CN102796039A - Method for continuous preparation of 2-chloro-5-chloromethylpyridine in microchannel - Google Patents
Method for continuous preparation of 2-chloro-5-chloromethylpyridine in microchannel Download PDFInfo
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Abstract
The invention discloses a method for continuous preparation of 2-chloro-5-chloromethylpyridine in a microchannel. The method consists of: taking 2-chloro-5-methylpyridine as a raw material, adopting sulfonyl chloride as a chlorinating reagent, employing azodiisobutyronitrile as an initiator, and using an organic solvent as a reaction medium, in a microchannel reactor, conducting a chlorination reaction under 80-130DEG C, controlling the retention time of the reaction by controlling the flow rate of a reaction solution, and after the reaction, collecting the effluent of the microchannel reactor, thus obtaining the 2-chloro-5-chloromethylpyridine. The method disclosed in the invention greatly shortens the reaction time, improves the reaction efficiency and the product quality, and makes the product selectivity up to 97.88%. The reaction system in the invention has no amplification effect, can realize amplification by several times through parallel connection, and has the advantages of continuous reaction stability, simple operation, short production cycle, cheap and easily available raw materials, simple production process and the like, thus being suitable for industrialized production.
Description
(1) technical field
The present invention relates to a kind of preparation method of 2-chloro-5-PMC, particularly a kind of in micro passage reaction serialization prepare the method for 2-chloro-5-PMC.
(2) background technology
2-chloro-5-PMC (2-chloro-5-chloromethylpyridine; Be called for short CCMP) be new and effective pesticide imidacloprid (Imidacloprid) and the pyrrole worm key intermediate of (NI-25) clearly, also be the part of tool insecticidal activity in this type pesticide molecule.And through it alkylated reaction, with the condensation reaction of heterocycle N-H and ammonification after with 1-nitro-2, the reaction of two (thiomethyl) ethene of 2-can prepare a series of new insecticidal/acaricidal agents.
Up to now more than surplus the synthesis technique of developing existing 10, but can be used for the few of suitability for industrialized production.Its synthetic route mainly can be classified as two types: directly from pyridine and verivate chlorination thereof or directly ring-closure reaction obtain.By the route of pyridine and verivate direct chlorination thereof, topmost is exactly the methyl chloride method of 2-chloro-5-picoline, and this synthetic method craft is ripe; Reactions step is few; Raw materials cost is low, but it is easily by degree of depth chlorination, generates 2-chloro-5-dichloro, nitrapyrin.And directly the cyclization method is an operational path by the exploitation of U.S. Rayleigh company, mainly is to be raw material with cyclopentadiene and propenal, obtains through series reaction.But this compound method reactions step is long, and cost of material is higher, and the ring-closure reaction yield is not very desirable.
Therefore; If can on the sophisticated operational path of script basis, overcome the problem that the chlorination degree of depth is a selectivity of product, obtain product in enormous quantities, that quality is more excellent; Realize serialization production simultaneously, this will have very big pushing effect to the development of agricultural chemicals and medicine from now on.
Little reaction technology is to substitute the traditional batch tank reactor with the micro passage reaction that is based upon on the continuous flow basis as an emerging reinforcement reaction technology.The characteristic dimension of micro passage reaction is usually between 10～2000 μ m.Because the channel size of process fluid is very little in the microreactor; For conventional tubular reactor; Its specific surface area volume ratio is very big; Therefore having high mixing efficiency (the Millisecond scope realizes radially mixing fully), strong exchange capability of heat and a narrow residence time distributes, and has broad application prospects in fields such as chemosynthesis, chemical kinetics research and process exploitations.Mainly have following advantage: (1) no scale effect need not pilot scale and directly can amplify; (2) temperature of reaction, time, material proportion etc. can accurately be controlled; (3) specific surface area is big, and mass-transfer efficiency is high, and material is evenly mixed with accurate ratio moment; (4) higher than heat transfer efficiency, the security of card production process; (5) has good operability.Be used for being difficult to control repercussion study under the normal conditions such as strong heat release rapid reaction, hydrocarbon catalyticing oxidation, organo-metallic catalysis coupling by more and more at present.
