CN109320457A - The preparation method and device of hydroxypyrazoles - Google Patents
The preparation method and device of hydroxypyrazoles Download PDFInfo
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- CN109320457A CN109320457A CN201811190791.3A CN201811190791A CN109320457A CN 109320457 A CN109320457 A CN 109320457A CN 201811190791 A CN201811190791 A CN 201811190791A CN 109320457 A CN109320457 A CN 109320457A
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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
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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
Abstract
The present invention provides the preparation method of hydroxypyrazoles and devices.The preparation method includes: to incite somebody to action using alkoxy acrylic ester as raw material AAs raw material B, raw material A and raw material B are continuously passed through in continuous reacting device and carry out continuous reaction, and continuous reacting device is continuously discharged in the crude product that reaction obtains；Wherein, R H, alkyl, unsaturated aliphatic hydrocarbyl moiety, aromatic radical, containing heteroatomic alkyl, containing heteroatomic unsaturated aliphatic hydrocarbyl moiety or contain heteroatomic aromatic radical；Separating-purifying crude product, obtains hydroxypyrazoles.Using alkoxy acrylic ester and
Description
Technical field
The present invention relates to organic synthesis fields, a kind of preparation method in particular to hydroxypyrazoles and
Device.
Background technique
Hydroxypyrazoles, 5- the or 3- hydroxypyrazoles that 1- especially therein replaces are widely used in preparing drug
Or plant herbicide.So far, the method for preparing 5- the or 3- hydroxypyrazoles of 1- substitution usually has following several:
Method one: by 2- methyl-1-(p-toluenesulfonyl)-3- pyrazolidone or 2- methyl-1-1- acetyl group-pyrazolidine
Ketone [sic] hydrolyzes (J.Prakt.Chem.313 (1971), 115-128 and J.Prakt.Chem.313 (1971), 1118-
1124).This method contains many steps, and complicated.And the introducing and removing of blocking group are difficult, it is meant that are needed
Many additional steps and reduce yield.
Two: 5- hydroxyl -1- alkyl pyrazole -4- alkyl carboxylates of method are by a kind of alkoxymethylene maleic acid dioxane
Base ester and alkyl hydrazine Cyclization, then to the aqueous solution that an inorganic acid is added in this reaction product, hydrolysis is completed at the same time de-
Carboxylation reaction (see JP61257974, JP60051175, JP58174369, JP58140073 and JP58140074, and
US4643757).This method equally includes many steps, and other than 1- alkyl -5- hydroxypyrazoles, is also reacting while generating
The region isomer of target compound, it is necessary to it can just be separated with target product using complicated method.Moreover, companion in synthesis
With lower C yield, because of the steric hindrance of C4, and carbon atom at the end of reaction is made to have to be broken again.
Method three: ethyl propionate and methyl hydrazine reaction obtain 5- hydroxyl -1- methylpyrazole (Annalen 686 (1965),
134-144).This method only describes the preparation of 1- methyl -5- hydroxypyrazoles, inevitably uses and is in excess in chemical meter significantly
The methyl hydrazine of amount, so that this method is uneconomic.In addition, the isomers 3- hydroxyl -1- methyl generated simultaneously in reaction
Pyrazoles, it has to be separated from 1- methyl -5- hydroxypyrazoles in purification process by complicated method.Moreover, because
Acrylate is more expensive, therefore this method is uneconomic.
Method four: corresponding hydrazone is obtained with aldehyde reaction with the 3- hydrazine propionic ester that acrylate addition is formed by hydrazine, then
Hydrazone is cyclized (see JP06166666, JP61229852 and JP61268659 and EP240001).This method is equally also comprising many
Step, process are complicated.And final step yield is very low, can also generate a large amount of by-product.
Method five: by 5- hydroxyl -1- methylpyrazole-3-carboxyl acid thermal cracking (Chem.Ber.109 (1976), 261).The method
The thermal cracking of use needs high temperature, and yield is very low, and only 6%
Method six: 1- methyl -5- hydroxyl is obtained by 3- alkoxy acrylic ester is corresponding with methyl hydrazine and ethyl hydrazine reaction
Pyrazoles and 1- ethyl -5- hydroxypyrazoles (see JPl89271/86, EP-A-837 058).This method can only synthesize 1- methyl -5- hydroxyl
Base pyrazoles, and batch synthesis technology is used, the reaction of gram-grade just has uncontrollable exothermic phenomenon, and reaction is unsuitable for industry and puts
Greatly.
