CN110078637A - The preparation process of diazomethane - Google Patents
The preparation process of diazomethane Download PDFInfo
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- CN110078637A CN110078637A CN201910425970.9A CN201910425970A CN110078637A CN 110078637 A CN110078637 A CN 110078637A CN 201910425970 A CN201910425970 A CN 201910425970A CN 110078637 A CN110078637 A CN 110078637A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C245/00—Compounds containing chains of at least two nitrogen atoms with at least one nitrogen-to-nitrogen multiple bond
- C07C245/12—Diazo compounds, i.e. compounds having the free valencies of >N2 groups attached to the same carbon atom
- C07C245/14—Diazo compounds, i.e. compounds having the free valencies of >N2 groups attached to the same carbon atom having diazo groups bound to acyclic carbon atoms of a carbon skeleton
- C07C245/16—Diazomethane
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C273/18—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas
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Abstract
The present invention provides a kind of preparation processes of diazomethane.The preparation process includes: step S1, and N- methylurea raw material is made continuously to prepare the first product system containing N-methyl-N-nitrosourea in flow reactor；Step S2 carries out continuous extraction, back extraction to the first product system, obtains N-methyl-N-nitrosourea solution；Step S3 makes N-methyl-N-nitrosourea solution and aqueous slkali carry out successive reaction in flow reactor, obtains the second product system containing diazomethane；And step S4, continuous liquid separation, freezing water removal are carried out to the second product system, obtain diazomethane.Use N- methylurea for raw material, it is reacted and is post-processed using Total continuity and obtain the 2- methyltetrahydrofuran solution of MNU, then it directly reuses Total continuity reaction and post-processing obtains anhydrous diazomethane solution, it is removed water using refrigerating process, it avoids using expensive semi-permeable membrane or Liquid liquid Separation device, therefore cost is cheaper.
Description
Technical field
The present invention relates to diazomethane preparation fields, in particular to a kind of preparation process of diazomethane.
Background technique
Diazomethane is that one kind has strong and stimulating smell yellow gas, is dissolved in ethyl alcohol and ether, is heated, meets fire, rub, hit
It hits and will lead to explosion.Its property is very active, and a plurality of types of reactions can occur, and is reagent in organic synthesis, mainly
For carboxyl, phenolic hydroxyl group, enol etc. methylation reaction, prepare homologation in diazo-ketones for ketone and carboxylic acid, 1,3 even
Polar ring addition reaction etc..Also, because its molecular weight is lower, the reaction that diazomethane participates in have preferable atomic efficiency and
Nitrogen is unique by-product after reaction.
But since its carcinogenicity and toxicity are stronger, and easily explode, the preparation and control for leading to diazomethane are in work
It is extremely difficult in industry production.The scale of most of diazomethane applications is at laboratory level.
The synthetic route of diazomethane mainly has following three:
This three routes are to generate diazomethane by N- methyl-N-nitroso class precursor compound and highly basic reaction.It examines
Consider availability and the pot-life of such compound, generally uses these three compound conducts of Diazald, MNU and MNNU
Precursor carries out the preparation of diazomethane.But the toxicity due to MNNU, irritation, easily it is carcinogenic and to mutability be three it is precursor
It closes and most by force, generallys use the preparation that Diazald and MNU carries out diazomethane in object at present.The diazomethane of batch preparation is anti-
Only excessive concentration is exploded, and is needed to dilute or be passed through in ether by nitrogen and is diluted to solution and reuses.
Aerojet-General Corporation (existing AMPAC Fine Chemicals) is earliest development diazomethane
The company of large-scale production and application, possesses that serialization prepares diazomethane (US5854405B2) and batch prepares diazomethane
(EP0916649) patent.Its serialization route does starting material and sodium nitrite/hydrochloric acid system using nontoxic N- methylurea
The diethyl ether solution that successive reaction prepares diazomethane precursor MNU is carried out, then generates diazomethane with the reactant aqueous solution of alkali
And it dissolves in organic solvent.Although its MNU's is prepared as successive reaction, the preparation of its diazomethane is actually to use three
The preparation that a reaction kettle (3000L) carries out, substantially or batch is reacted.The diazomethane that such mode is prepared may divide
A small amount of moisture content can be introduced during liquid, is led to not for the subsequent reactions to moisture sensitivity.
To obtain dry diazomethane gas, Phoenix Chemicals Ltd. has developed a kind of pilot-scale preparation
Use Diazald as the technique (Org.Process Res.Dev.2002,6,884.) for preparing diazomethane gas of precursor.
The device can produce 60 tons of diazomethane per year.
My company, which also once had developed, uses Diazald continuously to prepare the technique of diazomethane gas simultaneously as precursor compound
In feather weight production (CN101844063B).
