CN114409664B - Spiro heterocyclic tetrahydropyran compound and preparation method and application thereof - Google Patents
Spiro heterocyclic tetrahydropyran compound and preparation method and application thereof Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
Abstract
The invention provides a spiro heterocyclic tetrahydropyran compound, a preparation method and application thereof, and the structure of the spiro heterocyclic tetrahydropyran compound is shown as a formula (I). The pesticide has stable chemical property, higher insecticidal activity, excellent insecticidal activity under lower medicament concentration, higher insecticidal activity on aphids and red spiders, is a novel and efficient biological pesticide, can relieve the drug resistance of diseases and insect pests to spirotetramat or avermectin medicines, has high pesticide research value and has wide application prospect in agriculture.
Description
Technical Field
The invention relates to the technical field of agricultural chemicals and preparation, in particular to a spiro heterocyclic tetrahydropyran compound, a preparation method and application thereof.
Background
The spiro compound has a rigid structure and a stable structure, and has important application in various fields such as medicines, pesticides, high polymer adhesives and the like. The two ring planes of the spiro compound are perpendicular to each other, and the heterocyclic spiro compound may have special properties which are not possessed by general organic compounds such as spiro conjugation, spiro super conjugation or heterohead effect. Under certain conditions, asymmetric molecules or asymmetric molecules can be formed due to the existence of chiral axes, and the chiral spiro ring has strong rigidity and is not easy to racemize, which is incomparable with chiral carbon. Therefore, in recent years, spiro compounds have wide application prospects in the fields of medicine and biology, and many spiro compounds are important intermediates of medicines and pesticides.
The spirotetramat is one of the insecticides with double-inward sucking conductivity, can effectively prevent and treat various sucking mouthparts pests such as aphids, thrips, psyllids, mealybugs, scale insects and the like, has the advantages of broad spectrum, high efficiency and long lasting period, and is a pesticide for preventing and treating diseases and insect pests.
However, the effect of preventing and controlling diseases and insect pests of spirotetramat is obviously reduced at a lower application concentration, and the drug resistance of the diseases and insect pests is gradually enhanced along with the gradual increase of the use of spirotetramat in recent years. Therefore, the novel spiro compound is designed and synthesized to reduce the drug resistance of plant diseases and insect pests, and has very important significance for providing more efficient candidate compounds for the pesticide field.
Disclosure of Invention
In view of the above problems, the present invention provides a spiroheterocyclic tetrahydropyran compound, a preparation method and applications thereof.
In order to solve the technical problems, the technical scheme provided by the invention is as follows:
a spiroheterocyclic tetrahydropyran compound has a structure shown in a formula (I):
wherein R is methyl, ethyl or isopropyl; x is H, F, cl or Br.
The novel spiroheterocyclic tetrahydropyran compound is designed and synthesized, has stable chemical property, higher insecticidal activity, excellent insecticidal activity under lower medicament concentration, particularly higher insecticidal activity on aphids and red spiders, is a novel and efficient biological pesticide, can relieve the drug resistance of diseases and insect pests to spirotetramat or avermectin medicines, has high pesticide research value, and has wide application prospects in agriculture.
Preferably, the spiroheterocyclic tetrahydropyran compound has the structural formula:
the invention also provides a preparation method of the spiro-heterocyclic tetrahydropyran compound, which comprises the following steps:
step a, in an inert solvent a, furfuryl alcohol and m-chloroperoxybenzoic acid are subjected to ring-expanding reaction, and after the reaction is finished, organic alkali and organic alkali are added into a systemContinuously carrying out an acetylation reaction to obtain 5-carbonyl-5, 6-dihydro-2H-pyran-2-yl acetate; wherein R is 1 Is chloro or acetate;
step b, 5-carbonyl-5, 6-dihydro-2H-pyran-2-yl-acetate with R-OH in SnCl in inert solvent a 4 Carrying out substitution reaction under catalysis to obtain a compound shown in a formula (II); wherein R is methyl, ethyl or isopropyl;
step c, in an inert solvent b, carrying out catalytic hydrogenation on the compound shown in the formula (II) to obtain a compound shown in the formula (III);
step d, in a polar solvent, carrying out Bucherer-Bergs reaction on the compound shown in the formula (III), alkali metal cyanide and ammonium salt to obtain a compound shown in the formula (IV); then, carrying out hydrolysis reaction on the compound shown in the formula (IV) in an alkaline aqueous solution to obtain a compound shown in the formula (V);
step e, in a methanol solvent, performing methyl esterification reaction on the compound shown in the formula (V) and thionyl chloride to obtain a compound shown in the formula (VI);
step f, in an inert solvent c, carrying out an acylation reaction on a compound shown in a formula (VI) and a compound shown in a formula (VII) under the action of organic base to obtain a compound shown in a formula (VIII); then adding alkali metal hydride into the system to continue the ring closure reaction to obtain a compound shown in a formula (IX);
and g, carrying out esterification reaction on the compound shown in the formula (IX) and ethyl chloroformate under the action of organic base to obtain the compound shown in the formula (I). The specific reaction route is as follows:
preferably, in the step a, the inert solvent a is dichloromethane or dichloroethane, and the addition amount of the inert solvent a is 3-10 times of the mass of furfuryl alcohol.
