CN107988277A - A kind of method of lipase-catalyzed online synthesis S- benzyl palmitic acid thioesters - Google Patents
A kind of method of lipase-catalyzed online synthesis S- benzyl palmitic acid thioesters Download PDFInfo
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Abstract
The invention discloses a kind of method of lipase-catalyzed online synthesis S benzyl palmitic acid thioesters：Using dimethyl sulfoxide as reaction dissolvent, using molar ratio as 1:0.5~6 benzyl mercaptan and vinyl palmitate 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 S benzyl palmitic acid thioesters 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 method of lipase-catalyzed online synthesis S- benzyl palmitic acid thioesters.
(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.
The research of Enzyme catalyzed synthesis sulfur ester is also relatively fewer, and the synthesis of enzymatic sulfur ester is adopted more
With acylase, this method need the longer reaction time (48h) and the conversion ratio for specific substrates reaction be not it is especially desirable,
And reaction cost is higher.For the new technology for developing a kind of efficient green, economic and environment-friendly sulfur ester synthesizes, Wo Menyan
The method of lipase-catalyzed online synthesis S- benzyl palmitic acid thioesters in micro passage reaction is studied carefully, it is intended to find a kind of Efficient Ring
The new technology synthesized online of the S- benzyl palmitic acid thioesters of guarantor.
(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- benzyl palmitic acid thioesters, 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- benzyl palmitic acid thioesters, the method are anti-using microfluidic channel
Device is answered, the microfluidic channel reactor includes sequentially connected syringe, reaction channel and product collector, the injection
Device is installed in syringe pump, and the syringe is connected by the first connecting pipe with reaction channel entrance, the collection of products
Device is connected by the first connecting pipe and reaction channel outlet, and the reaction channel internal diameter is 0.8~2.4mm, and reaction channel is grown
For 0.5~1.0m；The described method includes：Using dimethyl sulfoxide as reaction dissolvent, using benzyl mercaptan and vinyl palmitate as raw material,
Using Lipozyme TL IM as catalyst, the raw material and the reaction dissolvent are placed in syringe, by fat
Enzyme LipozymeTL IM are uniformly filled in reaction channel, and the raw material and the reaction are made under the promotion of syringe pump
Solvent, 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, collects reaction solution, the reaction solution is post-treated to obtain S- benzyl palmitic acid thioesters online by product collector；
The ratio between the benzyl mercaptan and the amount of material of vinyl palmitate are 1:0.5~6；The addition of the catalyst is with institute
The volume for stating reaction dissolvent 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, 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 benzyl mercaptan and vinyl palmitate 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 benzyl mercaptan in the first syringe；Vinyl palmitate is dissolved with dimethyl sulfoxide
Loaded in the second syringe；Then raw material and reaction dissolvent is made to be passed through in reaction channel and carry out instead under the synchronous promotion of syringe pump
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- benzyls palmitic acid thioesters of liquid；The addition of the catalyst is 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 TL IM believe the business of (novozymes) company production using Novi
Product, it is a kind of by microorganism preparation, 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.
Further, the ratio between amount of material of the benzyl mercaptan and vinyl palmitate is preferably 1:1~3, be 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 be able to can be obtained by conventional post-processing approach
S- benzyl palmitic acid thioesters.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 posts, elution reagent is petroleum ether:Ethyl acetate=20:1, sample is wet after being dissolved with a small amount of elution reagent
Method upper prop, collects eluent, while TLC tracking elution processes, the obtained eluent containing single product is merged and is evaporated, can
It is S- benzyl palmitic acid thioesters to obtain white solid.
Compared with prior art, beneficial effects of the present invention are：
The present invention utilizes lipase-catalyzed online synthesis S- benzyl palmitic acid thioesters, the method in microfluidic channel reactor
The reaction time is not only significantly shortened, but also there is high conversion ratio and selectivity；Utilize economic lipase first at the same time
LipozymeTL 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.