Three above example is the example that current diazomethane carries out industrial applications, since diazomethane batch is extensive
The risk of preparation, the research and development for being continuously synthesizing to technology also have received widespread attention.
Rossi E. et al., which is reported, prepares diazomethane solution by raw material of NMU using special heart-shaped coil pipe, without
Separation buck is mutually passed directly into the esterification that reaction system carries out carboxylic acid.But this method is only applicable to water insensitive reactant
It is (Organic Process Research&Development, 2017,16 (5): 1146-1149.).Carlson E. et al.
It reports and prepares diazomethane gas by raw material of Diazald using reaction kettle, be passed directly into olefin substrate solution progress ring and add
At reaction.Maurya R.A. et al. reports anti-using the binary channels coil pipe with dimethyl silicone polymer (PMDS) semi-permeable membrane
Answer device reacted using Diazald as raw material preparing and separate diazomethane gas (Synthetic Communications,
2016,46(1):55-62.)。
Mastronardi F et al. reports tube-in-tube (the tube in for using AF-2400 material as semi-permeable membrane
Tube) using Diazald as raw material carry out technique that diazomethane continuously prepares and react (Organic Letters, 2013,15
(21):5590-5593.).Dallinger D. et al. equally also uses AF-2400 material as pipe (tube in the bottle of semi-permeable membrane
In flask) using Diazald as raw material carry out diazomethane continuously prepare and react (Journal of Organic
Chemistry,2016,81(14):5814-5823.).Lehmann H. et al. is using PFA coil pipe and with semi-transparent membrane structure
Liquid liquid Separation device realizes the two step Total continuities reaction of diazomethane precursor MNU and diazomethane using N- methylurea as raw material
(Green Chemistry,2016,19(6),1449.)。
It can be seen that the technique for preparing diazomethane in the prior art is primarily present following problems:
(1) due to the toxicity and explosion hazard of diazomethane itself when batch preparation amplification produces, security risk is very big, mesh
It is preceding to prepare diazomethane applied in industrial production almost without batch.
(2) continuous preparation needs to carry out the separation of diazomethane and water phase using expensive semi-permeable membrane or Liquid liquid Separation device
To carry out the subsequent reactions to moisture sensitivity, cause equipment investment big, production cost is higher.
Summary of the invention
The main purpose of the present invention is to provide a kind of preparation processes of diazomethane, in the prior art continuous to solve
Technique prepares the high problem of diazomethane equipment cost.
To achieve the goals above, according to an aspect of the invention, there is provided a kind of preparation process of diazomethane, is somebody's turn to do
Preparation process includes: step S1, prepares N- methylurea raw material continuously in flow reactor containing N-methyl-N-nitrosourea
The first product system；Step S2 carries out continuous extraction, back extraction to the first product system, it is molten to obtain N-methyl-N-nitrosourea
Liquid；Step S3 makes N-methyl-N-nitrosourea solution and aqueous slkali carry out successive reaction in flow reactor, is contained
Second product system of diazomethane；And step S4, continuous liquid separation, freezing water removal are carried out to the second product system, obtain weight
N-formyl sarcolysine alkane.
Further, above-mentioned steps S1 includes: that acid, solvent, sodium nitrite and N- methylurea are continuously introduced into successive reaction
It is reacted in device to prepare the first product system.
Further, above-mentioned acid is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, p-methyl benzenesulfonic acid and methanesulfonic acid
In any one, solvent includes water and organic solvent, and organic solvent is selected from chloroform, methylene chloride, ethyl acetate, tetrahydro furan
It mutters, any one or more in 2- methyltetrahydrofuran, benzene, toluene and dimethylbenzene.
Further, the reaction temperature of above-mentioned steps S1 be 0~120 DEG C, preferably 10~30 DEG C, preferably N- methylurea,
The molar ratio of sodium nitrite and acid is 1:1.5~2.5:1~2, and the volume ratio of water and organic solvent is 1:3~5 in preferred solvent；
The retention time of preferred steps S1 is 5~30min.
Further, above-mentioned flow reactor is continuous coil reactor.
Further, above-mentioned steps S2 include: by the first product system be continuously introduced into the first extraction column using extractant into
Row extraction, obtains extract liquor；Extract liquor is continuously introduced into the second extraction column to be stripped using alkaline stripping workshop, obtains N- first
Base-N- nitroso ureas solution, wherein extractant is selected from chloroform, methylene chloride, ethyl acetate, tetrahydrofuran, 2- methyl tetrahydro furan
It mutters, any one or more in benzene, toluene and dimethylbenzene, alkaline stripping workshop is selected from triethylamine, diisopropyl ethyl amine, uncle
Fourth ammonium, 1,4- diazabicylo, 11 carbon -7- alkene of 1,8- diazabicylo, KOH, NaOH, K2CO3、Na2CO3、NaHCO3、
Cs2CO3、KHCO3, the aqueous solution of any one in sodium acetate and potassium acetate, preferably the pH value of extraction system is in stripping process
5~7.