Preferably, in the step a, the molar ratio of the m-chloroperoxybenzoic acid to the furfuryl alcohol is 1:1-1.5:1.
Preferably, in step a, theThe molar ratio of the furfuryl alcohol to the furfuryl alcohol is 1.05:1-1.2:1.
Preferably, in step a, the organic base is triethylamine, tetramethyl ethylenediamine or pyridine, and the molar ratio of the organic base to furfuryl alcohol is 1.05:1-1.2:1
Preferably, the temperature of the ring expansion reaction and the acetylation reaction is 0-5 ℃, the time of the ring expansion reaction is 6-8 h, and the time of the acetylation reaction is 1.5-2 h.
Preferably, in the step b, the temperature of the substitution reaction is 20-30 ℃ and the reaction time is 3-4 h.
Preferably, in step b, the inert solvent a is dichloromethane or dichloroethane.
Preferably, in step b, the molar ratio of R-OH to furfuryl alcohol is 1:1-2:1.
Preferably, in step b, snCl 4 The molar ratio of the furfuryl alcohol to the furfuryl alcohol is 0.3:1-1:1.
Preferably, in the step c, the inert solvent b is ethyl acetate or tetrahydrofuran, and the addition amount of the inert solvent b is 3-5 times of the mass of the compound shown in the formula (II).
Preferably, in the step c, the hydrogenation catalyst is a 5% palladium carbon catalyst, and the mass ratio of the hydrogenation catalyst to the compound shown in the formula (II) is 0.001:1-0.01:1.
Illustratively, in step c, the catalytic hydrogenation is carried out at normal temperature and pressure.
Preferably, in the step d, the polar solvent is water, methanol, tetrahydrofuran or ethanol, and the mass ratio of the polar solvent to the compound shown in the formula (III) is 2.0:1-5:1.
Preferably, in step d, the alkali metal cyanide is sodium cyanide, potassium cyanide or ammonium cyanide.
Preferably, in step d, the ammonium salt is ammonium carbonate or ammonium bicarbonate.
Further preferably, in step d, the molar ratio of the compound of formula (III), the alkali metal cyanide and the ammonium salt is from 1:1:1 to 1:2:4.
Preferably, in the step d, the temperature of the Bucherer-Bergs reaction is 0-60 ℃ and the reaction time is 5-12 h.
Preferably, in the step d, the temperature of the hydrolysis reaction is 80-100 ℃, and the time of the hydrolysis reaction is 6-10 h.
Illustratively, in step d, the alkaline aqueous solution is an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution or an aqueous calcium hydroxide solution having a concentration of 10wt% to 20 wt%.
Preferably, in step d, the molar ratio of the compound of formula (IV) to the base is from 1:1 to 1:1.5.
Preferably, in the step e, the temperature of the methyl esterification reaction is between-5 ℃ and 0 ℃ and the reaction time is between 3h and 5h.
Preferably, in the step e, the thionyl chloride is added into the solution of the compound shown in the formula (V) in a slow dropwise manner.
Preferably, in the step e, the molar ratio of the compound shown in the formula (V) to the thionyl chloride is 1:1-1:1.5.
Preferably, in the step a, the addition amount of the methanol is 3 to 10 times the mass of the compound represented by the formula (V).
Preferably, in the step f, the organic base is triethylamine, tetramethyl ethylenediamine or pyridine, and the molar ratio of the organic base to the compound shown in the formula (VI) is 1:1-1.15:1.
