CN112010813A - Synthesis method and application of prothioconazole - Google Patents
Synthesis method and application of prothioconazole Download PDFInfo
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- CN112010813A CN112010813A CN202010988454.XA CN202010988454A CN112010813A CN 112010813 A CN112010813 A CN 112010813A CN 202010988454 A CN202010988454 A CN 202010988454A CN 112010813 A CN112010813 A CN 112010813A
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- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/64—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with three nitrogen atoms as the only ring hetero atoms
- A01N43/647—Triazoles; Hydrogenated triazoles
- A01N43/653—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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Abstract
The invention relates to the technical field of chemical drug synthesis, in particular to a method for synthesizing prothioconazole and application thereof. A method for synthesizing prothioconazole comprises the following steps: step 1: carrying out epoxidation reaction on the compound shown in the formula IV to obtain a compound shown in a formula III; step 2: carrying out nucleophilic addition reaction on the compound shown in the formula III and triazole to obtain a compound shown in a formula II; and step 3: carrying out a vulcanization reaction on the compound shown in the formula II to obtain prothioconazole shown in the formula I;
Description
Technical Field
The invention relates to the technical field of chemical drug synthesis, in particular to a method for synthesizing prothioconazole and application thereof.
Background
Prothioconazole currently has patent rights in the European and American countries, whereThe nation also has patent protection, but the synthetic method is reported little. Referring to relevant documents at home and abroad, the overall synthetic route is summarized as the following four routes: (1) zinc grignard reagent method: the o-chlorobenzyl chloride is used as an initial raw material to prepare (2-chlorobenzyl) - (1-chlorocyclopropyl) ketone, (2-chlorobenzyl) - (1-chlorocyclopropyl) ketone and (CH) through Grignard reaction and carbonylation reaction3) SOCl reacts to obtain 2- (2-chlorobenzyl) - (1-chloro-cyclopropane) ethylene oxide, then the ethylene oxide reacts with 1,2, 4-triazole to obtain 2- (1-chloropropyl) -3- (2-chlorphenyl) -2-hydroxypropyl-1, 2, 4-triazole, and finally the 2- (1-chloropropyl) -3- (2-chlorphenyl) -2-hydroxypropyl-1, 2, 4-triazole and sulfur undergo electrophilic addition reaction to prepare prothioconazole. The yield of the first step and the yield of the second step of the reaction route are both high, but the yield of the third step is low, so that the total yield of the product is influenced, the cost of the route is high, and the industrial production is not easy to realize. (2) Triazole method: 2-chloro-1- (1-chloro-cyclopropyl) ethanone is used as a raw material, nucleophilic substitution reaction is carried out to prepare (1,2, 4-triazole-1-yl-methyl) - (1-chloro-cyclopropane-1-yl) methanone, then the (1,2, 4-triazole-1-yl) -methyl-ketone reacts with o-chlorobenzyl grignard reagent to prepare 2- (1-chloropropyl) -3- (2-chlorphenyl) -2-hydroxypropyl-1, 2, 4-triazole, and finally electrophilic addition reaction is carried out on the 2-chloro-1- (1-chloro-cyclopropyl) ethanone and sulfur to prepare prothioconazole. The yield of the first step and the yield of the second step of the reaction route are both lower, the cost is higher, and the influence of the active sites and the steric hindrance on the first step reaction and the second step reaction is larger. Therefore, the route is not easy to be industrially produced. (3) Magnesium grignard reagent method: the prothioconazole is prepared by taking 1-acetyl-1-chlorocyclopropane as a raw material and carrying out chlorination, Grignard, nucleophilic addition, nucleophilic substitution and electrophilic addition reaction. The route is the main industrial production route at present. (4) Hydrazine hydrate method: the prothioconazole is prepared by taking 1-acetyl-1-chlorocyclopropane as a raw material through chlorination, Grignard, nucleophilic addition, nucleophilic substitution and cyclization reactions.
In the above synthetic route of prothioconazole and the currently disclosed synthetic method of prothioconazole, a benzyl-format reagent is inevitably used, and the reaction has a self-polymerization byproduct in the reaction, so that the utilization rate of raw materials is low, and the quality of the product at the later stage is affected.
In order to solve the technical problems, the invention provides a method for synthesizing prothioconazole, which has the advantages of low cost, safety, high efficiency, no potential safety hazard, high overall yield, mild reaction conditions, improvement of the utilization rate of raw materials and obvious reduction of three wastes.