Method seven: by aoxidize prepare 3- or 5- substitution hydroxypyrazoles (see WO9703969, WO9827062,
CN105061322B).The synthetic route need to use various oxidants of different strengths and weaknesses, and yield is unstable, and post-processing is complicated, the three wastes
It is more.In addition, the use of oxidant improves the risk of production amplification.
In addition to this, traditional synthetic method is to use batch intermittent reaction method, and exothermic phenomenon is serious, uncomfortable
Close commercial run.
Based on the above reasons, these synthetic routes be all unable to satisfy economic, efficient, safety preparation 1- replace 5- and
The requirement of 3- hydroxypyrazoles.
Summary of the invention
The main purpose of the present invention is to provide a kind of preparation method of hydroxypyrazoles and devices, existing to solve
The problem of cannot be considered in terms of economy, high efficiency, safety when having synthesis of hydroxy pyrazole compound in technology.
To achieve the goals above, according to an aspect of the invention, there is provided a kind of system of hydroxypyrazoles
Preparation Method, the hydroxypyrazoles have structure shown in Formulas I or Formula II:
Preparation method the following steps are included:
It, will using alkoxy acrylic ester as raw material AAs raw material B, raw material A and raw material B are continuously led to
Enter and carry out continuous reaction in continuous reacting device, and continuous reacting device is continuously discharged in the crude product that reaction obtains；
Wherein, Formulas I, Formula II andIn, R H, alkyl, unsaturated aliphatic hydrocarbyl moiety, aromatic radical, containing heteroatomic alkyl,
Containing heteroatomic unsaturated aliphatic hydrocarbyl moiety or contain heteroatomic aromatic radical；Separating-purifying crude product obtains hydroxypyrazoles chemical combination
Object.
Further, alkoxy acrylic ester is methoxy-methyl acrylate, ethoxy-c olefin(e) acid methyl esters, ethoxy propylene
Acetoacetic ester, propoxyl group methyl acrylate or propoxyl group propyl acrylate；Preferably methoxy-methyl acrylate, by raw material A and with
It includes: using alkoxy acrylic ester as former that raw material B, which is continuously passed through in continuous reacting device the step of carrying out continuous reaction,
Expect A；It willIt is dissolved in solvent and forms mixed solution, using mixed solution as raw material B；By raw material A and raw material B points
It is not passed through continuously in continuous reacting device and carries out continuous reaction；It is highly preferred that solvent is selected from water, acetic acid, n-butanol, tetrahydro
Furans, 2- methyltetrahydrofuran, 1,4- dioxane, glycol dimethyl ether, diethylene glycol dimethyl ether, benzene,toluene,xylene,
N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, N, N- diethylformamide, N-Methyl pyrrolidone, dimethyl sulfoxide,
One of acetonitrile, methanol, ethyl alcohol and isopropanol are a variety of.
Further, when hydroxypyrazoles are with structure shown in Formula II, during continuous reaction,
Lye is passed through into continuous reacting device simultaneously；Preferably, lye is inorganic base and/or organic base, and more preferable inorganic base is
NaOH aqueous solution and/or KOH aqueous solution, organic base be one of triethylamine, diethyl propylamine and diisopropyl ethyl amine or
It is a variety of.
Further, continuous reacting device is continuous coil reactor or CSTR flow reactor.
Further, Formulas I, Formula II andIn, R is hydrogen, methyl, ethyl, propyl, isopropyl, normal-butyl, different
Butyl or tert-butyl；Preferably, be passed through alkoxy acrylic ester in continuous reacting device andBetween rub
You are than being 1:1~1.2.
Further, during being passed through continuous reacting device, the charging rate of raw material A is 5~50g/min, raw material A
It is 20~40min with retention time of the raw material B in continuous reacting device.
Further, the reaction temperature of continuous reaction is 100~150 DEG C.
Further, the step of separating-purifying crude product includes: continuously to be passed through crude product in crystallization-filter device successively
Serialization crystallization and serialization filtering are carried out, hydroxypyrazoles are obtained.
Further, in the step of serialization crystallization, crude product is retained into 20~40min at 10~20 DEG C, so that slightly
The cooling precipitation of hydroxypyrazoles in product.