Further, the lye of above-mentioned steps S3 is potassium hydroxide solution, sodium hydroxide solution, lithium hydroxide solution, carbon
Sour potassium solution, sodium carbonate liquor, potassium bicarbonate solution or sodium bicarbonate solution.
Further, the reaction temperature of above-mentioned steps S3 be -20~100 DEG C, preferably 0~30 DEG C, preferred steps S3's
Retention time is 30~150 seconds.
Further, above-mentioned steps S4 includes: and the second product system is continuously introduced into third extraction column to carry out liquid separation processing,
Obtain upper layer overflow organic solution；Carrying out freezing processing to upper layer overflow organic solution keeps water-setting therein solid, obtains diazonium first
The organic solution of alkane.
Further, above-mentioned freezing processing include: by upper layer overflow organic solution be continuously introduced into successive reaction kettle and
It is cooled at -30~-50 DEG C 40~80min of holding under stirring condition, the organic solution of diazomethane is from the upper of successive reaction kettle
Layer overflow and go out, the overflow port of preferably successive reaction kettle is provided with strainer.
Apply the technical scheme of the present invention, use safe and non-toxic N- methylurea for raw material, using Total continuity reaction and after
Processing obtains the 2- methyltetrahydrofuran solution of diazomethane precursor MNU, then directly reuses Total continuity reaction and post-processing
Anhydrous diazomethane solution is obtained, wherein being removed water using refrigerating process, is avoided using expensive semi-permeable membrane or liquid liquid point
From device, therefore the preparation process is compared with existing batch diazomethane preparation process, more safely controllable；With it is existing continuous
Diazomethane preparation process compares, and cost is cheaper.
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.
As the application background technique is analyzed, diazomethane is continuously prepared in the prior art and is needed using the semi-transparent of valuableness
Film or Liquid liquid Separation device carry out the separation of diazomethane and water phase to carry out leading to equipment to the subsequent reactions of moisture sensitivity
Investment is big, and production cost is higher, and in order to solve this problem, this application provides a kind of preparation processes of diazomethane.In this Shen
Please be in a kind of typical embodiment, which includes: step S1, and N- methylurea raw material is made to exist
The first product system containing N-methyl-N-nitrosourea is continuously prepared in flow reactor；Step S2, to the first product system into
Row continuous extraction, back extraction, obtain N-methyl-N-nitrosourea solution；Step S3 makes N-methyl-N-nitrosourea solution and alkali
Solution carries out successive reaction in flow reactor, obtains the second product system containing diazomethane；And step S4, to
Two product systems carry out continuous liquid separation, freezing water removal, obtain diazomethane.
The above-mentioned preparation process of the application uses safe and non-toxic N- methylurea for raw material, uses Total continuity reaction and rear place
Reason obtains the 2- methyltetrahydrofuran solution of diazomethane precursor MNU, then directly reuses Total continuity reaction and post-processes
To anhydrous diazomethane solution, wherein being removed water using refrigerating process, avoid using expensive semi-permeable membrane or Liquid liquid Separation
Device, therefore the preparation process is compared with existing batch diazomethane preparation process, it is more safely controllable；With existing continuous weight
N-formyl sarcolysine alkane preparation process compares, and cost is cheaper.Specifically:
The preparation process of the application removes moisture film or equipment without using expensive, can obtain water content pole with lower cost
Low diazomethane solution, can directly with to water sensitive material or system react；
Using cheap, avirulent N- methylurea does starting material, and the MNU being continuously prepared need not be isolated and purified
The preparation that the continuous diazomethane of second step can directly be carried out reduces the wind for contacting easily carcinogenic, easy allergy material MNU
Danger, and used for reaction of the Diazald as diazomethane precursor relative to most of reactions, cost is lower, and the three wastes are more
It is few；
The distinctive attribute of serialization equipment (reaction system is small, and rate of heat exchange is much higher than batch equipment) makes reaction condition i.e.
Just more acutely, but safety is also above batch reaction；
Continuous process particular attribute produces almost without enlarge-effect, industrialization is suitble to reappear lab scale yield.
The reaction mechanism for preparing MNU using N- methylurea for raw material of the application is same as the prior art, preferably above-mentioned step
Rapid S1 includes: that acid, solvent, sodium nitrite and N- methylurea are continuously introduced into flow reactor to react to prepare first and produce
Objects system.Above-mentioned N- methylurea is dissolved in water and sour (being added in a manner of aqueous solution) then in advance by acid, water and N- methyl
The mixed solution of urea is continuously introduced into, and sodium nitrite is also to be continuously introduced into the state of aqueous solution, and above-mentioned solvent is contained for molten
Solve the solvent of sodium nitrite and N- methylurea.