Therefore; At traditional 2-chloro-5-picoline is on the chloromethyl method basis of raw material; Advantage by little anti-technology; Overcome the shortcoming of tank reactor, serialization prepares the technology of 2-chloro-5-PMC in the exploitation micro passage reaction, can simplify technology, improves selectivity, reduces synthetic cost, reduce the pollution substance discharging.
(3) summary of the invention
The object of the invention provides a kind of little reaction technology that utilizes, and serialization prepares the method for 2-chloro-5-PMC in micro passage reaction, simplifies technology, improves selectivity, reduces synthetic cost, reduces the pollution substance discharging.
The technical scheme that the present invention adopts is:
Serialization prepares the method for the chloro-of 2-shown in formula I 5-PMC in a kind of microchannel, and said method is: with 2-chloro-5-picoline is raw material, is chlorination reagent with the SULPHURYL CHLORIDE; With the Diisopropyl azodicarboxylate is initiator; With the organic solvent is reaction medium, in micro passage reaction, under 80 ~ 130 ℃ of conditions, carries out chlorination reaction; Control the residence time of reaction through the charging flow velocity of control reaction solution; After reacting completely, collect the micro passage reaction effluent, obtain said 2-chloro-5-PMC; Said organic solvent is a kind of (the preferred chlorobenzene) in chlorobenzene, methylene dichloride, trichloromethane or the tetracol phenixin, said micro passage reaction polyfluortetraethylene pipe micro passage reaction; Said 2-chloro-5-picoline is 1:0.006 ~ 0.012:0.5 ~ 1 (preferred 1:0.012:0.5) with the ratio of the amount of substance that feeds intake of Diisopropyl azodicarboxylate and SULPHURYL CHLORIDE, and said 2-chloro-5-picoline final concentration is 2.5 ~ 5mol/L (preferred 3mol/L).
Further, when the internal diameter of said micro passage reaction is 50 ~ 1500 microns, the residence time time of microchannel (reaction solution flow through) 15 ~ 75s, the speed that respective reaction liquid gets into micro passage reaction is 0.5 ~ 2.5m/min.
Further, the temperature of reaction of said reaction solution in micro passage reaction is 110 ~ 120 ℃.
Further; Preferred reaction liquid gets into micro passage reaction with the speed of 1.0 ~ 2.0m/min (preferred 2m/min), and the preferable residence time in micro passage reaction is 45 ~ 60s, and the internal diameter of corresponding micro passage reaction is 600 ~ 1200 microns; Length 0.5 ~ 2.5m, temperature of reaction is 110 ~ 120 ℃.
Further; The method that serialization prepares 2-chloro-5-PMC in the described microchannel recommends to carry out as follows: be dissolved in kind liquid A that is mixed with 2-chloro-5-picoline final concentration 2.5 ~ 5mol/L (preferred 3mol/L) among the chlorobenzene a after 2-chloro-5-picoline and Diisopropyl azodicarboxylate are mixed; SULPHURYL CHLORIDE is dissolved in the appearance liquid B that is mixed with SULPHURYL CHLORIDE final concentration 1.25 ~ 2.5mol/L (preferred 1.5mol/L) among the chlorobenzene b, and said 2-chloro-5-picoline is 1:0.012:0.5 with the ratio of the amount of substance that feeds intake of Diisopropyl azodicarboxylate and SULPHURYL CHLORIDE; With appearance liquid A and appearance liquid B form incoming flow with the speed of 1.0 ~ 2.0m/min (preferred 2.0m/min) respectively and with identical speed injection in micro passage reaction; Under 110 ~ 120 ℃ of conditions, in micro passage reaction, stop 45 ~ 60s; Collect the effusive reaction solution of micro passage reaction, obtain described 2-chloro-5-PMC; Said micro passage reaction is the polyfluortetraethylene pipe of 600 ~ 1000 microns of internal diameters, and length is 1.0 ~ 2.0m.
