CN106008348A - Method for synthesizing pyraclostrobin intermediate - Google Patents

Method for synthesizing pyraclostrobin intermediate Download PDF

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CN106008348A
CN106008348A CN201610396768.4A CN201610396768A CN106008348A CN 106008348 A CN106008348 A CN 106008348A CN 201610396768 A CN201610396768 A CN 201610396768A CN 106008348 A CN106008348 A CN 106008348A
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reaction
hydrochloride
chlorphenyl
chloride
catalyst
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CN106008348B (en
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刘虎
王文
马青伟
陈熙
李舟
张华�
王蕾
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Sichuan Fusida Biotechnology Development Co Ltd
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Sichuan Fusida Biotechnology Development Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
    • C07D231/18—One oxygen or sulfur atom
    • C07D231/20—One oxygen atom attached in position 3 or 5
    • C07D231/22—One oxygen atom attached in position 3 or 5 with aryl radicals attached to ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • C07C201/06—Preparation of nitro compounds
    • C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C241/00—Preparation of compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
    • C07C241/02—Preparation of hydrazines

Abstract

The invention discloses a method for synthesizing a pyraclostrobin intermediate. The synthetic method comprises the following steps: preparing an intermediate 1-(4-chlorophenyl)-3-hydroxy-1-h-pyrazole from 4-chlorophenylhydrazine hydrochloride prepared with p-bromochlorobenzene and hydrazine hydrate as reaction raw materials; reacting o-nitrotoluene with chlorine in the presence of a catalyst so as to prepare o-nitrobenzyl chloride; and subjecting 1-(4-chlorophenyl)-3-hydroxy-1-h-pyrazole and o-nitrobenzyl chloride to an etherification reaction so as to obtain the pyraclostrobin intermediate, i.e., an etherification product 2[(N-4-chlorophenyl)-3-pyrazolyl-oxymethyl]nitrobenzene. The synthetic method provided by the invention can greatly reduce the amount of waste water produced in the synthesis process of 4-chlorophenylhydrazine hydrochloride; with 4-chlorophenylhydrazine hydrochloride as a raw material, the produced intermediate 1-(4-chlorophenyl)-3-hydroxy-1-h-pyrazole has HPLC content of no less than 98% and yield of no less than 90%; since chlorine is used for replacing bromine or hydrobromic acid to prepare o-nitrobenzyl bromide, production cost and environmental protection burden are controlled; and the etherification product with a content of no less than 98% and yield of no less than 90% is obtained.

Description

A kind of method of synthesizing pyrazole kresoxim-methyl intermediate
Technical field
The present invention is a kind of method of synthesizing pyrazole kresoxim-methyl intermediate, is specifically related to the synthetic method of pyraclostrobin intermediate 2-[(N-4-chlorphenyl)-3-pyrazoles epoxide methyl] Nitrobenzol, belongs to the synthesis field of organic compound.
Background technology
Pyraclostrobin is a kind of effective broad spectrum type antibacterial, 2-[(N-4-chlorphenyl)-3-pyrazoles epoxide methyl] Nitrobenzol, as the important synthetic intermediate in its building-up process, can be reacted prepared by adjacent nitro benzyl bromide and 1-(4-chlorphenyl)-3-pyrazoles alcohol.Such as, the synthetic method of a patent documentation CN104592117A(pyraclostrobin, 2015.05.06) described in, to be raw material by parachloroanilinum, through diazotising, the p-hydrochloride that the steps such as reduction prepare, pass through ring-closure reaction, oxidation reaction prepares 1-(4-chlorphenyl)-3-pyrazoles alcohol, then, utilize ortho-methylnitrobenzene, bromide reagents etc. prepare adjacent nitro benzyl bromide for raw material by bromination reaction, above-mentioned 1-(4-the chlorphenyl)-3-pyrazoles alcohol prepared and the adjacent etherified reaction of nitro benzyl bromide are prepared the process of 2-[(N-4-chlorphenyl)-3-pyrazoles epoxide methyl] Nitrobenzol again.
In the synthetic method of existing pyraclostrobin, there is situations below:
1) p-hydrochloride is generally obtained through diazotising, bisulfite sodium reduction, hydrolysis by parachloroanilinum, in its production process, can use substantial amounts of acid and sulphite, can produce huge wastewater flow rate；There is potential safety hazard in diazotising and reduction process; the concentration of diazol can not be high; otherwise can improve the dangerous performance of production; in reduction process, sulphite used has the generation of by-product sulfur dioxide gas; along with in recent years environmental conservation and the green consciousness produced being strengthened; the raising day by day of safety requirements, the problem of safety and the three wastes has become the maximum restriction restrictive condition of diazotising hydrazine；
2) in the existing synthetic method of adjacent nitrobenzyl bromine, having several important shortcoming, the most importantly the bromine such as bromine or hydrobromic acid source is expensive, not readily transportable, and there is the Environmental assessment technology requirements such as bromine source recovery.At present, for overcoming this defect, people use adjacent nitro benzyl chloride to substitute adjacent nitro benzyl bromide, and adjacent nitro benzyl chloride has identical chemical property compared with adjacent nitro benzyl bromide, can be as the important replacement of nitro benzyl bromide adjacent in the synthetic method of pyraclostrobin.Its synthetic method mainly has two kinds: thermal chlorination and luminescence method (" Hubei Chemical ", the 4th phase in 1997, " adjacent nitro benzyl chloride new technique for synthesizing "), wherein, thermal chlorination method productivity is low, and general productivity is less than 5%.And on the one hand illumination chloridising is illumination in-convenience in use, be on the other hand that by-product is many, reaction effect is the best, and therefore, the most adjacent nitro benzyl chloride the most not yet has a low cost, the efficient synthesis of economic serviceability.
Summary of the invention
A kind of method that it is an object of the invention to provide synthesizing pyrazole kresoxim-methyl intermediate, p-hydrochloride synthesis 1-(4-chlorphenyl so that bromochlorobenzene and hydrazine hydrate are prepared)-3-pyrazoles alcohol, avoid existing synthetic method uses the defect of bromide reagent, the wastewater flow rate that produce can also be greatly reduced in building-up process by p-hydrochloride being prepared by bromochlorobenzene and hydrazine hydrate reaction, avoid sulfite reducing agent and the use of a large amount of acid, avoid the generation of harmful substance in technical process, it is achieved green produce；Replace adjacent nitro benzyl bromide with adjacent nitro benzyl chloride to react with 1-(4-chlorphenyl)-3-pyrazoles alcohol, prepare pyraclostrobin intermediate 2-[(N-4-chlorphenyl)-3-pyrazoles epoxide methyl] Nitrobenzol, avoid and existing use that etherate in adjacent nitro benzyl bromide synthetic method is difficult to purification and content is relatively low, bromine price height enterprise causes cost sodium bromide that is high and that produce to need the defects such as recovery, content >=98% can be prepared, the etherification product of productivity >=90%.
The present invention is achieved through the following technical solutions: a kind of method of synthesizing pyrazole kresoxim-methyl intermediate, comprises the following steps:
(1) with to bromochlorobenzene, hydrazine hydrate as reaction raw materials, add and prepare p-hydrochloride after phase transfer catalyst, solvent, catalyst reaction；
(2) p-hydrochloride prepared by step (1) and alkali, sodium alkoxide, acrylate reactions, in the presence of toluene, prepares the toluene solution of intermediate pyrazole ketone；
(3), after the toluene solution of step (2) being removed toluene, after adding alkali liquor, hydrogen peroxide oxidation, 1-(4-chlorphenyl is prepared)-3-pyrazoles alcohol；
(4) in ortho-methylnitrobenzene, add catalyst, heated and stirred, and be slowly introducing chlorine, after question response terminates, reclaim ortho-methylnitrobenzene, it is thus achieved that adjacent nitro benzyl chloride；
(5) the 1-(4-chlorphenyl that step (3) is prepared) the adjacent nitro benzyl chloride for preparing of-3-pyrazoles alcohol and step (4) carries out etherification reaction, it is thus achieved that 2-[(N-4-chlorphenyl)-3-pyrazoles epoxide methyl] Nitrobenzol.
Synthetic method of the present invention carries out etherification reaction with adjacent nitro benzyl chloride with 1-(4-chlorphenyl)-3-pyrazoles alcohol, prepare pyraclostrobin intermediate 2-[(N-4-chlorphenyl)-3-pyrazoles epoxide methyl] Nitrobenzol, wherein, adjacent nitro benzyl chloride is with ortho-methylnitrobenzene and chlorine as reaction raw materials, under the effect of catalyst, reaction generates adjacent nitro benzyl chloride, the thermal chlorination that its productivity causes apparently higher than thermal chlorination and initiator, from the point of view of course of reaction, its synthesis step is substantially better than light chlorination process；1-(4-chlorphenyl)-3-pyrazoles alcohol uses the p-hydrochloride and alkali preparing bromochlorobenzene and hydrazine hydrate, sodium alkoxide, acrylate reactions prepares the toluene solution of intermediate pyrazole ketone, then sodium hydrate aqueous solution is added, prepare after hydrogen peroxide oxidation, the wastewater flow rate that produce can be greatly reduced in building-up process by p-hydrochloride being prepared by bromochlorobenzene and hydrazine hydrate reaction, avoid sulfite reducing agent and the use of a large amount of acid, avoid the generation of harmful substance in whole technical process, therefore, the inventive method also includes a kind of effective, the simply adjacent nitro benzyl chloride of synthesis step and 1-(4-chlorphenyl) synthetic method of-3-pyrazoles alcohol.
Described step (1) including:
(1.1) with equivalent proportion as 1:(1～5) to bromochlorobenzene and 30～100% the hydrazine hydrate of concentration as reaction raw materials, add phase transfer catalyst, solvent, catalyst react, and described control bromochlorobenzene and the phase transfer catalyst of addition, catalyst, the weight ratio of solvent at 1:(0.01～0.15): (0.01～0.2): (1～20)；
(1.2) after question response terminates, filtering and separate solid, filtrate is through being distilled off solvent；
(1.3) adding 15～the hydrochloric acid of 36% in step (1.2) gained residue, regulation pH value is 1～3, then filters after being sufficiently stirred for；
(1.4) washed by filtering residue, drying obtains p-hydrochloride.
Owing to diazotising (acid adding becomes salt, sodium nitrite wiring solution-forming), reduction (reducing agent sulphite wiring solution-forming in advance), acidifying (acid adding decomposition sulfonate), product become the step such as salt, washing to be required to use water.Synthetic method step (1) of the present invention then eliminate diazotising, reduce, acidifying etc. needs to bring in a large number the step of water, only salt, washing is become to need to bring part water at product, therefore, synthetic method step (1) of the present invention considerably reduces the consumption of water and the generation of waste water compared with diazotising method.