According to another aspect of the present invention, a kind of preparation facilities of hydroxypyrazoles is additionally provided, the hydroxyl pyrrole
Azole compounds have structure shown in Formulas I or Formula II:
Above-mentioned preparation facilities includes: the first feeding device, for alkoxy acrylic ester without interruption as raw material A；The
Two feeding devices, for without interruptionAs raw material B, wherein Formulas I, Formula II andIn, R H,
Alkyl, aromatic radical, contains heteroatomic alkyl, containing heteroatomic unsaturated aliphatic hydrocarbyl moiety or containing miscellaneous original at unsaturated aliphatic hydrocarbyl moiety
The aromatic radical of son；Continuous reacting device, has feed inlet and discharge gate, and feed inlet is supplied with the first feeding device and second respectively
Material device is connected, and the thick of reaction generation is discharged for making raw material A and raw material B carry out continuous reaction in continuous reacting device
Product；Separating-purifying device, is connected with discharge gate, and separating-purifying device is used to carry out separating-purifying to crude product to obtain hydroxyl
Pyrazole compound.
Further, preparation facilities further includes that the second feeding device also has solvent inlet, and preparation facilities further includes third
Feeding device, third feeding device are connected with solvent inlet, for providing solvent so thatIt is dissolved in shape in solvent
At mixed solution, and using mixed solution as raw material B.
Further, when hydroxypyrazoles are with structure shown in Formula II, preparation facilities further includes the 4th confession
Expect device, the 4th feeding device is connected with the feed inlet of continuous reacting device, for supplying lye.
Further, continuous reacting device is continuous coil reactor or CSTR flow reactor.
Further, separating-purifying device is crystallization-filter device.
Hydroxypyrazoles provided by the invention the preparation method is as follows: using alkoxy acrylic ester as raw material A,
It willAs raw material B, raw material A and raw material B are continuously passed through in continuous reacting device and carry out continuous reaction, and
Continuous reacting device is continuously discharged in the crude product that reaction obtains；Wherein, Formulas I, Formula II andIn, R H, alkane
Base, aromatic radical, contains heteroatomic alkyl, containing heteroatomic unsaturated aliphatic hydrocarbyl moiety or containing hetero atom at unsaturated aliphatic hydrocarbyl moiety
Aromatic radical；Separating-purifying crude product, obtains hydroxypyrazoles.
Using alkoxy acrylic ester andReaction prepares hydroxypyrazoles, and route is shorter, reaction
Efficiency is higher, and cost is relatively low.Meanwhile the present invention uses continuous reaction mode synthesis of hydroxy pyrazole compound, Neng Gouyou
Effect improves the heat dissipation problem in batch reaction process, and continuous reaction is conducive to further increase reaction efficiency, is suitble to amplification
Production.In short, having had both economy, high efficiency and safety using method synthesis of hydroxy pyrazole compound provided by the invention
The advantage of property several respects.
Specific embodiment
It should be noted that in the absence of conflict, the features in the embodiments and the embodiments of the present application can phase
Mutually combination.Below in conjunction with embodiment, the present invention will be described in detail.
The application is described in further detail below in conjunction with specific embodiment, these embodiments should not be understood as limitation originally
Apply for range claimed.
As described in background technology part, economy cannot be considered in terms of when synthesis of hydroxy pyrazole compound in the prior art
Property, high efficiency and safety.
To solve the above-mentioned problems, the present invention provides a kind of preparation method of hydroxypyrazoles, the hydroxyl pyrroles
Azole compounds have structure shown in Formulas I or Formula II:
Above-mentioned preparation method is incited somebody to action the following steps are included: using alkoxy acrylic ester as raw material AAs original
The crude product expected B, raw material A and raw material B are continuously passed through in continuous reacting device and carry out continuous reaction, and reaction is obtained
Continuous discharge continuous reacting device；Wherein, Formulas I, Formula II andIn, R H, alkyl, unsaturated aliphatic hydrocarbyl moiety,
Aromatic radical contains heteroatomic alkyl, containing heteroatomic unsaturated aliphatic hydrocarbyl moiety or containing heteroatomic aromatic radical, obtains hydroxyl pyrrole
Azole compounds.
