CN107353211A - The synthetic method of enamine compound and the synthetic method of aromatic aldehyde compound - Google Patents
The synthetic method of enamine compound and the synthetic method of aromatic aldehyde compound Download PDFInfo
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- CN107353211A CN107353211A CN201710419195.7A CN201710419195A CN107353211A CN 107353211 A CN107353211 A CN 107353211A CN 201710419195 A CN201710419195 A CN 201710419195A CN 107353211 A CN107353211 A CN 107353211A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/60—Preparation of compounds containing amino groups bound to a carbon skeleton by condensation or addition reactions, e.g. Mannich reaction, addition of ammonia or amines to alkenes or to alkynes or addition of compounds containing an active hydrogen atom to Schiff's bases, quinone imines, or aziranes
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- 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
Abstract
The invention provides a kind of synthetic method of enamine compound and the synthetic method of aromatic aldehyde compound.The synthetic method of enamine compound includes initiation material A and N, N Dimethylformamide dimethyl acetal forming mixed solution；And mixed solution is continuously introduced into progress enamine in continuous reaction device and reacts to obtain enamine compound B, and continuously discharge enamine compound B from continuous reaction device when carrying out enamine reaction；Initiation material A has the structural formula shown in formula (1), and enamine compound B has the structural formula shown in formula (2).Enamine reaction is carried out by way of the mixed solution of reaction raw materials is continuously introduced into reactor realizes the serialization of enamine reaction, and then also achieves the continuous production of aromatic aldehyde compound, shortens the reaction time, improves reaction efficiency.The continuous reaction method can stop reaction or terminating reaction at any time according to actual conditions, post processing also can batch processing or merging treatment as needed, facilitate simple and direct.
Description
Technical field
The present invention relates to the field of chemical synthesis, in particular to a kind of synthetic method and aromatic aldehydes of enamine compound
The synthetic method of compound.
Background technology
Aromatic aldehyde compound is important organic synthesis intermediate, is widely used in biology, medicine, agricultural chemicals, material etc.
Field.Also it is easy to the aldehyde radical of modification because containing, and turns into the classical organic molecule skeleton for constructing each heterocyclic compounds.Such as：
Phenol aromatic aldehyde is important spices and catalyst synthetic intermediate.2- nitro -4- chlorobenzaldehydes are synthesizing anti-AIDS pharmaceuticals
Siamenol important intermediate.4- nitrobenzaldehydes and 4- cyanobenzaldehydes are widely used in synthesis of natural product and activity
Medicine etc..
Tradition prepares the aromatic aldehyde of substituent containing electron, and one of more classical method is reacted for Remier-Tiemann, i.e.,
Fragrant electrophilic substitution reaction occurs in alkaline protonic solvent, but many deficiencies generally be present in the reaction, if desired for denseer
Alkaline solution, excessive chloroform, reaction can only obtain moderate yield product and the limitations such as selectivity of product is poor.1994
Robert Aldred etc. find paraformaldehyde under the catalysis of magnesium chloride can Pyrogentisinic Acid carry out formylated, and obtain good yield
Product, this method is rapid expanded since then.
Comparatively, it is more various to prepare the aromatic aldehyde compound containing electron withdraw group.It can be divided mainly into (1) hydrolysis
Method, i.e., using the toluene derivative containing electron-withdrawing group as raw material, hydrolyze to obtain corresponding aromatic aldehyde again after chlorination (or bromination).
(2) direct nitrification process, such method are mainly used in aromatic aldehyde of the synthesis containing nitro.The technique not only needs consumption substantial amounts of dense
Sulfuric acid, environment is polluted, while can also produce isomers paranitrobenzaldehyde, the separation and purification to product bring difficulty.(3)
Direct oxidation side chain method and (4) Indirect Electrooxidation etc..
In summary, the synthetic method of electron withdraw group aromatic aldehyde of the prior art has the following disadvantages：(1) tradition system
Standby aromatic aldehyde containing electron-withdrawing group needs to use environment unfriendly, high-risk high poison raw material, as bromination method uses a large amount of bromines, nitrification process
Using substantial amounts of concentrated sulfuric acid etc., operational hazards, and corrosion reaction equipment.(2) existing enamine reaction is carried out using glass kettle
Reaction, high is required to equipment pressure high-temp resistant, reaction time length, efficiency is low, can not meet a large amount of demand of industrial production.(3) it is and more
Number enamine reactions steps yield is relatively low, it is necessary to which extra additive or catalyst could react.
