CN106800535A - A kind of preparation method of pyrazole compound - Google Patents
A kind of preparation method of pyrazole compound Download PDFInfo
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- CN106800535A CN106800535A CN201710026329.9A CN201710026329A CN106800535A CN 106800535 A CN106800535 A CN 106800535A CN 201710026329 A CN201710026329 A CN 201710026329A CN 106800535 A CN106800535 A CN 106800535A
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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
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Abstract
The invention discloses a kind of preparation method of the pyrazole compound as shown in formula III.Preparation method of the invention comprises the following steps：Compound shown in formula I and the compound as shown in Formula II are passed through micro passage reaction and are reacted through different pipelines respectively, you can；Wherein, reaction temperature is 10 60 DEG C；R1It is C1‑C4Alkyl；R2And R3It is each independently halogen；R4It is methyl or phenyl.Preparation method of the invention is carried out using micro passage reaction, reaction time is extremely short, reaction condition control is accurate, safe, is suitable for the quick preparation of product, can continuously produce, low cost, and pyrazole compound is prepared using micro passage reaction, the regioselectivity of reaction is high, target compound purity is good, more suitable for large-scale industrial production.
Description
Technical field
The present invention relates to technical field of organic synthesis, more particularly to a kind of preparation method of pyrazole compound.
Background technology
Pyrazole compound is widely used in fine chemistry industry, doctor as a kind of intermediate for synthesizing other pharmaceutical compounds
The fields such as medicine, organic synthesis.
There is knorr dehydrating condensations in hydrazine and 1,3- dicarbapentaborane class compound, be a kind of convenient synthesizing pyrazole class compound
Universal method.This method simple and effective, is used widely in the industrial production of pyrazole compound, but knorr
Reaction regional choice sex chromosome mosaicism existing in itself causes its side reaction to be difficult to avoid that isomers is more, has a strong impact on its industry
The raising of product yield and purity in metaplasia product.In addition in industrialized production, because reaction system is released during the course of the reaction
Substantial amounts of heat, local radiating is uneven easily to cause isomer impurities level larger；And, it is necessary to slow in reagent operation
Material slowly is added dropwise and continuous strong agitation is to control exothermic heat of reaction too fast and excessively acutely, prevent temperature of reactor too high,
Cause production accident.But being slowly added dropwise material prevents temperature of reactor too high, causes the reaction time to extend, industrialized production week
Phase is elongated, causes production efficiency low.
Therefore, this area need that a kind of reaction time is short, regioselectivity is high, safe, technique is easily controllable badly and
The preparation method of the pyrazole compound of low production cost.
The content of the invention
The technical problems to be solved by the invention are to overcome in the prior art using conventional synthesis process synthesizing pyrazole
Side reaction is serious during class compound, reaction time is long, under production efficiency and low production cost the problems such as, thus provide a kind of and existing
There is the preparation method of the entirely different pyrazole compound of technology, preparation method of the invention is carried out using micro passage reaction,
Reaction time is extremely short, and reaction condition control is accurate, safe, is suitable for the quick preparation of product, can continuously produce, cost
It is low, and pyrazole compound is prepared using micro passage reaction, the regioselectivity of reaction is high, and target compound purity is good,
More suitable for large-scale industrial production.
In the synthesis of pyrazole compound, the regioselectivity of Knorr reactions is always the problem for being difficult to capture.This Shen
Inventor please creatively uses micro passage reaction (also known as microreactor, it is intended that using the spy of precision processing technology manufacture
Microreactor of the size between 10-300 μm (or 1000 μm) is levied, Control of chemical reaction can be carried out in short space), come
The synthesis of pyrazole compound is carried out, the problem of such conversion zone poor selectivity is significantly improved, is directed to pyrazoles chemical combination
An important breakthrough for being conventionally synthesized technique of thing.
The present invention is to solve above-mentioned technical problem by following technical proposals.
The invention provides a kind of preparation method of the pyrazole compound as shown in formula III, it comprises the following steps：Will
Compound shown in formula I and the compound as shown in Formula II are passed through micro passage reaction and are reacted through different pipelines respectively,
；Wherein, reaction temperature is 10-60 DEG C；
Wherein, R1It is C1-C4Alkyl；R2And R3It is each independently halogen；R4It is methyl or phenyl.