In above-mentioned preparation method, using alkoxy acrylic ester andReaction prepares hydroxypyrazoles chemical combination
Object, route is shorter, and reaction efficiency is higher, and cost is relatively low.Meanwhile the present invention uses continuous reaction mode synthesis of hydroxy pyrazoles
Class compound, can be in high-temperature and high-pressure conditions, the heat dissipation problem that can be effectively improved in batch reaction process, and can will react
Even if product removes reaction system, it is possible to prevente effectively from the problems such as causing runaway reaction using hydrazine energy-rich compound, improves
The safety of reaction and the stability of yield.Meanwhile continuous reaction is conducive to further increase reaction efficiency, is suitble to amplification life
It produces.In short, having had both economy, high efficiency and safety using method synthesis of hydroxy pyrazole compound provided by the invention
The advantage of several respects.
In a preferred embodiment, alkoxy acrylic ester is methoxy-methyl acrylate, ethoxy-c olefin(e) acid
Methyl esters, the third methyl esters of ethoxy ethyl acrylate, propoxyl group methyl acrylate or propoxyl group acrylic acid；Preferably methoxy acrylic acid
Methyl esters；The step of being continuously passed through progress continuous reaction in continuous reacting device by raw material A and with raw material B includes: by alcoxyl
Base acrylate is as raw material A；It willIt is dissolved in solvent and forms mixed solution, using mixed solution as raw material B；
Raw material A and raw material B are continuously passed through in continuous reacting device respectively and carry out continuous reaction.
In this way, in advance willIt is configured to solution, itself and raw material A can be made to carry out in solvent environment, favorably
In the safety and stability for further increasing reaction.Specific solvent usage is that those skilled in the art can be imitated by reaction
What the factors such as rate determined, in preferred raw material BMass concentration be 40~80%.It is highly preferred that solvent be selected from water,
Acetic acid, n-butanol, tetrahydrofuran, 2- methyltetrahydrofuran, 1,4- dioxane, glycol dimethyl ether, diethylene glycol dimethyl ether,
Benzene,toluene,xylene, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, N, N- diethylformamide, N- methylpyrrole
One of alkanone, dimethyl sulfoxide, acetonitrile, methanol, ethyl alcohol and isopropanol are a variety of.
In a preferred embodiment, when hydroxypyrazoles are with structure shown in Formula II, continuous
During changing reaction, while lye is passed through into continuous reacting device.Lye, which is added, can promote reaction to generate 5- substitution
Hydroxypyrazoles.Preferably, lye be inorganic base and/or organic base, more preferable inorganic base be NaOH aqueous solution and/
Or KOH aqueous solution, organic base are the one or more of triethylamine, diethyl propylamine and diisopropyl ethyl amine.It is preferred that in lye
Alkali andMolar ratio be 1~1.2:1.
In a preferred embodiment, continuous reacting device is continuous coil reactor or CSTR successive reaction
Device.Using above two continuous reacting device, reaction complexity can be further decreased, improves reaction efficiency and safety
Property.
In a preferred embodiment, Formulas I, Formula II andIn, R is hydrogen, methyl, ethyl, propyl, different
Propyl, normal-butyl, isobutyl group or tert-butyl.In order to further increase the efficiency of reaction, it is preferable that be passed through continuous reacting device
In alkoxy acrylic ester andBetween molar ratio be 1:1~1.2.
Using the above method provided by the invention, hydroxypyrazoles are prepared in the form of continuous reaction, it will
After raw material A and raw material B are continuously passed through reaction unit, reaction raw materials are mixed and are reacted during being continuously traveling, formation it is thick
Reaction system is continuously discharged in product.In order to improve the conversion ratio and yield of reaction, while it is too long caused anti-to reduce the reaction time
Should equal insecurity factors easily out of control, in a preferred embodiment, it is above-mentioned be passed through continuous reacting device during, it is former
Expect A charging rate be 5~50g/min, the retention time of raw material A and raw material B in continuous reacting device be 20~
40min.The reaction temperature of more preferable continuous reaction is 100~150 DEG C.
In a preferred embodiment, the step of above-mentioned separating-purifying crude product includes: continuously to be passed through crude product
Serialization crystallization and serialization filtering are successively carried out in crystallization-filter device, obtain hydroxypyrazoles.Utilize serialization
Crystallization and filter process can be further improved the continuity of synthesis, are more advantageous to amplification metaplasia and produce.
In a preferred embodiment, in the step of serialization crystallization, crude product is retained 20 at 10~20 DEG C
~40min, so that the cooling precipitation of hydroxypyrazoles in crude product.Under this condition, the hydroxypyrazoles in crude product
Compound can more fully be precipitated, then isolated using filter type.It is preferred that after filtration step, to hydroxypyrazoles
Compound carries out drying and processing.