Therefore, for the synthesis for electron withdraw group aromatic aldehyde, a kind of efficiently simple and direct preparation method one how is developed
It is directly the focus of people's research.
The content of the invention
It is a primary object of the present invention to provide a kind of synthetic method of enamine compound and the synthesis of aromatic aldehyde compound
Method, to solve the problems, such as that enamine compound synthetic method efficiency is low in the prior art.
To achieve these goals, according to an aspect of the invention, there is provided a kind of synthetic method of enamine compound, is somebody's turn to do
Synthetic method includes initiation material A and N,N-dimethylformamide dimethylacetal forming mixed solution；And by mixed solution
Progress enamine reaction in continuous reaction device is continuously introduced into, obtains enamine compound B, and it is continuous when carrying out enamine reaction
Enamine compound B is discharged from continuous reaction device；Wherein, initiation material A has the structural formula shown in formula (1)：
Enamine compound B has the structural formula shown in formula (2)：
In above-mentioned formula (1) and formula (2), n=0~1, the X of diverse location is each independently selected from N, S, O or C；R1、R2、R3
And R4It is each independently selected from H, alkyl, aryl, nitro, halogen, ester group, cyano group or trifluoromethyl, R1、R2、R3And R4It is identical or
Differ.
Further, before mixed solution is sent into the step of continuous reaction device carries out enamine reaction, synthesis side
Method also includes：The step of continuous reaction device is heated to 165~180 DEG C, preferably 170~175 DEG C；Heating is preferably using oil
The mode of bath is carried out, and is more preferably carried out by the way of oil bath is circulated；It is further preferred that continuous reaction device reacts for coil pipe
Device.
Further, after the heating step, and mixed solution is sent into continuous reaction device and carries out enamine reaction
Before step, synthetic method also includes：At a temperature of 170~175 DEG C, protection solvent is sent into continuous reaction device, and is made
Pressure in continuous reaction device is 1.0~1.5MPa；Preferably, solvent is protected to be selected from dimethylformamide, acetonitrile, dimethyl
Acetamide or 1-METHYLPYRROLIDONE.
Further, according to 1.50~3.5g/min charging rate, preferably according to 1.8~2.5g/min charging rate
Mixed solution is continuously introduced into progress enamine reaction in continuous reaction device, obtains enamine compound B.
Further, it is 60~150min, preferably 80 into the residence time of the mixed solution in continuous reaction device
~120min.
Further, enamine compound B includes Part I and Part II, continuously by enamine compound B from continuous reaction
The step of being discharged in device includes mixed solution being continuously introduced into continuous reaction device, and continuously will when carrying out enamine reaction
The enamine compound B discharges of Part I；Enter line replacement to the enamine compound B of the Part II in reactor with protection solvent with even
The enamine compound B of continuous discharge Part II；Preferably, protect solvent be selected from dimethylformamide, acetonitrile, dimethyl acetamide or
1-METHYLPYRROLIDONE.
Further, after enamine compound B is obtained, synthetic method also includes carrying out cooling and stirring to enamine compound B
Step；It is preferred that the step of cooling and stirring, includes：Cooling and stirring is carried out at a temperature of enamine compound B is placed in into 0~10 DEG C, cooling is stirred
The time mixed is 0.5~1.0h so that enamine compound B crystallizations separate out.
To achieve these goals, according to an aspect of the invention, there is provided a kind of synthesis of aromatic aldehyde compound
Method, the synthetic method include：Synthesize enamine compound B；And enamine compound B is prepared into aldehyde compound C；Wherein, enamine
Compound B is synthesized using any of the above-described kind of synthetic method, and aldehyde compound C has the structural formula shown in formula (3)：
In formula (3), n=0~1, the X of diverse location is each independently selected from N, S, O or C；R1、R2、R3And R4It is each independent
Ground is selected from H, alkyl, aryl, nitro, halogen, ester group, cyano group or trifluoromethyl, R1、R2、R3And R4It is identical or differ.
Further, the step of enamine compound B being prepared into aldehyde compound C includes carrying out oxygen to enamine intermediate B
Change is handled, and obtains aldehyde compound C.
Further, oxidation processes are carried out to enamine intermediate B using oxidant, preferred oxidant is selected from periodic acid
Sodium, sodium hypochlorite or hydrogen peroxide.