Disclosure of Invention
In order to solve the above technical problems, a first aspect of the present invention provides a method for synthesizing prothioconazole, comprising the steps of:
step 1: carrying out epoxidation reaction on the compound shown in the formula IV to obtain a compound shown in a formula III;
step 2: carrying out nucleophilic addition reaction on the compound shown in the formula III and triazole to obtain a compound shown in a formula II;
and step 3: carrying out a vulcanization reaction on the compound shown in the formula II to obtain prothioconazole shown in the formula I;
as a preferable embodiment of the invention, the compound shown in the formula IV is obtained by chlorination of a compound shown in a formula V;
as a preferred embodiment of the invention, the compound shown in the formula V is obtained by electrophilic addition reaction of a compound shown in a formula VI;
as a preferred embodiment of the invention, the compound shown in the formula VI is obtained by performing a vinylation reaction on the compound shown in the formula VII;
as a preferred embodiment of the invention, the compound shown in the VII is obtained by performing amidation reaction on the compound shown in the formula VIII;
in a preferred embodiment of the present invention, the compound represented by the formula VIII is obtained by subjecting a compound represented by the formula IX to an acid chlorination reaction;
as a preferred embodiment of the present invention, the step 1 specifically includes: mixing alkali, halogenated sulfoxide and solvent, heating and refluxing for reaction for 20-80 min; then adding a compound shown in the formula IV, continuing refluxing and reacting for 1-5h, and stopping the reaction.
In a preferred embodiment of the present invention, the molar ratio of the base, the sulfoxide halide and the compound represented by the formula II is (1-5): (1-5): 1.
as a preferred embodiment of the present invention, the step 2 specifically includes: the step 2 specifically comprises the following steps: mixing the compound shown in the formula III, triazole, alkali and a solvent, heating and refluxing for reaction for 40-100min, and stopping the reaction; the molar ratio of the compound shown in the formula III, triazole and alkali is 1: (0.8-1.5): (1-5).
The second aspect of the invention provides the application of the prothioconazole, which is applied to the field of pesticides; the prothioconazole is prepared by the synthesis method.
Advantageous effects
The invention provides a method for synthesizing prothioconazole, which takes a compound shown as a formula IV as an initial raw material, and prepares the prothioconazole through epoxidation reaction, nucleophilic addition reaction and vulcanization reaction; in addition, the invention also provides a synthesis method of the compound shown in the formula IV, namely the compound is prepared by the acyl chlorination reaction, the amidation reaction, the vinylation reaction, the electrophilic addition reaction and the chlorination reaction of the compound shown in the formula IX. In the synthetic route of the prothioconazole, the raw materials are cheap and easy to obtain, a benzyl format reagent is not required, potential safety hazards are avoided, the reaction condition is mild, the post-treatment operation is simple, the overall yield is high, the environmental pollution is low, and the method has certain significance for industrial production.
Detailed Description
The technical features of the technical solutions provided by the present invention will be further clearly and completely described below with reference to the specific embodiments, and it should be apparent that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
It will be understood by those skilled in the art that, unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the prior art and will not be interpreted in an idealized or overly formal sense unless expressly so defined herein.
The words "preferred", "preferably", "more preferred", and the like, in the present invention, refer to embodiments of the invention that may provide certain benefits, under certain circumstances. However, other embodiments may be preferred, under the same or other circumstances. Furthermore, the recitation of one or more preferred embodiments does not imply that other embodiments are not useful, nor is it intended to exclude other embodiments from the scope of the invention.
The invention provides a method for synthesizing prothioconazole in a first aspect, which comprises the following steps:
step 1: carrying out epoxidation reaction on the compound shown in the formula IV to obtain a compound shown in a formula III;
step 2: carrying out nucleophilic addition reaction on the compound shown in the formula III and triazole to obtain a compound shown in a formula II;
and step 3: carrying out a vulcanization reaction on the compound shown in the formula II to obtain prothioconazole shown in the formula I;
step 1
In the invention, the step 1 is as follows: and carrying out epoxidation reaction on the compound shown in the formula IV to obtain a compound shown in a formula III.
In a preferred embodiment, the step 1 is specifically: mixing alkali, halogenated sulfoxide and solvent, heating and refluxing for reaction for 20-80 min; then adding a compound shown in the formula IV, continuing refluxing and reacting for 1-5h, and stopping the reaction.
In a preferred embodiment, the molar ratio of the base, the sulfoxide halide and the compound of formula II is (1-5): (1-5): 1.
in a more preferred embodiment, the molar ratio of the base, the sulfoxide halide, and the compound of formula ii is 2.5: 2: 1.
in a preferred embodiment, the concentration of the compound of formula IV in the solvent is from 0.2 to 1 mol/L.
In a preferred embodiment, the concentration of the compound of formula IV in the solvent is 0.6 mol/L.
In a preferred embodiment, the base is an inorganic base.
As the inorganic base, there can be mentioned sodium hydroxide, rubidium hydroxide, cesium hydroxide, potassium hydroxide, barium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, copper hydroxide, iron hydroxide, lead hydroxide, cobalt hydroxide, chromium hydroxide, zirconium hydroxide, nickel hydroxide, ammonium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, potassium carbonate, cesium fluoride, cesium carbonate, potassium phosphate, sodium phosphate, aqueous ammonia and the like.
In a more preferred embodiment, the inorganic base is a strong base.