In above process, the equivalent proportion preferred 1:(2～3 to bromochlorobenzene Yu hydrazine hydrate)；To bromochlorobenzene and phase transfer catalyst, catalyst, the weight ratio preferred 1:(0.02～0.08 of solvent): (0.05～0.10): (3～5).
In described step (1), phase transfer catalyst includes the combination of one or more in tetrabutylammonium chloride, tetrabutyl ammonium bromide, 4-butyl ammonium hydrogen sulfate, benzyltriethylammoinium chloride, tri-n-octyl methyl ammonium chloride, Dodecyl trimethyl ammonium chloride, tetradecyl trimethyl ammonium chloride, 18-crown-6, benzo 18-crown-6,15-crown-5, PEG400, PEG600, PEG800.
In described step (1), solvent includes the combination of one or more in water, ethylene glycol, propylene glycol, glycol monoethyl ether, glycol dimethyl ether, propylene glycol.
In described step (1), catalyst includes one or more in Nickel dichloride., copper sulfate, cobaltous chloride, Cu-lyt., copper chloride, copper bromide, cuprous bromide, Hydro-Giene (Water Science)..
In described step (1), course of reaction includes: slowly heats up and controls temperature to 100～180 DEG C, atmospheric pressure reflux or pressurize reaction, keeps thermotonus 1～15h, sampling HPLC detection to chlorophenyl hydrazine is not further added by, i.e. stopped reaction.Reaction temperature is controlled at 100～180 DEG C by the present invention, is conducive to being smoothed out of reaction, it is to avoid chlorophenyl hydrazine and hydrazine hydrate are decomposed by too high the making of temperature, cause the failure of reaction.
Described step (2) includes the step of following order:
(2.1) in the p-hydrochloride that step (1) prepares, add the toluene of 2～10 times of weight, under stirring, add alkali with the ratio of p-hydrochloride equivalent, 0～20% water of weight, it is sufficiently stirred for rear temperature rising reflux, is dehydrated to water content≤200pm, stops heating；
(2.2) after cooling, with the gauge of p-hydrochloride, adding the sodium alkoxide of 1.05～2.0 equivalent proportions, in maintaining, temperature is at 50～80 DEG C；
(2.3) with the gauge of p-hydrochloride, adding the acrylate of 1.0～2.0 equivalent proportions, after temperature rising reflux, low-boiling-point substance is sloughed in distillation；
(2.4) in fall, temperature is to 60～70 DEG C, and regulation pH value is 1～3, separates organic facies, after aqueous phase extracts with toluene, merges organic facies, prepares the toluene solution of intermediate pyrazole ketone.
In described step (2), alkali includes one or more in sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate or potassium bicarbonate.
Described sodium alkoxide is selected from Feldalat NM, Sodium ethylate and sodium tert-butoxide etc., and acrylate is selected from acrylic acid methyl ester., ethyl acrylate etc..
Described step (3) includes the step of following order:
(3.1) toluene solution of step (2) is after decompression is distilled off toluene, with the gauge of p-hydrochloride, adds alkali and the water of 2 ~ 10 times of weight of 1.2～2.0 equivalent proportions, is heated to 60～90 DEG C；
(3.2) while stirring add 30% hydrogen peroxide, in terms of chlorophenylhydxazine hydrochloride, added hydrogen peroxide amount control at 0.9～2.0 equivalents, after addition, be incubated 1～2 hour；
(3.3) stopped reaction when detecting pyrazolone content≤0.5% with HPLC；
(3.4) reactant liquor being down to room temperature, regulation pH value is 1～3, sucking filtration, and water washs, dried prepared 1-(4-chlorphenyl)-3-pyrazoles alcohol.
In described step (3.1), alkali includes one or more in Lithium hydrate, sodium hydroxide, potassium hydroxide, barium hydroxide or calcium hydroxide, preferably sodium hydroxide.
In described step (4), count in mass ratio, ortho-methylnitrobenzene: catalyst=1:(0.01～0.2), preferably 1:(0.05～0.10).
In described step (4), catalyst includes: the mixture of one or more in the activated carbon of 50～200 mesh, bromine, iodine, azodiisobutyronitrile, 2,2'-Azobis(2,4-dimethylvaleronitrile), phosphorus pentachloride, Phosphorous chloride., benzoyl peroxide, hyperis, DMF.
In described step (4), heating and temperature control is at 100～180 DEG C, and stir speed (S.S.) controls at >=200r/min.
In described step (4), in course of reaction, use gas chromatogram to follow the tracks of byproduct of reaction neighbour's nitro benzal chloride and reach 4～6%, stopped reaction.
In described step (4), after reaction terminates, at vacuum is less than 120 DEG C higher than-0.095Mpa, temperature, decompression distillation, reclaims ortho-methylnitrobenzene, and the ortho-methylnitrobenzene of recovery can continue cycling through chlorination and utilize, minimizing production cost.
In described step (4), reclaim the residue petroleum ether recrystallization purifying after ortho-methylnitrobenzene, it is thus achieved that the adjacent nitro benzyl chloride pressed powder of white crystalline.
In described step (5), etherification reaction includes: the adjacent organic solution of nitro benzyl chloride for preparing to 1-(4-chlorphenyl)-3-pyrazoles alcohol, step A, in the mixed solution of phase transfer catalyst, the lower aqueous solution dripping alkali of stirring, controlling reaction temperature is 0～100 DEG C, react 1～6 hour, after question response terminates, through extraction, recycling design, purification after drying, obtain 2-[(N-4-chlorphenyl)-3-pyrazoles epoxide methyl] Nitrobenzol.
Can be summarized as follows further at the etherification reaction that the present invention relates to: in container, add 1-(4-chlorphenyl)-3-pyrazoles alcohol, the organic solution of adjacent nitro benzyl chloride that step A prepares and phase transfer catalyst, it is thus achieved that mixed solution；In container, quickly drip the aqueous solution of alkali, preferable reaction temperature 20～60 DEG C, response time 2～4 hours under stirring；Reaction solution is sampled, with HPLC detection sampling sample, when amount≤1% of wherein 1-(4-chlorphenyl)-3-pyrazoles alcohol, stopped reaction；Regulation solution ph is to 3, then dried through extraction, recycling design, purification, it is thus achieved that etherification product 2-[(N-4-chlorphenyl)-3-pyrazoles epoxide methyl] Nitrobenzol.
The concentration of organic solution of described adjacent nitro benzyl chloride is 10～40%, and in described mixed solution, 1-(4-chlorphenyl)-3-pyrazoles alcohol, adjacent nitro benzyl chloride, the mol ratio of alkali are 1.0:(1.02～1.50): (1.05～1.6).
In described organic solution, adjacent nitro benzyl chloride controls at 1:(0.01～0.20 with the mass ratio of phase transfer catalyst).
In the etherification reaction that the present invention relates to, the organic solvent that the organic solution of the adjacent nitro benzyl chloride that step A prepares uses is selected from halogenated aliphatic hydrocarbon, such as dichloromethane, dichloroethanes, chloroform, carbon tetrachloride etc., aromatic hydrocarbon such as chlorine benzene,toluene,xylene etc.；Also selected from fatty ether, such as THF, Di Iso Propyl Ether, methyl tertiary butyl ether(MTBE), dioxane, methoxybenzene etc.；It is further selected from amide, such as DMF, DMA or NMP, alcohol such as methanol, ethanol, propanol, isopropanol, butanol, the tert-butyl alcohol etc., or selected from ketone such as acetone, methyl ethyl ketone etc.；And DMSO, acetonitrile and the mixture of above-mentioned solvent, wherein, preferably dichloroethanes, chlorobenzene and acetone and mixture thereof.
In the etherification reaction that the present invention relates to, alkali is selected from alkali and alkaline earth metal ions oxide, such as lithium oxide, sodium oxide, potassium oxide, magnesium oxide and calcium oxide etc.；Also selected from alkali and alkaline earth metal ions hydroxide, such as Lithium hydrate, sodium hydroxide, potassium hydroxide and calcium hydroxide etc.；Also selected from alkali and alkaline earth metal ions carbonate and bicarbonate, such as sodium carbonate, potassium carbonate, calcium carbonate, sodium bicarbonate and potassium bicarbonate etc.；Or selected from organic base, such as triethylamine, trimethylamine, N-methyl piperidine and pyridine etc., wherein, the preferred sodium hydroxide of alkali.
Can carry out in the two-phase system being made up of the aqueous solution of alkali and alkaline earth metal ions hydroxide or carbonate and organic facies (such as aromatic hydrocarbon or/and halogenated hydrocarbons etc.) at the etherification reaction that the present invention relates to.In the case, the PTC adding suitable catalytic amount is favourable to reaction, PTC is selected from ammonium halide, such as benzyltriethylammoinium chloride, tetrabutyl ammonium bromide, benzyl tributyl ammonium bromide, tetrabutylammonium chloride, cetyl trimethylammonium bromide etc., it is possible to selected from Polyethylene Glycol, such as PEG400, PEG600 and PEG800 etc., also selected from crown ether, such as 18-crown-6,15-crown-5 etc., or selected from tetrabutyl ammonium tetrafluoroborate etc., wherein, the particularly preferred benzyltriethylammoinium chloride of PTC.
The present invention compared with prior art, has the following advantages and beneficial effect:
(1) chlorophenylhydxazine hydrochloride that the present invention relates to be with equivalent proportion as 1:(1～5) to bromochlorobenzene, hydrazine hydrate as reaction raw materials, addition phase transfer catalyst, catalyst, solvent react, sampling HPLC detection is to stopped reaction when not being further added by chlorophenyl hydrazine, available after filtering, distill, be acidified, filter, wash, drying again, meet HPLC content >=99%, yield >=80%.
null(2) synthetic method of the present invention is simple，When preparing p-hydrochloride，Course of reaction is to slowly warm up to 100～180 DEG C，Atmospheric pressure reflux or pressurize reaction 1～15h again，Detect to sampling HPLC and chlorophenyl hydrazine is not further added by rear stopped reaction，Product is separated by filtration solid catalyst、Solvent is distilled off、Filter after adding hydrochloric acid stirring、Washing filtering residue、Chlorophenylhydxazine hydrochloride product is i.e. can get after drying，More existing commonly used with parachloroanilinum as raw material，Through diazonium、Reduction、Acidifying、Cooling、Filter、Washing、Discharging，Dry finished product synthetic method for，The consumption of about more than 90% water can be reduced and reduce the generation of more than 90% waste water，It is proven，This synthetic method is used often to synthesize 1000kg chlorophenylhydxazine hydrochloride product，Water consumption can be controlled in 0.8～1.2m3, the wastewater flow rate of generation can be controlled in 0.8～1.2m3, the beneficially smooth enforcement of subsequent technique.