Apply the technical scheme of the present invention, carried out by way of the mixed solution of reaction raw materials is continuously introduced into reactor
Enamine reacts, and realizes the serialization of enamine reaction, shortens the reaction time, improve reaction efficiency.The serialization is anti-
On the one hand it can should at any time stop reaction or terminating reaction according to actual conditions, post processing also may be used relative to traditional still reaction
Batch processing as needed or merging treatment, facilitate simple and direct；On the other hand largely solve because temperature is high, system pressure
Increase, the problem of consersion unit is difficult to bear, reduce the degree of danger of reaction.
Embodiment
It should be noted that in the case where not conflicting, the feature in embodiment and embodiment in the application can phase
Mutually combination.The present invention is described in detail below in conjunction with embodiment.
The fragrant phenolic compound of the application is the fragrant phenolic compound of substitution, similarly, aromatic aldehyde compound
For substituted aroma aldehyde compound.
As background technology is previously mentioned, the synthetic method of aromatic aldehyde compound in the prior art, especially containing electrophilic
There is the defects of reaction efficiency is low in the synthetic method of the aromatic aldehyde compound of group, to improve this situation, in the application one
In the typical embodiment of kind, there is provided a kind of synthetic method of enamine compound, the synthetic method include：By initiation material A with
N,N-dimethylformamide dimethylacetal forms mixed solution；Mixed solution is continuously introduced into continuous reaction device and carries out enamine
Change reaction, obtain enamine compound B, and continuously arrange enamine compound B from continuous reaction device when carrying out enamine reaction
Go out；Wherein, initiation material A has the structural formula shown in formula (1)：
Enamine compound B has the structural formula shown in formula (2)：
In above-mentioned formula (1) and formula (2), n=0~1, the X of diverse location is each independently selected from N, S, O or C；R1、R2、R3
And R4It is each independently selected from H, alkyl (alkyl), aryl (aryl), nitro (- NO2), halogen (halogen), ester group
(Ester), cyano group (Cyano) or trifluoromethyl, R1、R2、R3And R4It is identical or differ.
Above-mentioned synthetic method, it is anti-by way of the mixed solution of reaction raw materials is continuously introduced into reactor to carry out enamine
Should, the serialization of enamine reaction is realized, the reaction time is shortened, improves reaction efficiency.The continuous reaction relative to
Traditional still reaction, on the one hand it can stop reaction or terminating reaction at any time, post processing also can be as needed according to actual conditions
Batch processing or merging treatment, facilitate simple and direct；On the other hand largely solve because temperature is high, the increase of system pressure, instead
The problem of answering equipment to be difficult to bear, reduce the degree of danger of reaction.
In above-mentioned synthetic method, mixed solution is dissolved in solvent by reaction initiation material and formed, specific used molten
Agent carries out reasonable selection according to initiation material species, such as, when initiation material is 2- nitrotoleunes, using DMF conducts
Solvent.Specifically the amount ratio between initiation material A and solvent can be dissolved by initiation material A is defined, such as can be according to starting
Mass volume ratio (the g of raw material A and solvent:Ml it is) 1：10~20 ratio is dissolved.And in mixed solution, initiation material A
With the dosage of N,N-dimethylformamide dimethylacetal according to being advantageous to make reaction object space of overfulfiling a production target to be added to mobile ratio
Add, in order that initiation material A is more more thoroughly by enamine, preferably initiation material A and DMF two
The mass ratio of methyl acetal is 1:3~5 ratio mixing, more preferably mass ratio are 1:3.
Above-mentioned synthetic method carries out enamine reaction realization to enamine by the way that mixed solution is sent into continuous reaction device
Thing B's is continuously synthesizing to, and improves production efficiency.Thus, it is any before mixed solution to be sent into the continuous reaction device
Be advantageous to improve reaction efficiency, the operation for shortening the reaction time is applied to the application.In a kind of preferred embodiment of the application
In, before mixed solution is sent into the step of continuous reaction device carries out enamine reaction, the synthetic method also includes：Will be even
The step of continuousization reactor is heated to 165~180 DEG C, preferably 170~175 DEG C；Heating is carried out preferably by the way of oil bath,
More preferably carried out by the way of oil bath is circulated；It is further preferred that continuous reaction device is coil reactor.
In above-mentioned preferred embodiment, by the way that continuous reaction device first is heated into the temperature strip needed for enamine reaction
Part, enable to reaction mixture one to be reacted into reactor, improve reaction efficiency.It can additionally avoid progressively rising
Reaction mixed material is set to evaporate or generate at low temperature non-purpose product during temperature.Enamine is carried out at 165~180 DEG C
Reaction can effectively shorten the reaction time, and enamine reaction raw materials are carried out at 170~175 DEG C can realize maximum conversion.It is right
It is unlimited in specific mode of heating, as long as said temperature scope can be heated to continuous reaction device.And use oil bath
Mode carry out heating and contribute to insulation stable, circulation oil bath can save the dosage of heating medium, reduce energy consumption.Serialization is anti-
Answer device that there is high temperature resistant, pressure-resistant, the advantage such as acid and alkali-resistance using coil reactor.
