CN108060184A - A kind of method of lipase-catalyzed online synthesis S- thioacetic acid benzyl esters - Google Patents
A kind of method of lipase-catalyzed online synthesis S- thioacetic acid benzyl esters Download PDFInfo
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Abstract
The invention discloses a kind of methods of lipase-catalyzed online synthesis S thioacetic acid benzyl esters：Using dimethyl sulfoxide as reaction dissolvent, with the ratio between amount of substance for 1:0.5~6 benzyl mercaptan is raw material with vinyl acetate; 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 made continuously to be passed through in reaction channel device under the promotion of syringe pump and carries 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；Controlling acylation reaction temperature, the acylation reaction time is 20~40min for 20~60 DEG C, collects reaction solution online by product collector, reaction solution obtains S thioacetic acid benzyl esters 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 methods of lipase-catalyzed online synthesis S- thioacetic acid benzyl esters.
(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 plays an important role of 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 is generally using 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 generate the shortcomings of environmentally harmful substance.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 mild, 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 inhibits 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 synthesis 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 units collection such as the preparation of sample, reaction, separation, detection
Into on one piece of small chip, network is formed by microchannel, with controlled fluid through whole system, 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 for the first time
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；Far above conventional chemical reactor, it is acute also to can be applied to reaction for its heat transfer efficiency
Strong heat release or highly selective reaction.The easy control of reaction conditions such as reactant ratio, temperature, reaction time and flow velocity, it is secondary anti-
It should be less；It needs reactant dosage little, can not only reduce the dosage of expensive, toxic adverse reaction object, be generated 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
Mostly using acylase, this method needs the longer reaction time (48h) and for the conversion ratio of specific substrates reaction for the synthesis of object
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 the methods of lipase-catalyzed online synthesis S- thioacetic acid benzyl esters in micro passage reaction, it is intended to seek
Look for a kind of new technology synthesized online of the S- thioacetic acid benzyl esters of high-efficiency environment friendly.
(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 S- thioacetic acid benzyl esters has the advantages that the reaction time is short, yield is high, selectivity is good.
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 S- thioacetic acid benzyl esters, the method are reacted using microfluidic channel
Device, the microfluidic channel reactor include sequentially connected syringe, reaction channel and product collector, the syringe
It is installed in syringe pump, the syringe is connected by the first connecting pipe with reaction channel entrance, the product collector
It is connected by the second connecting pipe and reaction channel outlet, the reaction channel internal diameter is 0.8~2.4mm, and reaction channel is a length of
0.5~1.0m；The described method includes：Using dimethyl sulfoxide as reaction dissolvent, using benzyl mercaptan and vinyl acetate as raw material, with fat
Fat enzyme Lipozyme TL IM are catalyst, the raw material and the reaction dissolvent are placed in syringe, by lipase
Lipozyme TL IM are uniformly filled in reaction channel, make the raw material and the reaction molten under the promotion of syringe pump
Agent, which is continuously passed through in reaction channel, carries out acylation reaction, and controlling reaction temperature is 20~60 DEG C, and the reaction time is 20~40min
(the heretofore described reaction time refers to reactant and enters reaction channel to the reaction time left reaction channel and be detained), passes through
Product collector collects reaction solution online, and the reaction solution is post-treated to obtain S- thioacetic acid benzyl esters；The dibenzylsulfide
The ratio between amount of substance of alcohol and vinyl acetate is 1:0.5~6；The addition of the catalyst is with the body of reaction dissolvent used
Product is calculated as 0.025~0.05g/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, it is preferable to use 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 with the second note syringe and passes through the Y types or T-shaped
Pipeline is connected with the reaction channel, is increased by reactant molecule contact and the collision probability of microchannel, is made two bursts of reactions
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 substance is 1:0.5~6 benzyl mercaptan is raw material with vinyl acetate, with Lipozyme
TL IM are catalyst, and using dimethyl sulfoxide as reaction dissolvent, Lipozyme TL IM are uniformly filled in reaction channel
In, first with dimethyl sulfoxide dissolving benzyl mercaptan loaded in the first syringe；Second is loaded on dimethyl sulfoxide dissolving vinyl acetate
In syringe；Again then the first syringe, the second syringe are made loaded in same syringe pump under the synchronous promotion of syringe pump
Raw material and reaction dissolvent, which are summarized by the Y types or T-shaped pipeline and entered afterwards in reaction channel, to be reacted, control reaction temperature
It spends for 20~60 DEG C, the reaction time is 20~40min, collects reaction solution online by product collector, reaction solution is post-treated
S- thioacetic acid benzyl esters are made；The addition of the catalyst is 0.5~1g.