In the present invention, described C1-C4Alkyl be preferably methyl, ethyl, propyl group, isopropyl, normal-butyl, isobutyl group or
The tert-butyl group, described halogen is preferably F, Cl or Br.
In the present invention, described compound shown in formula I R preferably wherein2And R3It is F or is Cl, R1For methyl or
Ethyl；Compound further preferably shown in formula I is following any：
In the present invention, described micro passage reaction can be to be applicable to liquid-liquid homogeneous reaction described in the routine of this area
Micro passage reaction；It is of the invention preferably in set the micro passage reaction of some modules, including heat exchange module, mixing module and anti-
Answer module etc.；Two heat exchange modules are set in further preferably, a mixing module and reaction module (as shown in Figure 1)
Micro passage reaction.Wherein, generally corrosion-resistant, the pressure-resistant material of described module material, the present invention preferably special glass is single
Crystal silicon, ceramics, acid resisting material scribbles the stainless steel of corrosion resistant coating, scribbles the metal alloy of corrosion resistant coating, polytetrafluoroethylene (PTFE) or carbon
Composite etc..
In the present invention, the micro passage reaction of the preferred Britain Vapourtec companies production of described micro passage reaction is (such as
Vapourtec E-Series micro passage reactions), micro passage reaction (such as Advanced- of Corning Incorporated's production
FlowTMReactors-AFR micro passage reactions), or Chemtrix BV companies of Holland production reactor (such as Labtrix is micro-
Channel reactor) etc., further preferred healthy and free from worry Advanced-FlowTMReactors-AFR micro passage reactions, further
It is preferred that healthy and free from worry Advanced-FlowTMReactors-AFR G1 micro passage reactions, it is integrated with mixing module and reaction mould
Block, microchannel internal diameter is 1mm-5mm, and -30-200 DEG C of temperature, material is glass, pressure limit up to 1.8MPa.
In the present invention, described compound shown in formula I and the compound as shown in Formula II are each led into microchannel
During reactor, according to described in the routine of this area, after being typically diluted with organic solution or water, then respectively through different
Measuring pump is passed through described micro passage reaction.Wherein, described organic solvent can carry out the reaction routine using this area
One or more in polar organic solvent used, preferably toluene, dimethylbenzene, chlorobenzene, benzene, dichloromethane and ethyl acetate；
Further preferred dimethylbenzene and/or toluene.Described extension rate can for this area carried out using micro passage reaction it is such anti-
Should be conventional used.
In the present invention, compound shown in formula I is preferably configured to its toluene or xylene solution is passed through microchannel plate
Answer device；It is preferred that the compound as shown in Formula II is passed through micro passage reaction with water or dilution with toluene, according to as shown in Formula II
Solubility properties of the compound in related solvents, can be configured to its homogeneous phase solution or suspension is passed through micro passage reaction.
Below for described compound shown in formula I and the described compound as shown in Formula II described micro- logical
In the associated description reacted in road reactor, when described compound shown in formula I is referred to, refer both to it has accordingly
Machine solution, when the described compound as shown in Formula II is referred to, refers both to its corresponding organic solution or suspension.
In the present invention, preferred 15-55 DEG C of described reaction temperature, still more preferably further preferred 20-40 DEG C, 20-
35℃。
It is described when described micro passage reaction set when heat exchange module, mixing module and reaction module in the present invention
Compound shown in formula I and the compound as shown in Formula II the heat exchange module of micro passage reaction is passed through through measuring pump respectively
In, resynchronisation enters mixing module and forms mixture, finally flows into reaction module and is reacted.Described heat exchange module, mixing
The temperature of module and reaction module is 10-60 DEG C, preferably 15-55 DEG C, still more preferably further preferred 20-40 DEG C, 20-
35℃。
In the present invention, the mol ratio of described compound shown in formula I and the compound as shown in Formula II can be ability
The conventional mol ratio of such reaction of domain；The present invention preferably 1:1-1:1.6, further preferred 1:1-1:1.2, still more preferably 1:
1.05~1:1.1.The mol ratio of described compound shown in formula I and the compound as shown in Formula II can be defeated by both
Enter the velocity ratio of micro passage reaction to be controlled, the conversion relation between described velocity ratio and described mol ratio is such as
Under：Mol ratio=(the V of described compound shown in formula I and the compound as shown in Formula IIa×ρa/Ma):(Vb×ρb/
Mb), wherein VaRepresent the flow velocity of described compound shown in formula I, ρaRepresent the close of described compound shown in formula I
Degree, MaRepresent the relative molecular mass of compound shown in formula I, VbThe flow velocity of the described compound as shown in Formula II is represented,
ρbRepresent the density of described compound II, MbRepresent the relative molecular mass of the described compound as shown in Formula II；ρaAnd ρb
Unit it is consistent.