In order to further improve reaction efficiency, in a kind of preferred embodiment of the application, after the heating step, and will
Mixed solution was sent into before the step of continuous reaction device carries out enamine reaction, and the synthetic method also includes：Solvent will be protected
It is sent into continuous reaction device, and makes the pressure in continuous reaction device be 1.0~1.5MPa.
Above-mentioned preferred embodiment, by further purifying the environmental condition of continuous reaction, by continuous reaction device
The influence that the poor environments such as impurity that may be present are reacted enamine is minimized, and makes mixed solution in the reactor with preferable
Condition reacted.Also, by the Stress control in continuous reaction device in 1.0~1.5MPa, reaction system can be made
Stablize at high temperature and flow through coil pipe, and then be favorably improved reaction rate.
The above-mentioned protection solvent to enamine reaction is conventional protection solvent, includes but are not limited to dimethyl formyl
Amine, acetonitrile, dimethyl acetamide or 1-METHYLPYRROLIDONE.
In the step of above-mentioned continuous reaction, the charging rate of mixed solution depends on capacity and the guarantor of coil reactor
The time is stayed, unrelated with other, if reactor capacity is fixed, retention time is fixed, then charging rate is a fixed value, and is
One-to-one relationship.Thus charging rate can rationally be set according to reactor capacity and retention time.A kind of preferred
Embodiment in, according to 1.50~3.5g/min charging rate, will preferably be mixed according to 1.8~2.5g/min charging rate
Solution is continuously introduced into progress enamine reaction in continuous reaction device, obtains enamine compound B.
In the synthetic method of above-mentioned enamine compound, rationally set according to the difference of reactant feed species anti-into serialization
Answer the reaction time of the mixed solution of device.In a kind of preferred embodiment of the application, the mixing into continuous reaction device
The retention time of solution is 60~150min, preferably 80~120min.It is continuous that residence time herein refers to that the T1 moment enters
Change the time difference that the mixed solution in reactor is discharged at the T2 moment with enamine compound B.
During above-mentioned continuous reaction, reacted as raw material mixed solution is continuously entered in continuous reaction device,
Reaction product is also discharged to serialization from continuous reaction device, is connected until the last part of the mixed solution as raw material enters
After continuousization reactor, to realize that the serialization of the reaction product of this part material is discharged, existing continuous production can be used
Product discharge mode in technique is discharged, as long as this serialization discharge mode has no adverse effects to product property.
In a kind of preferred embodiment, enamine compound B includes Part I and Part II, continuously by enamine compound B
The step of being discharged from continuous reaction device includes：Mixed solution is continuously introduced into continuous reaction device, and is carrying out enamine
Continuously the enamine compound B of Part I is discharged when changing reaction；Enamine with protection solvent to the Part II in reactor
Thing B enters line replacement continuously to discharge the enamine compound B of Part II；Preferably, the volume for protecting solvent is continuous reaction device
1.5~3 times of volume, more preferably 2 times.
In above preferred embodiment, when raw material is sent into continuous reaction device successively carries out reaction generation enamine compound B, after
Mixed solution into continuous reaction device can gradually discharge reaction product enamine compound B, and mixing when last part
Close after solution is sent into continuous reaction device, using forming the protection solvent of mixed solution to the anti-of the mixed solution of last part
Product is answered to enter line replacement, so as to which the serialization discharge to reaction product can be realized, and due to using protection solvent, to anti-
Answer the performance of product to have no adverse effect, thus improve reaction efficiency.
According to the difference of the enamine compound B of synthesis subsequent applications purpose, different post-processing steps can be carried out.One
In kind preferred embodiment, after enamine compound B is obtained, the synthetic method also includes：Cooling and stirring is carried out to enamine compound B
The step of；It is preferred that the step of cooling and stirring, includes：Cooling and stirring is carried out at a temperature of enamine compound B is placed in into 0~10 DEG C, is but stirred
The time mixed is 0.5~1.0h.