(3) the raw materials used cleaning of synthetic method of the present invention, the output of the three wastes will not be increased, the particularly preparation of p-hydrochloride, avoid sulfite reducing agent and the use of a large amount of acid, the hydrazine hydrate of solvent and excess can be with recycled, catalyst is in simple process Returning reacting system, and whole preparation process produces without harmful gas, environmental protection.
(4) concentration of the present invention is the hydrazine hydrate of 30～100%, with equivalent proportion (1～5): 1 reacts with to bromochlorobenzene, it is particularly (2～3) in equivalent proportion: 1, control bromochlorobenzene and phase transfer catalyst, weight ratio 1:(0.01 of catalyst～0.15): (0.01～0.2), preferably 1:(0.02 ~ 0.08): (0.05 ~ 0.10), weight ratio 1:(1～20 to bromochlorobenzene Yu solvent), preferably 1:(3～5) in the case of, it is more beneficial for being smoothed out of reaction, improves the reaction efficiency to bromochlorobenzene.
(5) synthetic method of the present invention uses p-hydrochloride and equivalent alkali that step (1) prepares, 1.05～2.0 sodium alkoxide, 1.0～2.0 acrylate reactions of equivalent of equivalent, in the case of 2～10 times of weight of toluene are solvent, obtain the toluene solution of intermediate pyrazole ketone, can realize the conversion ratio higher to chlorophenyl hydrazine, conversion ratio is higher than 99.5%.
(6), in synthetic method of the present invention, the toluene solution prepared in step (2) reacts with sodium hydroxide, hydrogen peroxide during preparing pyraclostrobin intermediate, and one, in use sodium hydroxide and hydrochloric acid can reduce reaction cost；Two, pyrazolone is the most purified directly carries out oxidation reaction, simplifies technical process, improves yield；Three, stirring drip hydrogen peroxide in the presence of aqueous slkali, improves response speed, also substantially increases the reaction yield of this step, it is to avoid the use of organic solvent；Four, this oxidation step and step (1), step (2) composition complete set prepare pyraclostrobin intermediate 1-(4-chlorphenyl) the continuous processing step of-3-pyrazoles alcohol, pyrazoles alcohol HPLC content >=98% can be realized, the product attribute (yield is in terms of p-hydrochloride) of yield >=90%.
(7) synthetic method of the present invention uses cheap chlorine and ortho-methylnitrobenzene chlorination to generate adjacent nitro benzyl chloride, substitute in existing pyraclostrobin production process and carry out etherification reaction with adjacent nitro benzyl bromide with 1-(4-chlorphenyl)-3-pyrazoles alcohol, on the one hand, it is avoided that use bromine or the adjacent nitro benzyl bromide of hydrobromic acid preparation, reduce environmental protection pressure, on the other hand, use bromine or hydrobromic acid that cheap chlorine fictitious hosts is expensive, production cost can be reduced.
(8) synthesis technique of the present invention is simple, the synthesis of adjacent nitro benzyl chloride uses ortho-methylnitrobenzene and chlorine to be reaction raw materials, and the mass ratio controlling ortho-methylnitrobenzene and catalyst is 1:(0.01～0.2) react, sampled and when being about 40% with gas chromatography detecting and tracking ortho-methylnitrobenzene conversion ratio, i.e. stopped reaction, reduce pressure the most again distillation, residue is after petroleum ether crystallizes, i.e. available adjacent nitro benzyl chloride crystal, adjacent nitro benzyl chloride product yield (in terms of the ortho-methylnitrobenzene of actual consumption) of purity >=99% and productivity >=80% can be realized, product yield far above the thermal chlorination 5% that thermal chlorination 1.9% and initiator cause.
(9) in the step (4) that synthesis technique of the present invention relates to, for preparing the ortho-methylnitrobenzene of adjacent nitro benzyl chloride, after the completion of reaction, unreacted ortho-methylnitrobenzene can be recycled by the way of decompression is distilled, can realize reclaiming 90～about 95% the circulation chlorination of ortho-methylnitrobenzene utilize, the beneficially control of production cost.
(10) in step of the present invention (4), the mixture of one or both compositions in the preferred bromine of catalyst, Phosphorous chloride., there is raising selectivity, accelerate the effect of response speed, use the mass ratio 1:(0.01～0.2 of ortho-methylnitrobenzene and catalyst), particularly 1:(0.05～0.10), be conducive to controlling the consumption of catalyst, the most cost-effective, also allow for post processing.
(11) in step of the present invention (4), before being passed through chlorine, by controlling heating-up temperature 100～180 DEG C and stir speed (S.S.) >=200r/min, be conducive to being smoothed out of reaction, temperature is controlled at optimum range, it is to avoid occur that temperature low reaction process is slow, the many situations about even decomposing of temperature height side reaction；The absorption dispersion controlling to be conducive to leading to chlorine of stir speed (S.S.), accelerates reaction process.
(12) etherification reaction that the inventive method relates to is with the organic solution of adjacent nitro benzyl chloride that concentration is 10～40%, 1-(4-chlorphenyl)-3-pyrazoles alcohol is main, it is aided with the phase transfer catalyst of appropriate ratio and the aqueous solution of alkali again, control 1-(4-chlorphenyl)-3-pyrazoles alcohol, adjacent nitro benzyl chloride, the mol ratio of alkali controls at 1.0:(1.02～1.50): (1.05～1.6), adjacent nitro benzyl chloride is 1:(0.01～0.2 with the mass ratio of phase transfer catalyst) in the case of carry out etherification reaction, content >=98% can be obtained, the etherification product of productivity >=90%.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is described in further detail, but embodiments of the present invention are not limited to this.
Example 1 below～8 relates to the synthesis contrasting chlorophenylhydxazine hydrochloride.
Embodiment 1:
In the present embodiment, the synthesis step of p-hydrochloride is as follows:
(1.1) with equivalent proportion as 1:1 to bromochlorobenzene, hydrazine hydrate as reaction raw materials, addition phase transfer catalyst (4-butyl ammonium hydrogen sulfate), solvent (concentration is the glycol water of 85%), catalyst (mass ratio is the copper sulfate of 1:1, cobaltous chloride) react, wherein, the concentration of hydrazine hydrate is 100%, being 1:0.15:0.2 to bromochlorobenzene and phase transfer catalyst, the weight ratio of catalyst, the weight ratio to bromochlorobenzene Yu solvent is 1:1；
Course of reaction includes: slowly heating up and control temperature to 100 DEG C, atmospheric pressure reflux is reacted, and keeps thermotonus 1h, sampling HPLC detection to chlorophenyl hydrazine is not further added by, i.e. stopped reaction.
(1.2) after question response terminates, filtering and separate solid, filtrate is through being distilled off solvent.
(1.3) adding the hydrochloric acid of 15% in step B gained residue, regulation pH value is 1, then filters after being sufficiently stirred for.
(1.4) filtering residue washed, dry at 50 DEG C and obtain p-hydrochloride.
It is 80% that the present embodiment can realize the yield of p-hydrochloride, and HPLC content is 99%.
Embodiment 2:
In the present embodiment, the synthesis step of p-hydrochloride is as follows:
(1.1) with equivalent proportion as 1:3 to bromochlorobenzene, hydrazine hydrate as reaction raw materials, add phase transfer catalyst tetrabutyl ammonium bromide and the 4-butyl ammonium hydrogen sulfate of 2:1 (mass ratio be), solvent (glycol dimethyl ether), catalyst (copper bromide) react, wherein, the concentration of hydrazine hydrate is 55%, being 1:0.08:0.12 to bromochlorobenzene and phase transfer catalyst, the weight ratio of catalyst, the weight ratio to bromochlorobenzene Yu solvent is 1:12；
Course of reaction includes: slowly heating up and control temperature to 150 DEG C, pressurize is reacted, and keeps thermotonus 10h, sampling HPLC detection to chlorophenyl hydrazine is not further added by, i.e. stopped reaction.
(1.2) after question response terminates, filtering and separate solid, filtrate is through being distilled off solvent.
(1.3) adding the hydrochloric acid of 28% in step B gained residue, regulation pH value is 2.7, then filters after being sufficiently stirred for.
(1.4) filtering residue washed, dry at 60 DEG C and obtain p-hydrochloride.
It is 84.6% that the present embodiment can realize the yield of p-hydrochloride, and HPLC content is 99.2%.
Embodiment 3:
In the present embodiment, the synthesis step of p-hydrochloride is as follows:
(1.1) with equivalent proportion as 1:4.5 to bromochlorobenzene, hydrazine hydrate as reaction raw materials, add phase transfer catalyst (mass ratio is the tri-n-octyl methyl ammonium chloride of 2:1:3,15-crown-5 and PEG400), the solvent propylene glycol aqueous solution of 85% (concentration be), catalyst (Cu-lyt .) react, wherein, the concentration of hydrazine hydrate is 88%, being 1:0.11:0.09 to bromochlorobenzene and phase transfer catalyst, the weight ratio of catalyst, the weight ratio to bromochlorobenzene Yu solvent is 1:8.6；
Course of reaction includes: slowly heating up and control temperature to 120 DEG C, atmospheric pressure reflux is reacted, and keeps thermotonus 9h, sampling HPLC detection to chlorophenyl hydrazine is not further added by, i.e. stopped reaction.
(1.2) after question response terminates, filtering and separate solid, filtrate is through being distilled off solvent.
(1.3) adding the hydrochloric acid of 30% in step B gained residue, regulation pH value is 2.5, then filters after being sufficiently stirred for.
(1.4) filtering residue washed, dry at 65 DEG C and obtain p-hydrochloride.
It is 85.0% that the present embodiment can realize the yield of p-hydrochloride, and HPLC content is 99.1%.
Embodiment 4:
In the present embodiment, the synthesis step of p-hydrochloride is as follows:
(1.1) with equivalent proportion as 1:2.8 to bromochlorobenzene, hydrazine hydrate as reaction raw materials, addition phase transfer catalyst (benzo 18-crown-6), solvent (concentration is the aqueous solution of propylene glycol of 90%), catalyst (cuprous bromide) react, wherein, the concentration of hydrazine hydrate is 59.5%, being 1:0.15:0.2 to bromochlorobenzene and phase transfer catalyst, the weight ratio of catalyst, the weight ratio to bromochlorobenzene Yu solvent is 1:16.6；
Course of reaction includes: slowly heating up and control temperature to 172 DEG C, pressurize is reacted, and keeps thermotonus 5h, sampling HPLC detection to chlorophenyl hydrazine is not further added by, i.e. stopped reaction.
(1.2) after question response terminates, filtering and separate solid, filtrate is through being distilled off solvent.
(1.3) adding the hydrochloric acid of 24.8% in step B gained residue, regulation pH value is 1.8, then filters after being sufficiently stirred for.
(1.4) filtering residue washed, dry at 70 DEG C and obtain p-hydrochloride.