Acid, solvent for the application can be selected in the prior art using N- methylurea as the common acid of raw material and solvent,
In order to better adapt to successive reaction, preferably it is above-mentioned acid for selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, to toluene sulphur
Acid and any one in methanesulfonic acid, solvent include water and organic solvent, which is selected from chloroform, methylene chloride, acetic acid
Any one or more in ethyl ester, tetrahydrofuran, 2- methyltetrahydrofuran, benzene, toluene and dimethylbenzene.Include simultaneously in solvent
Water and organic solvent, the two form layered effect, are conducive to product and separate from reaction system.
The above-mentioned reaction temperature for preparing MNU can refer to the prior art, preferably the reaction temperature of above-mentioned steps S1 be 0~
120 DEG C, further preferably 10~30 DEG C, to guarantee the stability of reaction.In addition, in order to improve conversion ratio and be further ensured that
Safety, the preferably molar ratio of N- methylurea, sodium nitrite and acid are 1:1.5~2.5:1~2, by the original for adjusting each material
Proportion or pump speed are expected to realize above-mentioned molar ratio；The volume ratio of water and organic solvent is 1:3~5 in preferred solvent, is produced with improving
Object separative efficiency.In addition, improving the conversion ratio of material, the preferably reservation of above-mentioned steps S1 while improving reaction efficiency
Time is 5~30min.
Flow reactor employed in above-mentioned preparation process can use tubular type successive reaction commonly used in the prior art
Device or autoclave flow reactor, wherein not needing configuration semi-permeable membrane, preferably above-mentioned flow reactor is continuous coil reactor.
In a kind of embodiment of the application, above-mentioned steps S2 includes: that the first product system is continuously introduced into the first extraction column
It is extracted using extractant, obtains extract liquor；Extract liquor is continuously introduced into the second extraction column to carry out using alkaline stripping workshop
Back extraction, obtains N-methyl-N-nitrosourea solution, wherein extractant is selected from chloroform, methylene chloride, ethyl acetate, tetrahydro furan
It mutters, any one or more in 2- methyltetrahydrofuran, benzene, toluene and dimethylbenzene, alkaline stripping workshop is selected from triethylamine, two
Diisopropylethylamine, tertiary fourth ammonium, 1,4- diazabicylo (DABCO), 11 carbon -7- alkene (DBU) of 1,8- diazabicylo, KOH,
NaOH、K2CO3、Na2CO3、NaHCO3、Cs2CO3、KHCO3, the aqueous solution of any one in sodium acetate and potassium acetate, preferably instead
The pH value of extraction system is 5~7 during extraction.Continuous extraction separation, benefit are realized to the first product system by the first extraction column
Industrialized production is realized with its continuity, is not needed using expensive Liquid liquid Separation device.After extraction and separation, utilize
Lye is stripped, and the high efficiente callback to MNU is realized.
The application is also, the preferably lye of above-mentioned steps S3 identical with the prior art by the principle that MNU prepares diazomethane
For potassium hydroxide solution, sodium hydroxide solution, lithium hydroxide solution, solution of potassium carbonate, sodium carbonate liquor, potassium bicarbonate solution or
Sodium bicarbonate solution.
The reaction temperature of above-mentioned steps S3 can also refer to the prior art, for example the reaction temperature of above-mentioned steps S3 is -20
~100 DEG C, preferably 0~30 DEG C, in order to improve reaction efficiency, the retention time of preferred steps S3 is 30~150 seconds.
After completing above-mentioned reaction, need to isolate moisture therein to be suitable for the reaction of moisture-sensitive, it is preferably above-mentioned
Step S4 includes: that the second product system is continuously introduced into third extraction column to carry out liquid separation processing, obtains upper layer overflow organic solution；
Carrying out freezing processing to upper layer overflow organic solution keeps water-setting therein solid, obtains the organic solution of diazomethane.Utilizing extraction
After taking column to carry out liquid separation processing, by most of moisture in the second product system, then not using the freezing point of water and diazomethane
Consolidate water-setting therein with freezing processing is carried out, and then obtains the organic solution of diazomethane.