Serialization prepares in the method for 2-chloro-5-PMC in the microchannel of the present invention; Collect the micro passage reaction effluent, through high resolution gas chromatography appearance (Shimadzu GC-14B, Japanese Shimadzu company) detection reaction fluid component; Productive rate, the target product selectivity of external standard method calculating raw material 2-chloro-5-picoline are respectively and are reaction end more than 30%, 90%; If not reaching reaction end then adjusts the reaction flow velocity, the control residence time, reaction solution is reacted completely.
Reaction according to the invention can also be collected the micro passage reaction effluent with Erlenmeyer flask after finishing, and in effluent, adds mass concentration 10% aqueous sodium hydroxide solution and removes unreacted SULPHURYL CHLORIDE; Stir; Filter, filtration cakes torrefaction obtains said 2-chloro-5-PMC.
The process of appearance liquid A according to the invention and appearance liquid B formation incoming flow can be carried out in micro-mixer or Y-type mixing tank or T-type mixing tank in advance, and also available volume pump is metered in the micro passage reaction separately.Reaction solution is laminar flow regime in micro passage reaction.
Micro passage reaction according to the invention is the known technology; Various types of micro passage reactions all can use; The preferred micro passage reaction of the present invention is processed by polyfluortetraethylene pipe, also can use other material such as stainless steel, glass, pottery, silicon or other metal.
Appearance liquid A according to the invention and appearance liquid B are the charging appearance liquid that different step prepares, and name for ease of differentiation, and letter itself does not have implication; Said chlorobenzene a and chlorobenzene b are chlorobenzene, name for ease of distinguishing the used chlorobenzene amount difference of different step, and alphabetical a, b itself do not have implication.
Compared with prior art, beneficial effect of the present invention is mainly reflected in:
The inventive method is because the micro passage reaction heat-transfer capability is strong, and mixing uniformity is good, has shortened the reaction times greatly, compared to conventional intermittent reaction, shortens to 60 seconds by original 2 hours; The microchannel internal diameter is little, and specific surface area is big, and material can improve reaction efficiency and quality product with accurate ratio moment uniform mixing, makes selectivity of product up to 97.88%; This reactive system does not have scale effect, can realize the several times amplification through parallel connection; And the stability with successive reaction, and easy and simple to handle, with short production cycle, advantage such as raw material cheaply is easy to get, production technique is simple are applicable to suitability for industrialized production; This micro passage reaction is by gathering PTFE preparation, and advantage such as have therefore that preparation is simple, solvent resistance is good and corrodibility is strong helps industrial application.
(4) description of drawings
Fig. 1 microchannel reaction schema, 1 is appearance liquid A, and 2 is appearance liquid B, and 3 are microchannel reaction pipe, and 4 is the reaction solution receiving bottle.
Fig. 2 embodiment 1 product gas chromatogram.
(5) embodiment
Below in conjunction with specific embodiment the present invention is described further, but protection scope of the present invention is not limited in this:
Embodiment 1 (optimum process condition)
6.38g (0.05mol) 2-chloro-5-picoline and 0.1g (0.0006mol) Diisopropyl azodicarboxylate (AIBN) mixing are dissolved in the mixing solutions that is mixed with 2-chloro-5-picoline final concentration 0.003mol/ml in the 12.5ml chlorobenzene, as appearance liquid A; Measure sulfuryl chloride SO
2Cl
23.38g (0.025mol), be dissolved in the mixing solutions that forms SULPHURYL CHLORIDE final concentration 0.0015mol/ml in the 16ml chlorobenzene, as appearance liquid B.Syringe pump of appearance liquid A and each warp calibration of appearance liquid B (model LSP01-1A, producer: Baoding LanGe constant flow pump Co., Ltd) deliver in the micro passage reaction, overall flow rate is 2.0m/min; Before the beginning sample introduction micro passage reaction temperature is risen to 110 ℃, appearance liquid A and appearance liquid B are 60s in the residence time in the micro passage reaction (inside diameter D=0.6mm, the polyfluortetraethylene pipe of long L=2m); Collect the effluent of micro passage reaction outlet, promptly obtain the reaction solution of 2-chloro-5-PMC, through gc (model: GC-14B; Producer: Japan Shimadzu company), GC conditions: 80 ℃ keep 2min, and 20 ℃/min heats up; To 260 ℃ of maintenance 2min, detect once through yield 43.06%, the selectivity 97.88% of principal product 2-chloro-5-PMC; The result sees shown in Fig. 1 and the table 1, raw material 2-chloro-5-picoline RT 3.891, product 2-chloro-5-PMC RT 6.103; By product 2-chloro-5,5 '-dichloromethyl pyridine RT 6.725.