It is 86.3% that the present embodiment can realize the yield of p-hydrochloride, and HPLC content is 99.2%.
Embodiment 5:
In the present embodiment, the synthesis step of p-hydrochloride is as follows:
(1.1) in reaction vessel add reaction raw materials: 96.5g to bromochlorobenzene and the hydrazine hydrate of 4 equivalents, concentration of hydrazine hydrate is 40%, add the phase transfer catalyst (tetrabutylammonium chloride) of 12% weight ratio, the solvent (ethylene glycol) of 14 times of weight and the catalyst (copper sulfate) of 12% weight, react；
Course of reaction includes: slowly heating up and control temperature to 162 DEG C, pressurize is reacted, and keeps thermotonus 8h, sampling HPLC detection to chlorophenyl hydrazine is not further added by, i.e. stopped reaction.
(1.2) after question response terminates, filtering and separate solid, filtrate is through being distilled off solvent.
(1.3) adding the hydrochloric acid of 20.5% in step B gained residue, regulation pH value is 2.2, then filters after being sufficiently stirred for.
(1.4) filtering residue washed, dry at 60 DEG C and obtain p-hydrochloride.
It is 84.6% that the present embodiment can realize the yield of p-hydrochloride, and HPLC content is 99.3%.
Embodiment 6:
In the present embodiment, the synthesis step of p-hydrochloride is as follows:
(1.1) in reaction vessel add reaction raw materials: 98.25g to bromochlorobenzene and the hydrazine hydrate of 3.3 equivalents, concentration of hydrazine hydrate is 71%, add catalyst copper sulfate and the cobaltous chloride of 3:1 (mass ratio be) of the phase transfer catalyst (PEG400) of 10% weight ratio, the solvent (propylene glycol) of 3 times of weight and 20% weight, react；
Course of reaction includes: slowly heats up and controls temperature to 152 DEG C, atmospheric pressure reflux or pressurize reaction, keeps thermotonus 10h, sampling HPLC detection to chlorophenyl hydrazine is not further added by, i.e. stopped reaction.
(1.2) after question response terminates, filtering and separate solid, filtrate is through being distilled off solvent.
(1.3) adding the hydrochloric acid of 30% in step B gained residue, regulation pH value is 3, then filters after being sufficiently stirred for.
(1.4) filtering residue washed, dry at 55 DEG C and obtain p-hydrochloride.
It is 88.1% that the present embodiment can realize the yield of p-hydrochloride, and HPLC content is 99.29%.
Embodiment 7:
In the present embodiment, the synthesis step of p-hydrochloride is as follows:
(1.1) in reaction vessel add reaction raw materials: 95.36g to bromochlorobenzene and the hydrazine hydrate of 2 equivalents, concentration of hydrazine hydrate is 86%, add the phase transfer catalyst (mass ratio is the 18-crown-6 of 1:5:1, PEG600, tetrabutyl ammonium bromide) of 14% weight ratio, the solvent propylene glycol aqueous solution of 75% (concentration be) of 5 times of weight and the catalyst (copper chloride) of 2% weight, react；
Course of reaction includes: slowly heating up and control temperature to 180 DEG C, pressurize is reacted, and keeps thermotonus 4h, sampling HPLC detection to chlorophenyl hydrazine is not further added by, i.e. stopped reaction.
(1.2) after question response terminates, filtering and separate solid, filtrate is through being distilled off solvent.
(1.3) adding the hydrochloric acid of 30% in step B gained residue, regulation pH value is 1.5, then filters after being sufficiently stirred for.
(1.4) filtering residue washed, dry at 65 DEG C and obtain p-hydrochloride.
It is 85.0% that the present embodiment can realize the yield of p-hydrochloride, and HPLC content is 99.6%.
Embodiment 8:
In the present embodiment, the synthesis step of p-hydrochloride is as follows:
(1.1) in reaction vessel add reaction raw materials: 97.55g to bromochlorobenzene and the hydrazine hydrate of 1.8 equivalents, concentration of hydrazine hydrate is 80%, add the catalyst (mass ratio is the copper sulfate of 2:1:1, cobaltous chloride, Cu-lyt .) of phase transfer catalyst (mass ratio is the benzyltriethylammoinium chloride of 2:1, tetrabutyl ammonium bromide), the solvent (ethylene glycol) of 6 times of weight and 19% weight of 8% weight ratio, react；
Course of reaction includes: slowly heating up and control temperature to 120 DEG C, atmospheric pressure reflux is reacted, and keeps thermotonus 10h, sampling HPLC detection to chlorophenyl hydrazine is not further added by, i.e. stopped reaction.
(1.2) after question response terminates, filtering and separate solid, filtrate is through being distilled off solvent.
(1.3) adding the hydrochloric acid of 35% in step B gained residue, regulation pH value is 1.2, then filters after being sufficiently stirred for.
(1.4) filtering residue washed, dry at 70 DEG C and obtain p-hydrochloride.
It is 86. 2% that the present embodiment can realize the yield of p-hydrochloride, and HPLC content is 99.7%.
Example 9 below～16 is to prepare p-hydrochloride with embodiment 1～8 to prepare the building-up process of intermediate pyrazole ketone toluene solution for raw material.
Embodiment 9:
The building-up process that the present embodiment relates to includes following sequence step:
(2.1) in the p-hydrochloride that embodiment 1 prepares, add the toluene of 5 times of weight, under stirring, add alkali (sodium hydroxide) with the ratio of p-hydrochloride equivalent, be sufficiently stirred for rear temperature rising reflux, be dehydrated to water content 185pm, stop heating；
(2.2) after cooling, with the gauge of p-hydrochloride, adding the sodium alkoxide (Feldalat NM) of 1.5 equivalent proportions, in maintaining, temperature is at 60 DEG C；
(2.3) with the gauge of p-hydrochloride, adding the acrylate (acrylic acid methyl ester .) of 1.2 equivalent proportions, after temperature rising reflux, distillation is sloughed low-boiling-point substance to interior temperature about 85 DEG C and is stopped distillation, now detects chlorophenyl hydrazine content 0.35% with HPLC；
(2.4) in fall, temperature is to 65 DEG C, and regulation pH value is 2, separates organic facies, after aqueous phase extracts with toluene, merges organic facies, prepares the toluene solution of intermediate pyrazole ketone.
Embodiment 10:
The building-up process that the present embodiment relates to includes following sequence step:
(2.1) in the p-hydrochloride that embodiment 2 prepares, add the toluene of 10 times of weight, under stirring, add alkali (sodium carbonate) with the ratio of p-hydrochloride equivalent, the water of 20% weight, temperature rising reflux, is dehydrated to water content 180pm, stops heating；
(2.2) after cooling, with the gauge of p-hydrochloride, adding the sodium alkoxide (Sodium ethylate) of 2.0 equivalent proportions, in maintaining, temperature is at 80 DEG C；
(2.3) with the gauge of p-hydrochloride, adding the acrylate (ethyl acrylate) of 2.0 equivalent proportions, after temperature rising reflux, distillation is sloughed low-boiling-point substance to interior temperature about 85 DEG C and is stopped distillation, now detects chlorophenyl hydrazine content 0.5% with HPLC；
(2.4) in fall, temperature is to 70 DEG C, and regulation pH value is 3, separates organic facies, after aqueous phase extracts with toluene, merges organic facies, prepares the toluene solution of intermediate pyrazole ketone.
Embodiment 11:
The building-up process that the present embodiment relates to includes following sequence step:
(2.1) in the p-hydrochloride that embodiment 3 prepares, add the toluene of 2 times of weight, under stirring, add alkali (potassium hydroxide) with the ratio of p-hydrochloride equivalent, the water of 15% weight, temperature rising reflux, is dehydrated to water content 200pm, stops heating；
(2.2) after cooling, with the gauge of p-hydrochloride, adding the sodium alkoxide (sodium tert-butoxide) of 1.05 equivalent proportions, in maintaining, temperature is at 50 DEG C；
(2.3) with the gauge of p-hydrochloride, adding the acrylate (ethyl acrylate) of 1.0 equivalent proportions, after temperature rising reflux, distillation is sloughed low-boiling-point substance to interior temperature about 85 DEG C and is stopped distillation, now detects chlorophenyl hydrazine content 0.44% with HPLC；
(2.4) in fall, temperature is to 60 DEG C, and regulation pH value is 1, separates organic facies, after aqueous phase extracts with toluene, merges organic facies, prepares the toluene solution of intermediate pyrazole ketone.
Embodiment 12:
The building-up process that the present embodiment relates to includes following sequence step:
(2.1) in the p-hydrochloride that embodiment 4 prepares, add the toluene of 8 times of weight, under stirring, add alkali (potassium bicarbonate) with the ratio of p-hydrochloride equivalent, the water of 10% weight, temperature rising reflux, is dehydrated to water content 190pm, stops heating；
(2.2) after cooling, with the gauge of p-hydrochloride, adding the sodium alkoxide (Feldalat NM) of 1.05 equivalent proportions, in maintaining, temperature is at 70 DEG C；
(2.3) with the gauge of p-hydrochloride, adding the acrylate (acrylic acid methyl ester .) of 1.5 equivalent proportions, after temperature rising reflux, distillation is sloughed low-boiling-point substance to interior temperature about 85 DEG C and is stopped distillation, now detects chlorophenyl hydrazine content 0.30% with HPLC；
(2.4) in fall, temperature is to 65 DEG C, and regulation pH value is 2, separates organic facies, after aqueous phase extracts with toluene, merges organic facies, prepares the toluene solution of intermediate pyrazole ketone.
Embodiment 13:
The building-up process that the present embodiment relates to includes following sequence step:
(2.1) p-hydrochloride that embodiment 5 prepares is transferred in container, the toluene of 5 times of weight is added to this container, it is slowly stirred down, alkali (sodium hydroxide solution of 2:1 and sodium carbonate) is added with the ratio of p-hydrochloride equivalent, the water of 15% weight, temperature rising reflux, is dehydrated to water content 160pm, stops heating；
(2.2) after being cooled to 70 DEG C, with the gauge of p-hydrochloride, adding the sodium alkoxide (Feldalat NM) of 1.6 equivalent proportions, in maintaining, temperature is at 65 DEG C；
(2.3) with the gauge of p-hydrochloride, dripping the acrylate (ethyl acrylate) of 1.8 equivalent proportions, 0.8h dropping is complete, after temperature rising reflux 1h, distillation is sloughed low-boiling-point substance to interior temperature about 85 DEG C and is stopped distillation, now detects chlorophenyl hydrazine content 0.4% with HPLC；
(2.4) in fall, temperature, to 60 DEG C, adds 500ml water, and dropping salt acid for adjusting pH value is 2, separates organic facies, after aqueous phase extracts with toluene, merges organic facies, prepares the toluene solution of intermediate pyrazole ketone.