According to another aspect of the present invention, a kind of preparation facilities of hydroxypyrazoles is additionally provided, the hydroxyl pyrrole
Azole compounds have structure shown in Formulas I or Formula II:
Above-mentioned preparation facilities includes the first feeding device, the second feeding device, continuous reacting device and separating-purifying dress
It sets；First feeding device is for alkoxy acrylic ester without interruption as raw material A；Second feeding device is for without interruptionAs raw material B, wherein Formulas I, Formula II andIn, R H, alkyl, unsaturated aliphatic hydrocarbyl moiety, fragrance
Base contains heteroatomic alkyl, containing heteroatomic unsaturated aliphatic hydrocarbyl moiety or containing heteroatomic aromatic radical；Continuous reacting device
With feed inlet and discharge gate, feed inlet is connected with the first feeding device and the second feeding device respectively, continuous reacting device
For making raw material A and raw material B carry out continuous reaction, and the crude product that reaction generates is discharged；Separating-purifying device and discharge gate
It is connected, separating-purifying device is used to carry out separating-purifying to crude product to obtain hydroxypyrazoles.
Prepare hydroxypyrazoles using the device, using alkoxy acrylic ester andReaction preparation
Hydroxypyrazoles, route is shorter, and reaction efficiency is higher, and cost is relatively low.Meanwhile the present invention is filled using continuous reaction
Synthesis of hydroxy pyrazole compound is set, the heat dissipation problem that can be effectively improved in batch reaction process, and can be by reaction product
Even if reaction system is removed, it is possible to prevente effectively from the problems such as causing runaway reaction using hydrazine energy-rich compound, improves reaction
Safety and yield stability.Meanwhile continuous reaction is conducive to further increase reaction efficiency, is suitble to amplification production.
In short, having had both economy, high efficiency and several sides of safety using device synthesis of hydroxy pyrazole compound provided by the invention
The advantage in face.
In a preferred embodiment, preparation facilities further includes that the second feeding device also has solvent inlet, preparation
Device further includes third feeding device, and third feeding device is connected with solvent inlet, for providing solvent so that
It is dissolved in solvent and forms mixed solution, and using mixed solution as raw material B.
In a preferred embodiment, when hydroxypyrazoles are with structure shown in Formula II, preparation dress
Setting further includes the 4th feeding device, and the 4th feeding device is connected with the feed inlet of continuous reacting device, for supplying lye.
In a preferred embodiment, continuous reacting device is continuous coil reactor or CSTR successive reaction
Device.
In a preferred embodiment, separating-purifying device is crystallization-filter device.
Beneficial effects of the present invention are further illustrated by the following examples:
Embodiment 1
The continuous coil reactor of dried and clean is heated to 120 DEG C, 1687.0g (16.0mol) A is taken, is placed in dnockout bottle 1
In.It takes 80% hydrazine hydrate of 1000.0g (16.0mol) to be placed in dnockout bottle 2, starts dnockout after coil temperature is stablized, pump 1 (alkane
Oxygroup acrylate) charging rate setting: 31.4g/min, pump 2 (hydrazine hydrate) charging rates setting: 18.6g/min.Conversion zone
Retention time 30min, internal pressure are controlled in 1.0~2.0MPa.Discharge port is directly connected to continuous crystallization-filtration system, and 10~20 DEG C
Lower cooling crystallization, retention time 30min, crystallization system is separated by solid-liquid separation through continuous filtration system later.The filter cake isolated
It collects, 40~50 DEG C drying to constant weight, obtains 1100.1g product, purity 99%, yield 90.2%.
Embodiment 2
The continuous coil reactor of dried and clean is heated to 120 DEG C, 1687.0g (16.0mol) A is taken, is placed in dnockout bottle 1
In.It takes 40% methyl hydrazine solution of 2556.0g (16.0mol) to be placed in dnockout bottle 2, starts dnockout, pump 1 after coil temperature is stablized
The setting of (alkoxy acrylic ester) charging rate: 11.9g/min pumps 2 (40% methyl hydrazines): 18.1g/min.When conversion zone retains
Between 30min, internal pressure control in 1.0~2.0MPa.Discharge port is directly connected to continuous crystallization-filtration system, cooling at 10~20 DEG C
Crystallization, retention time 30min, crystallization system is separated by solid-liquid separation through continuous filtration system later.The filter cake isolated is collected,
40~50 DEG C drying to constant weight, obtains 1297.1g product, purity 99%, yield 91.2%.