In a kind of embodiment of the application, above-mentioned freezing processing includes: to be continuously introduced into upper layer overflow organic solution continuously
It in reaction kettle and is cooled at -30~-50 DEG C under agitation and keeps 40~80min, the organic solution of diazomethane is from even
Continue the upper layer overflow of reaction kettle and go out, the overflow port of preferably successive reaction kettle is provided with strainer.It is freezed under agitation,
Be conducive to being sufficiently separated for moisture and organic matter；Additionally, due to being continuously introduced into for upper layer overflow organic solution, therefore freezing processing
The organic solution of diazomethane can voluntarily be gone out by overflow in successive reaction kettle afterwards.In order to avoid carrying ice bits in overflow secretly,
Strainer is arranged to intercept to ice bits in overflow port, and then improves water rem oval.
Below with reference to embodiment and comparative example, the beneficial effect of the application is further illustrated.
Embodiment 1
Configuration dnockout system A: 100g N- methylurea is added in dnockout bottle A, and 100ml water is added, is slowly added to 266g
37% hydrochloric acid, stirring to dissolution.
Configuration dnockout system B: 1750mL 2-Me-THF is added in dnockout bottle B.
Configuration dnockout system C: 140g sodium nitrite is added in dnockout bottle C, and 400ml water, stirring to dissolution is added.
Configuration dnockout system D: 600mL 2-Me-THF is added in dnockout bottle D.
Configuration dnockout system E: saleratus is added in dnockout bottle E, and 654ml water, stirring to dissolution is added.
Equipment prepares: about 500ml tap water being added into the first extraction column, until at pillar height half；Into the second extraction column
About 200ml potassium bicarbonate aqueous solution is added, until at the 1/4 of pillar height.
Tap water will be made in 200ml the first tetrafluoro coil reactor to 23~27 DEG C (25 DEG C of target temperature), temperature is steady
After determining 10min, dnockout can be carried out.
Dnockout: dnockout bottle A, dnockout bottle B and dnockout bottle C are connected with the four-way of the first tetrafluoro coil reactor of 200ml
And dnockout pumps A, dnockout pumps B and dnockout pumps C are set on respective connecting line, dnockout pumps A, dnockout pumps B and dnockout pumps C are opened,
And controlling each self-flow rate is respectively 3.57g/min；11.42g/min；4.11g/min, three strands of materials are converged at four-way into
One tetrafluoro coil reactor is reacted, retention time 10min.
Extraction: the first tetrafluoro coil reactor is connected with the first extraction column upper end, by dnockout bottle D and the first extraction column lower end
It is connected, and dnockout pumps D is set on connecting line, starts dnockout pumps D for 600mL 2-Me-THF by the first extraction column lower end
Be pumped into and be continuously stripped, dnockout pumps D flow velocity are as follows: 3.95g/min, the lower end of the first extraction column release water phase, upper end it is organic
Mutually enter the second extraction column, the effective liquid holdup~400ml, theoretical RT=30min of the first extraction column are controlled in extraction process.
Back extraction: the organic phase that the first extraction column upper end comes out is pumped by the lower end of the second extraction column, by dnockout bottle E and second
The upper end of extraction column is connected and dnockout pumps E is arranged on connecting line, starts dnockout pumps E for potassium bicarbonate solution (163g carbonic acid
Hydrogen potassium+654mL water) it is continuously pumped between the continuous tune pH to 5~7 of the second extraction column progress, the flow velocity of dnockout pumps E are as follows: 4.0ml/
Min, lower end release water phase.Liquid holdup~400ml of the second extraction column, theoretical RT=20min are controlled in stripping process.
Rewinding: receive the organic phase of the second extraction column, and the yield for measuring QNMR is 81% and pH value is 6.4, wherein surveying
Method is determined to sample using after deuterated chloroform dissolution, and mesitylene is added and does internal standard compound, then carries out nmr analysis.
Configure dnockout system F: by the 2- methyltetrahydrofuran solution of organic phase N- nitroso-N-methylurea obtained above
It is added in dnockout bottle F.
Configure dnockout system G: potassium hydroxide is soluble in water, and stirring to solid is dissolved, and is configured to the solution of 15%wt.
Equipment prepares: tap water is added into third extraction column, until the half of pillar height.
Part potassium hydroxide solution is squeezed into 20mL the second tetrafluoro coil reactor, until being full of hydrogen at two stock material convergences
Second tetrafluoro coil reactor is placed in ice-water bath by potassium oxide solution, and 0~5 DEG C of temperature control.
Dnockout: dnockout bottle F, dnockout bottle G are connected and respective company with the threeway of the second tetrafluoro coil reactor of 200ml
The setting of adapter tube road dnockout pumps F, dnockout pumps G, open dnockout pumps F, dnockout pumps G, and controlling self-flow rate is respectively 14.75g/min；
5.25g/min, two strands of materials converge at threeway, are reacted subsequently into 20ml the second tetrafluoro coil reactor, when reservation
Between 1min.