Embodiment 14:
The building-up process that the present embodiment relates to includes following sequence step:
(2.1) p-hydrochloride that embodiment 6 prepares is transferred in container, the toluene of 8 times of weight is added to this container, it is slowly stirred down, alkali (sodium carbonate) is added with the ratio of p-hydrochloride equivalent, the water of 12% weight, temperature rising reflux, is dehydrated to water content 200pm, stops heating；
(2.2) after being cooled to 70 DEG C, with the gauge of p-hydrochloride, adding the sodium alkoxide (Sodium ethylate) of 1.2 equivalent proportions, in maintaining, temperature is at 80 DEG C；
(2.3) with the gauge of p-hydrochloride, dripping the acrylate (ethyl acrylate) of 1.4 equivalent proportions, 1.0h dropping is complete, after temperature rising reflux 1h, distillation is sloughed low-boiling-point substance to interior temperature about 85 DEG C and is stopped distillation, now detects chlorophenyl hydrazine content 0.3% with HPLC；
(2.4) in fall, temperature, to 60 DEG C, adds 500ml water, and dropping salt acid for adjusting pH value is 3, separates organic facies, after aqueous phase extracts with toluene, merges organic facies, prepares the toluene solution of intermediate pyrazole ketone.
Embodiment 15:
The building-up process that the present embodiment relates to includes following sequence step:
(2.1) p-hydrochloride that embodiment 6 prepares is transferred in container, the toluene of 4 times of weight is added to this container, it is slowly stirred down, alkali (sodium bicarbonate) is added with the ratio of p-hydrochloride equivalent, the water of 5% weight, temperature rising reflux, is dehydrated to water content 200pm, stops heating；
(2.2) after being cooled to 70 DEG C, with the gauge of p-hydrochloride, adding the sodium alkoxide (sodium tert-butoxide) of 1.8 equivalent proportions, in maintaining, temperature is at 70 DEG C；
(2.3) with the gauge of p-hydrochloride, dripping the acrylate (acrylic acid methyl ester .) of 1.1 equivalent proportions, 0.9h dropping is complete, after temperature rising reflux 1h, distillation is sloughed low-boiling-point substance to interior temperature about 85 DEG C and is stopped distillation, now detects chlorophenyl hydrazine content 0.28% with HPLC；
(2.4) in fall, temperature, to 60 DEG C, adds 500ml water, and dropping salt acid for adjusting pH value is 2, separates organic facies, after aqueous phase extracts with toluene, merges organic facies, prepares the toluene solution of intermediate pyrazole ketone.
Embodiment 16:
The building-up process that the present embodiment relates to includes following sequence step:
(2.1) p-hydrochloride that embodiment 6 prepares is transferred in container, the toluene of 5 times of weight is added to this container, it is slowly stirred down, alkali (sodium hydroxide) is added with the ratio of p-hydrochloride equivalent, the water of 20% weight, temperature rising reflux, is dehydrated to water content 168pm, stops heating；
(2.2) after being cooled to 70 DEG C, with the gauge of p-hydrochloride, adding the sodium alkoxide (Feldalat NM) of 1.2 equivalent proportions, in maintaining, temperature is at 75 DEG C；
(2.3) with the gauge of p-hydrochloride, dripping the acrylate (acrylic acid methyl ester .) of 1.3 equivalent proportions, 1.2h dropping is complete, after temperature rising reflux 1h, distillation is sloughed low-boiling-point substance to interior temperature about 85 DEG C and is stopped distillation, now detects chlorophenyl hydrazine content 0.36% with HPLC；
(2.4) in fall, temperature, to 65 DEG C, adds 500ml water, and dropping salt acid for adjusting pH value is 1, separates organic facies, after aqueous phase extracts with toluene, merges organic facies, prepares the toluene solution of intermediate pyrazole ketone.
Example 1 below 7～24 is to prepare the toluene solution of intermediate pyrazole ketone with embodiment 9～16 to prepare pyraclostrobin intermediate 1-(4-chlorphenyl for raw material) building-up process of-3-pyrazoles alcohol.
Embodiment 17:
The building-up process that the present embodiment relates to includes following sequence step:
(3.1) toluene solution that embodiment 9 prepares is after decompression is distilled off toluene, with the gauge of p-hydrochloride, adds alkali (sodium hydroxide) and the water of 2 times of weight of 1.2 equivalent proportions, is heated to 60 DEG C；
(3.2) adding the hydrogen peroxide of 30% while stirring, in terms of p-hydrochloride, the amount of added hydrogen peroxide controls at 0.9 equivalent, after addition, is incubated 1 hour；
(3.3) stopped reaction when detecting pyrazolone content 0.5% with HPLC；
(3.4) reactant liquor being down to room temperature, regulation pH value is 1, sucking filtration, and water washs, dried prepared 1-(4-chlorphenyl)-3-pyrazoles alcohol, its HPLC content 98%, yield 90%.
Embodiment 18:
The building-up process that the present embodiment relates to includes following sequence step:
(3.1) toluene solution that embodiment 10 prepares is after decompression is distilled off toluene, with the gauge of p-hydrochloride, adds alkali (potassium hydroxide of 1:1 and sodium hydroxide) liquid and the water of 5 times of total amounts of 2.0 equivalent proportions, is heated to 90 DEG C；
(3.2) adding the hydrogen peroxide of 30% while stirring, in terms of p-hydrochloride, the amount of added hydrogen peroxide controls at 2.0 equivalents, after addition, is incubated 2 hours；
(3.3) stopped reaction when detecting pyrazolone content 0.26% with HPLC；
(3.4) reactant liquor being down to room temperature, regulation pH value is 3, sucking filtration, and water washs, dried prepared 1-(4-chlorphenyl)-3-pyrazoles alcohol, its HPLC content 99.5%, yield 91.2%.
Embodiment 19:
The building-up process that the present embodiment relates to includes following sequence step:
(3.1) toluene solution that embodiment 11 prepares is after decompression is distilled off toluene, with the gauge of p-hydrochloride, adds alkali (Lithium hydrate) and the water of 3.5 times of weight of 1.5 equivalent proportions, is heated to 65 DEG C；
(3.2) adding the hydrogen peroxide of 30% while stirring, in terms of p-hydrochloride, the amount of added hydrogen peroxide controls at 1.2 equivalents, after addition, is incubated 1.5 hours；
(3.3) stopped reaction when detecting pyrazolone content 0.33% with HPLC；
(3.4) reactant liquor being down to room temperature, regulation pH value is 2, sucking filtration, and water washs, dried prepared 1-(4-chlorphenyl)-3-pyrazoles alcohol, its HPLC content 99.1%, yield 90.5%.
Embodiment 20:
The building-up process that the present embodiment relates to includes following sequence step:
(3.1) toluene solution that embodiment 12 prepares is after decompression is distilled off toluene, with the gauge of p-hydrochloride, adds alkali (2:1:1 sodium hydroxide, barium hydroxide, calcium hydroxide) and the water of 10 times of weight of 1.8 equivalent proportions, is heated to 80 DEG C；
(3.2) adding the hydrogen peroxide of 30% while stirring, in terms of p-hydrochloride, the amount of added hydrogen peroxide controls at 1.6 equivalents, after addition, is incubated 1.5 hours；
(3.3) stopped reaction when detecting pyrazolone content 0.4% with HPLC；
(3.4) reactant liquor being down to room temperature, regulation pH value is 1.8, sucking filtration, and water washs, dried prepared 1-(4-chlorphenyl)-3-pyrazoles alcohol, its HPLC content 99.2%, yield 92.0%.
Embodiment 21:
The building-up process that the present embodiment relates to includes following sequence step:
(3.1) toluene solution that embodiment 13 prepares is proceeded in another container, after decompression is distilled off toluene, with the gauge of p-hydrochloride, adds alkali (2:1 potassium hydroxide and calcium hydroxide) and the water of 8 times of weight of 1.8 equivalent proportions, be heated to 85 DEG C；
(3.2) being slowly added dropwise the hydrogen peroxide of 30% under quickly stirring, in terms of p-hydrochloride, the amount of added hydrogen peroxide controls at 1.1 equivalents, after dropping, is incubated 2 hours；
(3.3) stopped reaction when detecting pyrazolone content 0.35% with HPLC；
(3.4) reactant liquor being down to room temperature, dropping salt acid for adjusting pH value is 2, sucking filtration, and water washs, and prepares 1-(4-chlorphenyl after 50 DEG C of drying under reduced pressure)-3-pyrazoles alcohol, its HPLC content 99.0%, yield 91.8%.
Embodiment 22:
The building-up process that the present embodiment relates to includes following sequence step:
(3.1) toluene solution that embodiment 14 prepares is proceeded in another container, after decompression is distilled off toluene, with the gauge of p-hydrochloride, adds alkali (1:2 Lithium hydrate and sodium hydroxide) and the water of 4.5 times of weight of 1.7 equivalent proportions, be heated to 70 DEG C；
(3.2) being slowly added dropwise the hydrogen peroxide of 30% under quickly stirring, in terms of p-hydrochloride, the amount of added hydrogen peroxide controls at 1.7 equivalents, after dropping, is incubated 1.5 hours；
(3.3) stopped reaction when detecting pyrazolone content 0.30% with HPLC；
(3.4) reactant liquor being down to room temperature, dropping salt acid for adjusting pH value is 1, sucking filtration, and water washs, and prepares 1-(4-chlorphenyl after 80 DEG C of drying under reduced pressure)-3-pyrazoles alcohol, its HPLC content 98.9%, yield 90.8%.
Embodiment 23:
The building-up process that the present embodiment relates to includes following sequence step:
(3.1) toluene solution that embodiment 15 prepares is proceeded in another container, after decompression is distilled off toluene, with the gauge of p-hydrochloride, adds 1.4 equivalent proportion alkali (sodium hydroxide) and the water of 5 times of weight, be heated to 80 DEG C；
(3.2) being slowly added dropwise the hydrogen peroxide of 30% under quickly stirring, in terms of p-hydrochloride, the amount of added hydrogen peroxide controls at 1.9 equivalents, after dropping, is incubated 1.8 hours；
(3.3) stopped reaction when detecting pyrazolone content 0.4% with HPLC；
(3.4) reactant liquor being down to room temperature, dropping salt acid for adjusting pH value is 2, sucking filtration, and water washs, and prepares 1-(4-chlorphenyl after 60 DEG C of drying under reduced pressure)-3-pyrazoles alcohol, its HPLC content 99.1%, yield 91.2%.