In above preferred embodiment, cooling and stirring is carried out to the enamine compound B continuously discharged so that enamine compound B cooling analysis
Go out, suction filtration obtains red-brown powder shape solid, convenient storage.And the original by the temperature control of cooling in the range of 0~10 DEG C
Because being that product crystallization in this temperature range is complete, while stirring is to accelerate cooling to promote to separate out, and specific mixing time can root
According to need to rationally be set, can be achieved to separate out in 0.5~1.0h.
In another typical embodiment of the application, there is provided a kind of synthetic method of aromatic aldehyde compound, should
Synthetic method includes synthesis enamine compound B；Enamine compound B is prepared into aromatic aldehyde compound C；Wherein, enamine compound B is used
Any of the above-described kind of synthetic method synthesis；Aldehyde compound C has the structural formula shown in formula (3)：
In formula (3), n=0~1, the X of diverse location is each independently selected from N, S, O or C；R1、R2、R3、R4It is each independent
Ground is selected from H, alkyl (alkyl), aryl (aryl), nitro (- NO2), halogen (halogen), ester group (Ester), cyano group
(Cyano) or trifluoromethyl, above-mentioned R1、R2、R3And R4It is identical or differ.
The synthetic method of above-mentioned aldehyde compound, by using enamine compound B is continuously synthesizing to, realize enamine reaction
Serialization, shorten the reaction time, improve reaction efficiency.Enamine compound B is prepared into aromatic aldehydes on this basis
Compound C, equally improve the combined coefficient of aldehyde compound.The continuous reaction is relative to traditional still reaction, one side
Reaction or terminating reaction can be stopped at any time according to actual conditions, post processing also can batch processing or merging treatment as needed, just
Just it is simple and direct；On the other hand largely solve because of the problem of temperature is high, the increase of system pressure, and consersion unit is difficult to bear,
Reduce the degree of danger of reaction.
In the synthetic method of above-mentioned aldehyde compound, the step of enamine compound B is prepared into aromatic aldehyde compound C, uses
Existing preparation method.In a kind of preferred embodiment of the application, enamine compound B is prepared into aromatic aldehyde compound C
The step of include：Oxidation processes are carried out to enamine intermediate B and obtain aldehyde compound C.Preferably, oxygen is carried out using oxidant
Change is handled, and more preferably oxidant is selected from sodium metaperiodate, sodium hypochlorite or hydrogen peroxide.
In above preferred embodiment, by being aoxidized to obtain corresponding aldehyde compound to enamine compound B.Specific oxygen
Agent uses the reagent with oxidative function, and above-mentioned oxidizability of oxidants is stronger, and source is easy to get.
Below the enamine compound of the application and the synthesis side of aldehyde compound are further illustrated with a kind of exemplary embodiments
Method.Specific synthetic route is as follows：
Step 1：
(1) specification of equipment：
250mL coil pipes, diameter 6mmCharging rate=2.0g/min；Retention time=120min, outlet back pressure 1.5
± 0.5MPa (coil pipe material is steel), circulate oil bath, 50ml plunger pumps, 5000g balances, 1.0L charging bottles.
(2) synthesis step of enamine compound：
Mixed solution：2- nitrotoleunes 13.7g, 10vol DMF and 41.1g (3.0g/g) N, N- is added into dnockout bottle
Dimethylformamide dimethyl acetal (DMF-DMA), shakes up stand-by.Bath temperature outside coil reactor is risen to 170 DEG C, to coil pipe
DMF is pumped into reactor, untill system back pressure is stable, mixed solution is connected on pump 1, retention time 120min is set, entered
Expect speed 1.90g/min dnockouts into coil reactor.The system for exporting out from coil reactor is directly entered in receiving bottle.
After mixed solution is all pumped into reactor, keep flow velocity constant, reaction is replaced with the DMF equivalent to two times of coil reactor volumes
System.Pump and the outer bath oil bath of reaction are closed after being replaced.Post processing, 0~10 DEG C of temperature control, is slowly added under stirring into system
10vol purified waters, 0.5~1.0h of insulated and stirred, production separate out, and suction filtration obtains red-brown powder shape solid 17.49g, yield 91%.
Step 2：
20~30 DEG C of temperature control, above-mentioned N, N- dimethyl -2- nitros-styrylamine, 6.33g/g are added into four-hole bottle
DMF, stir entirely molten to solid.8.23g/g purified waters, 1.99g/g sodium metaperiodates are added into another four-hole bottle, stirs lower heat up
To 40~55 DEG C, N, N- dimethyl -2- nitrostyrolene amine aqueous solutions is added dropwise.Raw material is tracked in 40~55 DEG C of insulation reaction HPLC
≤ 0.5 area %.System is cooled to 0~10 DEG C, 16.08g/g purified waters are added dropwise into system, is incubated 2~4h.System is taken out
Filter, water wash filter cake is purified with 2g/g, filter cake dries to obtain product 11.19g, yield 82%.