Preferably, in the step f, the inert solvent c is toluene, dichloromethane or dichloroethane, and the mass ratio of the inert solvent c to the compound shown in the formula (VI) is 4-10:1.
Preferably, in the step f, the alkali metal hydride salt is sodium hydride or potassium hydride, and the molar ratio of the alkali metal hydride salt to the compound shown in the formula (VI) is 2:1-2.3:1.
Preferably, in the step f, the temperature of the acylation reaction is between-5 ℃ and 0 ℃ and the reaction time is between 1h and 1.5h.
Preferably, in the step f, the temperature of the ring closing reaction is between-5 ℃ and 0 ℃ and the reaction time is between 3h and 5h.
Illustratively, in step f, when X is halogen, the process for preparing the compound of formula (VII) comprises the steps of:
s101, in a first inert solvent, reacting 2, 5-dimethylbenzene acetic acid with N-chlorosuccinimide under the action of an initiator at 60-80 ℃ for 4-6 hours to obtain chloro-2, 5-dimethylbenzene acetic acid;
in a first inert solvent, 2, 5-dimethylbenzene acetic acid and N-bromosuccinimide react for 4-6 hours at 60-80 ℃ under the action of an initiator to obtain bromo2, 5-dimethylbenzene acetic acid;
s102, in a second inert solvent, reacting chloro-2, 5-dimethylbenzene acetic acid or bromo-2, 5-dimethylbenzene acetic acid with sodium fluoride at 120-150 ℃ for 5-8 h to obtain fluoro-2, 5-dimethylbenzene acetic acid;
s103, in a third inert solvent, reacting halogenated 2, 5-dimethylbenzene acetic acid with thionyl chloride for 0.5-2 hours at the temperature of 0-30 ℃ under the action of a catalyst, wherein the compound is shown in a formula (VII);
wherein the halogenated 2, 5-dimethylbenzene acetic acid is chloro 2, 5-dimethylbenzene acetic acid or bromo 2, 5-dimethylbenzene acetic acid prepared in the step 1 or fluoro 2, 5-dimethylbenzene acetic acid prepared in the step 2.
Further, in step S101, the first inert solvent is 1, 2-dichloroethane or dimethylformamide, and the mass ratio of the first inert solvent to 2, 5-dimethylbenzeneacetic acid is 4:1-10:1.
Further, in step S101, the molar ratio of the N-chlorosuccinimide or the N-bromosuccinimide to the 2, 5-dimethylbenzeneacetic acid is 1:1-2:1.
Further, in step S101, the initiator is azobisisobutyronitrile, and the molar ratio of the initiator to 2, 5-dimethylbenzeneacetic acid is 0.05:1 to 0.1:1.
Further, in step S102, the second inert solvent is N, N-dimethylformamide or N, N-dimethylacetamide, and the mass ratio of the second inert solvent to halogenated 2, 5-dimethylbenzeneacetic acid is 3:1-6:1.
Further, in step S102, the molar ratio of the sodium fluoride to the chloro-2, 5-dimethylbenzeneacetic acid or bromo-2, 5-dimethylbenzeneacetic acid is 1:1-3:1.
Further, in step S103, the third inert solvent is dichloromethane or 1, 2-dichloroethane, and the mass ratio of the third inert solvent to halogenated 2, 5-dimethylbenzeneacetic acid is 3:1-10:1.
Further, in step S103, the catalyst is N, N-dimethylformamide or N, N-dimethylacetamide, and the mass ratio of the catalyst to halogenated 2, 5-dimethylbenzeneacetic acid is 0.001:1 to 0.01:1.
Further, in step S103, the molar ratio of the thionyl chloride to the halogenated 2, 5-dimethylbenzeneacetic acid is 1:1-1.5:1.
Preferably, in step g, the organic base is triethylamine, tetramethyl ethylenediamine or pyridine, and the molar ratio of the organic base to the compound represented by formula (IX) is 1.05:1-1.2:1.
Preferably, in the step g, the molar ratio of the compound shown in the formula (IX) to ethyl chloroformate is 1:1-1:1.1.
Preferably, in the step g, the temperature of the esterification reaction is between-5 ℃ and 0 ℃ and the reaction time is between 0.5h and 1h.
Illustratively, in step f, when X is H, the process for preparing the compound of formula (VII) comprises the steps of:
in a third inert solvent, 2, 5-dimethylbenzene acetic acid and thionyl chloride react for 0.5-2h at the temperature of 0-30 ℃ under the action of a catalyst, and a compound shown in a formula (VII).