Embodiment 3
The continuous coil reactor of dried and clean is heated to 120 DEG C, 1687.0g (16.0mol) A is taken, is placed in dnockout bottle 1
In.40% methyl hydrazine solution of 2556.0g (16.0mol) is taken to be placed in dnockout bottle 2, it is another to configure 20%NaOH aqueous solution 3.2kg
(16.0molNaOH), as in dnockout bottle 3.Start dnockout, pump 1 (alkoxy acrylic ester) charging after coil temperature is stablized
Speed setting: 8.5g/min pumps 2 (40% methyl hydrazines): 12.7g/min, pumps 3 (20%NaOH aqueous solutions): 16.0g/min.Instead
A section retention time 30min is answered, internal pressure is controlled in 1.0~2.0MPa.Discharge port is directly connected to continuous crystallization-filtration system, 10~
Cooling crystallization at 20 DEG C, retention time 30min, crystallization system is separated by solid-liquid separation through continuous filtration system later.It isolates
Filter cake is collected, and 40~50 DEG C drying to constant weight, obtains 1243.0g product, purity 98%, yield 87.4%.
Embodiment 4
The continuous coil reactor of dried and clean is heated to 120 DEG C, 2094.2g (16.0mol) F is taken, is placed in dnockout bottle 1
In.It takes 80% hydrazine hydrate of 1000.0g (16.0mol) to be placed in dnockout bottle 2, starts dnockout after coil temperature is stablized, pump 1 (alkane
Oxygroup acrylate) charging rate setting: 23.1g/min, pump 2 (hydrazine hydrate) charging rates setting: 18.6g/min.Conversion zone
Retention time 30min, internal pressure are controlled in 1.0~2.0MPa.Discharge port is directly connected to continuous crystallization-filtration system, and 10~20 DEG C
Lower cooling crystallization, retention time 30min, crystallization system is separated by solid-liquid separation through continuous filtration system later.The filter cake isolated
It collects, 40~50 DEG C drying to constant weight, obtains 1039.1g product, purity 99%, yield 85.2%.
Embodiment 5
The continuous coil reactor of dried and clean is heated to 120 DEG C, 1687.0g (16.0mol) A is taken, is placed in dnockout bottle 1
In.It takes 2700.0g (16.0mol) phenyl hydrazine to be placed in dnockout bottle 2, starts dnockout after coil temperature is stablized, pump 1 (alkoxy
Acrylate) charging rate setting: 31.4g/min, pump 2 (hydrazine hydrate) charging rates setting: 50.22g/min.Conversion zone retains
Time 30min, internal pressure are controlled in 1.0~2.0MPa.Discharge port is directly connected to continuous crystallization-filtration system, cold at 10~20 DEG C
But crystallization, retention time 30min, crystallization system is separated by solid-liquid separation through continuous filtration system later.The filter cake isolated is received
Collection, 40~50 DEG C drying to constant weight, obtains 2046.1g product, purity 99%, yield 88.1%.
Embodiment 6
Preparation route with embodiment 1, the difference is that: use CSTR flow reactor, reaction temperature be 100 DEG C, take
1687.0g (16.0mol) A, is placed in dnockout bottle 1.80% hydrazine hydrate of 1200.0g (19.2mol) is taken to be placed in dnockout bottle 2, to
Temperature of reactor starts dnockout after stablizing, pump 1 (alkoxy acrylic ester) charging rate setting: the 31.4g/min, (hydration of pump 2
Hydrazine) charging rate setting: 22.3g/min.Conversion zone retention time 40min, internal pressure are controlled in 1.0~2.0MPa.Discharge port is straight
Continue crystallization-filtration system in succession, cooling crystallization at 10~20 DEG C, retention time 30min, crystallization system is through continuous mistake later
Filter system, is separated by solid-liquid separation.The filter cake isolated is collected, and 40~50 DEG C drying to constant weight, obtains 1158g product, purity 99%,
Yield 94.9%.