The map analysis of table 1 product gc
Appearance liquid A, appearance liquid B is with embodiment 1; Appearance liquid A is expelled in the micro passage reaction by certain flow rate with an appearance liquid B reacts; Processing parameters such as overall flow rate, temperature of reaction, the residence time, internal diameter are seen table 2, collect effusive reaction solution, promptly obtain the reaction solution of 2-chloro-5-PMC; Through gc (model: GC-14B; Producer: detect once through yield more than 30 ~ 68% Japan Shimadzu company), the selectivity 90 ~ 99% of principal product 2-chloro-5-PMC is specifically seen shown in the table 2.
Each more excellent processing condition of table 2 are to the influence of reaction
Comparative Examples 1
6.38g (0.05mol) 2-chloro-5-picoline and 0.1g (0.0006mol) Diisopropyl azodicarboxylate (AIBN) are added in the there-necked flask simultaneously, add the 30ml chlorobenzene, heated and stirred, temperature of reaction T=110 ℃.2-chloro-5-picoline and chlorination reagent SO
2C1
2The amount of substance proportioning is 2:l; Slowly splash into sulfuryl chloride in the there-necked flask with tap funnel; Reaction times 2h promptly obtains the reaction solution of 2-chloro-5-PMC, through gc (model: GC-14B; Producer: detecting yield Japan Shimadzu company) is 71%, the selectivity 89.7% of principal product 2-chloro-5-PMC.
Claims (4)
1. serialization prepares the method for 2-chloro-5-PMC in the microchannel, and it is characterized in that said method is: with 2-chloro-5-picoline is raw material, is chlorination reagent with the SULPHURYL CHLORIDE; With the Diisopropyl azodicarboxylate is initiator; With the organic solvent is reaction medium, in micro passage reaction, under 80 ~ 130 ℃ of conditions, carries out chlorination reaction; Charging flow velocity through the control reaction solution is controlled the reaction solution residence time; After reacting completely, collect the micro passage reaction effluent, obtain said 2-chloro-5-PMC; Said organic solvent is chlorobenzene, methylene dichloride, trichloromethane or tetracol phenixin; Said micro passage reaction is the polyfluortetraethylene pipe micro passage reaction; Said 2-chloro-5-picoline is 1:0.006 ~ 0.012:0.5 ~ 1 with the ratio of the amount of substance that feeds intake of Diisopropyl azodicarboxylate and SULPHURYL CHLORIDE, and said 2-chloro-5-picoline final concentration is 2.5 ~ 5mol/L.
2. serialization prepares the method for 2-chloro-5-PMC in the microchannel as claimed in claim 1; When the internal diameter that it is characterized in that said micro passage reaction is 50 ~ 1500 microns; The residence time 15 ~ 75s, the said reaction solution flow velocity 0.5 ~ 2.5m/min in micro passage reaction.
3. serialization prepares the method for 2-chloro-5-PMC in the microchannel as claimed in claim 1; The internal diameter that it is characterized in that micro passage reaction is 600 ~ 1200 microns; The flow velocity that said reaction solution gets into micro passage reaction is 1.0 ~ 2.0m/min; The residence time is 45 ~ 60s, 110 ~ 120 ℃ of temperature of reaction.