The invention also provides application of the spiroheterocyclic tetrahydropyran compound in preventing and controlling plant diseases and insect pests.
Preferably, the spiroheterocyclic tetrahydropyran compound shown in the formula (I) has a high control effect on aphids and red spiders.
The spiroheterocyclic tetrahydropyran compound shown in the formula (I) can be applied to the control of agricultural diseases and insect pests, and has a high control effect on aphids and red spiders.
The invention also provides a pharmaceutical composition for preventing and treating aphids or red spiders, which comprises the spiroheterocyclic tetrahydropyran compound shown in the formula (I).
When used as a pharmaceutical active ingredient for controlling crop diseases and insect pests, various methods or techniques are available. The spiroheterocyclic tetrahydropyran compound shown in the formula (I) and conventional auxiliary agents in the pesticide field are prepared into various dosage forms, such as emulsifiable concentrates, granules or powder, and the like, and the spiroheterocyclic tetrahydropyran compound is applied to plant roots and stems or leaves to control plant diseases and insect pests by a conventional pesticide application method, such as dipping or spraying, and the like, and the concentration of the preparation is 0.75-0.04 mg/L, so that the spiroheterocyclic tetrahydropyran compound has a high control effect on aphids or red spiders.
Detailed Description
The present invention will be described in further detail with reference to the following examples in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.
Example 1
The present example provides a process for preparing a compound of formula (iii):
adding 500g of dichloromethane and 68.7g of furfuryl alcohol (0.7 mol) into a 1L four-port bottle, controlling the temperature to be 0-5 ℃, adding 173g (1.0 mol) of m-chloroperoxybenzoic acid, carrying out heat preservation and stirring for reaction for 6 hours, filtering to remove insoluble substances, controlling the temperature of the obtained clarified mother liquor to be 0-5 ℃, adding 80.8g (0.8 mol) of triethylamine, stirring for 10 minutes, slowly dripping 60.4g (0.77 mol) of acetyl chloride, carrying out heat preservation and reaction for 2 hours after dripping is finished, then adding 50mL of saturated sodium bicarbonate solution into the reaction solution, stirring for 30 minutes, separating the solution, extracting a water layer with 30mL of dichloromethane multiplied by 2 times, combining organic phases and drying anhydrous magnesium sulfate to obtain a dichloromethane solution of 5-carbonyl-5, 6-dihydro-2H-pyran-2-yl acetate;
84g (1.4 mol) of isopropyl alcohol was added to a methylene chloride solution of dried 5-carbonyl-5, 6-dihydro-2H-pyran-2-yl acetate, and 91g (0.35 mol) of SnCl was slowly dropped at room temperature 4 After stirring and reacting for 4 hours, adding 50mL of saturated sodium bicarbonate solution into the reaction solution, stirring for 30min, separating liquid, extracting the water phase with 30mL multiplied by 2 times of ethyl acetate, combining organic phases, drying by anhydrous magnesium sulfate, and concentrating to dryness;
the obtained product is dissolved by 250g of ethyl acetate, dried by anhydrous magnesium sulfate, added into a 500mL reaction bottle, added with 0.5g of 5% Pd/C catalyst, added with hydrogen balloon, provided with hydrogen by the hydrogen balloon, stirred at room temperature for reaction for 1.5h, filtered to remove the catalyst, concentrated and purified by column chromatography (eluent is ethyl acetate and n-hexane with volume ratio of 10:1), and distilled under reduced pressure to obtain colorless oily matter, namely 75.2g of compound shown in formula (II) (namely compound IIa), the yield is 68% and the purity is 99.5%.
Taking a small amount of the colorless oily reaction product, concentrating and drying, and carrying out structure confirmation:
1 HNMR(DMSO)δppm：4.58(dd,J 1 ＝8.2,J 2 ＝3.5,2H),4.20(t,J＝2.2,lH),3.19(m,1H),2.50(m,2H),2.0(m,lH),1.75(m,lH),1.13(s,3H),1.10(s,3H)。
LC-MS[M+H] + ：159.10。
the compound of formula (II) can be prepared by using other reaction conditions and reaction solvents as defined in the specification of the present invention, and the technical effects basically equivalent to those described above can be achieved.
Examples 2 to 3
The synthesis of compounds IIIb and IIIc was carried out according to the procedure described above, and the specific process parameters were adjusted as usual in example 1.