Liquid separation is with water removal: the second tetrafluoro coil reactor is connected with third extraction column upper end makes the second tetrafluoro coil reactor
The second product system carry out the second extraction column in liquid separation, stirred in the CSTR of -40 DEG C of yellow organic phase overflow entrance at the middle and upper levels
1h freezing water removal is mixed, water is frozen into ice at low temperature to separate with system, and the organic solution of upper layer diazomethane is passed through with filter
The overflow port overflow of net, wherein using nuclear-magnetism verifying products therefrom for diazomethane, using karl Fischer (KF) moisture determination instrument
Moisture content is detected, measures HPLC external standard, yield 57% after deriving using excessive benzoic acid.Obtained diazomethane solution can be direct
Overflow enters the preparation that mixed anhydride solution carries out diazo-ketones.
Embodiment 2
Difference from Example 1 is, -50 DEG C of the yellow organic phase overflow entrance at the middle and upper levels of liquid separation and removal process
Stir 40min freezing water removal in CSTR, water is frozen into ice at low temperature to separating with system, upper layer diazomethane it is organic molten
Liquid passes through the overflow port overflow with strainer.
Embodiment 3
Difference from Example 1 is, -30 DEG C of the yellow organic phase overflow entrance at the middle and upper levels of liquid separation and removal process
Stir 80min freezing water removal in CSTR, water is frozen into ice at low temperature to separating with system, upper layer diazomethane it is organic molten
Liquid passes through the overflow port overflow with strainer.
Embodiment 4
Difference from Example 1 is that the acid in dnockout bottle A is 162g acetic acid, dnockout pumps A dnockout speed 2.77g/
min。
Embodiment 5
Difference from Example 1 is that the acid in dnockout bottle A is to obtain using the 464g p-methyl benzenesulfonic acid that 693g water dissolves
The acid solution arrived, dnockout pumps A dnockout speed 9.63g/min.
Embodiment 6
Difference from Example 1 is, is the methylene chloride of 1750mL in dnockout bottle B, and the solvent in dnockout bottle D is
388mL methylene chloride.
Embodiment 7
Difference from Example 1 is, is toluene in dnockout bottle B, and the solvent in dnockout bottle D is toluene.
Embodiment 8
Difference from Example 1 is, is the ethyl acetate of 1750mL in dnockout bottle B, and the solvent in dnockout bottle D is
The ethyl acetate of 573ml.
Embodiment 9
Difference from Example 1 is that the temperature of the first tetrafluoro coil reactor is 50 DEG C or so.
Embodiment 10
Difference from Example 1 is that the temperature of the first tetrafluoro coil reactor is 120 DEG C or so.
Embodiment 11
Difference from Example 1 is that the temperature of the first tetrafluoro coil reactor is 10 DEG C or so.
Embodiment 12
Difference from Example 1 is that the temperature of the first tetrafluoro coil reactor is 0 DEG C or so.
Embodiment 13
Difference from Example 1 is, is 5min in the first tetrafluoro coil reactor retention time.
Embodiment 14
Difference from Example 1 is, is 30min in the first tetrafluoro coil reactor retention time.
Embodiment 15
Difference from Example 1 is that the alkaline solution in dnockout pumps E is triethylamine.
Embodiment 16
Difference from Example 1 is that the alkaline solution in dnockout pumps E is DBU.
Embodiment 17
Difference from Example 1 is that the alkaline solution in dnockout pumps E is potassium hydroxide.
Embodiment 18
Difference from Example 1 is that the alkaline solution in dnockout pumps E is potassium carbonate.
Embodiment 19
Difference from Example 1 is that the temperature of the second tetrafluoro coil reactor is -20 DEG C or so, and retention time is
150 seconds.
Embodiment 20
Difference from Example 1 is that the temperature of the second tetrafluoro coil reactor is 30 DEG C or so.
Embodiment 21
Difference from Example 1 is that the temperature of the second tetrafluoro coil reactor is 100 DEG C or so, and retention time is
30 seconds.
Embodiment 22
Difference from Example 1 is that the temperature of the second tetrafluoro coil reactor is -10 DEG C or so, and retention time is
180 seconds.
Embodiment 23
Difference from Example 1 is, joined the hydrochloric acid of 200g 37% in dnockout bottle A.
Embodiment 24
Difference from Example 1 is, joined the hydrochloric acid of 333g 37% in dnockout bottle A.
Embodiment 25
Difference from Example 1 is, joined the hydrochloric acid of 380g 37% in dnockout bottle A.
Embodiment 26
Difference from Example 1 is that the sodium nitrite dosage 93.1g in dnockout bottle C, water consumption is still 400g, is beaten
The dnockout speed of material pump C is 3.82g/min.