Strong base (Strong base) refers to a substance in which the anions ionized in an aqueous solution are all hydroxide ions. A strong base reacts with an acid to form a salt and water. The strong base and the weak base are relatively strong bases which are dissolved in water and can be completely ionized. The alkali and partial alkaline earth metal corresponding bases are generally strong bases. The pH of the solution is >12 in the standard case (concentration 0.1 mol/L).
In a most preferred embodiment, the inorganic base is sodium hydroxide.
In a preferred embodiment, the temperature of the solvent is not lower than 60 ℃.
In a more preferred embodiment, the solvent is selected from at least one of dimethyl sulfoxide, N-dimethylformamide, N-methylpyrrolidone, xylene, toluene, butanone, acetonitrile toluene, tetrahydrofuran, dioxane, dichloroethane, trichloroethane, carbon tetrachloride, and trichloroethylene.
In a most preferred embodiment, the solvent is dichloroethane.
In a preferred embodiment, the halogenated sulfoxide is selected from at least one of trimethyl sulfoxide chloride, trimethyl sulfoxide bromide and trimethyl sulfoxide iodide.
In a more preferred embodiment, the halogenated sulfoxide is trimethyl thionyl chloride.
In a preferred embodiment, the processing method of step 1 is: detecting that the compound shown in the formula IV completely reacts through GC, and then cooling to normal temperature; then adding water into the reaction system, and extracting to obtain an organic phase; and finally, removing the solvent and the dimethyl sulfoxide through reduced pressure evaporation to obtain a yellow oily substance, namely the compound shown in the formula III.
The inventor finds that alcohol can be directly generated by the traditional condensation reaction of the Grignard reagent and ketone, but the reaction does not need water and oxygen, the reaction conditions are harsh, and the formula IV as a reaction raw material has more active sites, more byproducts, low yield and difficult post-treatment. The invention carries out Corey-Chaykovsky reaction by the formula IV to directly obtain epoxidation reaction, has mild reaction conditions, safety and environmental protection, almost no byproduct, reaction yield of more than 95 percent, simple post-treatment and benefit for subsequent reaction. The reaction mechanism is as follows: forming carbanions by trimethyl sulfoxide halide under the action of alkali, and transferring negative charges to carbonyl oxygen after the carbanions attack carbonyl carbon on the compound shown in the formula IV; then the negative charge on the carbonyl oxygen of the compound shown in the formula IV continuously attacks the carbon (neutral) of the original trimethyl sulfoxide halide carbanion, at the moment, the pair electrons on the carbon-sulfur bond are transferred to the sulfur atom, the positive charge on the sulfur atom is neutralized, the carbon-sulfur bond is broken, and the ethylene oxide product and the dimethyl sulfoxide are generated. In the research process, the inventor finds that when the alkali is strong alkali sodium hydroxide and the boiling point of the solvent is not lower than 60 ℃ (the temperature of the reflux reaction is the boiling point temperature of the solvent), trimethyl thionyl chloride has higher reaction activity under the strong alkali condition, the generation amount of molecular carbanions is increased, the collision and reaction probability with the compound shown in the formula IV is improved, and the reaction rate is improved; and higher reaction temperatures favor the formation of thermodynamic products, and especially when the molar ratio of the base, the sulfoxide halide and the compound of formula II is (1-5): (1-5): 1, the reaction rate can be effectively improved, the generation of byproducts is inhibited, and the conversion rate of the compound shown in the formula IV and the yield of the compound shown in the formula III are improved.
Step 2
In the invention, the step 2 is as follows: and carrying out nucleophilic addition reaction on the compound shown in the formula III and triazole to obtain the compound shown in the formula II.
In a preferred embodiment, the step 2 is specifically: and (3) mixing the compound shown in the formula III, triazole, alkali and a solvent, heating and refluxing for reaction for 40-100min, and stopping the reaction.
In a preferred embodiment, the molar ratio of the compound shown in the formula III, triazole and alkali is 1: (0.8-1.5): (1-5).
In a more preferred embodiment, the molar ratio of the compound shown in the formula III, triazole and alkali is 1: 1: 2.
in a preferred embodiment, the concentration of the compound of formula III in the solvent is from 0.8 to 2 mol/L.
In a more preferred embodiment, the concentration of the compound of formula III in the solvent is 1.2 mol/L.
In a preferred embodiment, the base is an organic base and/or an inorganic base.
In a more preferred embodiment, the alkali is an inorganic base.
In a more preferred embodiment, the base is a weak base.
A weak base refers to a base that does not ionize completely in aqueous solution, i.e. the protonation reaction is incomplete. The pH value range of general alkali is 7-14, wherein 7 is neutral, 14 is strong alkali, and weak alkali has poor proton accepting capability from water molecules compared with strong alkali, so that the concentration of H & lt + & gt in the solution is higher, and the pH value is lower. The pH of the weak base is greater than 7 but close to 7.
In a most preferred embodiment, the base is sodium carbonate.
In a preferred embodiment, the solvent is a protic solvent.