Example 4
Preparation of a compound represented by formula (IV):
120g (1.52 mol) of ammonium bicarbonate, 20g (0.4 mol) of sodium cyanide are weighed and added into a mixed solution of 30g of water and 100g of tetrahydrofuran, stirring and suspending are carried out, 60.6g (0.38 mol) of the compound IIa prepared in example 3 is added at room temperature, after uniform mixing, the temperature is raised to 55 ℃ for heat preservation and reaction for 6 hours, filtering is carried out, filter cakes are washed by 20g of tetrahydrofuran, mother solutions are combined, concentrated to dryness and dried, and white solid 85.7g (compound IVa) is obtained, and the yield is 98% and the purity is 96.2%.
The synthesis of the compounds IVb and IVc is carried out by the above-mentioned methods, and the specific process parameters can be adjusted conventionally according to the above-mentioned examples.
Example 5
Preparation of the Compound of formula (VII):
preparation of 3-chloro-2, 5-dimethylbenzene acetyl acid and 4-chloro-2, 5-dimethylbenzene acetyl acid:
16.4g of 2, 5-dimethylbenzeneacetic acid is weighed and placed in a 250mL reaction bottle, 80g of 1, 2-dichloroethane, 15g N-chlorosuccinimide, 0.9g of azobisisobutyronitrile and 30g of dimethylformamide are added, the mixture is reacted for 5 hours at 80 ℃, the mixture is filtered, mother liquor is concentrated and then subjected to column chromatography (eluent is a mixed solution of dichloromethane, methanol and glacial acetic acid with the volume ratio of 20:1:0.001), and the mixture is evaporated and concentrated to obtain 9.6g of 3-chloro-2.5-dimethylbenzeneacetic acid and 7.0g of 4-chloro-2.5-dimethylbenzeneacetic acid.
Preparation of 3-bromo-2.5-dimethylbenzene acetyl acid and 4-bromo-2.5-dimethylbenzene acetyl acid:
16.4g of 2, 5-dimethylbenzeneacetic acid is weighed and placed in a 250mL reaction bottle, 80g of 1, 2-dichloroethane, 20.2-g N-bromosuccinimide, 0.9g of azobisisobutyronitrile and 30g of dimethylformamide are added, the reaction is carried out for 5 hours at 80 ℃, filtration is carried out, mother liquor is concentrated, and then column chromatography (eluent is a mixed solution of dichloromethane, methanol and glacial acetic acid with the volume ratio of 20:1:0.001) is carried out, and evaporation concentration is carried out, thus obtaining 12.2g of 3-bromo-2.5-dimethylbenzeneacetic acid and 9.7g of 4-bromo-2.5-dimethylbenzeneacetic acid.
Preparation of 3-fluoro-2.5-dimethylbenzeneacetic acid:
9.6g of 3-chloro-2, 5-dimethylbenzeneacetic acid is placed in a 100mL reaction bottle, 40g of dimethylformamide and 4.0g of sodium fluoride are added, the mixture is uniformly mixed, the mixture is reacted at 150 ℃ for 5 hours, the reaction solution is poured into 200mL of ice water, then 50mL of acetic acid is used for extraction for 3 times, the organic phases are combined, and the mixture is dried by anhydrous magnesium sulfate, so that 7.1g of 3-fluoro-2.5-dimethylbenzeneacetic acid is obtained.
Preparation of 3-chloro-2, 5-dimethylbenzene acetyl chloride:
9.6g of 3-chloro-2, 5-dimethylbenzene acetic acid is weighed and placed in a 100mL reaction bottle, 40g of methylene dichloride and 0.1g of dimethylformamide are added, 7.0g of thionyl chloride is slowly dripped into the reaction bottle at 30 ℃, the reaction bottle is stirred for 2 hours under heat preservation, and the reaction bottle is concentrated under reduced pressure to obtain yellow oily matter, namely 10.6g of 3-chloro-2, 5-dimethylbenzene acetyl chloride, and the yield is 95 percent and the purity is 95 percent.
Other halo-2, 5-dimethylbenzeneacetic acid can be used to prepare other compounds of formula (VII) according to the above-described methods, and specific process conditions can be adjusted conventionally with reference to the method for 3-chloro-2, 5-dimethylbenzeneacetyl chloride.