Embodiment 27
Difference from Example 1 is that the sodium nitrite dosage 186.3g in dnockout bottle C, water consumption is still 400g, is beaten
The dnockout speed of material pump C is 4.38g/min.
Embodiment 28
Difference from Example 1 is that dnockout system B is 1500mL 2-MeTHF, dnockout pumps A, dnockout pumps B and dnockout
Pumping each self-flow rate of C is respectively 3.88g/min；10.73g/min；4.49g/min.
Embodiment 29
Difference from Example 1 is that dnockout system B is 2500mL 2-MeTHF, dnockout pumps A, dnockout pumps B and dnockout
Pumping each self-flow rate of C is respectively 2.82g/min；13.01g/min；3.27g/min.
Using the method for embodiment 1, to the yield of the MNU in the various embodiments described above, the yield of diazomethane and wherein
Moisture content be measured, measurement result is shown in Table 1.
Table 1
| MNU yield (%) | Diazomethane yield (%) | Moisture content (ppm) | |
| Embodiment 1 | 81 | 57 | 453 |
| Embodiment 2 | 81 | 57 | 501 |
| Embodiment 3 | 81 | 57 | 700 |
| Embodiment 4 | 65 | 54 | 429 |
| Embodiment 5 | 42 | 55 | 490 |
| Embodiment 6 | 75 | 58 | 460 |
| Embodiment 7 | 55 | 30 | 431 |
| Embodiment 8 | 72 | 45 | 476 |
| Embodiment 9 | 60 | 55 | 402 |
| Embodiment 10 | 37 | 49 | 458 |
| Embodiment 11 | 79 | 56 | 442 |
| Embodiment 12 | 77 | 55 | 435 |
| Embodiment 13 | 62 | 58 | 481 |
| Embodiment 14 | 80 | 54 | 488 |
| Embodiment 15 | 80 | 21 | 416 |
| Embodiment 16 | 81 | 44 | 493 |
| Embodiment 17 | 79 | 56 | 443 |
| Embodiment 18 | 81 | 41 | 402 |
| Embodiment 19 | 76 | 36 | 451 |
| Embodiment 20 | 80 | 25 | 480 |
| Embodiment 21 | 81 | 14 | 403 |
| Embodiment 22 | 79 | 39 | 437 |
| Embodiment 23 | 76 | 55 | 454 |
| Embodiment 24 | 80 | 56 | 453 |
| Embodiment 25 | 79 | 50 | 456 |
| Embodiment 26 | 60 | 50 | 452 |
| Embodiment 27 | 80 | 55 | 452 |
| Embodiment 28 | 62 | 57 | 434 |
| Embodiment 29 | 80 | 56 | 410 |
It can be seen from the above description that the above embodiments of the present invention realized the following chievements:
The above-mentioned preparation process of the application uses safe and non-toxic N- methylurea for raw material, uses Total continuity reaction and rear place
Reason obtains the 2- methyltetrahydrofuran solution of diazomethane precursor MNU, then directly reuses Total continuity reaction and post-processes
To anhydrous diazomethane solution, wherein being removed water using refrigerating process, avoid using expensive semi-permeable membrane or Liquid liquid Separation
Device, therefore the preparation process is compared with existing batch diazomethane preparation process, it is more safely controllable；With existing continuous weight
N-formyl sarcolysine alkane preparation process compares, and cost is cheaper.
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 (10)
1. a kind of preparation process of diazomethane, which is characterized in that the preparation process includes:
Step S1 makes N- methylurea raw material continuously prepare the first production containing N-methyl-N-nitrosourea in flow reactor
Objects system；
Step S2 carries out continuous extraction, back extraction to first product system, obtains N-methyl-N-nitrosourea solution；
Step S3 makes the N-methyl-N-nitrosourea solution and aqueous slkali carry out successive reaction in flow reactor, obtains
The second product system containing diazomethane；And
Step S4 carries out continuous liquid separation, freezing water removal to second product system, obtains the diazomethane.
2. preparation process according to claim 1, which is characterized in that the step S1 includes:
Acid, solvent, sodium nitrite and the N- methylurea are continuously introduced into the flow reactor and are reacted to prepare
State the first product system.
3. preparation process according to claim 2, which is characterized in that it is described acid for selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid,
Any one in formic acid, acetic acid, p-methyl benzenesulfonic acid and methanesulfonic acid, the solvent include water and organic solvent, described organic molten
Agent is any in chloroform, methylene chloride, ethyl acetate, tetrahydrofuran, 2- methyltetrahydrofuran, benzene, toluene and dimethylbenzene
It is one or more.