Embodiment 24:
The building-up process that the present embodiment relates to includes following sequence step:
(3.1) toluene solution that embodiment 16 prepares is proceeded in another container, after decompression is distilled off toluene, with the gauge of p-hydrochloride, adds alkali (1:1 sodium hydroxide and potassium hydroxide) and the water of 6 times of weight of 1.3 equivalent proportions, be heated to 85 DEG C；
(3.2) being slowly added dropwise the hydrogen peroxide of 30% under quickly stirring, in terms of p-hydrochloride, the amount of added hydrogen peroxide controls at 1.6 equivalents, after dropping, is incubated 2 hours；
(3.3) stopped reaction when detecting pyrazolone content 0.45% with HPLC；
(3.4) reactant liquor being down to room temperature, dropping salt acid for adjusting pH value is 1.2, sucking filtration, and water washs, and prepares 1-(4-chlorphenyl after 70 DEG C of drying under reduced pressure)-3-pyrazoles alcohol, its HPLC content 99.6%, yield 90.7%.
Example 2 below 5～32 relates to the synthesis of adjacent nitro benzyl chloride.
Embodiment 25:
In the present embodiment, the building-up process of adjacent nitro benzyl chloride is as follows:
Catalyst (activated carbon of 50 mesh) is added in ortho-methylnitrobenzene, ortho-methylnitrobenzene controls at 1:0.01 with the mass ratio of catalyst, 100 DEG C it are stirred and heated under 200r/min speed, it is slowly introducing chlorine, follow the tracks of byproduct of reaction neighbour's nitro benzal chloride by gas chromatogram and reach 4%, ortho-methylnitrobenzene conversion ratio 39.7%, stopped reaction；After question response terminates, decompression distillation at vacuum-0.097Mpa, temperature 110 DEG C, reclaim ortho-methylnitrobenzene, continue cycling through chlorination and utilize；Reclaim the residue petroleum ether recrystallization purifying after ortho-methylnitrobenzene, it is thus achieved that the adjacent nitro benzyl chloride pressed powder of white crystalline.
The present embodiment can realize adjacent nitro benzyl chloride purity 99.3% and the production effect (in terms of the ortho-methylnitrobenzene of actual consumption) of productivity 83.7%.
Embodiment 26:
In the present embodiment, the building-up process of adjacent nitro benzyl chloride is as follows:
Catalyst (mass ratio is the activated carbon of 2:1200 mesh and the mixture of DMF composition) is added in ortho-methylnitrobenzene, ortho-methylnitrobenzene controls at 1:0.2 with the mass ratio of catalyst, 180 DEG C it are stirred and heated under 400r/min speed, it is slowly introducing chlorine, follow the tracks of byproduct of reaction neighbour's nitro benzal chloride by gas chromatogram and reach 6%, ortho-methylnitrobenzene conversion ratio 41%, stopped reaction；After question response terminates, decompression distillation at vacuum-0.098Mpa, temperature 100 DEG C, reclaim ortho-methylnitrobenzene, continue cycling through chlorination and utilize；Reclaim the residue petroleum ether recrystallization purifying after ortho-methylnitrobenzene, it is thus achieved that the adjacent nitro benzyl chloride pressed powder of white crystalline.
The present embodiment can realize adjacent nitro benzyl chloride purity 99.6% and the production effect (in terms of the ortho-methylnitrobenzene of actual consumption) of productivity 80.0%.
Embodiment 27:
In the present embodiment, the building-up process of adjacent nitro benzyl chloride is as follows:
Catalyst (mass ratio is 1:1:2 bromine, azodiisobutyronitrile and the mixture of 2,2'-Azobis(2,4-dimethylvaleronitrile) composition) is added in ortho-methylnitrobenzene, ortho-methylnitrobenzene controls at 1:0.15 with the mass ratio of catalyst, 130 DEG C it are stirred and heated under 300r/min speed, it is slowly introducing chlorine, follow the tracks of byproduct of reaction neighbour's nitro benzal chloride by gas chromatogram and reach 5%, ortho-methylnitrobenzene conversion ratio 40.2%, stopped reaction；After question response terminates, decompression distillation at vacuum-0.097Mpa, temperature 115 DEG C, reclaim ortho-methylnitrobenzene, continue cycling through chlorination and utilize；Reclaim the residue petroleum ether recrystallization purifying after ortho-methylnitrobenzene, it is thus achieved that the adjacent nitro benzyl chloride pressed powder of white crystalline.
The present embodiment can realize adjacent nitro benzyl chloride purity 99.0% and the production effect (in terms of the ortho-methylnitrobenzene of actual consumption) of productivity 82.9%.
Embodiment 28:
In the present embodiment, the building-up process of adjacent nitro benzyl chloride is as follows:
Catalyst (mass ratio is 2:1 bromine, the mixture of 2,2'-Azobis(2,4-dimethylvaleronitrile) composition) is added in ortho-methylnitrobenzene, ortho-methylnitrobenzene controls at 1:0.05 with the mass ratio of catalyst, 140 DEG C it are stirred and heated under 315r/min speed, it is slowly introducing chlorine, follow the tracks of byproduct of reaction neighbour's nitro benzal chloride by gas chromatogram and reach 4%, ortho-methylnitrobenzene conversion ratio 40.1%, stopped reaction；After question response terminates, decompression distillation at vacuum-0.098Mpa, temperature 110 DEG C, reclaim ortho-methylnitrobenzene, continue cycling through chlorination and utilize；Reclaim the residue petroleum ether recrystallization purifying after ortho-methylnitrobenzene, it is thus achieved that the adjacent nitro benzyl chloride pressed powder of white crystalline.
The present embodiment can realize adjacent nitro benzyl chloride purity 99.2% and the production effect (in terms of the ortho-methylnitrobenzene of actual consumption) of productivity 86.0%.
Embodiment 29:
In the present embodiment, the building-up process of adjacent nitro benzyl chloride is as follows:
Catalyst (hyperis) is added in ortho-methylnitrobenzene, ortho-methylnitrobenzene controls at 1:0.9 with the mass ratio of catalyst, 155 DEG C it are stirred and heated under 305r/min speed, it is slowly introducing chlorine, follow the tracks of byproduct of reaction neighbour's nitro benzal chloride by gas chromatogram and reach 5%, ortho-methylnitrobenzene conversion ratio 40.6%, stopped reaction；After question response terminates, decompression distillation at vacuum-0.095Mpa, temperature 118 DEG C, reclaim ortho-methylnitrobenzene, continue cycling through chlorination and utilize；Reclaim the residue petroleum ether recrystallization purifying after ortho-methylnitrobenzene, it is thus achieved that the adjacent nitro benzyl chloride pressed powder of white crystalline.
The present embodiment can realize adjacent nitro benzyl chloride purity 99.2% and the production effect (in terms of the ortho-methylnitrobenzene of actual consumption) of productivity 85.2%.
Embodiment 30:
In the present embodiment, the building-up process of adjacent nitro benzyl chloride is as follows:
Catalyst (2,2'-Azobis(2,4-dimethylvaleronitrile)) is added in ortho-methylnitrobenzene, ortho-methylnitrobenzene controls at 1:0.84 with the mass ratio of catalyst, 160 DEG C it are stirred and heated under 345r/min speed, it is slowly introducing chlorine, follow the tracks of byproduct of reaction neighbour's nitro benzal chloride by gas chromatogram and reach 6%, ortho-methylnitrobenzene conversion ratio 42%, stopped reaction；After question response terminates, decompression distillation at vacuum-0.098Mpa, temperature 112 DEG C, reclaim ortho-methylnitrobenzene, continue cycling through chlorination and utilize；Reclaim the residue petroleum ether recrystallization purifying after ortho-methylnitrobenzene, it is thus achieved that the adjacent nitro benzyl chloride pressed powder of white crystalline.
The present embodiment can realize adjacent nitro benzyl chloride purity 99.4% and the production effect (in terms of the ortho-methylnitrobenzene of actual consumption) of productivity 83.8%.
Embodiment 31:
In the present embodiment, the building-up process of adjacent nitro benzyl chloride is as follows:
In four mouthfuls of round-bottomed flasks of 1000ml, add 288.72g ortho-methylnitrobenzene and quantitative catalyst (mass ratio is 3:1:2:1 phosphorus pentachloride, elemental iodine, hyperis, the mixture of DMF composition), ortho-methylnitrobenzene controls at 1:0.72 with the mass ratio of catalyst, 135 DEG C it are stirred and heated under 350r/min speed, it is slowly introducing chlorine, sample after two hours, follow the tracks of byproduct of reaction neighbour's nitro benzal chloride by gas chromatogram and reach 6%, ortho-methylnitrobenzene conversion ratio 40.4%, stopped reaction；After question response terminates, decompression distillation at vacuum-0.095Mpa, temperature 115 DEG C, reclaim ortho-methylnitrobenzene, continue cycling through chlorination and utilize；Reclaim the residue petroleum ether recrystallization purifying after ortho-methylnitrobenzene, it is thus achieved that the adjacent nitro benzyl chloride pressed powder of white crystalline.
The present embodiment can realize adjacent nitro benzyl chloride purity 99.6% and the production effect (in terms of the ortho-methylnitrobenzene of actual consumption) of productivity 85.8%.
Embodiment 32:
In the present embodiment, the building-up process of adjacent nitro benzyl chloride is as follows:
In four mouthfuls of round-bottomed flasks of 1000ml, add 312.56g ortho-methylnitrobenzene and quantitative catalyst (mass ratio is 10:1 bromine and the mixture of iodine composition), ortho-methylnitrobenzene controls at 1:0.08 with the mass ratio of catalyst, 140 DEG C it are stirred and heated under 235r/min speed, it is slowly introducing chlorine, samples after two hours, follow the tracks of byproduct of reaction neighbour's nitro benzal chloride by gas chromatogram and reach 5%, ortho-methylnitrobenzene conversion ratio 41%, stopped reaction；After question response terminates, decompression distillation at vacuum-0.098Mpa, temperature 109 DEG C, reclaim ortho-methylnitrobenzene, continue cycling through chlorination and utilize；Reclaim the residue petroleum ether recrystallization purifying after ortho-methylnitrobenzene, it is thus achieved that the adjacent nitro benzyl chloride pressed powder of white crystalline.
The present embodiment can realize adjacent nitro benzyl chloride purity 99.2% and the production effect (in terms of the ortho-methylnitrobenzene of actual consumption) of productivity 86.1%.
Example 3 below 3～40 is to prepare the etherification reaction process of pyraclostrobin intermediate for raw material with the adjacent nitro benzyl chloride of embodiment 25～33 synthesis.