In the present invention, the flow velocity of described compound shown in formula I and the compound as shown in Formula II is described micro-
Within the scope of channel reactor flow velocity in itself is allowed, such reaction routine can be carried out using micro passage reaction for this area
Flow velocity used；Wherein, the flow velocity of described compound shown in formula I is preferably 0.01-60mL/min, more preferably
20-30mL/min, is still more preferably 25mL/min.The flow velocity of the described compound as shown in Formula II is preferably 0.01-
60mL/min, more preferably 4-10mL/min, are still more preferably 4.5-5mL/min, such as 4.3mL/min.
In the present invention, the velocity ratio of described compound shown in formula I and the compound as shown in Formula II can use micro-
Channel reactor carries out the velocity ratio used by such reaction routine, and the present invention is preferably 10:1-1:1, further preferred 5:1-3:
1, still more preferably 25:4.3-4:1.
In the present invention, described reaction time may be configured as this area carried out under the conditions of micro passage reaction it is such
The popular response residence time of reaction, the present invention be preferably 10-600s, more preferably 20-390s, still more preferably for
200-210s, 230-240s, 240-360s or 290-300s.Wherein, described reaction time is the conventional art of this area
Since language, refer generally to reaction mass residence time in micro passage reaction entering micro passage reaction.
In the present invention, preferably described preparation method comprises the steps：By the first of described compound shown in formula I
Benzene or xylene solution, and the aqueous solution or toluene suspension liquid of the described compound as shown in Formula II are logical by measuring pump respectively
Enter healthy and free from worry Advanced-FlowTMReacted in Reactors-AFR G1 micro passage reactions, 10-60 DEG C of design temperature；Control
Both systems flow velocity is 0.01-60mL/min, and the two velocity ratio is 10:1-1:1, reaction time is 10-600s, you can.
Specific reaction process flow refers to the reaction process flow chart of synthesizing pyrazole class compound in Fig. 1.
In the present invention, described preparation method preferably also includes last handling process, and described last handling process can be using this
The conventional post-processing operation and condition of the such reaction in field, present invention preferably comprises following steps：By reaction liquid layer, divide and go to give up
Water layer, adds 30% NaOH and water, is warming up to 60-65 DEG C, and 1 hour is incubated at 60-65 DEG C, sampling detection, layering, water layer
Lower step acidification is carried out, organic layer enters solvent recovering system.To hydrochloric acid and water is thrown in reactor, 70-80 DEG C, drop are warming up to
Plus water layer is stated, temperature is maintained at drop in 70-80 DEG C, 2h and finishes, pH<2,15min is incubated, cool to incubation at room temperature 30min, mistake
Filter, is washed with water, and wet product water and isopropanol are beaten, and filtration washing, wet product is dried：Vacuum, jacket temperature<60 DEG C, obtain dry product.
On the basis of common sense in the field is met, above-mentioned each optimum condition can be combined, and obtain final product each preferable reality of the present invention
Example.
Agents useful for same of the present invention and raw material are commercially available.
Positive effect of the invention is：1st, the reaction process is continuous stream reaction, and the reaction time shorten to several seconds
To a few minutes, yield is improve, significantly improve reaction efficiency and production efficiency；2nd, raw material mixes effect in micro passage reaction
It is really splendid, easy temperature control system, and without convention stir, equipment is simplified, reduce energy consumption；What the 3rd, the technique was used is micro-
Channel reactor mass-and heat-transfer is better, maintain the constant of temperature, it is to avoid hot-spot, reduces the product of accessory substance
It is raw；4th, the method can carry out mass-and heat-transfer by fluid kinetic energy in itself, without the mechanical agitation process of conventional reactor, also
Continuation course of reaction outside without reaction channel is obtained with the yield higher than conventional reactor；5th, compared with traditional handicraft,
The technique has reaction condition precise control, continuous production, and conversion is completed within the extremely short time, reduces accessory substance
The advantages of formation；The fluctuation of temperature and concentration in course of reaction is avoided simultaneously, it is safer.