One class of solvents that can provide hydrogen bonding association of protons with solute molecules or form coordinating cations is generally compounds containing hydroxyl or amino groups, such as: h2O，C2H5OH，HCOOH，CH3COOH，C2H5NH2And so on. They tend to form unstable reactive intermediates for polar solute molecules, have catalytic effects, promote ion formation, and facilitate unimolecular reactions (e.g., SN1 reactions).
In a more preferred embodiment, the solvent is an alcoholic solvent and or an amine solvent.
In a more preferred embodiment, the solvent is selected from at least one of methanol, ethanol, isopropanol, triethylamine.
In a most preferred embodiment, the solvent is methanol.
In the invention, the processing method of the step 2 comprises the following steps: after the compound represented by the formula iii was completely reacted as detected by GC, it was cooled to room temperature, and water was added to the reaction system in a ratio of 1: (2-6); then repeatedly extracting with dichloroethane (the volume ratio of dichloromethane to solvent added each time is 1 (0.5-1.5)); and finally, carrying out reduced pressure distillation on the organic phase to obtain a crude product of the compound shown in the formula II, and then recrystallizing the crude product with toluene to obtain a white solid, namely the compound shown in the formula II.
The inventor finds that the compound shown in the formula II is generated by directly carrying out nucleophilic addition reaction on the formula III and triazole, so that the yield of the reaction can be improved, the generation of byproducts is reduced, the post-treatment step is simplified, the reaction process is green and environment-friendly, and no pollutant is generated. The inventors believe that the reason is probably that, firstly, the choice of base in the reaction is particularly important since the system according to the invention generates one molecule of hydrogen chloride per molecule of the product compound of formula II. The inventor finds that if the alkali used is strong alkali, the heat release is violent in the reaction process, the compound shown in the formula III is hydrolyzed due to too strong alkali, side reactions are increased, the yield is reduced, and the post-treatment is difficult; if the alkali used is too weak, hydrolysis products tend to be produced, resulting in a decrease in yield. Therefore, the alkalinity of the sodium carbonate and the potassium carbonate is optimal, the sodium carbonate and the potassium carbonate are suitable for the system, and particularly when the potassium carbonate is used as the alkali, the reaction speed and the yield are highest. The reason for this is probably that triazole forms potassium salt and sodium salt with potassium carbonate and sodium carbonate respectively, the radius of potassium ion is larger than that of sodium ion, and potassium ion is easy to leave compared with sodium ion, so that not only side reaction does not occur, but also the reaction rate and yield can be improved. In addition, the inventor finds that the polar solvent in the system promotes the reaction, but the nonpolar solvent is not reacted, and particularly, when methanol is used as the solvent, the reaction can be promoted, the generation of side reactions can be reduced, and the post-treatment step can be simplified.
The inventor also unexpectedly finds that in the formula III prepared from the formula IV, the reaction active site is ethylene oxide, lone-pair electrons on triazole nitrogen attack methylene of the ethylene oxide to generate a carbon-nitrogen bond, the carbon-oxygen bond is transferred to oxygen, and the compound shown in the formula II is generated by combining protons in a solvent to generate hydroxyl, no other product is generated in the reaction process, and the atom conversion rate is high.
Step 3
In the invention, the step 3 is as follows: and (3) carrying out vulcanization reaction on the compound shown as the formula II to obtain the prothioconazole shown as the formula I.
In a preferred embodiment, the step 3 is specifically: and (3) mixing the compound shown in the formula II, sulfur and a solvent, heating and refluxing for 3-10h, and stopping the reaction.
In a preferred embodiment, the solvent has a boiling point of not less than 150 ℃.
In a preferred embodiment, the solvent is selected from at least one of dimethylacetamide, N-dimethylformamide, xylene, dimethylsulfoxide, N-methylpyrrolidone.
In a more preferred embodiment, the solvent is dimethyl sulfoxide.
In the invention, the processing method of the step 3 comprises the following steps: after the reaction is stopped, cooling the reaction system to room temperature, and filtering to remove the residual sulfur in the reaction; then carrying out reduced pressure distillation on the filtrate to obtain a crude product of the compound shown in the formula I; finally, toluene is used for recrystallization to obtain a white solid, namely the compound shown in the formula I.
In the research process, the inventor finds that when the solvent is dimethyl sulfoxide, the yield of the reaction is optimal, the amount of the generated by-products is less, and the yield is higher.
In the invention, the compound shown in the formula IV is obtained by chlorination reaction of a compound shown in a formula V;
in the present invention, the specific reaction conditions for preparing the compound represented by the formula iv by chlorination reaction using the compound represented by the formula v as a raw material are not particularly limited, and are well known to those skilled in the art.
In a preferred embodiment, the compound of formula v of the present invention is prepared by chlorination reaction of the compound of formula v as follows: mixing the compound shown in the formula V, alkali and a solvent at-50- (-80) DEG C under an inert gas environment, and stirring for 20-60 min; then adding carbon tetrachloride dropwise, continuing stirring for 1-5h after the dropwise addition is finished, and stopping the reaction.