Embodiment 7
Preparation route with embodiment 1, the difference is that: use CSTR flow reactor, reaction temperature be 100 DEG C, take
1687.0g (16.0mol) A, is placed in dnockout bottle 1.80% hydrazine hydrate of 1200.0g (19.2mol) is taken to be placed in dnockout bottle 2, to
Temperature of reactor starts dnockout after stablizing, pump 1 (alkoxy acrylic ester) charging rate setting: 50g/min pumps 2 (hydrazine hydrates)
Charging rate setting: 35.5g/min.Conversion zone retention time 40min, internal pressure are controlled in 1.0~2.0MPa.Discharge port directly connects
Continue crystallization-filtration system in succession, cooling crystallization at 10~20 DEG C, retention time 30min, crystallization system is through continuous filtering system later
System, is separated by solid-liquid separation.The filter cake isolated is collected, and 40~50 DEG C drying to constant weight, obtains 1060g product, purity 99%, yield
86.9%.
It can be seen from the above description that the above embodiments of the present invention realized the following chievements:
With the equipment of serialization, the reaction to raw material is rapidly completed under conditions of realization high temperature, high pressure.Pass through continuous rear place
Science and engineering skill terminates reaction in time, separates product, avoids the problem that product is rotten in post-processing.Continuous process, equipment heat exchange
It is high-efficient, for high energy reaction, produces almost without enlarge-effect, industrialization is suitble to reappear lab scale yield.Specifically:
(1) reaction step is short, and a step directly synthesizes target product.By using high temperature, the serialization equipment of high pressure, greatly
Improve reaction rate, reduce by-product generation time, to improve yield.
(2) the distinctive attribute of serialization equipment (reaction system is small, and rate of heat exchange is much higher than batch equipment) makes to react item
Even if part is more acutely, but safety is also above batch reaction.
(3) continuous process particular attribute produces almost without enlarge-effect, industrialization is suitble to reappear lab scale yield.
According to technical solution provided by the invention, reaction yield is greater than 85%.Part reaction is amplified to 10kg scale, yield
Stablize, repeatability is strong, practical.
The foregoing is only a preferred embodiment of the present invention, is not intended to restrict the invention, for the skill of this field
For art personnel, the invention may be variously modified and varied.All within the spirits and principles of the present invention, made any to repair
Change, equivalent replacement, improvement etc., should all be included in the protection scope of the present invention.
Claims (14)
1. a kind of preparation method of hydroxypyrazoles, which is characterized in that the hydroxypyrazoles have Formulas I or
Structure shown in Formula II:
The preparation method comprises the following steps:
It, will using alkoxy acrylic ester as raw material AAs raw material B, the raw material A and the raw material B are connected
Continuous be passed through in continuous reacting device carries out continuous reaction, and will crude product that reaction obtains that the serialization is continuously discharged is anti-
Answer device；Wherein, the Formulas I, the Formula II and describedIn, R H, alkyl, unsaturated aliphatic hydrocarbyl moiety, fragrance
Base contains heteroatomic alkyl, containing heteroatomic unsaturated aliphatic hydrocarbyl moiety or containing heteroatomic aromatic radical；
Crude product described in separating-purifying obtains the hydroxypyrazoles.
2. preparation method according to claim 1, which is characterized in that the alkoxy acrylic ester is methoxy acrylic acid
Methyl esters, ethoxy-c olefin(e) acid methyl esters, ethoxy ethyl acrylate, propoxyl group methyl acrylate or propoxyl group propyl acrylate；It is excellent
It is selected as methoxy-methyl acrylate, the raw material A and the described and raw material B are continuously passed through in the continuous reacting device
The step of carrying out the continuous reaction include:
Using the alkoxy acrylic ester as the raw material A；
It will be describedIt is dissolved in solvent and forms mixed solution, using the mixed solution as the raw material B；
The raw material A and the raw material B are continuously passed through in the continuous reacting device carry out the continuous reaction respectively；
It is highly preferred that the solvent be selected from water, acetic acid, n-butanol, tetrahydrofuran, 2- methyltetrahydrofuran, Isosorbide-5-Nitrae-dioxane,
Glycol dimethyl ether, diethylene glycol dimethyl ether, benzene,toluene,xylene, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide,
One of N, N- diethylformamide, N-Methyl pyrrolidone, dimethyl sulfoxide, acetonitrile, methanol, ethyl alcohol and isopropanol are more
Kind.
3. preparation method according to claim 1 or 2, which is characterized in that when the hydroxypyrazoles have institute
When stating structure shown in Formula II, alkali is passed through during the continuous reaction, while into the continuous reacting device
Liquid；
Preferably, the lye is inorganic base and/or organic base, and the more preferable inorganic base is NaOH aqueous solution and/or KOH water
Solution, the organic base are one of triethylamine, diethyl propylamine and diisopropyl ethyl amine or a variety of.
