)，1.40(dt，J＝49.3，13.1Hz，1H).HRMS[ESI-]for C17H19NO3[(M-H)-]，m/z Calcd：285.14；Found：285.34.
Compound 10 c: white solid, mp 117-.1H NMR(600MHz，CDCl3)δ7.45(s，1H)，2.94-2.74(m，2H)，1.89-1.59(m，8H)，1.50(d，J＝13.4Hz，2H)，1.45-1.29(m，6H)，0.92(t，J＝7.3Hz，4H).HRMS[ESI-]for C14H21NO3[(M-H)-]，m/z Calcd：251.15；Found：251.33.
10. Synthesis of Compounds 11a to 11c
Synthesis of 3-benzoyl-2-oxo-1-azaspiro [4.5] dec-3-en-4-yl acetate (11a)
Glacial acetic acid (0.87g, 7.5mmol), DMAP (0.92g, 7.5mmol) and EDC & HCl (1.44g, 7.5mmol) were dissolved in an anhydrous dichloromethane solution (20mL) in a 100mL eggplant-shaped bottle, and after stirring at room temperature for 30 minutes, a 10a (2.71g, 5mmol) dichloromethane solution was added dropwise to the mixed solution. The reaction was carried out at room temperature for 16 hours and TLC followed until the starting material had reacted completely. After the reaction is complete, filtration is carried out, the filtrate is diluted with 20mL of dichloromethane and the organic phase is diluted with 5% NaHCO3The solution (30 mL each), 1mol/L hydrochloric acid (30 mL each), pure water (30 mL each) washed three times. The dichloromethane phase was dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (ethyl acetate: petroleum ether 3: 1, vol.) to give the title product 11a as a white solid. Melting point 161-. Yield, 98%.1H NMR(600MHz，CDCl3)δ8.26-8.14(m，1H)，7.72(s，1H)，7.62-7.53(m，1H)，7.51-7.44(m，1H)，2.17-2.12(s，3H)1.93-1.69(m，4H)，1.58(d，J＝12.2Hz，1H)，1.50-1.26(m，2H).HRMS[ESI-]for C18H19NO4[(M-H)-]，m/z Calcd：313.13；Found：313.35.
Synthesis of 4-acetoxy-5-benzyl-2-oxo-2, 5-dihydro-1H-pyrrole-3-carboxylic acid methyl ester (11b)
Glacial acetic acid (0.87g, 7.5mmol), DMAP (0.92g, 7.5mmol) and EDC.HCl (1.44g, 7.5mmol) were dissolved in anhydrous dichloromethane solution (20mL) in a 100mL eggplant-shaped bottle, and after stirring at room temperature for 30 minutes, a 3e (1.23g, 5mmol) dichloromethane solution was added dropwise to the mixed solution. The reaction was carried out at room temperature for 16 hours and TLC followed until the starting material had reacted completely. After the reaction is complete, filtration is carried out, the filtrate is diluted with 20mL of dichloromethane and the organic phase is diluted with 5% NaHCO3The solution (30 mL each), 1mol/L hydrochloric acid (30 mL each), pure water (30 mL each) washed three times. The dichloromethane phase was dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (ethyl acetate: petroleum ether 4: 1, vol.) to give the title product 11b as a white solid. Melting point 145-147 ℃. Yield, 94%. .1H NMR(600MHz，CDCl3)δ7.29(t，J＝6.7Hz，1H)，7.22-7.13(m，2H)，6.37(s，1H)，4.17(s，1H)，3.92(s，2H)，2.74(s，1H)，2.21(s，1H)，2.15-2.10(s，3H)1.98(s，1H).HRMS[ESI-]for C13H18NO4[(M-H)-]，m/z Calcd：252.1236；Found：254.1236。
Synthesis of methyl 4-acetoxy-5- (cyclohexylmethyl) -2-oxo-2, 5-dihydro-1H-pyrrole-3-carboxylate (11c)
Glacial acetic acid (0.87g, 7.5mmol), DMAP (0.92g, 7.5mmol) and EDC & HCl (1.44g, 7.5mmol) were dissolved in an anhydrous dichloromethane solution (20mL) in a 100mL eggplant-shaped bottle, and after stirring at room temperature for 30 minutes, a 3m (1.26, 5mmol) dichloromethane solution was added dropwise to the mixed solution. The reaction was carried out at room temperature for 16 hours and TLC followed until the starting material had reacted completely. After the reaction is complete, filtration is carried out, the filtrate is diluted with 20mL of dichloromethane and the organic phase is diluted with 5% NaHCO3The solution (30 mL each), 1mol/L hydrochloric acid (30 mL each), pure water (30 mL each) washed three times. The dichloromethane phase was dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (ethyl acetate: petroleum ether 3: 1, vol.) to give the title product 11c as a white solid. Melting point 155-. Yield, 95%.1H NMR(600MHz，DMSO)δ7.85(s，1H)，7.21(d，J＝7.4Hz，2H)，7.15(d，J＝7.1Hz，3H)，4.23(d，J＝4.7Hz，1H)，3.57(s，3H)，2.99(dd，J＝13.9，4.5Hz，1H)，2.93-2.75(m，1H).2.16-2.12(s，3H)HRMS[ESI-]for C13H13NO4[(M-H)-]，m/z Calcd：247.08；Found：247.25。
The compounds prepared according to the above process, using different starting materials, are specified in tables 3 and 4:
TABLE 3
Moiety R1The structure of the compound with a cyclic structure is as follows, and is specifically shown in the table 4:
TABLE 4
Example 2 insecticidal Activity test of the amino acid derivatives
The aphid belongs to homoptera pests, has a sucking mouth device and is a common crop pest. The Aphis fabae (Aphis cracivora) is taken as a test object and tested by adopting a dipping method.
Accurately weighing various samples and spirotetramat standard substances, respectively adding N, N-dimethylformamide to prepare 10g/L mother liquor, and diluting the mother liquor to 500 mu g/mL by using an aqueous solution containing 0.2mL/L Triton X-100 during experiment. After the wingless adult aphids are stably sucked on the bean sprouts, immersing the wingless adult aphids and the bean sprouts into the liquid medicine with the concentration of 500 mu g/ml, taking out the wingless adult aphids and the bean sprouts after 5s, sucking the redundant liquid medicine by using absorbent paper, and transferring the wingless adult aphids into a clean vessel for constant-temperature culture at 23 ℃. Each concentration was repeated 3 times, and the blank was an aqueous solution containing 0.2mL/L Triton X-100. After 24 hours of treatment. And counting the number of dead aphids of the aphids and calculating the mortality (%). The results are shown in Table 5.
The plant hopper belongs to homoptera pests, has a sucking device, and is a common crop pest. Brown planthopper (Nilaparvata lugens) was used as a test object and tested by a spray method.
The operation process is as follows: accurately preparing the compound to be detected into a solution with a certain concentration, and treating with clear water as a blank control and spirotetramat as a positive control. Each treatment was repeated 3 times. 2mL of the solution was uniformly sprayed per cup with a small hand sprayer. 10 rice planthoppers are inoculated in each pot 6 hours before pesticide application. A total of 3 batches of the test were run sequentially. After 24 hours of treatment, the number of dead insects of the test insects was counted, and the mortality (%) was calculated. The results are shown in Table 5.
TABLE 5
Note: the numbers in table 5 correspond to the numbers in tables 2 to 4.
Experiments show that the tetramic acid derivative has good insecticidal activity on mealybugs and whiteflies.
Although the invention has been described in detail hereinabove with respect to a general description and specific embodiments thereof, it will be apparent to those skilled in the art that modifications or improvements may be made thereto based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.
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