Example 6
84.4g (0.37 mol) of the compound IVa prepared in example 4 is added into a reaction bottle, 222g of 10wt% sodium hydroxide aqueous solution is added, the temperature is raised to 80 ℃ for reaction for 10 hours, the temperature is reduced to 0 ℃, the pH is regulated to 6.5-7.2 by 5wt% dilute hydrochloric acid, the temperature is kept and stirred for 30 minutes, and the concentration is carried out, so that 70.0g of the compound shown in the formula (Va) is obtained as a earthy yellow solid, the yield is 93%, and the purity is 98.2%.
The synthesis of compounds vb and vb c is carried out by the methods described above, and the specific process parameters can be adjusted conventionally as in the examples described above.
Example 7
Preparation of the Compound of formula VI:
63.8g (0.31 mol) of compound Va prepared in example 6 is added into a 500mL four-necked flask, 200g of methanol is added, the temperature is reduced to-5 ℃ to 0 ℃, 44.8g (0.38 mol) of thionyl chloride is slowly added dropwise, the temperature is controlled to be not more than 0 ℃, the reaction is carried out for 3 hours after the dropwise addition, and 73.5g of yellow solid is obtained after the reaction, namely the compound VIa is obtained by spin drying.
63.4g (0.25 mol) of compound VIa is added into a four-mouth bottle, 300g of toluene is added, 46.6g (0.256 mol) of 2, 5-dimethylbenzene acetyl chloride is slowly added dropwise, the temperature is reduced to-5 ℃ to 0 ℃, 28g (0.277 mol) of triethylamine is slowly added dropwise, the reaction is carried out for 1h after the dropwise addition, then 20g (0.5 mol) of sodium hydride solid with the content of 60wt% is slowly added, the reaction is carried out for 3h after the dropwise addition, dilute hydrochloric acid is slowly added after the reaction of the detection raw materials is finished to adjust the pH value to 3-4, the mixture is stirred for 10min at room temperature, the separated liquid is dried by anhydrous magnesium sulfate, 35g (0.30 mol) of tetramethyl ethylenediamine is added into the dried organic phase, the temperature is reduced to-5 ℃ to 0 ℃, 27.1g (0.25 mol) of ethyl chloroformate is slowly added dropwise, the reaction temperature is controlled to be not higher than 0 ℃, 50mL of water is added into the system after the dropwise addition is finished, the reaction is carried out for 30min, stirring is carried out for 30min, the separated liquid, the organic phase is rotationally dried at the end, and the organic phase is obtained, the organic phase is dried at the dry temperature, and the yield is 86% of the compound with the content of formula I is shown as 98%.
Product structure identification data:
1 H NMR(CDCl 3 )δppm：8.01(s,1H),7.04(m,3H),4.96(t,J＝3.26,1H),4.20(q,J＝2.26,2H),4.08(m,4H),3.20(m,1H),2.48(s,3H),2.40(s,3H),1.90(m,4H),1.29(t,J＝3.36,3H),1.24(m,6H)。
13 C NMR(CDCl 3 )δppm：165.5,153.8,147.5,134.6,132.4,129.0,128.3,126.8,107.7,98.5,67.4,63.7,62.5,54.1,26.2,22.8,23.3,21.3,14.5,13.3。
LC-MS[M+H] + :403.46; the calculated values are: 403.46.
examples 8 to 12
The synthesis of compounds Ib-if was carried out according to the procedure described above, the specific process parameters being obtained by conventional adjustment as described in example 7.
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Test of efficacy
The compounds of formula (I) prepared in examples 7-12, abamectin and spirotetramat were tested in an indoor environment for toxicity to faba aphids and cotton red spiders, and their insecticidal activity was evaluated by comparison.
Test conditions
1.1 test targets
The broad bean sprouts (Aphis fabae) are used for raising sensitive strains for many years indoors, and the experimental insect is 3-day-old Aphis.
The facial red spider (tetranychus sticae) line was kept indoor with young broad beans for years of sensitive strain, and the test insects were healthy adult mites.
1.2 culture conditions
The culture conditions of the target to be tested and the target after the test are that the temperature is 25+/-5 ℃, the relative humidity is 65+/-5%, and the illumination period is 12/12h (L/D).
Test method
2.1 test Agents
Compound Ia, compound Ib, compound Ic, compound Id, compound Ie, compound If, avermectin and spirotetramat compounds are all provided by hebei wegener biochemical limited.