(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 S- benzyl palmitic acid thioesters
Device is with reference to figure 1：Benzyl mercaptan (1.0mmol) is dissolved in 10mLDMSO, vinyl palmitate (2.0mmol)
It is dissolved in 10mL DMSO, is then loaded on respectively spare in 10mL syringes；0.87g Lipozyme TL IM are uniformly filled out
Fill in reaction channel, under the promotion of PHD2000 syringe pumps, two-way reaction solution is respectively with 10.4 μ Lmin-1Flow velocity pass through
" Y " connector, which enters in reaction channel, to be reacted, and controlling temperature of reactor by constant temperature water box, reaction solution is reacting at 50 DEG C
Continuous flowing reactive 30min, reaction result pass through thin-layer chromatography TLC tracing detections in passage.
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 white solid, obtain S- benzyl palmitic acid thioesters, HPLC detection benzyl thiol conversions
85%, selectivity 96%.
Nuclear-magnetism characterization result is as follows：
1H NMR(500MHz,CDCl3):δ=7.30 (dd, J=11.2,7.8Hz, 5H), 4.14 (s, 2H), 2.61-2.54
(m, 2H), 1.66 (dd, J=41.7,34.3Hz, 2H), 1.47-1.23 (m, 24H), 0.91 (t, J=7.0Hz, 3H)13C NMR
(125MHz,CDCl3):δ=198.9,137.8,129.3,129.0,128.8,128.6,127.2,43.9,33.1,31.9,
29.7,29.6–29.1,29.0,25.6,22.7,14.1.
Embodiment 2-6
Change the ratio between amount of substrate materials of benzyl mercaptan and vinyl palmitate in micro-fluidic micro passage reaction, control
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 palmitate substrate materials
| Embodiment | Benzyl mercaptan:Vinyl palmitate | Conversion ratio [%] | Selectivity [%] |
| 2 | 1:0.5 | 25 | 95 |
| 3 | 1:1 | 61 | 95 |
| 1 | 1:2 | 85 | 96 |
| 4 | 1:3 | 79 | 96 |
| 5 | 1:4 | 73 | 94 |
| 6 | 1:5 | 70 | 97 |
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 palmitate, the conversion ratio of reaction is also with increasing
Add, when substrate than benzyl mercaptan and vinyl palmitate is 1:When 2, the conversion ratio of reaction is optimal, so micro-fluidic in the present invention
The ratio between amount of optimal substrate materials is 1 in 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 | 60 | 95 |
| 8 | 45 | 76 | 97 |
| 1 | 50 | 85 | 96 |
| 9 | 55 | 80 | 96 |
| 10 | 60 | 75 | 97 |
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 benzyl mercaptan and vinyl palmitate material is 1:2, benzyl concentrations of mercaptans in reaction system
When being 0.05mmol/mL, when reaction temperature is in 50 DEG C, the conversion ratio of reaction is optimal, and temperature or Tai Gao or too low will
Influence the activity of enzyme.So optimum temperature is 50 DEG C in micro-fluidic micro passage reaction in the present invention.
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 | 66 | 97 |
| 12 | 25 | 76 | 98 |
| 1 | 30 | 85 | 96 |
| 13 | 35 | 80 | 94 |
| 14 | 40 | 75 | 98 |
Table 3 the result shows that, when reactor is using DMSO as organic solvent, reactant benzyl mercaptan and vinyl palmitate thing
The ratio between amount of matter is 1:2, reaction temperature is 50 DEG C, when reacted between when be 30min, reaction conversion ratio 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
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.Using bacillus alkaline protease catalytic reaction, S- benzyl palmitic acid thioesters
Conversion ratio is 22%.And the reaction is catalyzed using Novozym 435, the conversion ratio of S- benzyl palmitic acid thioesters is only 10%.From
The result of table 4 sees that for the acylation reaction of enzymatic benzyl mercaptan in microfluidic channel reactor, most effective catalyst is
Lipozyme TL IM, the conversion ratio of benzyl mercaptan is 85%, and selectivity is 96%.