Embodiment 33:
The etherification reaction process that the present embodiment relates to is as follows:
null1-(4-the chlorphenyl)-3-pyrazoles alcohol prepared to embodiment 17、(organic solvent is selected from halogenated aliphatic hydrocarbon to the organic solution of the adjacent nitro benzyl chloride that embodiment 25 prepares，Such as dichloromethane、Dichloroethanes、Chloroform、Carbon tetrachloride etc.)、Phase transfer catalyst (is selected from ammonium halide，Such as benzyltriethylammoinium chloride、Tetrabutyl ammonium bromide、Benzyl tributyl ammonium bromide、Tetrabutylammonium chloride、Cetyl trimethylammonium bromide etc.) mixed solution in，Drip alkali under stirring and (be selected from alkali and alkaline earth metal ions oxide，Such as lithium oxide、Sodium oxide、Potassium oxide、Magnesium oxide and calcium oxide etc.) aqueous solution，Controlling reaction temperature is 0 DEG C，React 6 hours，After question response terminates，Through extraction、Recycling design、Purification is dried，Obtain etherification product 2-[(N-4-chlorphenyl)-3-pyrazoles epoxide methyl] Nitrobenzol.
In said process, the concentration of organic solution of adjacent nitro benzyl chloride is 40%, and in mixed solution, 1-(4-chlorphenyl)-3-pyrazoles alcohol, adjacent nitro benzyl chloride, the mol ratio of alkali are 1.0:1.02:1.05；In organic solution, adjacent nitro benzyl chloride controls at 1:0.01 with the mass ratio of phase transfer catalyst.
The present embodiment can realize 2-[(N-4-chlorphenyl)-3-pyrazoles epoxide methyl] nitrobenzene 98.0%, the production effect of productivity 90.0%.
Embodiment 34:
The etherification reaction process that the present embodiment relates to is as follows:
1-(4-the chlorphenyl)-3-pyrazoles alcohol prepared to embodiment 18, (organic solvent is selected from aromatic hydrocarbon to the organic solution of the adjacent nitro benzyl chloride that embodiment 26 prepares, such as chlorobenzene, toluene, dimethylbenzene etc.), phase transfer catalyst (is selected from Polyethylene Glycol, such as PEG400, PEG600 and PEG800 etc.) mixed solution in, drip alkali under stirring and (be selected from alkali and alkaline earth metal ions hydroxide, such as Lithium hydrate, sodium hydroxide, potassium hydroxide and calcium hydroxide etc.) aqueous solution, controlling reaction temperature is 100 DEG C, react 1 hour, after question response terminates, through extraction, recycling design, purification is dried, obtain etherification product 2-[(N-4-chlorphenyl)-3-pyrazoles epoxide methyl] Nitrobenzol.
In said process, the concentration of organic solution of adjacent nitro benzyl chloride is 10%, and in mixed solution, 1-(4-chlorphenyl)-3-pyrazoles alcohol, adjacent nitro benzyl chloride, the mol ratio of alkali are 1.0:1.50:1.6；In organic solution, adjacent nitro benzyl chloride controls at 1:0.20 with the mass ratio of phase transfer catalyst.
The present embodiment can realize 2-[(N-4-chlorphenyl)-3-pyrazoles epoxide methyl] nitrobenzene 99.0%, the production effect of productivity 91.8%.
Embodiment 35:
The etherification reaction process that the present embodiment relates to is as follows:
Add prepared 1-(4-the chlorphenyl)-3-pyrazoles alcohol of embodiment 19 in container, (organic solvent is selected from amide to the organic solution of the prepared adjacent nitro benzyl chloride of embodiment 27, such as DMF, DMA or NMP etc.) and phase transfer catalyst (be selected from crown ether, such as 18-crown-6,15-crown-5 etc.), it is thus achieved that mixed solution；Quickly dripping the aqueous solution of alkali (being selected from alkali and alkaline earth metal ions carbonate and bicarbonate, such as sodium carbonate, potassium carbonate, calcium carbonate, sodium bicarbonate and potassium bicarbonate etc.) under stirring in container, reaction temperature is 20 DEG C, 4 hours response time；Reaction solution is sampled, with HPLC detection sampling sample, when the amount of wherein 1-(4-chlorphenyl)-3-pyrazoles alcohol is 0.8%, stopped reaction；Regulation solution ph is to 3, then dried through extraction, recycling design, purification, it is thus achieved that etherification product 2-[(N-4-chlorphenyl)-3-pyrazoles epoxide methyl] Nitrobenzol.
In said process, the concentration of organic solution of adjacent nitro benzyl chloride is 20%, and in mixed solution, 1-(4-chlorphenyl)-3-pyrazoles alcohol, adjacent nitro benzyl chloride, the mol ratio of alkali are 1.0:1.11:1.20；In organic solution, adjacent nitro benzyl chloride controls at 1:0.08 with the mass ratio of phase transfer catalyst.
The present embodiment can realize 2-[(N-4-chlorphenyl)-3-pyrazoles epoxide methyl] nitrobenzene 98.5%, the production effect of productivity 92.2%.
Embodiment 36:
The etherification reaction process that the present embodiment relates to is as follows:
Add prepared 1-(4-the chlorphenyl)-3-pyrazoles alcohol of embodiment 20 in container, (organic solvent is selected from alcohol to the organic solution of the prepared adjacent nitro benzyl chloride of embodiment 28, such as methanol, ethanol, propanol, isopropanol, butanol, the tert-butyl alcohol etc.) and phase transfer catalyst (being selected from tetrabutyl ammonium tetrafluoroborate etc.), it is thus achieved that mixed solution；Quickly dripping the aqueous solution of alkali (being selected from organic base, such as triethylamine, trimethylamine, N-methyl piperidine and pyridine etc.) under stirring in container, reaction temperature is 60 DEG C, 2 hours response time；Reaction solution is sampled, with HPLC detection sampling sample, when the amount of wherein 1-(4-chlorphenyl)-3-pyrazoles alcohol is 0.9%, stopped reaction；Regulation solution ph is to 3, then dried through extraction, recycling design, purification, it is thus achieved that etherification product 2-[(N-4-chlorphenyl)-3-pyrazoles epoxide methyl] Nitrobenzol.
In said process, the concentration of organic solution of adjacent nitro benzyl chloride is 30%, and in mixed solution, 1-(4-chlorphenyl)-3-pyrazoles alcohol, adjacent nitro benzyl chloride, the mol ratio of alkali are 1.0:1.30:1.52；In organic solution, adjacent nitro benzyl chloride controls at 1:0.12 with the mass ratio of phase transfer catalyst.
The present embodiment can realize 2-[(N-4-chlorphenyl)-3-pyrazoles epoxide methyl] nitrobenzene 98.7%, the production effect of productivity 92.5%.
Embodiment 37:
The etherification reaction process that the present embodiment relates to is as follows:
1-(4-chlorphenyl)-3-pyrazoles alcohol, the organic solution (organic solvent is acetone) of the prepared adjacent nitro benzyl chloride of embodiment 29 and phase transfer catalyst (benzyltriethylammoinium chloride) that embodiment 21 prepares is added, it is thus achieved that mixed solution in container；Quickly dripping the aqueous solution of alkali (sodium hydroxide) under stirring in container, reaction temperature is 40 DEG C, 3 hours response time；Reaction solution is sampled, with HPLC detection sampling sample, when the amount of wherein 1-(4-chlorphenyl)-3-pyrazoles alcohol is 1%, stopped reaction；Regulation solution ph is to 3, then dried through extraction, recycling design, purification, it is thus achieved that etherification product 2-[(N-4-chlorphenyl)-3-pyrazoles epoxide methyl] Nitrobenzol.
In said process, the concentration of organic solution of adjacent nitro benzyl chloride is 35%, and in mixed solution, 1-(4-chlorphenyl)-3-pyrazoles alcohol, adjacent nitro benzyl chloride, the mol ratio of alkali are 1.0:1.4:1.2；In organic solution, adjacent nitro benzyl chloride controls at 1:0.1 with the mass ratio of phase transfer catalyst.
The present embodiment can realize 2-[(N-4-chlorphenyl)-3-pyrazoles epoxide methyl] nitrobenzene 99.5%, the production effect of productivity 92.7%.
Embodiment 38:
The etherification reaction process that the present embodiment relates to is as follows:
1-(4-chlorphenyl)-3-pyrazoles alcohol, the organic solution (organic solvent is mass ratio 2:1:1 dichloroethanes, chlorobenzene and the mixture of acetone) of the prepared adjacent nitro benzyl chloride of embodiment 30 and phase transfer catalyst (tetrabutyl ammonium bromide) that embodiment 22 prepares is added, it is thus achieved that mixed solution in container；Quickly dripping the aqueous solution of alkali (sodium hydroxide) under stirring in container, reaction temperature is 50 DEG C, 4 hours response time；Reaction solution is sampled, with HPLC detection sampling sample, when the amount of wherein 1-(4-chlorphenyl)-3-pyrazoles alcohol is 0.5%, stopped reaction；Regulation solution ph is to 3, then dried through extraction, recycling design, purification, it is thus achieved that etherification product 2-[(N-4-chlorphenyl)-3-pyrazoles epoxide methyl] Nitrobenzol.
In said process, the concentration of organic solution of adjacent nitro benzyl chloride is 25%, and in mixed solution, 1-(4-chlorphenyl)-3-pyrazoles alcohol, adjacent nitro benzyl chloride, the mol ratio of alkali are 1.0:1.2:1.2；In organic solution, adjacent nitro benzyl chloride controls at 1:0.15 with the mass ratio of phase transfer catalyst.
The present embodiment can realize 2-[(N-4-chlorphenyl)-3-pyrazoles epoxide methyl] nitrobenzene 99.3%, the production effect of productivity 93.0%.
Embodiment 39:
The etherification reaction process that the present embodiment relates to is as follows:
1-(4-chlorphenyl)-3-pyrazoles alcohol, the organic solution (organic solvent is chlorobenzene) of the prepared adjacent nitro benzyl chloride of embodiment 31 and phase transfer catalyst (benzyltriethylammoinium chloride) that embodiment 23 prepares is added, it is thus achieved that mixed solution in container；Quickly dripping the aqueous solution of alkali (potassium hydroxide) under stirring in container, reaction temperature is 50 DEG C, 2 hours response time；Reaction solution is sampled, with HPLC detection sampling sample, when the amount of wherein 1-(4-chlorphenyl)-3-pyrazoles alcohol is 0.6%, stopped reaction；Regulation solution ph is to 3, then dried through extraction, recycling design, purification, it is thus achieved that etherification product 2-[(N-4-chlorphenyl)-3-pyrazoles epoxide methyl] Nitrobenzol.
In said process, the concentration of organic solution of adjacent nitro benzyl chloride is 40%, and in mixed solution, 1-(4-chlorphenyl)-3-pyrazoles alcohol, adjacent nitro benzyl chloride, the mol ratio of alkali are 1.0:1.50:1.46；In organic solution, adjacent nitro benzyl chloride controls at 1:0.16 with the mass ratio of phase transfer catalyst.
The present embodiment can realize 2-[(N-4-chlorphenyl)-3-pyrazoles epoxide methyl] nitrobenzene 98.6%, the production effect of productivity 92.4%.