Above-described embodiment passes through the coil reactor of serialization using the methylbenzenes containing electron withdraw group as raw material
As consersion unit, with DMF dimethylacetal (DMF-DMA) enamine, prepared further across oxidation all kinds of
Aromatic aldehyde containing electron-withdrawing group, the reaction retention time is short, and reaction yield is high, and post-processing operation is simple, has good functional group
Compatibility.
The program passes through two-step reaction according to existing synthesis technique, you can prepares a series of substituted aromatic aldehydes chemical combination
Thing, not only separation yield is more than 80%；Process stabilizing after the substrate amplification of part, repeatability is strong, and wide application range of substrates.And
Cost is low, environmentally friendly, and providing one for all kinds of substituted aromatic aldehyde synthesis efficiently synthesizes approach.
Illustrate the beneficial effect of the application in conjunction with specific embodiments further below.It should be noted that following reality
Apply in example
Embodiment 1
(1) synthesis step of enamine compound：
Mixed solution：2- nitrotoleunes 13.7g, 10vol DMF and 41.1g (3.0g/g) N, N- is added into dnockout bottle
Dimethylformamide dimethyl acetal, shake up stand-by.
Bath temperature outside coil reactor is risen to 175 DEG C, DMF is pumped into coil reactor, system back pressure reaches
0.5MPa and it is stable untill, mixed solution is connected on pump, the mixed solution into coil reactor is set in reactor
Mean residence time be 120min, charging rate 1.90g/min dnockouts into coil reactor.Exported out from coil reactor
The system come is directly entered in receiving bottle.After mixed solution is all pumped into reactor, keep flow velocity constant, with equivalent to two times disks
The DMF displacement reaction systems of pipe reactor volume.Pump and the outer bath oil bath of reaction are closed after being replaced.Then reaction product is placed in
At 0 DEG C, and 10vol purified waters are slowly added into system under agitation, insulated and stirred 0.5h, product separates out, and filters
To red-brown powder shape solid (N, N- dimethyl -2- nitrostyrolenes amine) 17.49g, yield 91%.
(2) using sodium metaperiodate as oxidant, the product of step (1) is aoxidized, obtains aromatic aldehyde.
At a temperature of 20 DEG C, above-mentioned N, N- dimethyl -2- nitros-styrylamine, 6.33g/g are added into four-hole bottle
DMF, stir entirely molten to solid.8.23g/g purified waters, 1.99g/g sodium metaperiodates are added into another four-hole bottle, and in stirring bar
40 DEG C are warming up under part, N, N- dimethyl -2- nitrostyrolene amine aqueous solutions is then wherein added dropwise.After being added dropwise, system is put
In 40 DEG C of insulation reactions, and starting material left is tracked to by HPLC and (referred to less than≤0.5 area % in HPLC detections, raw material integration
Area accounts for the ratio of the system gross area).System is cooled to 0 DEG C, 16.08g/g purified waters are added dropwise into system, is incubated 2h.Body
System filters, and purifies water wash filter cake with 2g/g, filter cake dries to obtain product 11.19g, yield 82%.
Remaining embodiment utilizes the raw material in table 1, and reaction condition in table 2 to be prepared, and specifically prepares product warp
Nuclear-magnetism detects, and testing result is as follows：
Embodiment 1~6 and 10：
2- nitrobenzaldehydes1H NMR(500MHz,CDCl3)δ=10.43 (s, 1H), 8.13 (m, 1H), 7.96 (m, 1H),
7.80(m,2H)。
Embodiment 7：4- formoxyl cyanophenyls：1H NMR(500MHz,CDCl3) δ=10.10 (s, 1H), 8.01 (m, 2H),
7.86(m,2H)。
Embodiment 8：
The chloro- 2- nitrobenzaldehydes of 4-：1H NMR(500MHz,CDCl3) δ=10.39 (s, 1H), 8.11 (d, J=1.95Hz,
1H), 7.95 (d, J=8.25Hz, 1H), 7.77 (m, 1H).
Embodiment 9：
4- nitrobenzaldehydes：1H NMR(500MHz,CDCl3) δ=10.17 (s, 1H), 8.41 (d, J=1.95Hz, 1H),
7.95(m,2H),8.08(m,2H)。
Yield in the product yield and unit interval of the various embodiments described above is counted, statistical result is shown in Table 3.