Brief description of the drawings
Fig. 1 is the reaction process flow chart of synthesizing pyrazole class compound of the present invention.
Fig. 2 is the process flow diagram of healthy and free from worry micro passage reaction used in the present invention.
Wherein, 1 and 2 head tank is represented, 3 and 4 represent measuring pump, and 5 and 6 represent stop valve, and 7 represent Corning microchannels
Reactor, 8 represent collecting tank.
Specific embodiment
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to described reality
Apply among a scope.The experimental technique of unreceipted actual conditions in the following example, conventionally and condition, or according to business
Product specification is selected.
Unless otherwise instructed, following embodiments use healthy and free from worry Advanced-FlowTMReactors-AFR G1 microchannels
Reactor is reacted, and it is integrated with mixing module and reaction module, and microchannel internal diameter is 1mm-5mm, -30-200 DEG C of temperature,
Material is glass, pressure limit up to 1.8MPa.Raw material is input into microchannel reaction system by measuring pump, and the inventory of material is equal
It is controlled by changing flow, (i.e. head tank to the pipeline between micro passage reaction discharging opening) installs on its material pipeline
There are pressure gauge, safety valve, check valve, counterbalance valve etc..Specific operating procedure can refer to Fig. 2 to be carried out.
Unless otherwise instructed, isomers detected in following embodiments 1,4-12 is
Embodiment 1：
1st, raw material is prepared：Weigh Compound a (31.5g, 0.142mol) configures its xylene solution (80.0mL), is put into appearance
In device, stirring makes its well mixed sealing, is put in head tank 1；Weigh Compound b (the 40% methyl hydrazine aqueous solution, 17.2g,
0.149mol, 19.8mL), it is put in head tank 2；
2nd, using installation drawing of the invention 2, as steps described below：(1) by the xylene solution of compound a in head tank 1
Corning micro passage reactions 7 are entered by measuring pump 3, the 40% methyl hydrazine aqueous solution in head tank 2 is entered by measuring pump 4
Enter Corning micro passage reactions 7；(2) set each measuring pump 3 and measuring pump 4 controls the xylene solution and 40% of compound a
The methyl hydrazine aqueous solution is respectively 20mL/min and 5.0mL/min, sets heat exchange temperature as 25 DEG C, reaction time 240s；
(3) refluence of material is prevented on reaction channel by stop valve 5 and 6；(4) mix by Corning micro passage reactions 7
After reaction, product continuous discharge is collected into collecting tank 8, and product is analyzed by LC.
3rd, the purity of compound c is 89.6% (LC analysis results are see table 3), yield 85.7% in product.
Embodiment 2：
1st, raw material is prepared：Weigh Compound d (36.2g, 0.142mol) prepares its toluene solution (180.0mL), is put into appearance
In device, stirring makes its well mixed sealing, is put in head tank 1；Weigh Compound e (phenylhydrazine, 16.9g, 0.156mol), is configured to
Its toluene suspension liquid (60.0mL), is put in head tank 2；
2nd, using installation drawing of the invention 2, as steps described below：(1) toluene solution of compound d in head tank 1 is led to
Cross measuring pump 3 and enter Corning micro passage reactions 7, the toluene suspension liquid of the phenylhydrazine in head tank 2 is entered by measuring pump 4
Corning micro passage reactions 7；(2) toluene solution and the first of phenylhydrazine of each measuring pump 3 and the control compound of measuring pump 4 d are set
Benzene suspension is respectively 30mL/min and 10.0mL/min, sets heat exchange temperature as 55 DEG C, reaction time 360s；(3)
The refluence of material is prevented on reaction channel by stop valve 5 and 6；(4) mix instead by Corning micro passage reactions 7
Ying Hou, product continuous discharge is collected into collecting tank 8, and product is analyzed by LC.