4. preparation process according to claim 3, which is characterized in that the reaction temperature of the step S1 is 0~120 DEG C,
Preferably 10~30 DEG C, the molar ratio of the preferably described N- methylurea, the sodium nitrite and the acid be 1:1.5~2.5:1~
2, the volume ratio of water described in the preferably described solvent and the organic solvent is 1:3~5；It is preferred that the retention time of the step S1
For 5~30min.
5. preparation process according to claim 1, which is characterized in that the flow reactor is continuous coil reactor.
6. preparation process according to claim 1, which is characterized in that the step S2 includes:
First product system is continuously introduced into the first extraction column to extract using extractant, obtains extract liquor；
The extract liquor is continuously introduced into the second extraction column to be stripped using alkaline stripping workshop, obtains the N- methyl-N-
Nitroso ureas solution,
Wherein, the extractant is selected from chloroform, methylene chloride, ethyl acetate, tetrahydrofuran, 2- methyltetrahydrofuran, benzene, toluene
With any one or more in dimethylbenzene, it is described alkalinity stripping workshop be selected from triethylamine, diisopropyl ethyl amine, tertiary fourth ammonium,
1,4- diazabicylo, 11 carbon -7- alkene of 1,8- diazabicylo, KOH, NaOH, K2CO3、Na2CO3、NaHCO3、Cs2CO3、
KHCO3, the aqueous solution of any one in sodium acetate and potassium acetate, the pH value of extraction system is 5 in the preferably described stripping process
~7.
7. preparation process according to claim 1, which is characterized in that the lye of the step S3 be potassium hydroxide solution,
Sodium hydroxide solution, lithium hydroxide solution, solution of potassium carbonate, sodium carbonate liquor, potassium bicarbonate solution or sodium bicarbonate solution.
8. preparation process according to claim 1, which is characterized in that the reaction temperature of the step S3 is -20~100
DEG C, preferably 0~30 DEG C, the retention time of the preferably described step S3 is 30~150 seconds.
9. preparation process according to claim 1, which is characterized in that the step S4 includes:
Second product system is continuously introduced into third extraction column and carries out liquid separation processing, obtains upper layer overflow organic solution；
Carrying out freezing processing to the upper layer overflow organic solution keeps water-setting therein solid, obtains the organic molten of the diazomethane
Liquid.
10. preparation process according to claim 9, which is characterized in that the freezing processing includes:
The upper layer overflow organic solution is continuously introduced into successive reaction kettle and is cooled to -30~-50 DEG C under agitation
The organic solution of 40~80min of lower holding, the diazomethane go out from the upper layer overflow of the successive reaction kettle, preferably described
The overflow port of successive reaction kettle is provided with strainer.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111423338A (en) * | 2020-04-30 | 2020-07-17 | 山东微井化工科技股份有限公司 | Industrial production system of diazomethane |
| CN114014778A (en) * | 2021-12-07 | 2022-02-08 | 山东科加工业技术研究院有限公司 | Device and method for preparing diazomethane by continuous liquid separation and drying stages |
| CN115956066A (en) * | 2020-08-24 | 2023-04-11 | 科学与工业研究委员会 | Automatic diazomethane generator, reactor and solid phase quenching agent |
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| US5854405A (en) * | 1997-11-13 | 1998-12-29 | Aerojet-General Corporation | Continuous process for diazomethane from an n-methyl-n-nitrosoamine and from methylurea through n-methyl-n-nitrosourea |
| JP2001354638A (en) * | 2000-06-09 | 2001-12-25 | Otsuka Chem Co Ltd | Method for producing azoalkyl ester compound and method for purifying the same |
| CN1980885A (en) * | 2004-06-23 | 2007-06-13 | 诺贝尔炸药及系统技术有限责任公司 | Method for producing gaseous diazoalkanes |
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| US5854405A (en) * | 1997-11-13 | 1998-12-29 | Aerojet-General Corporation | Continuous process for diazomethane from an n-methyl-n-nitrosoamine and from methylurea through n-methyl-n-nitrosourea |
| JP2001354638A (en) * | 2000-06-09 | 2001-12-25 | Otsuka Chem Co Ltd | Method for producing azoalkyl ester compound and method for purifying the same |
| CN1980885A (en) * | 2004-06-23 | 2007-06-13 | 诺贝尔炸药及系统技术有限责任公司 | Method for producing gaseous diazoalkanes |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111423338A (en) * | 2020-04-30 | 2020-07-17 | 山东微井化工科技股份有限公司 | Industrial production system of diazomethane |
| CN115956066A (en) * | 2020-08-24 | 2023-04-11 | 科学与工业研究委员会 | Automatic diazomethane generator, reactor and solid phase quenching agent |
| CN114014778A (en) * | 2021-12-07 | 2022-02-08 | 山东科加工业技术研究院有限公司 | Device and method for preparing diazomethane by continuous liquid separation and drying stages |
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