CN107988279A - A kind of method of lipase-catalyzed online synthesis 6- ((4- chlorobenzyls) sulfenyl) -6- oxo vinyl caproates - Google Patents
A kind of method of lipase-catalyzed online synthesis 6- ((4- chlorobenzyls) sulfenyl) -6- oxo vinyl caproates Download PDFInfo
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Abstract
The invention discloses a kind of method of 6 ((4 chlorobenzyl) sulfenyl) 6 oxo vinyl caproates of lipase-catalyzed online synthesis：Using dimethyl sulfoxide as reaction dissolvent, using molar ratio as 1:0.5~6 4 chloro benzyl mercaptans and vinyl hexanediacetate are raw material; using Lipozyme TL IM as catalyst; raw material and reaction dissolvent are placed in syringe; Lipozyme TL IM are uniformly filled in the reaction channel of microfluidic channel reactor; raw material and reaction dissolvent is continuously passed through in reaction channel device under the promotion of syringe pump and carry out acylation reaction; the reaction channel internal diameter of the microfluidic channel reactor is 0.8~2.4mm, a length of 0.5~1.0m of reaction channel；It is 20~60 DEG C to control acylation reaction temperature, and the acylation reaction time is 20~40min, collects reaction solution online by product collector, reaction solution obtains 6 ((4 chlorobenzyl) sulfenyl) 6 oxo vinyl caproates through conventional post processing.The present invention has the advantages that short reaction time, high selectivity and yield are high.
Description
(1) technical field
The present invention relates to a kind of lipase-catalyzed online synthesis 6- ((4- chlorobenzyls) sulfenyl) -6- oxo vinyl caproates
Method.
(2) background technology
Many artificial synthesized or natural organic compounds containing sulfur all has bioactivity.Sulfur ester is unique because of it
Chemical constitution and with anti-oxidant, antibacterial, the pharmacological activity such as antitumor, be in important in organic synthesis and chemical biology
Mesosome.Meanwhile thioesters class formation also has the function that to protect unstable thiol functionalities, increases its pharmaceutical activity, covers SH
The smell of key, in food, medicine, pesticide and cosmetic industry extensive use.
The synthesis of sulfur ester generally uses esterification process, and this method is mainly using strong acid such as sulfuric acid, benzene sulfonic acids as urging
Agent, this kind of catalytic erosion is strong, harsh to equipment requirement, and environmental pollution is serious.Separately have been reported that using fluoroform sulphonate
Or it is transition metal-catalyzed prepare sulfur ester, this kind of reaction prepares difficult, expensive, easy there are transition metal complex
Loss, more difficult recycling, can produce the shortcomings of environmentally harmful material.With becoming increasingly conspicuous for problem of environmental pollution, compel highly necessary
The green high-efficient synthetic method for seeking development less to human health and environmental hazard.
Enzymic catalytic reaction is an emphasis of Green Chemistry research.Enzymatic reaction is because its reaction condition is gentle, high selectivity
And substrate specificity scope extensively causes extensive concern in organic synthesis.But enzymatic reaction is when generally requiring longer reaction
Between, and for specific substrates there are the restriction that reaction medium suppresses substrate dissolving with enzyme activity, thus in biocatalytic reaction
On the basis of develop a kind of enzymatic sulfur ester based on micro-fluidic reaction technology become our research hotspot.
Microflow control technique a special kind of skill emerging since being 20th century 90, be it is a kind of be empty as the scale of the order of magnitude using micron
Between to reactant carry out manipulation for main feature technology, can be by the operating unit collection such as the preparation of sample, reaction, separation, detection
Into on one piece of small chip, network is formed by microchannel, whole system is run through with controlled fluid, so as to substitute routine biochemistry
The multiple functions in laboratory.Microflow control technique is widely used in fields such as biology, chemistry and medicine.
Nineteen ninety-five, micro-system are applied to chemistry and biology in WESTERN GERMANY Mainz laboratory first
Reaction, this can regard the micro-system widely applied beginning as.The first international conference on microtechnology is held within 1997
(IMRET1).So far, micro-fluidic chip reactor has been successfully used to a variety of organic synthesis, and illustrates and be widely applied
Prospect.With the development of microring array, micro-reacting tcchnology in micro-fluidic chip, synthetic reaction is carried out in the chips and has become miniflow
Control one of research hotspot of chip field.