The concentration of vinyl acetate is usually 0.05~0.6mmol/mL described in second syringe.
Heretofore described first syringe is consistent with the specification of the second syringe, benzyl mercaptan described in the first syringe
Concentration be usually 0.1mmol/mL.
Further, the microfluidic channel reactor further includes insulating box, and the reaction channel is placed in insulating box,
It 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 TL IM believe the business of (novozymes) company production using Novi
Product, be it is a kind of prepared by microorganism, the system of 1,3 position-specifics, food-grade lipase (EC3.1.1.3) on particle silica gel
Agent.It is obtained from Thermomyceslanuginosus, with a kind of gene-modified aspergillus oryzae (Aspergillusoryzae)
Microorganism is by submerged fermentation production.
Lipozyme TLIM is uniformly filled in reaction channel by the method for the present invention, can directly will by Physical
Granular catalyst is uniformly fixed in reaction channel.
Further, the ratio between amount of substance of the benzyl mercaptan and vinyl acetate is preferably 1:1~3, it is most preferably 1:
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 can be obtained by conventional post-processing approach
S- thioacetic acid benzyl esters.It is described routine post-processing approach can be：The vacuum distillation of gained reaction solution removes solvent, uses 200-300
Mesh silica gel wet method dress post, elution reagent are petroleum ether:Ethyl acetate volume ratio=20:1, after sample is dissolved with a small amount of elution reagent
Wet method upper prop collects eluent, while TLC tracking elution processes, the obtained merging of the eluent containing single product is evaporated,
Pale yellow oil can be obtained, is S- thioacetic acid benzyl esters.
Compared with prior art, beneficial effects of the present invention are：
The present invention is using lipase-catalyzed online synthesis S- thioacetic acid benzyl esters in microfluidic channel reactor, and the method is not
The reaction time is only significantly shortened, and with high conversion ratio and selectivity；Utilize economic lipase for the first time simultaneously
Lipozyme TL IM are catalyzed thioesters acylation reaction, reduce reaction cost, have the advantage of economical and efficient.
(4) illustrate
Fig. 1 is the structure diagram for the microfluidic channel reactor that the embodiment of the present invention uses.In figure, 1,2- syringes,
3- reaction channels, 4- product collectors, 5- constant temperature water box.(5)
Specific 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 (is not shown including a syringe pump
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 S- thioacetic acid benzyl esters
Device is with reference to figure 1：Benzyl mercaptan (1.0mmol) is dissolved in 10mL DMSO, vinyl acetate (2.0mmol)
It is dissolved in 10mL DMSO, then respectively loaded on spare in 10mL syringes.0.87g Lipozyme TL IM are uniform
It is filled in reaction channel, under the promotion of 2000 syringe pumps of PHD, two-way reaction solution is respectively with 10.4 μ Lmin-1Flow velocity lead to
It crosses " Y " connector and enters in reaction channel and reacted, controlling temperature of reactor by constant temperature water box, reaction solution is anti-at 50 DEG C
Continuous flowing reactive 30min, reaction result in passage is answered to pass through thin-layer chromatography TLC tracing detections.
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 volume ratio=20:1, pillar height 35cm, column diameter 4.5cm, a small amount of elution of sample
Wet method upper prop after reagent dissolving, eluent collect flow velocity 2mLmin-1, while TLC tracking elution processes, it will obtain containing single
The eluent merging of one product is evaporated, and obtains yellow oil, obtains S- thioacetic acid benzyl esters, HPLC detection benzyl mercaptan conversions
Rate 75%, selectivity 98%.