In a preferred embodiment, the molar ratio of the compound of formula v, the base, and carbon tetrachloride is 1: (1-5): (1-5).
In a more preferred embodiment, the compound of formula v, the base and carbon tetrachloride are present in a molar ratio of 1: 3: 3.
in a preferred embodiment, the base is a strong organic base; lithium diisopropylamide is preferred.
In the invention, the treatment method for preparing the compound shown in the formula IV by chlorination reaction of the compound shown in the formula V comprises the following steps: after detecting that the compound shown as the formula V completely reacts through GC, adding saturated NH into the reaction system4And (3) extracting the Cl solution with dichloroethane, concentrating an organic phase, and distilling under reduced pressure to obtain the compound shown in the formula IV.
According to the invention, the compound shown in the formula V is obtained by electrophilic addition reaction of a compound shown in a formula VI;
in the present invention, the specific reaction conditions for obtaining the compound of formula v from the compound of formula vi by electrophilic addition are not particularly limited, and are well known to those skilled in the art.
In a preferred embodiment, the electrophilic addition reaction of the compound of formula VI according to the present invention to prepare the compound of formula V comprises the following steps: mixing alkali, halogenated sulfoxide and solvent, heating and refluxing for reaction for 30-80 min; then adding a compound shown in the formula VI, continuously heating and refluxing for reaction for 1-5h, and stopping the reaction.
In a preferred embodiment, the molar ratio of the base, the sulfoxide halide, and the compound of formula VI is (1-5): (1-5): 1.
in a more preferred embodiment, the molar ratio of the base, the sulfoxide halide, and the compound of formula vi is 2.5: 2: 1.
in a preferred embodiment, the solvent is selected from at least one of dimethyl sulfoxide, N-dimethylformamide, N-methylpyrrolidone, xylene, toluene, butanone, acetonitrile toluene, tetrahydrofuran, dioxane, dichloroethane, trichloroethane, carbon tetrachloride, trichloroethylene.
In a preferred embodiment, the base is selected from at least one of sodium hydroxide, rubidium hydroxide, cesium hydroxide, potassium hydroxide, barium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, copper hydroxide, iron hydroxide, lead hydroxide, cobalt hydroxide, chromium hydroxide, zirconium hydroxide, nickel hydroxide, ammonium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium carbonate, cesium fluoride, cesium carbonate, potassium phosphate, sodium phosphate, and ammonia.
In a preferred embodiment, the halogenated sulfoxide is selected from at least one of trimethyl sulfoxide chloride, trimethyl sulfoxide bromide and trimethyl sulfoxide iodide.
According to the invention, the treatment method for preparing the compound shown in the formula V by electrophilic addition reaction by using the compound shown in the formula VI comprises the following steps: detecting the compound shown in the formula V by GC, cooling to normal temperature, adding water, extracting with dichloroethane, collecting an organic phase, and distilling under reduced pressure to obtain the compound shown in the formula V.
In the invention, the compound shown in the formula VI is obtained by performing a vinylation reaction on the compound shown in the formula VII;
in the present invention, the specific reaction conditions for preparing the compound represented by the formula vi by vinylation using the compound represented by the formula vii as a raw material are not particularly limited, and are well known to those skilled in the art.
In a preferred embodiment, the compound of formula VII is prepared by the following steps: mixing the compound shown in the formula VII with a solvent at the temperature of-10-10 ℃ under the protection of inert gas, then dropwise adding a vinylation reagent, stirring for 20-80min, and stopping the reaction.
In a preferred embodiment, the vinylating agent is allyl magnesium bromide.
In a preferred embodiment, the weight ratio of said compound of formula VII to vinylation reagent is 1: (1-5).
In a more preferred embodiment, the weight ratio of said compound of formula VII to vinylation reagent is 1: 2.
in the invention, the treatment method for preparing the compound shown in the formula VI by carrying out the vinylation reaction on the compound shown in the formula VII comprises the following steps: after the compound shown as the formula VII is detected to be completely reacted by GC, saturated NH is added into the reaction system4And (3) extracting the Cl solution by using dichloroethane, collecting an organic phase, and distilling under reduced pressure to obtain the catalyst.
In the invention, the compound shown in the VII is obtained by amidation reaction of a compound shown in a formula VIII;
in the present invention, the specific reaction conditions for preparing the compound represented by the formula vii through amidation reaction using the compound represented by the formula viii as a raw material are not particularly limited, and are well known to those skilled in the art.
In a preferred embodiment, the compound of formula VIII according to the present invention is prepared by an amidation reaction as follows: stirring a compound shown as a formula VIII, an amidation reagent, alkali and a solvent for 20-80min at the temperature of-10-5 ℃ under the protection of a multi-property gas; then the temperature is increased to 20-30 ℃, the stirring is continued for 0.5-2h, and the reaction is stopped.