4. serialization prepares the method for 2-chloro-5-PMC in the microchannel as claimed in claim 1; It is characterized in that said method carries out as follows: be dissolved in the appearance liquid A that is mixed with 2-chloro-5-picoline final concentration 2.5 ~ 5mol/L among the chlorobenzene a after 2-chloro-5-picoline and Diisopropyl azodicarboxylate are mixed; SULPHURYL CHLORIDE is dissolved in the appearance liquid B that is mixed with SULPHURYL CHLORIDE final concentration 1.25 ~ 2.5mol/L among the chlorobenzene b; Said 2-chloro-5-picoline is 1:0.012:0.5 with the ratio of the amount of substance that feeds intake of Diisopropyl azodicarboxylate and SULPHURYL CHLORIDE; With appearance liquid A and appearance liquid B form incoming flow with the speed of 1.0 ~ 2.0m/min respectively and with identical speed injection in micro passage reaction; Temperature of reaction is 110 ~ 120 ℃, the residence time 45 ~ 60s, collects the effusive reaction solution of micro passage reaction, obtains described 2-chloro-5-PMC; Said micro passage reaction is the polyfluortetraethylene pipe of 600 ~ 1000 microns of internal diameters, and length is 1.0 ~ 2.0m.
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| CN104447522A (en) * | 2014-10-31 | 2015-03-25 | 爱斯特（成都）生物制药有限公司 | Preparation method of 5-nitro-2-aminopyridine |
| CN105801472A (en) * | 2016-03-31 | 2016-07-27 | 常州大学 | Synthetic method of 4-(chloromethyl)-2-(3-(trifluoromethyl)phenoxy)pyridine |
| CN106187869A (en) * | 2016-07-28 | 2016-12-07 | 南京红太阳生物化学有限责任公司 | A kind of method of synthesis 2 chlorine 5 chloromethylpyridine |
| CN106243019A (en) * | 2016-07-28 | 2016-12-21 | 南京红太阳生物化学有限责任公司 | A kind of method preparing 2 chlorine 5 chloromethylpyridine |
| CN109456295A (en) * | 2018-12-11 | 2019-03-12 | 苏州华道生物药业股份有限公司 | The microchannel method synthesis technology of 3- isochromanome |
| CN109574918A (en) * | 2019-01-17 | 2019-04-05 | 内蒙古元正精细化工有限责任公司 | The method for preparing 2-vhloro-5-chloromethylpyridine using micro passage reaction serialization |
| CN115974772A (en) * | 2023-01-05 | 2023-04-18 | 山东铂源药业股份有限公司 | Method for preparing pyridine-3-sulfonyl chloride by using microchannel reactor |
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| CN104447522A (en) * | 2014-10-31 | 2015-03-25 | 爱斯特（成都）生物制药有限公司 | Preparation method of 5-nitro-2-aminopyridine |
| CN104447522B (en) * | 2014-10-31 | 2017-03-29 | 爱斯特（成都）生物制药有限公司 | The preparation method of 5 nitro, 2 aminopyridine |
| CN105801472A (en) * | 2016-03-31 | 2016-07-27 | 常州大学 | Synthetic method of 4-(chloromethyl)-2-(3-(trifluoromethyl)phenoxy)pyridine |
| CN106187869A (en) * | 2016-07-28 | 2016-12-07 | 南京红太阳生物化学有限责任公司 | A kind of method of synthesis 2 chlorine 5 chloromethylpyridine |
| CN106243019A (en) * | 2016-07-28 | 2016-12-21 | 南京红太阳生物化学有限责任公司 | A kind of method preparing 2 chlorine 5 chloromethylpyridine |
| CN109456295A (en) * | 2018-12-11 | 2019-03-12 | 苏州华道生物药业股份有限公司 | The microchannel method synthesis technology of 3- isochromanome |
| CN109456295B (en) * | 2018-12-11 | 2022-03-01 | 苏州华道生物药业股份有限公司 | Micro-channel method synthesis process of 3-isochromanone |
| CN109574918A (en) * | 2019-01-17 | 2019-04-05 | 内蒙古元正精细化工有限责任公司 | The method for preparing 2-vhloro-5-chloromethylpyridine using micro passage reaction serialization |
| CN109574918B (en) * | 2019-01-17 | 2020-06-05 | 内蒙古元正精细化工有限责任公司 | Method for continuously preparing 2-chloro-5-chloromethyl pyridine by using microchannel reactor |
| CN115974772A (en) * | 2023-01-05 | 2023-04-18 | 山东铂源药业股份有限公司 | Method for preparing pyridine-3-sulfonyl chloride by using microchannel reactor |
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