Nuclear-magnetism characterization result is as follows：
1H NMR(500MHz,CDCl3):δ=7.32-7.26 (m, 5H), 4.15 (s, 2H), 2.37 (s, 3H)13C NMR
(125MHz,CDCl3):δ=195.0,137.6,128.8,128.6,127.2,33.4,30.2.
Embodiment 2-5
On the basis of the dosage of benzyl mercaptan, change benzyl mercaptan and vinyl acetate in micro-fluidic micro passage reaction
The ratio between amount of substrate materials controls temperature 50 C, other are with embodiment 1, and the results are shown in Table 1：
Table 1:Benzyl mercaptan and the influence for comparing reaction of the amount of vinyl acetate substrate materials
Table 1 the result shows that, when flow velocity be 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 acetate, the conversion ratio of reaction also increases as,
When substrate than benzyl mercaptan and vinyl acetate is 1:When 2, the conversion ratio of reaction is optimal, so micro-fluidic microchannel in the present invention
The ratio between amount of optimal substrate materials is 1 in reactor:2.
Embodiment 6-9
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 [%] |
| 6 | 40 | 53 | 95 |
| 7 | 45 | 67 | 98 |
| 1 | 50 | 75 | 97 |
| 8 | 55 | 72 | 96 |
| 9 | 60 | 68 | 95 |
Table 2 the result shows that, when flow velocity be 10.4 μ Lmin-1, the reaction time is 30min, and reactor is using DMSO to have
The ratio between amount of solvent, reactant benzyl mercaptan and vinyl acetate substance is 1:2, when reaction temperature is in 50 DEG C, instead
The conversion ratio answered is optimal, temperature or the Tai Gao or too low activity that will all influence enzyme.So micro-fluidic microchannel plate should in the present invention
Optimum temperature is 50 DEG C in device.
Embodiment 10-13
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 [DEG C] | Conversion ratio [%] | Selectivity [%] |
| 10 | 20 | 54 | 95 |
| 11 | 25 | 68 | 98 |
| 1 | 30 | 75 | 98 |
| 12 | 35 | 71 | 95 |
| 13 | 40 | 69 | 97 |
Table 3 the result shows that, when reactor is using DMSO as organic solvent, reactant benzyl mercaptan and vinyl acetate substance
The ratio between amount be 1:2, reaction temperature is 50 DEG C, when reacted between be 30min when, reaction conversion ratio 75%.Institute
With 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 4 institute of table
Show.
Table 4：Influence of the different enzymes to reaction conversion ratio and selectivity
| Comparative example | Enzyme source | Conversion ratio [%] | Selectivity [%] |
| 1 | PPL | 18 | 75 |
| 2 | Novozym 435 | 9 | 95 |
| 3 | Bacillus alkaline protease | 20 | 85 |
| Embodiment 1 | Lipozyme TL IM | 75 | 98 |
Table 4 the result shows that, it is different for the acylation reaction of enzymatic benzyl mercaptan in microfluidic channel reactor
Enzyme has fairly obvious influence to reaction.The reaction is catalyzed using bacillus alkaline protease, S- thioacetic acid benzyl esters
Conversion ratio is 20%.And 435 catalytic reactions of Novozym are utilized, the conversion ratio of S- thioacetic acid benzyl esters is only 9%.From table 4
As a result see, for the acylation reaction of enzymatic benzyl mercaptan in microfluidic channel reactor, most effective catalyst is fat
Enzyme Lipozyme TL IM, the conversion ratio of benzyl mercaptan is 75%, and selectivity is 98%.