Embodiment 40:
The etherification reaction process that the present embodiment relates to is as follows:
1-(4-chlorphenyl)-3-pyrazoles alcohol, the organic solution (organic solvent is dichloroethanes) of the prepared adjacent nitro benzyl chloride of embodiment 32 and phase transfer catalyst (PEG400) that embodiment 24 prepares is added, it is thus achieved that mixed solution in container；Quickly dripping the aqueous solution of alkali (sodium hydroxide) under stirring in container, reaction temperature is 60 DEG C, 3 hours response time；Reaction solution is sampled, with HPLC detection detection sampling sample, when the amount of wherein 1-(4-chlorphenyl)-3-pyrazoles alcohol is 0.8%, stopped reaction；Regulation solution ph is to 3, then dried through extraction, recycling design, purification, it is thus achieved that etherification product 2-[(N-4-chlorphenyl)-3-pyrazoles epoxide methyl] Nitrobenzol.
In said process, the concentration of organic solution of adjacent nitro benzyl chloride is 30%, and in mixed solution, 1-(4-chlorphenyl)-3-pyrazoles alcohol, adjacent nitro benzyl chloride, the mol ratio of alkali are 1.0:1.08:1.30；In organic solution, adjacent nitro benzyl chloride controls at 1:0.10 with the mass ratio of phase transfer catalyst.
The present embodiment can realize 2-[(N-4-chlorphenyl)-3-pyrazoles epoxide methyl] nitrobenzene 99.0%, the production effect of productivity 92.5%.
The above, be only presently preferred embodiments of the present invention, and the present invention not does any pro forma restriction, every above example is made according to the technical spirit of the present invention any simple modification, equivalent variations, within each falling within protection scope of the present invention.

Claims (19)

1. the method for a synthesizing pyrazole kresoxim-methyl intermediate, it is characterised in that: comprise the following steps:
(1) with to bromochlorobenzene, hydrazine hydrate as reaction raw materials, add and prepare p-hydrochloride after phase transfer catalyst, solvent, catalyst reaction；
(2) p-hydrochloride prepared by step (1) and alkali, sodium alkoxide, acrylate reactions, in the presence of toluene, prepares the toluene solution of intermediate pyrazole ketone；
(3), after the toluene solution of step (2) being removed toluene, after adding alkali liquor, hydrogen peroxide oxidation, 1-(4-chlorphenyl is prepared)-3-pyrazoles alcohol；
(4) in ortho-methylnitrobenzene, add catalyst, heated and stirred, and be slowly introducing chlorine, after question response terminates, reclaim ortho-methylnitrobenzene, it is thus achieved that adjacent nitro benzyl chloride；
(5) the 1-(4-chlorphenyl that step (3) is prepared) the adjacent nitro benzyl chloride for preparing of-3-pyrazoles alcohol and step (4) carries out etherification reaction, it is thus achieved that 2-[(N-4-chlorphenyl)-3-pyrazoles epoxide methyl] Nitrobenzol.
The method of a kind of synthesizing pyrazole kresoxim-methyl intermediate the most according to claim 1, it is characterised in that: described step (1) including:
(1.1) with equivalent proportion as 1:(1～5) to bromochlorobenzene and 30～100% the hydrazine hydrate of concentration as reaction raw materials, add phase transfer catalyst, solvent, catalyst react, and described control bromochlorobenzene and the phase transfer catalyst of addition, catalyst, the weight ratio of solvent at 1:(0.01～0.15): (0.01～0.2): (1～20)；
(1.2) after question response terminates, filtering and separate solid, filtrate is through being distilled off solvent；
(1.3) adding 15～the hydrochloric acid of 36% in step (1.2) gained residue, regulation pH value is 1～3, then filters after being sufficiently stirred for；
(1.4) washed by filtering residue, drying obtains p-hydrochloride.
The method of a kind of synthesizing pyrazole kresoxim-methyl intermediate the most according to claim 1, it is characterized in that: in described step (1), phase transfer catalyst includes the combination of one or more in tetrabutylammonium chloride, tetrabutyl ammonium bromide, 4-butyl ammonium hydrogen sulfate, benzyltriethylammoinium chloride, tri-n-octyl methyl ammonium chloride, Dodecyl trimethyl ammonium chloride, tetradecyl trimethyl ammonium chloride, 18-crown-6, benzo 18-crown-6,15-crown-5, PEG400, PEG600, PEG800.
The method of a kind of synthesizing pyrazole kresoxim-methyl intermediate the most according to claim 1, it is characterized in that: in described step (1), solvent includes the combination of one or more in water, ethylene glycol, propylene glycol, glycol monoethyl ether, glycol dimethyl ether, propylene glycol.
The method of a kind of synthesizing pyrazole kresoxim-methyl intermediate the most according to claim 1, it is characterized in that: in described step (1), catalyst includes one or more in Nickel dichloride., copper sulfate, cobaltous chloride, Cu-lyt., copper chloride, copper bromide, cuprous bromide, Hydro-Giene (Water Science)..
The method of a kind of synthesizing pyrazole kresoxim-methyl intermediate the most according to claim 1, it is characterized in that: in described step (1), course of reaction includes: slowly heats up and controls temperature to 100～180 DEG C, atmospheric pressure reflux or pressurize reaction, keep thermotonus 1～15h, chlorophenyl hydrazine is not extremely further added by by sampling HPLC detection, i.e. stopped reaction.
The method of a kind of synthesizing pyrazole kresoxim-methyl intermediate the most according to claim 1, it is characterised in that: described step (2) includes the step of following order:
(2.1) in the p-hydrochloride that step (1) prepares, add the toluene of 2～10 times of weight, under stirring, add alkali with the ratio of p-hydrochloride equivalent, 0～20% water of weight, it is sufficiently stirred for rear temperature rising reflux, is dehydrated to water content≤200pm, stops heating；
(2.2) after cooling, with the gauge of p-hydrochloride, adding the sodium alkoxide of 1.05～2.0 equivalent proportions, in maintaining, temperature is at 50～80 DEG C；
(2.3) with the gauge of p-hydrochloride, adding the acrylate of 1.0～2.0 equivalent proportions, after temperature rising reflux, low-boiling-point substance is sloughed in distillation；
(2.4) in fall, temperature is to 60～70 DEG C, and regulation pH value is 1～3, separates organic facies, after aqueous phase extracts with toluene, merges organic facies, prepares the toluene solution of intermediate pyrazole ketone.
The method of a kind of synthesizing pyrazole kresoxim-methyl intermediate the most according to claim 1, it is characterised in that: in described step (2), alkali includes one or more in sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate or potassium bicarbonate.
The method of a kind of synthesizing pyrazole kresoxim-methyl intermediate the most according to claim 1, it is characterised in that: described step (3) includes the step of following order:
(3.1) toluene solution of step (2) is after decompression is distilled off toluene, with the gauge of p-hydrochloride, adds alkali and the water of 2 ~ 10 times of weight of 1.2～2.0 equivalent proportions, is heated to 60～90 DEG C；
(3.2) while stirring add 30% hydrogen peroxide, in terms of chlorophenylhydxazine hydrochloride, added hydrogen peroxide amount control at 0.9～2.0 equivalents, after addition, be incubated 1～2 hour；
(3.3) stopped reaction when detecting pyrazolone content≤0.5% with HPLC；
(3.4) reactant liquor being down to room temperature, regulation pH value is 1～3, sucking filtration, and water washs, dried prepared 1-(4-chlorphenyl)-3-pyrazoles alcohol.
The method of a kind of synthesizing pyrazole kresoxim-methyl intermediate the most according to claim 9, it is characterised in that: in described step (3.1), alkali includes one or more in Lithium hydrate, sodium hydroxide, potassium hydroxide, barium hydroxide or calcium hydroxide.
The method of 11. a kind of synthesizing pyrazole kresoxim-methyl intermediate according to claim 1, it is characterised in that: in described step (4), count in mass ratio, ortho-methylnitrobenzene: catalyst=1:(0.01～0.2).
The method of 12. a kind of synthesizing pyrazole kresoxim-methyl intermediate according to claim 1, it is characterized in that: in described step (4), catalyst includes: the mixture of one or more in the activated carbon of 50～200 mesh, bromine, iodine, azodiisobutyronitrile, 2,2'-Azobis(2,4-dimethylvaleronitrile), phosphorus pentachloride, Phosphorous chloride., benzoyl peroxide, hyperis, DMF.
The method of 13. a kind of synthesizing pyrazole kresoxim-methyl intermediate according to claim 1, it is characterised in that: in described step (4), heating and temperature control is at 100～180 DEG C, and stir speed (S.S.) controls at >=200r/min.
The method of 14. a kind of synthesizing pyrazole kresoxim-methyl intermediate according to claim 1, it is characterised in that: in described step (4), in course of reaction, use gas chromatogram to follow the tracks of byproduct of reaction neighbour's nitro benzal chloride and reach 4～6%, stopped reaction.
The method of 15. a kind of synthesizing pyrazole kresoxim-methyl intermediate according to claim 1, it is characterised in that: in described step (4), after reaction terminates, at vacuum is less than 120 DEG C higher than-0.095Mpa, temperature, decompression distillation, reclaims ortho-methylnitrobenzene.
The method of 16. a kind of synthesizing pyrazole kresoxim-methyl intermediate according to claim 1, it is characterized in that: in described step (4), reclaim the residue petroleum ether recrystallization purifying after ortho-methylnitrobenzene, it is thus achieved that the adjacent nitro benzyl chloride pressed powder of white crystalline.
The method of 17. a kind of synthesizing pyrazole kresoxim-methyl intermediate according to claim 1, it is characterized in that: in described step (5), etherification reaction includes: the adjacent organic solution of nitro benzyl chloride for preparing to 1-(4-chlorphenyl)-3-pyrazoles alcohol, step A, in the mixed solution of phase transfer catalyst, the lower aqueous solution dripping alkali of stirring, controlling reaction temperature is 0～100 DEG C, react 1～6 hour, after question response terminates, through extraction, recycling design, purification after drying, 2-[(N-4-chlorphenyl)-3-pyrazoles epoxide methyl] Nitrobenzol is obtained.
The method of 18. a kind of synthesizing pyrazole kresoxim-methyl intermediate according to claim 17, it is characterized in that: the concentration of organic solution of described adjacent nitro benzyl chloride is 10～40%, in described mixed solution, 1-(4-chlorphenyl)-3-pyrazoles alcohol, adjacent nitro benzyl chloride, the mol ratio of alkali are 1.0:(1.02～1.50): (1.05～1.6).
The method of 19. a kind of synthesizing pyrazole kresoxim-methyl intermediate according to claim 17, it is characterised in that: in described organic solution, adjacent nitro benzyl chloride controls at 1:(0.01～0.20 with the mass ratio of phase transfer catalyst).
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