CN107955824A - A kind of lipase-catalyzed online synthesis S-（4- chlorobenzyls）The method of laurate thioesters - Google Patents

A kind of lipase-catalyzed online synthesis S-（4- chlorobenzyls）The method of laurate thioesters Download PDF

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CN107955824A
CN107955824A CN201711393694.XA CN201711393694A CN107955824A CN 107955824 A CN107955824 A CN 107955824A CN 201711393694 A CN201711393694 A CN 201711393694A CN 107955824 A CN107955824 A CN 107955824A
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reaction
laurate
thioesters
syringe
chlorobenzyls
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杜理华
龙瑞杰
沈乐
罗锡平
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Zhejiang University of Technology ZJUT
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Abstract

The invention discloses a kind of method of lipase-catalyzed online synthesis S (4 chlorobenzyl) laurate thioesters：Using dimethyl sulfoxide as reaction dissolvent, using molar ratio as 1:0.5~6 4 chloro benzyl mercaptans and vinyl laurate 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 (4 chlorobenzyl) laurate thioesters through conventional post processing.The present invention has the advantages that short reaction time, high selectivity and yield are high.

Description

A kind of method of lipase-catalyzed online synthesis S- (4- chlorobenzyls) laurate thioesters
(1) technical field
The present invention relates to a kind of method of lipase-catalyzed online synthesis S- (4- chlorobenzyls) laurate 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.
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 the side of lipase-catalyzed online synthesis S- (4- chlorobenzyls) laurate thioesters in micro passage reaction Method, it is intended to find a kind of new technology synthesized online of S- of high-efficiency environment friendly (4- chlorobenzyls) laurate thioesters.
(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- (4- chlorobenzyls) laurate 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- (4- chlorobenzyls) laurate thioesters, it is characterised in that：The side 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, and the syringe is entered by the first connecting pipe with reaction channel Mouth connection, the product collector are 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- chloro benzyl mercaptans It is raw material with vinyl laurate, it is using Lipozyme TL IM as catalyst, the raw material and the reaction is molten Agent is placed in syringe, and Lipozyme TL IM are uniformly filled in reaction channel, institute is made under the promotion of syringe pump The raw material and the reaction dissolvent stated, which are continuously passed through in reaction channel, carries out acylation reaction, and controlling reaction temperature is 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 S- (4- chlorobenzyls) laurate thioesters；The ratio between the 4- chloro benzyl mercaptans and the amount of material of vinyl laurate are 1:0.5~ 6；The addition of the catalyst is calculated as 0.025~0.05g/mL with the volume of the reaction dissolvent.
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 laurate 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；Vinyl laurate is dissolved with dimethyl sulfoxide Ester is loaded in the second syringe；Then raw material and reaction dissolvent is made to be passed through in reaction channel and carry out under the synchronous promotion of syringe pump Reaction, controlling reaction temperature are 20~60 DEG C, and the reaction time is 20~40min, and reaction solution is collected online by product collector, Post-treated obtained S- (4- chlorobenzyls) the laurate thioesters of reaction solution；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 4- chloro benzyl mercaptans and vinyl laurate is preferably 1:1~3, most preferably For 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- (4- chlorobenzyls) laurate 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 dissolved with a small amount of elution reagent Wet method upper prop afterwards, collects eluent, while TLC tracking elution processes, the obtained eluent containing single product is merged and is steamed It is dry, yellow oily liquid can be obtained, is S- (4- chlorobenzyls) laurate thioesters.