In a preferred embodiment, the amidation agent is methoxymethylamine.
In a preferred embodiment, the base is pyridine.
In the present invention, the amount of pyridine is not particularly limited, and it may be added as a base conventionally used, or may be used as a reaction solvent for neutralizing an acid generated during the amidation reaction.
In a preferred embodiment, the compound of formula viii, the amidation agent, and pyridine are present in a molar ratio of 1: (1-2): (2-5).
In a more preferred embodiment, the compound of formula viii, the amidation agent, and pyridine are present in a molar ratio of 1: 1.2: 2.2.
in the invention, the treatment method for preparing the compound shown in the formula VII by the amidation reaction of the compound shown in the formula VIII comprises the following steps: detecting that the compound shown as the formula VIII completely reacts through GC, adding water into the reaction, and collecting an organic phase after layering; then, repeatedly washing the organic phase by using water and a saturated sodium chloride solution respectively; and finally, collecting an organic phase, and carrying out reduced pressure distillation to obtain the organic phase.
In the invention, the compound shown in the formula VIII is obtained by performing acyl chlorination on a compound shown in a formula IX;
in the present invention, the specific reaction conditions for preparing the compound represented by the formula VIII by the acid chlorination reaction using the compound represented by the formula IX as a starting material are not particularly limited, and are well known to those skilled in the art.
In a preferred embodiment, the compound of formula IX of the present invention is prepared by subjecting a compound of formula VIII to an acid chlorination reaction as follows: mixing a compound shown as the formula IX with a solvent, then dropwise adding an acyl chlorination reagent at-10-5 ℃, heating the temperature of a reaction system to room temperature after dropwise adding, stirring for 20-80min, and stopping reaction.
In a preferred embodiment, the acid chlorination reagent is thionyl chloride.
In a preferred embodiment, the solvent is a mixture of dichloroethane and N, N-dimethylformamide.
In a more preferred embodiment, the dichloroethane and N, N-dimethylformamide are in a volume of (250-) -450: 1.
in a preferred embodiment, the compound of formula IX and the acyl chlorination reagent are present in a molar ratio of 1: (1-1.5).
In a more preferred embodiment, the compound of formula IX and the acyl chlorination reagent are present in a molar ratio of 1: 1.1.
in the invention, the processing method for preparing the compound shown in the formula VIII by carrying out the acyl chlorination reaction on the compound shown in the formula IX comprises the following steps: after the compounds shown in the formula VIII are detected to be completely reacted by GC, the solvent and the residual thionyl chloride in the reaction system are distilled out by distillation, and then the compounds are obtained by reduced pressure distillation.
Compared with the existing synthesis route of prothioconazole, the reaction route provided by the invention has the advantages of cheap and easily-obtained raw materials, convenient treatment in the whole process, no generation of three wastes, high overall yield, no need of using a format reagent and oxidants such as ferric trichloride and the like, and has certain significance for industrial production.
The present invention will be specifically described below by way of examples. It should be noted that the following examples are only for illustrating the present invention and should not be construed as limiting the scope of the present invention, and that the insubstantial modifications and adaptations of the present invention by those skilled in the art based on the above disclosure are still within the scope of the present invention.
In addition, the starting materials used are all commercially available, unless otherwise specified.
Examples
Example 1
The compound of formula IX is o-chlorophenylacetic acid, CAS number 2444-36-2, commercially available.
1. Synthesis of compound represented by formula VIII (o-chlorobenzoyl chloride)
171g of a compound represented by the formula IX (1.1mol), 300mL of dichloroethane and 1mL of N, N-dimethylformamide are sequentially added into a 1L four-mouth bottle at 25 ℃, then 148.5g of thionyl chloride (1.3mol, 1.1eq.) is dropwise added into the reaction at 0 ℃, the temperature is raised to 25 ℃ after half an hour of dropwise addition, and the stirring is carried out for 0.5 h; the reaction completion of the o-chlorophenylacetic acid was detected by GC, the solvent and the remaining thionyl chloride were distilled off by distillation, and the remaining liquid was distilled under reduced pressure to give 190g of a compound of formula VIII: 99%, yield: 99 percent.
2. Synthesis of Compound (2- (2-chlorobenzene) -N-ethoxy-N-methylacetamide) represented by formula VII
At 0 ℃ N2Under the conditions, 190g (1mol) of a compound represented by the formula VIII, 73.2(1.2mol, 1.2eq.) of methoxymethylamine and 400mL of dichloroethane were sequentially added to a 1L four-necked flask, 174g (2.2mol, 2.2eq.) of pyridine was added dropwise over 0.5h, and after the addition was completed, stirring was continued at 0 ℃ for 0.5h, and then stirring was continued at normal temperature for 1 h. After the completion of the reaction of the compound of formula VIII by GC, 500mL of water was added to the reaction, after separation of the layers, the organic phase was washed with water (200 mL. times.2) and saturated sodium chloride solution (200 mL. times.1), respectively, and finally the organic phase was distilled under reduced pressure to give 212g of a compound of formula VII in an amount: 99%, yield: 98 percent.