3rd, the purity of compound f is 96.3% (LC analysis results), yield 91.7% in product.
Embodiment 3：
1st, raw material is prepared：Weigh Compound g (41.6g, 0.200mol) prepares its toluene solution (160.0mL), is put into appearance
In device, stirring makes its well mixed sealing, is put in head tank 1；Weigh Compound b (the 40% methyl hydrazine aqueous solution, 24.2g,
0.210mol, 27.8mL), it is put in head tank 2；
2nd, using installation drawing of the invention 2, as steps described below：(1) toluene solution of compound g in head tank 1 is led to
Cross measuring pump 3 and enter Corning micro passage reactions 7, the 40% methyl hydrazine aqueous solution in head tank 2 is entered by measuring pump 4
Corning micro passage reactions 7；(2) toluene solution and 40% methyl of each measuring pump 3 and the control compound of measuring pump 4 g are set
The hydrazine aqueous solution is respectively 25mL/min and 4.3mL/min, sets heat exchange temperature as 40 DEG C, reaction time 390s；(3) it is anti-
Answer the refluence for preventing material on passage by stop valve 5 and 6；(4) by the hybrid reaction of Corning micro passage reactions 7
Afterwards, product continuous discharge is collected into collecting tank 8, and product is analyzed by LC.
3rd, the purity of compound h is 92.6% (LC analysis results), yield 88.0% in product.
Embodiment 4：
1st, raw material is prepared：Weigh Compound a (31.5g, 0.142mol) configures its xylene solution (80.0mL), is put into appearance
In device, stirring makes its well mixed sealing, is put in head tank 1；Weigh Compound b (the 40% methyl hydrazine aqueous solution, 17.2g,
0.149mol, 19.8mL), it is put in head tank 2；
2nd, using installation drawing of the invention 2, as steps described below：(1) by the xylene solution of compound a in head tank 1
Corning micro passage reactions 7 are entered by measuring pump 3, the 40% methyl hydrazine aqueous solution in head tank 2 is entered by measuring pump 4
Enter Corning micro passage reactions 7；(2) set each measuring pump 3 and measuring pump 4 controls the xylene solution and 40% of compound a
The methyl hydrazine aqueous solution is respectively 20mL/min and 5.0mL/min, sets heat exchange temperature as 35 DEG C, reaction time 240s；
(3) refluence of material is prevented on reaction channel by stop valve 5 and 6；(4) mix by Corning micro passage reactions 7
After reaction, product continuous discharge is collected into collecting tank 8, and product is analyzed by LC.
3rd, the purity of compound c is 89.6% (LC analysis results are see table 3) in product.
Embodiment 5-12：Investigate the influence of temperature and reaction time to reacting in micro passage reaction technique
In embodiment 5-12, in addition to the parameter shown in following table 1 and 2, other specification with the complete phase of embodiment 1
Together, and according to the technical process in embodiment 1 reacted (its product LC analysis results are see table 1,2).
Tables of data of the temperature on reaction influence in the micro passage reaction technique of table 1
Tables of data of the reaction time on reaction influence in the micro passage reaction technique of table 2
Comparative example 1：
To putting into dimethylbenzene 100.0g, the 40% methyl hydrazine aqueous solution (17.2g, 0.149mol, 19.8mL) in reactor,
The xylene solution (31.5g, 0.0.142mol, dimethylbenzene 100.0g) of compound a is added dropwise at 25 DEG C, in 30min at 25 DEG C
Drip off, be incubated 15min, layering adds 2% NaOH sodium chloride solution wash temperature to be maintained at 19-21 DEG C in organic layer,
Organic layer send survey LC analyses (its analysis result is see table 3).By reaction liquid layer, divide and go waste water layer, add 30% NaOH
And water, 60-65 DEG C is warming up to, 1 hour is incubated at 60-65 DEG C, sampling detection, layering, water layer carries out lower step acidification, organic
Layer enters solvent recovering system.To hydrochloric acid and water is thrown in reactor, 70-80 DEG C is warming up to, above-mentioned water layer is added dropwise, temperature is maintained at
70-80 DEG C, drop finishes in 2h, pH<2, be incubated 15min, cool to incubation at room temperature 30min, filter, wash with water, wet product water and
Isopropanol is beaten, filtration washing, and wet product is dried：Vacuum, jacket temperature<60 DEG C, obtain dry product.