Claims (9)
- A kind of 1. method of lipase-catalyzed online synthesis S- benzyl palmitic acid thioesters, it is characterised in that：The method is using micro- Flow control channel reactor, the microfluidic channel reactor include sequentially connected syringe, reaction channel and collection of products Device, the syringe are installed in syringe pump, and the syringe is connected by the first connecting pipe with reaction channel entrance, institute Product collector to be stated to connect by the first connecting pipe and reaction channel outlet, the reaction channel internal diameter is 0.8~2.4mm, A length of 0.5~the 1.0m of reaction channel；The described method includes：Using dimethyl sulfoxide as reaction dissolvent, with benzyl mercaptan and palmitic acid second Enester is raw material, and using Lipozyme TL IM as catalyst, the raw material and the reaction dissolvent are placed in note In emitter, Lipozyme TL IM are uniformly filled in reaction channel, the original is made under the promotion of syringe pump Material and the reaction dissolvent, which are continuously passed through in reaction channel, carries out acylation reaction, and controlling reaction temperature is 20~60 DEG C, reaction Time is 20~40min, collects reaction solution online by product collector, the reaction solution is post-treated to obtain S- benzyls palm fibre Palmitic acid acid thioesters；The ratio between the benzyl mercaptan and the amount of material of vinyl palmitate are 1:0.5~6；The catalyst Addition is calculated as 0.025~0.05g/mL with the volume of the reaction dissolvent.
- 2. the method for lipase-catalyzed online synthesis S- benzyl palmitic acid thioesters as claimed in claim 1, it is characterised in that：Institute The syringe stated has two, is the first syringe and the second syringe respectively, and first connecting pipe is Y types or T-shaped pipe Road, first syringe are connected to two interfaces of the Y types or T-shaped pipeline with the second note syringe and pass through The Y types or T-shaped pipeline parallel connection are connected with the reaction channel again.
- 3. the method for lipase-catalyzed online synthesis S- benzyl palmitic acid thioesters as claimed in claim 2, it is characterised in that：Institute The method stated comprises the following steps：The ratio between amount with material is 1:0.5~6 benzyl mercaptan and vinyl palmitate are raw material, It is using dimethyl sulfoxide as reaction dissolvent, Lipozyme TL IM is equal using Lipozyme TL IM as catalyst It is even to be filled in reaction channel, first it is loaded on dimethyl sulfoxide dissolving benzyl mercaptan in the first syringe；Palm fibre is dissolved with dimethyl sulfoxide Palmitic acid vinyl acetate is loaded in the second syringe；Then raw material and reaction dissolvent is made to be passed through reaction and lead under the synchronous promotion of syringe pump Reacted in road, controlling reaction temperature is 20~60 DEG C, and the reaction time is 20~40min, is received online by product collector Collect reaction solution, the post-treated obtained S- benzyls palmitic acid thioesters of reaction solution；The addition of the catalyst is 0.5~1g.
- 4. the method for lipase-catalyzed online synthesis S- benzyl palmitic acid thioesters as claimed in claim 1, it is characterised in that：Institute Stating microfluidic channel reactor includes insulating box, and the reaction channel is placed in insulating box.
- 5. the method for lipase-catalyzed online synthesis S- benzyl palmitic acid thioesters as claimed in claim 3, it is characterised in that：Institute Stating 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- benzyl palmitic acid thioesters as described in one of Claims 1 to 5, its feature It is：The ratio between amount of material of the benzyl mercaptan and vinyl palmitate is 1:1~3.
- 7. the method for the lipase-catalyzed online synthesis S- benzyl palmitic acid thioesters as described in one of Claims 1 to 5, its feature It is：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- benzyl palmitic acid thioesters as described in one of Claims 1 to 5, its feature It is：The ratio between amount of material of the benzyl mercaptan and vinyl palmitate is 1:2.
- 9. the method for the lipase-catalyzed online synthesis S- benzyl palmitic acid thioesters as described in one of Claims 1 to 5, its feature It is that the post-processing approach is：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=20:1 mixed solvent, crude product 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 white solid, is S- benzyl palmitic acid thioesters.
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| CN109735582A (en) * | 2018-12-24 | 2019-05-10 | 浙江工业大学 | A kind of method of lipase-catalyzed online synthesizing cyclohexane 1 alcohols beta-alkamine derivative |
| CN109762853A (en) * | 2018-12-24 | 2019-05-17 | 浙江工业大学 | A kind of method of lipase-catalyzed online petrohol class beta-alkamine derivative |
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| CN109988787A (en) * | 2018-12-24 | 2019-07-09 | 浙江农林大学 | A kind of method of lipase-catalyzed online synthesis 2- phenylamino cyclohexanol |
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