4. preparation method according to any one of claim 1 to 3, which is characterized in that the continuous reacting device is
Continuous coil reactor or CSTR flow reactor.
5. preparation method according to any one of claim 1 to 3, which is characterized in that the Formulas I, the Formula II and institute
It statesIn, R is hydrogen, methyl, ethyl, propyl, isopropyl, normal-butyl, isobutyl group or tert-butyl；Preferably, it is passed through
The alkoxy acrylic ester in the continuous reacting device and describedBetween molar ratio be 1:1~
1.2。
6. preparation method according to claim 5, which is characterized in that during being passed through the continuous reacting device,
The charging rate of the raw material A is 5~50g/min, and the raw material A and the raw material B are in the continuous reacting device
Retention time is 20~40min.
7. preparation method according to claim 5, which is characterized in that the reaction temperature of the continuous reaction be 100~
150℃。
8. preparation method according to any one of claim 1 to 3, which is characterized in that crude product described in separating-purifying
Step includes: that the crude product is continuously passed through in crystallization-filter device successively to carry out serialization crystallization and serialization filtering, is obtained
To the hydroxypyrazoles.
9. preparation method according to claim 8, which is characterized in that, will be described thick in the step of the serialization crystallization
Product retains 20~40min at 10~20 DEG C, is precipitated so that the hydroxypyrazoles in the crude product are cooling.
10. a kind of preparation facilities of hydroxypyrazoles, which is characterized in that the hydroxypyrazoles have Formulas I
Or structure shown in Formula II:
The preparation facilities includes:
First feeding device, for alkoxy acrylic ester without interruption as raw material A；
Second feeding device, for without interruptionAs raw material B, wherein the Formulas I, the Formula II and describedIn, R H, alkyl, unsaturated aliphatic hydrocarbyl moiety, aromatic radical, contains heteroatomic alkyl, contains heteroatomic insatiable hunger
With aliphatic group or containing heteroatomic aromatic radical；
Continuous reacting device, has feed inlet and a discharge gate, the feed inlet respectively with first feeding device and described
Second feeding device is connected, and the continuous reacting device is used to that the raw material A and the raw material B to be made to carry out continuous reaction,
And the crude product that reaction generates is discharged；
Separating-purifying device is connected with the discharge gate, and the separating-purifying device is used to carry out the crude product separation to mention
It is pure to obtain the hydroxypyrazoles.
11. preparation facilities according to claim 10, which is characterized in that the preparation facilities further includes the second feeding device
Also there is solvent inlet, the preparation facilities further includes third feeding device, the third feeding device and the solvent inlet
It is connected, for providing solvent so that describedIt is dissolved in the solvent and forms mixed solution, and by the mixing
Solution is as the raw material B.
12. preparation facilities according to claim 10, which is characterized in that described in having when the hydroxypyrazoles
Shown in Formula II when structure, the preparation facilities further includes the 4th feeding device, the 4th feeding device and the serialization
The feed inlet of reaction unit is connected, for supplying lye.
13. preparation facilities according to any one of claims 10 to 12, which is characterized in that the continuous reacting device
For continuous coil reactor or CSTR flow reactor.
14. preparation facilities according to any one of claims 10 to 12, which is characterized in that the separating-purifying device is
Crystallization-filter device.
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| CN109761741A (en) * | 2019-02-18 | 2019-05-17 | 吉林凯莱英制药有限公司 | Prepare the device and method of difluoro cyclopropanes compound |
| CN110105349A (en) * | 2019-04-29 | 2019-08-09 | 河北科技大学 | The synthetic method and its application of topramezone impurity |
| CN112480008A (en) * | 2020-12-21 | 2021-03-12 | 浙江工业大学 | Synthesis method of 1-methyl-5-hydroxypyrazole |
| CN112892436A (en) * | 2020-12-30 | 2021-06-04 | 杭州新本立医药有限公司 | Full continuous flow production process of 1-alkyl-5-hydroxypyrazole |
| CN112979550A (en) * | 2021-03-26 | 2021-06-18 | 山东亿盛实业股份有限公司 | Method for preparing 1-methyl-5-hydroxypyrazole by using microchannel reactor |
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