Compared with conventional chemical reactor, microchannel has the specific surface area of micron-sized internal diameter scale and super large, it
Diffusion length want it is short very much, mass transfer velocity is fast；Its heat transfer efficiency is also far above conventional chemical reactor, and it is acute to can be applied to reaction
Strong heat release or the reaction of high selectivity.The easy control of reaction conditions such as reactant ratio, temperature, reaction time and flow velocity, it is secondary anti-
Should be less；Need reactant dosage little, can not only reduce the dosage of expensive, poisonous adverse reaction thing, be produced in reaction process
Environmental contaminants it is also few, be a kind of environmental-friendly, study on the synthesis novel substance technology.
Up to the present, the research of Enzyme catalyzed synthesis sulfur ester is also relatively fewer, and enzymatic thioesters class chemical combination
The synthesis of thing uses acylase more, and this method needs the longer reaction time (48h) and for the conversion ratio of specific substrates reaction
It is not especially desirable, and reaction cost is higher.In order to develop a kind of efficient green, economic and environment-friendly sulfur ester synthesizes
New technology, we have studied lipase-catalyzed online synthesis 6- ((4- chlorobenzyls) sulfenyl) -6- oxos in micro passage reaction oneself
The method of vinyl acetate, it is intended to find a kind of 6- of high-efficiency environment friendly ((4- chlorobenzyls) sulfenyl) -6- oxo vinyl caproates
The new technology of line synthesis.
(3) content of the invention
The technical problem to be solved in the present invention is to provide lipase-catalyzed online synthesis in a kind of microfluidic channel reactor
The new process of 6- ((4- chlorobenzyls) sulfenyl) -6- oxo vinyl caproates, with the reaction time is short, yield is high, selectivity is good
Advantage.
In order to solve the above technical problems, the present invention adopts the following technical scheme that：
A kind of method of lipase-catalyzed online synthesis 6- ((4- chlorobenzyls) sulfenyl) -6- oxo vinyl caproates, it is described
Method uses microfluidic channel reactor, and the microfluidic channel reactor includes sequentially connected syringe, reaction channel
And product collector, the syringe are installed in syringe pump, the syringe passes through the first connecting pipe and reaction channel
Entrance connects, and the product collector is connected by the first connecting pipe and reaction channel outlet, and the reaction channel internal diameter is
0.8~2.4mm, a length of 0.5~1.0m of reaction channel；The described method includes：Using dimethyl sulfoxide as reaction dissolvent, with 4- benzyl chloride sulphur
Alcohol and vinyl hexanediacetate are raw material, using Lipozyme TL IM as catalyst, by the raw material and described anti-
Answer solvent to be placed in syringe, Lipozyme TL IM are uniformly filled in reaction channel, under the promotion of syringe pump
The raw material and the reaction dissolvent is continuously passed through in reaction channel and is carried out acylation reaction, controlling reaction temperature for 20~
60 DEG C, the reaction time is 20~40min, collects reaction solution online by product collector, the reaction solution is post-treated to be obtained
To 6- ((4- chlorobenzyls) sulfenyl) -6- oxo vinyl caproates；The 4- chloro benzyl mercaptans and the material of vinyl hexanediacetate
The ratio between amount be 1:0.5~6；The addition of the catalyst is calculated as 0.025~0.05g/ with the volume of the reaction dissolvent
mL。
Further, in the microfluidic channel reactor that the present invention uses, the syringe number can be one or more,
Depending on specific reaction requirement.Reaction raw materials of the present invention are two kinds, preferably using two syringes, specifically, the injection
Device is the first syringe and the second syringe respectively, and first connecting pipe is Y types or T-shaped pipeline, first note
Emitter is connected to two interfaces of the Y types or T-shaped pipeline and by the Y types or T-shaped with the second note syringe
Pipeline parallel connection is connected with the reaction channel again, is increased by reactant molecule contact and the collision probability of microchannel, is made two
Stock reaction liquid stream is mixed and reacted in public reaction channel.