3. Synthesis of compound (1- (2-chlorobenzene) -2-carbonyl-3-vinyl propane) shown as formula VI
At 0 ℃ N2Under the conditions, 107g (0.5mol) of the compound represented by the formula VII and 200mL of tetrahydrofuran were sequentially added to a 2L four-necked flask, and then 1L of a vinyl magnesium bromide solution (1M, 1mol, 2eq.) was added dropwise to the reaction, followed by further stirring at 0 ℃ for 0.5 h. After the reaction of the compound represented by the formula VII was detected by GC, saturated NH was added to the reaction4500mL of Cl solution, followed by extraction with dichloroethane (200 mL. times.3), collection of the organic phase, and distillation under reduced pressure gave 85g of the compound of formula VI: 95%, yield: 89 percent.
4. Synthesis of compound (1-cyclopropyl-2-o-chloroacetophenone) shown in formula V
Adding 45g of sodium hydroxide (1.1mol, 2.5eq.) and 198g of trimethyl sulfoxide iodide (0.9mol, 2eq.) and 200mL of dichloroethane into a 500mL four-mouth bottle in sequence at 25 ℃, heating and refluxing for 1h, adding 85g of the compound shown in the formula VI into the reaction, continuing refluxing for 2h, detecting the completion of the reaction of the compound shown in the formula VI by GC, cooling to normal temperature, adding 200mL of water, extracting with dichloroethane (100mL multiplied by 3), collecting an organic phase, and distilling under reduced pressure to obtain 79g of the compound shown in the formula V, wherein the content of the compound is as follows: 99%, yield: 90 percent.
5. Synthesis of compound (1- (1-chlorocyclopropyl) -2-o-chloroacetophenone) shown in formula IV
At-78 ℃ N2Under the conditions, 79g of the compound represented by the formula V (0.4mol), 600mL of LDA tetrahydrofuran solution (2M, 3eq.) and 200mL of THF were sequentially added to a 1L four-necked flask, and then stirring was continued at-78 ℃ for 0.5h, followed by dropwise addition of 116mL of CCl4(1.2mol, 3eq.) to the reaction, and after completion of the dropwise addition, stirring was continued at that temperature for 2 h. After the reaction of the compound of formula V was completed by GC detection, 200mL of saturated NH was added to the reaction4The Cl solution was extracted with dichloroethane (200 mL. times.3), and the organic phase was collected, concentrated, and distilled under reduced pressure to obtain 71g of a compound represented by the formula IV: 95%, yield: 73 percent.
6. Synthesis of compound (1- (1-chlorocyclopropyl) -2-o-chlorobenzyl oxirane) shown as formula III
At 25 ℃, 29g of sodium hydroxide (0.73mol, 2.5eq.) and 74g of trimethyl sulfoxide iodide (0.58mol, 2eq.) are sequentially added into a 500mL four-neck flask, after heating and refluxing for 1h, 71g of the compound represented by formula iv (0.29mol) is added into the reaction, the reaction is continuously refluxed for 2h, then after the compound represented by formula iv is completely reacted by GC detection, the temperature is reduced to normal temperature, 200mL of water is added, an organic phase is separated and collected, and the organic solvent is evaporated under reduced pressure, so that 60g of the compound represented by formula iii is obtained as a yellow oily matter, the content: 96% and the yield thereof was found to be 82%.
7. Synthesis of compound (2- [2- (1-chlorocyclopropyl) -3-o-chlorobenzyl-2-hydroxypropyl ] -triazole) shown as formula II
To a 500mL four-necked flask, 200mL of methanol, 17g of triazolone (0.24mol,1eq), 66g of potassium carbonate (0.48mol, 2eq) and 60g of the compound represented by the formula III (0.24mol) were added in this order at 25 ℃ and then heated under reflux for 1 hour. After the reaction of the compound shown in the formula III is detected to be complete by GC, the temperature is reduced to 25 ℃, 50mL of water is added, dichloroethane (150mL multiplied by 3) is used for extraction, an organic phase is collected and is subjected to reduced pressure distillation to obtain a crude product of the compound shown in the formula II, and then 350mL of toluene is used for recrystallization to obtain 68g of white solid, namely the compound shown in the formula II, wherein the content of the white solid is as follows: 99%, yield: 90 percent.
8. Synthesis of compound (2- [2- (1-chlorocyclopropyl) -3-o-chlorobenzyl-2-hydroxypropyl ] -1,2, 4-triazolethione; prothioconazole) shown as formula I
At 25 ℃, 150mL of DMSO, 17g of elemental sulfur (0.53mol, 2.5eq) and 68g of compound shown as a formula II (0.21mol) are sequentially added into a 500mL four-mouth bottle, and then the mixture is heated and refluxed for reaction for 6 hours and cooled to the normal temperature; removing excessive elemental sulfur in a reaction system by filtering, collecting filtrate, distilling under reduced pressure to obtain a crude product of the compound shown in the formula I, adding 250mL of toluene, heating for dissolving, cooling to 10 ℃, separating out white solid, and filtering to obtain 50g of white solid, namely the compound shown in the formula I, wherein the content of the white solid is as follows: 99%, yield: 74 percent.