Compared with prior art, beneficial effects of the present invention are：
The present invention utilizes lipase-catalyzed online synthesis S- (4- chlorobenzyls) laurate sulphur in microfluidic channel reactor Ester, which not only significantly shortens the reaction time, but also has high conversion ratio and selectivity；Utilize economy first at the same time 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.
(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- (4- chlorobenzyls) laurate thioesters
Device is with reference to figure 1：4- chloro benzyl mercaptans (1.0mmol) are dissolved in 10mLDMSO, vinyl laurate (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-1's Flow velocity is entered in reaction channel by " Y " connector to be reacted, and controls temperature of reactor at 50 DEG C by constant temperature water box, reaction Liquid continuous flowing reactive 30min, reaction result in reaction channel 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=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 oily liquid, obtain S- (4- chlorobenzyls) laurate thioesters, HPLC detection 4- benzyl chloride sulphur Alcohol conversion 78%, selectivity 99%.
Nuclear-magnetism characterization result is as follows：
1H NMR(500MHz,CDCl3):δ=7.34 (dd, J=18.5,7.6Hz, 4H), 4.16 (s, 2H), 2.59 (t, J =7.2Hz, 2H), 1.75 (d, J=7.0Hz, 2H), 1.32 (s, 16H), 0.96 (t, J=6.0Hz, 3H)13C NMR (125MHz,CDCl3):δ=199.3,139.8,132.6,131.5,128.7,43.8,33.1,32.0,29.7,29.6- 29.2,28.7,25.6,22.7,14.0.
Embodiment 2-6
Change the ratio between amount of substrate materials of 4- chloro benzyl mercaptans and vinyl laurate in micro-fluidic micro passage reaction, control Temperature 50 C processed, 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 laurate 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 laurate, the conversion ratio of reaction is also with increasing Add, when substrate than 4- chloro benzyl mercaptan and vinyl laurate is 1:When 2, the conversion ratio of reaction is optimal, so miniflow in the present invention It is 1 to control the ratio between amount of optimal substrate materials 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 54 98
8 45 70 97
1 50 78 99
9 55 72 98
10 60 69 96
Table 2 the result shows that, when flow velocity is 10.4 μ Lmin-1, the reaction time is 30min, reactor using DMSO as The ratio between amount of organic solvent, reactant 4- chloro benzyl mercaptans and vinyl laurate 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 64 98
12 25 72 99
1 30 78 99
13 35 75 98
14 40 71 97
Table 3 the result shows that, when reactor is using DMSO as organic solvent, reactant 4- chloro benzyl mercaptans and vinyl laurate The ratio between amount of material is 1:2, reaction temperature is 50 DEG C, when reacted between when be 30min, reaction conversion ratio is up to 78%.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 15 76
2 Novozym 435 7 99
3 Bacillus alkaline protease 18 84
Embodiment 1 LipozymeTL IM 78 99
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, S- (4- chlorobenzyls) bay The conversion ratio of sour thioesters is 18%.And it is catalyzed the reaction, the conversion of S- (4- chlorobenzyls) laurate thioesters using Novozym 435 Rate is only 7%.In terms of the result of table 4, for the acylation reaction of enzymatic 4- chloro benzyl mercaptans in microfluidic channel reactor, most Effective catalyst is that the conversion ratio of Lipozyme TL IM, 4- chloro benzyl mercaptans is 78%, and selectivity is 99%.

Claims (9)