Further, more specifically, method of the present invention comprises the following steps：
The ratio between amount with material is 1:0.5~6 4- chloro benzyl mercaptans and vinyl hexanediacetate are raw material, with lipase
Lipozyme TLIM are catalyst, and using dimethyl sulfoxide as reaction dissolvent, Lipozyme TLIM is uniformly filled in instead
Answer in passage, be first loaded on dimethyl sulfoxide dissolving 4- chloro benzyl mercaptans in the first syringe；Adipic acid diethyl is dissolved with dimethyl sulfoxide
Enester is loaded in the second syringe；Then syringe pump it is synchronous promote under make raw material and reaction dissolvent be passed through in reaction channel into
Row reaction, controlling reaction temperature are 20~60 DEG C, and the reaction time is 20~40min, collects reaction online by product collector
Liquid, post-treated obtained 6- ((4- chlorobenzyls) the sulfenyl) -6- oxo vinyl caproates of reaction solution；The addition of the catalyst
For 0.5~1g.
Further, the microfluidic channel reactor further includes insulating box, and the reaction channel is placed in insulating box,
Can effective controlling reaction temperature with this.The insulating box can voluntarily be selected according to reaction temperature requirement, for example water-bath is permanent
Incubator etc..
The present invention is unlimited for the material of reaction channel, it is recommended to use green, the material of environmental protection, such as silicone tube；For
The shape of reaction channel is preferably shaped form, it is ensured that reaction solution stably passes through.
In the present invention, the Lipozyme TLIM believes the commodity of (novozymes) company production using Novi,
It is a kind of by microorganism preparation, the preparation of 1,3 position-specifics, food-grade lipase (EC3.1.1.3) on particle silica gel.
It is being obtained from Thermomyceslanuginosus, micro- with a kind of gene-modified aspergillus oryzae (Aspergillusoryzae)
Biology is by submerged fermentation production.
Further, the ratio between amount of material of the 4- chloro benzyl mercaptans and vinyl hexanediacetate is preferably 1:1~3, it is optimal
Elect 1 as:2.
Further, the acylation reaction temperature is preferably 45~55 DEG C, is most preferably 50 DEG C.
Further, the acylation reaction time is preferably 25~35min, is most preferably 30min.
The reaction product of the present invention can collect online, and gained reaction solution be able to can be obtained by conventional post-processing approach
6- ((4- chlorobenzyls) sulfenyl) -6- oxo vinyl caproates.It is described routine post-processing approach can be：The decompression of gained reaction solution is steamed
Solvent is removed in distillation, and with 200-300 mesh silica gel wet method dress posts, elution reagent is petroleum ether:Ethyl acetate=20:1, sample is with a small quantity
Wet method upper prop after elution reagent dissolving, collects eluent, while TLC tracking elution processes, will obtain containing single product
Eluent, which merges, to be evaporated, and can obtain yellow oil, is 6- ((4- chlorobenzyls) sulfenyl) -6- oxo vinyl caproates.
Compared with prior art, beneficial effects of the present invention are：
The present invention utilizes lipase-catalyzed online synthesis 6- ((4- chlorobenzyls) sulfenyl) -6- in microfluidic channel reactor
Oxo vinyl caproate, which not only significantly shortens the reaction time, but also has high conversion ratio and selectivity；It is first at the same time
It is secondary to be catalyzed thioesters acylation reaction using economic Lipozyme TL IM, reaction cost is reduced, there is economical and efficient
Advantage.
(4) illustrate
Fig. 1 is the structure diagram for the microfluidic channel reactor that the embodiment of the present invention uses.
(5) embodiment
Protection scope of the present invention is described further with specific embodiment below, but protection scope of the present invention is unlimited
In this：
The structural reference Fig. 1 for the microfluidic channel reactor that the embodiment of the present invention uses, including a syringe pump (are not shown
Show), two syringes 1 and 2, reaction channel 3, constant temperature water box (5, only show its floor map) and product collector 4；Two
A syringe 1 and 2 is installed in syringe pump, is connected by a Y types interface with 3 entrance of reaction channel, the reaction channel 3 is put
In constant temperature water box 5, by 5 controlling reaction temperature of constant temperature water box, the internal diameter 2.0mm of the reaction channel 3, pipe range
1m, the outlet of reaction channel 3 are connected by an interface with product collector 4.