Comparative example 2：
To putting into dimethylbenzene 100.0g, the 40% methyl hydrazine aqueous solution (17.2g, 0.149mol, 19.8mL) in reactor,
The xylene solution (31.5g, 0.0.142mol, dimethylbenzene 100.0g) of compound a is added dropwise at 35 DEG C, in 30min at 35 DEG C
Drip off, be incubated 15min, layering adds 2% NaOH sodium chloride solution wash temperature to be maintained at 19-21 DEG C in organic layer,
Organic layer send survey LC analyses (its analysis result is see table 3).By reaction liquid layer, divide and go waste water layer, add 30% NaOH
And water, 60-65 DEG C is warming up to, 1 hour is incubated at 60-65 DEG C, sampling detection, layering, water layer carries out lower step acidification, organic
Layer enters solvent recovering system.To hydrochloric acid and water is thrown in reactor, 70-80 DEG C is warming up to, above-mentioned water layer is added dropwise, temperature is maintained at
70-80 DEG C, drop finishes in 2h, pH<2, be incubated 15min, cool to incubation at room temperature 30min, filter, wash with water, wet product water and
Isopropanol is beaten, filtration washing, and wet product is dried：Vacuum, jacket temperature<60 DEG C, obtain dry product.
The common process of table 3 collects with some experimental data of micro passage reaction technique
Claims (10)
1. the preparation method of a kind of pyrazole compound as shown in formula III, it comprises the following steps：By change shown in formula I
Compound and the compound as shown in Formula II are passed through micro passage reaction and are reacted through different pipelines respectively, you can；Wherein, react
Temperature is 10-60 DEG C；
Wherein, R1It is C1-C4Alkyl；R2And R3It is each independently halogen；R4It is methyl or phenyl.
2. preparation method as claimed in claim 1, it is characterised in that wherein, described C1-C4Alkyl for methyl, ethyl,
Propyl group, isopropyl, normal-butyl, isobutyl group or the tert-butyl group；
And/or, described halogen is F, Cl or Br.
3. preparation method as claimed in claim 1, it is characterised in that wherein, R2And R3It is F or is Cl, R1For methyl or
Ethyl.
4. preparation method as claimed in claim 1, it is characterised in that wherein, described compound shown in formula I is as follows
It is any：
5. preparation method as claimed in claim 1, it is characterised in that described micro passage reaction is Vapourtec E-
Series micro passage reactions, healthy and free from worry Advanced-FlowTMReactors-AFR micro passage reactions or Chemtrix BV
Labtrix micro passage reactions, preferably healthy and free from worry Advanced-FlowTMReactors-AFR micro passage reactions, further preferably
Healthy and free from worry Advanced-FlowTMReactors-AFR G1 micro passage reactions.
6. preparation method as claimed in claim 1, it is characterised in that by described compound shown in formula I and such as Formula II
When shown compound each leads into micro passage reaction, again respectively through different after being diluted with organic solution or water
Measuring pump is passed through described micro passage reaction；Wherein, described organic solvent is selected from toluene, dimethylbenzene, chlorobenzene, benzene, dichloro
One or more in methane and ethyl acetate；Preferably dimethylbenzene and/or toluene.
7. preparation method as claimed in claim 1, it is characterised in that wherein,
Described reaction temperature is 15-55 DEG C, preferably 20~40 DEG C, further preferred 20-35 DEG C；
And/or, the mol ratio of described compound shown in formula I and the compound as shown in Formula II is 1:1-1:1.6, preferably
1:1-1:1.2, further preferred 1:1.05~1:1.1；
And/or, the flow velocity of described compound shown in formula I is 0.01-60mL/min, preferably 20-30mL/min, enters one
Step is preferably 25mL/min；
And/or, the flow velocity of the described compound as shown in Formula II is 0.01-60mL/min, preferably 4-10mL/min, enters one
Step is preferably 4.5-5mL/min, still more preferably 4.3mL/min；
And/or, described reaction time is 10-600s, preferably 20-390s, further preferred 200-210s, 230-
240s, 240-360s or 290-300s.