2.2 preparation of pharmaceutical formulations
The test agent is prepared into agents with different concentrations by taking N, N-dimethylformamide as a solvent, tween-80 as an emulsifying agent and water as a diluting agent. Wherein the content of N, N-dimethylformamide in the medicament is 0.2wt%, and the content of Tween-80 is 0.2wt%.
The concentration of the drug for aphid as a test target was 0.75mg/L, 0.1875mg/L, 0.046875mg/L.
The concentration of the drug used as a test target for the cotton red spiders is 0.75mg/L, 0.1875mg/L and 0.046875mg/L.
2.3 test procedure
Reference is made to "evaluation of pesticide biological Activity SOP".
The broad bean aphid adopts an immersion method. Cutting off the young broad beans with 3-day-old broad bean Aphis, soaking in the prepared medicinal preparation for 15 seconds, taking out, sucking the excessive medicinal liquid around the plant and insect body with filter paper, inserting into water-absorbing sponge, covering Ma Dengzhao, and repeating the process for 3 times. After the treatment is finished, the culture is put into a recovery room for cultivation, observation is carried out at regular time, death conditions are checked and recorded after 48 hours, and the death rate is calculated.
The cotton red spider adopts a spraying method. The two-leaf one-heart broad bean seedlings with red spider adults are pulled out along roots, placed in a beaker filled with clean water, the mouth of the beaker is sealed by a Parafilm sealing film, a plastic gasket is clamped, and the spraying treatment is carried out by an electric throat sprayer, wherein the spraying amount is 2 mL/plant, and the treatment is repeated for 4 times. Covering Ma Dengzhao after the plants are dried, putting the plants into a recovery room for cultivation, checking and recording death conditions after 72 hours, and calculating the death rate.
3. Investigation method and biological Activity evaluation method
3.1 investigation method
After 72 hours, the death condition of the test insects is checked and recorded, and the death judgment standard of the test insects is as follows: the death is marked by the non-response of the light contact test insects of the writing brush.
3.2 method for evaluating biological Activity
The initial screening at a minimum concentration mortality rate above 50% allows for further screening.
4. Analysis of results
The results of the test agents at different concentrations for insecticidal activity against aphids are shown in table 1.
TABLE 1 mortality of aphids at different concentrations of test agent
As can be seen from the above table, compound Ib, compound Ie and compound If have high insecticidal activity against aphids, wherein compound Ie has the highest insecticidal activity, the mortality of the target pests at the three test doses of the primary screen is 94.54%, 85.59%, 65.89%, and the mortality of the target pests at the three test doses of the primary screen is 86.75%, 47.73% and 40.26%, respectively, of compound Ib. And the insecticidal activity on aphids is obviously better than that of avermectin and spirotetramat under the condition of low medicament concentration (0.1875 mg/L and 0.046875 mg/L).
The results of the test agents at different concentrations for insecticidal activity against cotton red spiders are shown in Table 1.
TABLE 2 mortality of cotton red spiders with different concentrations of test agents
| Experiment number | Numbering of compounds | 0.75(mg/L) | 0.1875(mg/L) | 0.046875(mg/L) |
| 1 | Ia | 95.10 | 32.80 | 10.80 |
| 2 | Ib | 97.73 | 41.99 | 24.67 |
| 3 | Ic | 100.00 | 28.55 | 5.20 |
| 4 | Id | 95.76 | 39.63 | 11.14 |
| 5 | Ie | 97.14 | 77.58 | 57.69 |
| 6 | If | 92.76 | 34.38 | 12.83 |
| 7 | Spirotetramat | 78.47 | 61.39 | 24.90 |
| 8 | Avermectins | 100.00 | 100.00 | 98.48 |
As can be seen from the above table, only compound Ib, compound Ie and abamectin in the test samples had high insecticidal activity against cotton red spiders, wherein the mortality of the target pests of compound Ie at the three test doses of the primary screening was 97.14%, 57.58% and 37.69%, respectively. And still has higher insecticidal activity under the condition of low medicament concentration (0.1875 mg/L and 0.046875 mg/L).
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, or alternatives falling within the spirit and principles of the invention.
Claims (9)
1. A spiro heterocyclic tetrahydropyran compound is characterized in that the structure is shown as a formula (I):
formula (I);
wherein R is ethyl; x is H, F, cl or Br.