Embodiment 1：The synthesis of 6- ((4- chlorobenzyls) sulfenyl) -6- oxo vinyl caproates
Device is with reference to figure 1：4- chloro benzyl mercaptans (1.0mmol) are dissolved in 10mLDMSO, vinyl hexanediacetate
(2.0mmol) is dissolved in 10mL DMSO, is then loaded on respectively spare in 10mL syringes.0.87g Lipozymes TL
IM is uniformly filled in reaction channel, and under the promotion of PHD2000 syringe pumps, two-way reaction solution is respectively with 10.4 μ Lmin-1Stream
Speed is entered in reaction channel by " Y " connector is reacted, and controls temperature of reactor at 50 DEG C by constant temperature water box, reaction solution
Continuous flowing reactive 30min, reaction result pass through thin-layer chromatography TLC tracing detections in reaction channel.
Reaction solution is collected by product collector online, vacuum distillation removes solvent, is filled with 200-300 mesh silica gel wet method
Column, elution reagent are petroleum ether:Ethyl acetate=20:1, pillar height 35cm, column diameter 4.5cm, sample are molten with a small amount of elution reagent
Wet method upper prop after solution, eluent collect flow velocity 2mLmin-1, while TLC tracking elution processes, contain single product by what is obtained
Eluent merge and be evaporated, obtain yellow oil, obtain 6- ((4- chlorobenzyls) sulfenyl) -6- oxo vinyl caproates, HPLC
Detect 4- chloro benzyl mercaptans conversion ratio 85%, selectivity 96%.
Nuclear-magnetism characterization result is as follows：
1H NMR(500MHz,CDCl3):δ=7.25 (dd, J=18.0,7.8Hz, 4H), 7.15 (s, H), 4.78 (ddd, J
=14.0,3.4,1.6Hz, 1H), 4.57 (ddd, J=6.3,2.4,1.7Hz, 2H), 4.25 (d, J=3.5Hz, 1H), 2.62
(m,2H),2.48-2.36(m,2H),1.86-1.46(m,4H).13C NMR(125MHz,CDCl3):δ=199.1,173.6,
141.2,134.5,132.2,130.7,128.8,97.6,43.8,33.6,30.3,24.9,24.1.
Embodiment 3-6
Change the ratio between amount of substrate materials of 4- chloro benzyl mercaptans and vinyl hexanediacetate in micro-fluidic micro passage reaction,
Temperature 50 C is controlled, other are with embodiment 1, and the results are shown in Table 1：
Table 1:4- chloro benzyl mercaptans and the influence for comparing reaction of the amount of vinyl hexanediacetate substrate materials
Table 1 the result shows that, when flow velocity is 10.4 μ Lmin-1, the reaction time is 30min, and reaction temperature is 50
DEG C, reactor is using DMSO as organic solvent, and with the increase of reactant vinyl hexanediacetate, the conversion ratio of reaction is also with increasing
Add, when substrate than 4- chloro benzyl mercaptan and vinyl hexanediacetate is 1:When 2, the conversion ratio of reaction is optimal, so micro- in the present invention
The ratio between amount of optimal substrate materials is 1 in flow control micro passage reaction:2.
Embodiment 7-10
Change the temperature of microfluidic channel reactor, with embodiment 1, reaction result is as shown in table 2 for other：
Table 2：Influence of the temperature to reaction
| Embodiment | Temperature [DEG C] | Conversion ratio [%] | Selectivity [%] |
| 7 | 40 | 65 | 96 |
| 8 | 45 | 79 | 98 |
| 1 | 50 | 85 | 96 |
| 9 | 55 | 80 | 97 |
| 10 | 60 | 77 | 95 |
Table 2 the result shows that, when flow velocity is 10.4 μ Lmin-1, the reaction time is 30min, and reactor is using DMSO to have
The ratio between amount of solvent, reactant 4- chloro benzyl mercaptans and vinyl hexanediacetate material is 1:2, when reaction temperature is in 50 DEG C
When, the conversion ratio of reaction is optimal, temperature or the Tai Gao or too low activity that will all influence enzyme.So micro-fluidic microchannel in the present invention
Optimum temperature is 50 DEG C in reactor.