Table 1：
| Initiation material A | Protect solvent | Oxidant | ||
| Embodiment 1 | 2- nitrotoleunes | DMF-DMA | DMF | Sodium metaperiodate |
| Embodiment 2 | 2- nitrotoleunes | DMF-DMA | DMF | Sodium metaperiodate |
| Embodiment 3 | 2- nitrotoleunes | DMF-DMA | CH3CN | Sodium metaperiodate |
| Embodiment 4 | 2- nitrotoleunes | DMF-DMA | DMAc | Sodium metaperiodate |
| Embodiment 5 | 2- nitrotoleunes | DMF-DMA | NMP | Sodium metaperiodate |
| Embodiment 6 | 2- nitrotoleunes | DMF-DMA | DMF | Sodium metaperiodate |
| Embodiment 7 | 4- cyano group toluene | DMF-DMA | CH3CN | Hydrogen peroxide |
| Embodiment 8 | 2- methyl -4- chloronitrobenzenes | DMF-DMA | DMAc | Sodium hypochlorite |
| Embodiment 9 | 4- nitrotoleunes | DMF-DMA | NMP | Sodium metaperiodate |
| Embodiment 10 | 2- nitrotoleunes | DMF-DMA | DMF | Sodium metaperiodate |
Table 2：
Table 3：
Comparative example
It is identical with the raw material of embodiment 1, reacted using tank reactor of the prior art, using 1mol raw materials as
Standard, when the reaction time is identical with the total time of embodiment 1, its product yield is 50%, and the yield in the unit interval is 3.97g/
h.It can be seen that embodiments herein has higher yield from above-described embodiment 1 to 9 and the effect data of comparative example, and
Yield in unit interval also significantly improves.
From above-described embodiment 1~6 as can be seen that when the substrate for participating in reaction is identical, residence time and heating-up temperature are right
The yield of product is relatively large impact, but the yield in the yield and unit interval for corresponding to product in the range of the application optimum condition
It is higher.
The active different of differential responses substrate are can be seen that from embodiment 1~6 from the comparison of embodiment 7~9, reaction is received
Rate also has difference, the yield in the unit interval also with reaction substrate difference and there is some difference.
As can be seen from the above description, the above embodiments of the present invention realize following technique effect：
(1) by using serialization equipment, the first benzene and its derivative of electron withdraw group is contained as raw material using ortho position, and N,
Dinethylformamide dimethylacetal (DMF-DMA) carries out continuous reaction and realizes enamine.
(2) the present invention program first step enamine step, the reaction time is short, and product yield is high, and post-processing operation is simple, sum total
It is low into route cost, it is environmentally friendly, provide one for all kinds of substituted aromatic aldehyde synthesis and efficiently synthesize approach.
(3) this patent synthetic method is versatile, fragrant for the aryl containing electron rich or electron deficient substituent or heteroaryl
The synthesis of aldehyde, higher yield can be obtained, there is good functional group compatibility.
(4) use of serialization equipment, has saved human cost, is beneficial to industry's enlarging production.
(5) use of serialization equipment, is largely solved because temperature is high, the increase of system pressure, and consersion unit is difficult
The problem of to bear, reaction degree of danger reduce.
(6) the relatively conventional reaction of the continuous reaction, reaction or terminating reaction can be stopped at any time according to actual conditions, after
Processing also can batch processing or merging treatment as needed, facilitate simple and direct.
The preferred embodiments of the present invention are the foregoing is only, are not intended to limit the invention, for the skill of this area
For art personnel, the present invention can have various modifications and variations.Within the spirit and principles of the invention, that is made any repaiies
Change, equivalent substitution, improvement etc., should be included in the scope of the protection.
Claims (10)
1. a kind of synthetic method of enamine compound, it is characterised in that the synthetic method includes：
Initiation material A and N,N-dimethylformamide dimethylacetal are formed into mixed solution；
The mixed solution is continuously introduced into progress enamine reaction in continuous reaction device, obtains enamine compound B, and entering
The row enamine continuously discharges the enamine compound B when reacting from the continuous reaction device；
Wherein, the initiation material A has the structural formula shown in formula (1)：
The enamine compound B has the structural formula shown in formula (2)：
In above-mentioned formula (1) and formula (2), n=0~1, the X of diverse location is each independently N, S, O or C；R1、R2、R3And R4Each
Independently selected from H, alkyl, aryl, nitro, halogen, ester group, cyano group or trifluoromethyl, the R1、R2、R3And R4Identical or not phase
Together.