8. preparation method as claimed in claim 1, it is characterised in that wherein, described compound shown in formula I and such as formula
The velocity ratio of the compound shown in II is 10:1-1:1, preferably 5:1-3:1, further preferred 25:4.3-4:1.
9. preparation method as claimed in claim 1, it is characterised in that described preparation method comprises the steps：Will be described
Compound shown in formula I toluene or the aqueous solution or toluene of xylene solution and the described compound as shown in Formula II
Suspension is passed through healthy and free from worry Advanced-Flow by measuring pump respectivelyTMCarried out in Reactors-AFR G1 micro passage reactions anti-
Should, 10-60 DEG C of design temperature；It is 0.01-60mL/min to control the two flow velocity, and the two velocity ratio is 10:1-1:1, reaction stops
It is 10-600s to stay the time, you can.
10. preparation method as claimed in claim 1, it is characterised in that described preparation method also includes last handling process, institute
The last handling process stated preferably includes following steps：By reaction liquid layer, divide and go waste water layer, add 30% NaOH and water,
60-65 DEG C is warming up to, 1 hour is incubated at 60-65 DEG C, sampling detection, layering, water layer carries out lower step acidification, and organic layer enters
Enter solvent recovering system；To hydrochloric acid and water is thrown in reactor, 70-80 DEG C is warming up to, above-mentioned water layer is added dropwise, temperature is maintained at 70-
80 DEG C, drop finishes in 2h, PH<2,15min is incubated, incubation at room temperature 30min is cooled to, filter, wash with water, wet product water and isopropyl
Alcohol is beaten, filtration washing, and wet product is dried：Vacuum, jacket temperature<60 DEG C, you can.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109574935A (en) * | 2019-01-11 | 2019-04-05 | 中化农业（临沂）研发中心有限公司 | Process for preparing 3, 4-dimethylpyrazole and its phosphate |
| CN110452173A (en) * | 2018-11-07 | 2019-11-15 | 福建永晶科技股份有限公司 | A kind of new method for manufacturing pyrazoles or pyrimidone |
| CN112062720A (en) * | 2020-09-10 | 2020-12-11 | 江苏七洲绿色化工股份有限公司 | Continuous preparation method of 1-methyl-3-hydroxypyrazole-4-carboxylic acid ethyl ester |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101679281A (en) * | 2007-05-31 | 2010-03-24 | 先正达参股股份有限公司 | Process for the production of pyrazoles |
| CN102702104A (en) * | 2012-06-08 | 2012-10-03 | 巨化集团公司 | Method for continuously synthesizing 3-difluoromethyl-1-methylpyrazole-4-ethyl formate |
| CN105722829A (en) * | 2013-12-23 | 2016-06-29 | 伊萨格洛公司 | Process for the regioselective synthesis of pyrazoles |
-
2017
- 2017-01-13 CN CN201710026329.9A patent/CN106800535A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101679281A (en) * | 2007-05-31 | 2010-03-24 | 先正达参股股份有限公司 | Process for the production of pyrazoles |
| CN102702104A (en) * | 2012-06-08 | 2012-10-03 | 巨化集团公司 | Method for continuously synthesizing 3-difluoromethyl-1-methylpyrazole-4-ethyl formate |
| CN105722829A (en) * | 2013-12-23 | 2016-06-29 | 伊萨格洛公司 | Process for the regioselective synthesis of pyrazoles |
Non-Patent Citations (2)
| Title |
|---|
| 赵临襄: "《化学制药工艺学》", 31 August 2015, 北京：中国医药科技出版社 * |
| 钟平等: "微反应器技术在有机合成中的应用", 《化学试剂》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110452173A (en) * | 2018-11-07 | 2019-11-15 | 福建永晶科技股份有限公司 | A kind of new method for manufacturing pyrazoles or pyrimidone |
| CN109574935A (en) * | 2019-01-11 | 2019-04-05 | 中化农业（临沂）研发中心有限公司 | Process for preparing 3, 4-dimethylpyrazole and its phosphate |
| CN112062720A (en) * | 2020-09-10 | 2020-12-11 | 江苏七洲绿色化工股份有限公司 | Continuous preparation method of 1-methyl-3-hydroxypyrazole-4-carboxylic acid ethyl ester |
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