Embodiment 11-14
Change the reaction time of microfluidic channel reactor, with embodiment 1, reaction result is as shown in table 3 for other：
Table 3：Influence of the reaction time to reaction
| Embodiment | Time [min] | Conversion ratio [%] | Selectivity [%] |
| 11 | 20 | 65 | 93 |
| 12 | 25 | 77 | 95 |
| 1 | 30 | 85 | 96 |
| 13 | 35 | 78 | 97 |
| 14 | 40 | 73 | 96 |
Table 3 the result shows that, when reactor is using DMSO as organic solvent, reactant 4- chloro benzyl mercaptans and adipic acid divinyl
The ratio between amount of ester material is 1:2, reaction temperature is 50 DEG C, when reacted between when be 30min, reaction conversion ratio reaches
85%.So optimum reacting time 30min in micro-fluidic micro passage reaction in the present invention.
Comparative example 1-3
Change the catalyst in micro-fluidic micro passage reaction, be changed to porcine pancreatic lipase PPL (comparative example 1), fat respectively
Enzyme Novozym 435 (comparative example 2), bacillus alkaline protease (comparative example 3), other are with embodiment 1, as a result such as the institute of table 4
Show.
Table 4：Influence of the different enzymes to reaction conversion ratio and selectivity
| Comparative example | Enzyme source | Conversion ratio [%] | Selectivity [%] |
| 1 | PPL | 19 | 73 |
| 2 | Novozym 435 | 12 | 95 |
| 3 | Bacillus alkaline protease | 23 | 82 |
| Embodiment 1 | LipozymeTL IM | 85 | 96 |
Table 4 the result shows that, it is different for the acylation reaction of enzymatic 4- chloro benzyl mercaptans in microfluidic channel reactor
Enzyme to reaction have fairly obvious influence.Utilize bacillus alkaline protease catalytic reaction, 6- ((4- chlorobenzyls) sulphur
Base) -6- oxo vinyl caproates conversion ratio be 23%.And it is catalyzed the reaction, 6- ((4- chlorobenzyls) using Novozym 435
Sulfenyl) conversion ratios of -6- oxo vinyl caproates is only 19%.In terms of the result of table 4, for enzyme in microfluidic channel reactor
For the acylation reaction for promoting 4- chloro benzyl mercaptans, most effective catalyst turns for Lipozyme TL IM, 4- chloro benzyl mercaptans
Rate is 85%, and selectivity is 96%.
Claims (9)
1. a kind of method of lipase-catalyzed online synthesis 6- ((4- chlorobenzyls) sulfenyl) -6- oxo vinyl caproates, its feature
It is：The method uses microfluidic channel reactor, the microfluidic channel reactor include sequentially connected syringe,
Reaction channel and product collector, the syringe are installed in syringe pump, the syringe by the first connecting pipe with
Reaction channel entrance connects, and the product collector is connected by the first connecting pipe and reaction channel outlet, and the reaction is logical
Road internal diameter is 0.8~2.4mm, a length of 0.5~1.0m of reaction channel；The described method includes：Using dimethyl sulfoxide as reaction dissolvent, with
4- chloro benzyl mercaptans and vinyl hexanediacetate are raw material, using Lipozyme TL IM as catalyst, by the raw material
It is placed in the reaction dissolvent in syringe, Lipozyme TL IM is uniformly filled in reaction channel, are being noted
Penetrating under the promotion of pump makes the raw material and the reaction dissolvent continuously be passed through in reaction channel and carry out acylation reaction, and control is anti-
It is 20~60 DEG C to answer temperature, and the reaction time is 20~40min, and reaction solution, the reaction are collected online by product collector
Liquid is post-treated to obtain 6- ((4- chlorobenzyls) sulfenyl) -6- oxo vinyl caproates；The 4- chloro benzyl mercaptans and adipic acid two
The ratio between amount of material of vinyl acetate is 1:0.5~6；The addition of the catalyst is calculated as with the volume of the reaction dissolvent
0.025~0.05g/mL.