2. synthetic method according to claim 1, it is characterised in that anti-the mixed solution is sent into the serialization
Before the step of answering device to carry out enamine reaction, the synthetic method also includes：The continuous reaction device is heated to 165~
180 DEG C, preferably 170~175 DEG C the step of；The heating is carried out preferably by the way of oil bath, more preferably using recycle oil
The mode of bath is carried out；It is further preferred that the continuous reaction device is coil reactor.
3. synthetic method according to claim 2, it is characterised in that after the heating stepses, and by the mixing
Solution was sent into before the step of continuous reaction device carries out enamine reaction, and the synthetic method also includes：170~
At a temperature of 175 DEG C, protection solvent is sent into the continuous reaction device, and makes the pressure in the continuous reaction device be
1.0~1.5MPa；
Preferably, the protection solvent is selected from dimethylformamide, acetonitrile, dimethyl acetamide or 1-METHYLPYRROLIDONE.
4. synthetic method according to any one of claim 1 to 3, it is characterised in that according to 1.50~3.5g/min's
Charging rate, the mixed solution is preferably continuously introduced into the continuous reaction according to 1.8~2.5g/min charging rate
The enamine reaction is carried out in device, obtains the enamine compound B.
5. synthetic method according to any one of claim 1 to 3, it is characterised in that enter the continuous reaction device
In residence time of the mixed solution be 60~150min, preferably 80~120min.
6. synthetic method according to any one of claim 1 to 3, it is characterised in that the enamine compound B includes first
Part and Part II, the step of continuously discharging the enamine compound B from the continuous reaction device, include：
The mixed solution is continuously introduced into the continuous reaction device, and when carrying out the enamine reaction continuously by institute
State the enamine compound B discharges of Part I；
Line replacement is entered to the enamine compound B of the Part II in the reactor with protection solvent continuously to discharge described the
The enamine compound B of two parts；
Preferably, the protection solvent is selected from dimethylformamide, acetonitrile, dimethyl acetamide or 1-METHYLPYRROLIDONE.
7. synthetic method according to claim 6, it is characterised in that after the enamine compound B is obtained, the synthesis
Method also includes：
The step of cooling and stirring is carried out to the enamine compound B；
It is preferred that the step of cooling and stirring, includes：Cooling is carried out at a temperature of the enamine compound B is placed in into 0~10 DEG C to stir
Mix, the time of the cooling and stirring is 0.5~1.0h so that enamine compound B crystallizations separate out.
8. a kind of synthetic method of aromatic aldehyde compound, it is characterised in that the synthetic method includes：
Synthesize enamine compound B；And
The enamine compound B is prepared into aldehyde compound C；
Wherein, the enamine compound B is using the synthetic method synthesis any one of claim 1 to 7, the aldehydes chemical combination
Thing C has the structural formula shown in formula (3)：
In formula (3), n=0~1, the X of diverse location is each independently selected from N, S, O or C；R1、R2、R3And R4Select independently of one another
From H, alkyl, aryl, nitro, halogen, ester group, cyano group or trifluoromethyl, the R1、R2、R3And R4It is identical or differ.
9. synthetic method according to claim 8, it is characterised in that the enamine compound B is prepared into aldehyde compound C
The step of include：
Oxidation processes are carried out to the enamine intermediate B, obtain the aldehyde compound C.
10. synthetic method according to claim 9, it is characterised in that entered using oxidant to the enamine intermediate B
The row oxidation processes, preferably described oxidant are selected from sodium metaperiodate, sodium hypochlorite or hydrogen peroxide.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109879843A (en) * | 2019-02-11 | 2019-06-14 | 常州制药厂有限公司 | A kind of intermediate of Ba Luoshawei and the preparation method and application thereof |
| CN111662263A (en) * | 2019-03-07 | 2020-09-15 | 广东东阳光药业有限公司 | Preparation method of pyrone compound |
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| US9597333B2 (en) * | 2015-03-06 | 2017-03-21 | Hoffmann-La Roche Inc. | Benzazepine dicarboxamide compounds |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109879843A (en) * | 2019-02-11 | 2019-06-14 | 常州制药厂有限公司 | A kind of intermediate of Ba Luoshawei and the preparation method and application thereof |
| CN111662263A (en) * | 2019-03-07 | 2020-09-15 | 广东东阳光药业有限公司 | Preparation method of pyrone compound |
| CN111662263B (en) * | 2019-03-07 | 2022-08-12 | 广东东阳光药业有限公司 | Preparation method of pyrone compound |
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