2. The spiroheterocyclic tetrahydropyran compound of claim 1, having the structural formula:
。
3. a process for the preparation of spiroheterocyclic tetrahydropyran compounds according to claim 1 or 2, characterized by comprising the steps of:
step a, in an inert solvent a, furfuryl alcohol and m-chloroperoxybenzoic acid are subjected to ring-expanding reaction, and after the reaction is finished, organic alkali and organic alkali are added into a systemContinuously carrying out an acetylation reaction to obtain 5-carbonyl-5, 6-dihydro-2H-pyran-2-yl acetate; wherein R is 1 Is chloro or acetate;
step b, 5-carbonyl-5, 6-dihydro-2H-pyran-2-yl-acetate with R-OH in SnCl in inert solvent a 4 Carrying out substitution reaction under catalysis to obtain a compound shown in a formula (II); wherein R is ethyl;
step c, in an inert solvent b, carrying out catalytic hydrogenation on the compound shown in the formula (II) to obtain a compound shown in the formula (III);
formula (II) and formula (III);
step d, in a polar solvent, carrying out Bucherer-Bergs reaction on the compound shown in the formula (III), alkali metal cyanide and ammonium salt to obtain a compound shown in the formula (IV); then, carrying out hydrolysis reaction on the compound shown in the formula (IV) in an alkaline aqueous solution to obtain a compound shown in the formula (V);
formula (IV) formula (V);
step e, in a methanol solvent, performing methyl esterification reaction on the compound shown in the formula (V) and thionyl chloride to obtain a compound shown in the formula (VI);
formula (VI);
step f, in an inert solvent c, carrying out an acylation reaction on a compound shown in a formula (VI) and a compound shown in a formula (VII) under the action of organic base to obtain a compound shown in a formula (VIII); then adding alkali metal hydride into the system to continue the ring closure reaction to obtain a compound shown in a formula (IX);
formula (VII) formula (VIII) formula (IX);
and g, carrying out esterification reaction on the compound shown in the formula (IX) and ethyl chloroformate under the action of organic base to obtain the compound shown in the formula (I).
4. A process for the preparation of spiroheterocyclic tetrahydropyran compounds as claimed in claim 3, wherein in step a and step b, the inert solvent a is dichloromethane or dichloroethane; and/or
In the step a, the step f and the step g, the organic base is triethylamine, tetramethyl ethylenediamine or pyridine; and/or
In the step a, the temperature of the ring expansion reaction and the acetylation reaction is 0-5 ℃, the time of the ring expansion reaction is 6-8 h, and the time of the acetylation reaction is 1.5-2 h.
5. The process for producing a spiroheterocyclic tetrahydropyran compound as described in claim 3, wherein in the step b, the temperature of the substitution reaction is 20 to 30 ℃ and the reaction time is 3 to 4 hours; and/or
In the step c, the inert solvent b is ethyl acetate or tetrahydrofuran.
6. The process for producing a spiroheterocyclic tetrahydropyran compound as described in claim 3, wherein in the step d, the polar solvent is water, methanol or ethanol; and/or
In step d, the alkali metal cyanide is sodium cyanide, potassium cyanide or ammonium cyanide; and/or
In the step d, the ammonium salt is ammonium carbonate or ammonium bicarbonate; and/or
In the step d, the temperature of the Bucherer-Bergs reaction is 0-60 ℃ and the reaction time is 5-12 h; and/or
In the step d, the temperature of the hydrolysis reaction is 80-100 ℃, and the time of the hydrolysis reaction is 6-10 h.
7. The process for producing a spiroheterocyclic tetrahydropyran compound as described in claim 3, wherein in the step e, the methyl esterification reaction is carried out at a temperature of-5 ℃ to 0 ℃ for a reaction time of 3h to 5h; and/or
In the step f, the inert solvent c is toluene, dichloromethane or dichloroethane; and/or
In the step f, the temperature of the acylation reaction is between-5 and 0 ℃ and the reaction time is between 1 and 1.5 hours; and/or
In the step f, the temperature of the ring closing reaction is between-5 ℃ and 0 ℃ and the reaction time is between 3h and 5h; and/or
In the step g, the temperature of the esterification reaction is between-5 and 0 ℃ and the reaction time is between 0.5 and 1 hour.
8. Use of the spiroheterocyclic tetrahydropyran compounds according to claim 1 or 2 for combating aphids and red spiders.
9. A pharmaceutical composition for controlling aphids or red spiders comprising the spiroheterocyclic tetrahydropyran compound of claim 1 or 2.
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