Claims (9)
- A kind of 1. method of lipase-catalyzed online synthesis S- thioacetic acid benzyl esters, it is characterised in that：The method uses miniflow Channel reactor is controlled, the microfluidic channel reactor includes sequentially connected syringe, reaction channel and product collector, The syringe is installed in syringe pump, and the syringe is connected by the first connecting pipe with reaction channel entrance, described Product collector is connected by the second connecting pipe and reaction channel outlet, and the reaction channel internal diameter is 0.8~2.4mm, instead Answer a length of 0.5~1.0m of passage；The described method includes：Using dimethyl sulfoxide as reaction dissolvent, with benzyl mercaptan and vinyl acetate For raw material, using Lipozyme TL IM as catalyst, the raw material and the reaction dissolvent are placed in syringe In, Lipozyme TL IM are uniformly filled in reaction channel, make under the promotion of syringe pump the raw material and The reaction dissolvent, which is continuously passed through in reaction channel, carries out acylation reaction, and controlling reaction temperature is 20~60 DEG C, the reaction time For 20~40min, reaction solution is collected by product collector online, the reaction solution is post-treated to obtain S- thioacetic acid benzyls Ester；The ratio between the benzyl mercaptan and the amount of substance of vinyl acetate are 1:0.5~6；The addition of the catalyst with The volume of reaction dissolvent used is calculated as 0.025~0.05g/mL.
- 2. the method for lipase-catalyzed online synthesis S- thioacetic acid benzyl esters as described in claim 1, it is characterised in that：It is described Syringe there are two, be the first syringe and the second syringe respectively, first connecting pipe is Y types or T-shaped pipeline, First syringe and the second note syringe is connected to two interfaces of the Y types or T-shaped pipeline and passes through institute The Y types or T-shaped pipeline stated are connected with the reaction channel.
- 3. the method for lipase-catalyzed online synthesis S- thioacetic acid benzyl esters as claimed in claim 2, it is characterised in that：It is described Method comprise the following steps：The ratio between amount with substance is 1:0.5~6 benzyl mercaptan is raw material with vinyl acetate, with fat Fat enzyme Lipozyme TL IM are catalyst, and using dimethyl sulfoxide as reaction dissolvent, Lipozyme TL IM are uniformly filled out It fills in reaction channel, first with dimethyl sulfoxide dissolving benzyl mercaptan loaded in the first syringe；Acetic acid second is dissolved with dimethyl sulfoxide Enester is loaded in the second syringe；The first syringe, the second syringe are loaded in same syringe pump again, then in syringe pump Raw material and reaction dissolvent is made after by the Y types or T-shaped pipeline summarizing simultaneously to enter in reaction channel under synchronous promotion to carry out instead Should, controlling reaction temperature is 20~60 DEG C, and the reaction time is 20~40min, collects reaction solution online by product collector, instead Answer the post-treated obtained S- thioacetic acids benzyl ester of liquid；The addition of the catalyst is 0.5~1g.
- 4. the method for lipase-catalyzed online synthesis S- thioacetic acid benzyl esters as described in claim 1, it is characterised in that：It is described Microfluidic channel reactor includes insulating box, and the reaction channel is placed in insulating box.
- 5. the method for lipase-catalyzed online synthesis S- thioacetic acid benzyl esters as claimed in claim 3, it is characterised in that：It is described Microfluidic channel reactor includes insulating box, and the reaction channel is placed in insulating box.
- 6. the method for the lipase-catalyzed online synthesis S- thioacetic acid benzyl esters as described in one of Claims 1 to 5, feature exist In：The ratio between amount of substance of the benzyl mercaptan and vinyl acetate is 1:1~3.
- 7. the method for the lipase-catalyzed online synthesis S- thioacetic acid benzyl esters as described in one of Claims 1 to 5, feature exist In：The acylation reaction temperature is 40~60 DEG C, and the acylation reaction time is 25~35min.
- 8. the method for the lipase-catalyzed online synthesis S- thioacetic acid benzyl esters as described in one of Claims 1 to 5, feature exist In：The ratio between amount of substance of the benzyl mercaptan and vinyl acetate is 1:2.
- 9. the method for the lipase-catalyzed online synthesis S- thioacetic acid benzyl esters as described in one of Claims 1 to 5, feature exist It is in the post-processing approach：The vacuum distillation of gained reaction solution removes solvent, and gained crude on silica gel column chromatography for separation is used 200-300 mesh silica gel wet method dress posts, elution reagent is petroleum ether:Ethyl acetate volume ratio 20:1 mixed solvent, crude product are used Wet method upper prop after a small amount of elution reagent dissolving collects eluent, while TLC tracking elution processes, will obtain containing single production The eluent merging of object is evaporated, and can obtain pale yellow oil, is S- thioacetic acid benzyl esters.
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