2. lipase-catalyzed online synthesis 6- ((4- chlorobenzyls) sulfenyl) -6- oxo vinyl caproates as claimed in claim 1
Method, it is characterised in that：The syringe has two, is the first syringe and the second syringe respectively, and described first
Connecting pipe is Y types or T-shaped pipeline, and first syringe is connected to the Y types or T-shaped with the second note syringe
Two interfaces of pipeline are simultaneously connected with the reaction channel again by the Y types or T-shaped pipeline parallel connection.
3. lipase-catalyzed online synthesis 6- ((4- chlorobenzyls) sulfenyl) -6- oxo vinyl caproates as claimed in claim 2
Method, it is characterised in that：The method comprises the following steps：The ratio between amount with material is 1:0.5~6 4- chloro benzyl mercaptans
It is raw material with vinyl hexanediacetate,, will using dimethyl sulfoxide as reaction dissolvent using Lipozyme TL IM as catalyst
Lipozyme TL IM are uniformly filled in reaction channel, are first loaded on the first note with dimethyl sulfoxide dissolving 4- chloro benzyl mercaptans
In emitter；It is loaded on dimethyl sulfoxide dissolving vinyl hexanediacetate in the second syringe；Then under the synchronous promotion of syringe pump
Raw material and reaction dissolvent is passed through in reaction channel and is reacted, controlling reaction temperature is 20~60 DEG C, the reaction time for 20~
40min, reaction solution, post-treated obtained 6- ((4- chlorobenzyls) the sulfenyl) -6- oxygen of reaction solution are collected by product collector online
For vinyl caproate；The addition of the catalyst is 0.5~1g.
4. lipase-catalyzed online synthesis 6- ((4- chlorobenzyls) sulfenyl) -6- oxo vinyl caproates as claimed in claim 1
Method, it is characterised in that：The microfluidic channel reactor includes insulating box, and the reaction channel is placed in insulating box.
5. lipase-catalyzed online synthesis 6- ((4- chlorobenzyls) sulfenyl) -6- oxo vinyl caproates as claimed in claim 3
Method, it is characterised in that：The microfluidic channel reactor includes insulating box, and the reaction channel is placed in insulating box.
6. lipase-catalyzed online synthesis 6- ((4- chlorobenzyls) sulfenyl) -6- oxo caproic acids as described in one of Claims 1 to 5
The method of vinyl acetate, it is characterised in that：The ratio between amount of material of the 4- chloro benzyl mercaptans and vinyl hexanediacetate is 1:1~3.
7. lipase-catalyzed online synthesis 6- ((4- chlorobenzyls) sulfenyl) -6- oxo caproic acids as described in one of Claims 1 to 5
The method of vinyl acetate, it is characterised in that：The acylation reaction temperature is 40~60 DEG C, the acylation reaction time for 25~
35min。
8. lipase-catalyzed online synthesis 6- ((4- chlorobenzyls) sulfenyl) -6- oxo caproic acids as described in one of Claims 1 to 5
The method of vinyl acetate, it is characterised in that：The ratio between amount of material of the 4- chloro benzyl mercaptans and vinyl hexanediacetate is 1:2.
9. lipase-catalyzed online synthesis 6- ((4- chlorobenzyls) sulfenyl) -6- oxo caproic acids as described in one of Claims 1 to 5
The method of vinyl acetate, it is characterised in that the post-processing approach is：The vacuum distillation of gained reaction solution removes solvent, gained crude product
Separated through silica gel column chromatography, with 200-300 mesh silica gel wet method dress posts, elution reagent is petroleum ether:Ethyl acetate=20:1 it is mixed
Bonding solvent, wet method upper prop after crude product is dissolved with a small amount of elution reagent, collects eluent, while TLC tracking elution processes, will
To eluent containing single product merge and be evaporated, yellow oil can be obtained, be 6- ((4- chlorobenzyls) sulfenyl) -6-
Oxo vinyl caproate.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711394428.9A CN107988279A (en) | 2017-12-21 | 2017-12-21 | A kind of method of lipase-catalyzed online synthesis 6- ((4- chlorobenzyls) sulfenyl) -6- oxo vinyl caproates |
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