Performance testing
And (3) carrying out structure detection on the prepared compound:
1. the hydrogen spectrum data of the compound 2- (2-chlorobenzene) -N-ethoxy-N-methylacetamide shown in the formula VII are as follows:1HNMR(400Hz，CDCl3)：7.2-7.4(4H，m)，3.9(2H，s)，3.7(3H，s)，3.2(3H，s)。
2. the hydrogen spectrum data of the compound 1- (1-chlorocyclopropyl) -2-o-chloroacetophenone shown in the formula IV are as follows:1HNMR(400Hz，CDCl3)：6.7-7.4(4H，m)，3.7(2H，s)，1.6-1.7(2H，m)，1.3-1.4(2H，m)。
3. the hydrogen spectrum data of the compound 1- (1-chlorocyclopropyl) -2-o-chlorobenzyl ethylene oxide shown in the formula III are as follows:1HNMR(400Hz，d6-DMSO)：7.0-7.5(4H，m)，3.7(2H，s)，3.4(2H，s)1.6-1.6(2H，m)，1.2-1.4(2H，m)。
4. a compound 2- [2- (1-chlorocyclopropyl) -3-o-chlorobenzyl-2-hydroxypropyl represented by a formula II]Mass spectral data of triazole are as follows: HRMS (ESI) m/z: calcd for C14H15Cl2N3O[M+H]+：311.0590。
5. The hydrogen spectrum data of the compound prothioconazole shown in the formula I are as follows:1HNMR(400Hz，d6-DMSO)：12.5(bs，1H)，7.9(s，1H)，7.5-7.6(m，1H)，7.3-7.4(m，1H)，7.2-7.3(m，2H)，4.8(d，J＝18.5，1H)，4.5(d，J＝18.5，1H)，4.2(s，1H)，3.6(d，J＝17.5，1H)，3.2(d，J＝17.5，1H)，0.9-1.0(m，1H)，0.8-0.9(m，3H)。
the foregoing examples are merely illustrative and serve to explain some of the features of the method of the present invention. The appended claims are intended to claim as broad a scope as is contemplated, and the examples presented herein are merely illustrative of selected implementations in accordance with all possible combinations of examples. Accordingly, it is applicants' intention that the appended claims are not to be limited by the choice of examples illustrating features of the invention. Also, where numerical ranges are used in the claims, subranges therein are included, and variations in these ranges are also to be construed as possible being covered by the appended claims.
Claims (10)
1. A method for synthesizing prothioconazole is characterized by comprising the following steps:
step 1: carrying out epoxidation reaction on the compound shown in the formula IV to obtain a compound shown in a formula III;
step 2: carrying out nucleophilic addition reaction on the compound shown in the formula III and triazole to obtain a compound shown in a formula II;
and step 3: carrying out a vulcanization reaction on the compound shown in the formula II to obtain prothioconazole shown in the formula I;
2. the method for synthesizing prothioconazole of claim 1, wherein the compound shown in formula IV is obtained by chlorination of a compound shown in formula V;
3. the method for synthesizing prothioconazole of claim 2, wherein the compound represented by the formula V is obtained by electrophilic addition reaction of a compound represented by the formula VI;
4. the method for synthesizing prothioconazole of claim 3, wherein the compound shown in the formula VI is obtained by performing a vinylation reaction on the compound shown in the formula VII;
5. the method for synthesizing prothioconazole of claim 4, wherein the compound represented by VII is obtained by amidation reaction of a compound represented by a formula VIII;
6. the method for synthesizing prothioconazole of claim 5, wherein the compound represented by the formula VIII is obtained by performing acyl chlorination on a compound represented by the formula IX;
7. the method for synthesizing prothioconazole according to claim 1, wherein the step 1 specifically comprises: mixing alkali, halogenated sulfoxide and solvent, heating and refluxing for reaction for 20-80 min; then adding a compound shown in the formula IV, continuing refluxing and reacting for 1-5h, and stopping the reaction.
8. The method of synthesizing prothioconazole of claim 7, wherein the molar ratio of the base, the halogenated sulfoxide and the compound represented by formula II is (1-5): (1-5): 1.
9. the method for synthesizing prothioconazole according to claim 1, wherein the step 2 specifically comprises: mixing the compound shown in the formula III, triazole, alkali and a solvent, heating and refluxing for reaction for 40-100min, and stopping the reaction; the molar ratio of the compound shown in the formula III, triazole and alkali is 1: (0.8-1.5): (1-5).
10. The application of prothioconazole is characterized by being applied to the field of pesticides; the prothioconazole prepared by the synthetic method of any one of claims 1 to 9.
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