  1. A kind of 1. method of lipase-catalyzed online synthesis S- (4- chlorobenzyls) laurate thioesters, it is characterised in that：The method Using microfluidic channel reactor, the microfluidic channel reactor includes sequentially connected syringe, reaction channel and production Thing collector, the syringe are installed in syringe pump, and the syringe passes through the first connecting pipe and reaction channel entrance Connection, the product collector are connected by the first connecting pipe and reaction channel outlet, the reaction channel internal diameter for 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 laurate is raw material, using Lipozyme TL IM as catalyst, the raw material and the reaction is molten Agent is placed in syringe, and Lipozyme TL IM are uniformly filled in reaction channel, are made under the promotion of syringe pump The raw 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, the reaction time is 20~40min, collects reaction solution online by product collector, the reaction solution is post-treated to be obtained S- (4- chlorobenzyls) laurate thioesters；The ratio between the 4- chloro benzyl mercaptans and the amount of material of vinyl laurate are 1:0.5~ 6；The addition of the catalyst is calculated as 0.025~0.05g/mL with the volume of the reaction dissolvent.
  2. 2. the method for lipase-catalyzed online synthesis S- (4- chlorobenzyls) laurate thioesters as claimed in claim 1, its feature It is：The syringe has two, is the first syringe and the second syringe respectively, and first connecting pipe is Y types Or T-shaped pipeline, first syringe and the second note syringe are connected to the Y types or two of T-shaped pipeline connect Mouth is simultaneously connected with the reaction channel again by the Y types or T-shaped pipeline parallel connection.
  3. 3. the method for lipase-catalyzed online synthesis S- (4- chlorobenzyls) laurate thioesters as claimed in claim 2, its feature It is：The method comprises the following steps：The ratio between amount with material is 1:0.5~6 4- chloro benzyl mercaptans and vinyl laurate Ester is raw material, using Lipozyme TL IM as catalyst, using dimethyl sulfoxide as reaction dissolvent, by Lipozyme TL IM are uniformly filled in reaction channel, are first loaded on dimethyl sulfoxide dissolving 4- chloro benzyl mercaptans in the first syringe；It is sub- with diformazan Sulfone dissolving vinyl laurate is loaded in the second syringe；Then lead to raw material and reaction dissolvent under the synchronous promotion of syringe pump Enter in reaction channel and reacted, controlling reaction temperature is 20~60 DEG C, and the reaction time is 20~40min, passes through collection of products Device collects reaction solution, post-treated obtained S- (4- chlorobenzyls) the laurate thioesters of reaction solution online；The addition of the catalyst Measure as 0.5~1g.
  4. 4. the method for lipase-catalyzed online synthesis S- (4- chlorobenzyls) laurate thioesters as claimed in claim 1, its feature It is：The microfluidic channel reactor includes insulating box, and the reaction channel is placed in insulating box.
  5. 5. the method for lipase-catalyzed online synthesis S- (4- chlorobenzyls) laurate thioesters as claimed in claim 3, its feature It is：The microfluidic channel reactor includes insulating box, and the reaction channel is placed in insulating box.
  6. 6. the method for lipase-catalyzed online synthesis S- (4- chlorobenzyls) laurate thioesters as described in one of Claims 1 to 5, It is characterized in that：The ratio between amount of material of the 4- chloro benzyl mercaptans and vinyl laurate is 1:1~3.
  7. 7. the method for lipase-catalyzed online synthesis S- (4- chlorobenzyls) laurate thioesters as described in one of Claims 1 to 5, It is characterized in that：The acylation reaction temperature is 40~60 DEG C, and the acylation reaction time is 25~35min.
  8. 8. the method for lipase-catalyzed online synthesis S- (4- chlorobenzyls) laurate thioesters as described in one of Claims 1 to 5, It is characterized in that：The ratio between amount of material of the 4- chloro benzyl mercaptans and vinyl laurate is 1:2.
  9. 9. the method for lipase-catalyzed online synthesis S- (4- chlorobenzyls) laurate thioesters as described in one of Claims 1 to 5, It is characterized in that the post-processing approach is：The vacuum distillation of gained reaction solution removes solvent, gained crude on silica gel column chromatography Separation, with 200-300 mesh silica gel wet method dress posts, elution reagent is petroleum ether:Ethyl acetate=20:1 mixed solvent, crude product Wet method upper prop after being dissolved with a small amount of elution reagent, collects eluent, while TLC tracking elution processes, will obtain containing single The eluent of product, which merges, to be evaporated, and can obtain yellow oily liquid, is S- (4- chlorobenzyls) laurate thioesters.
CN201711393694.XA 2017-12-21 2017-12-21 A kind of lipase-catalyzed online synthesis S-（4- chlorobenzyls）The method of laurate thioesters Withdrawn CN107955824A (en)

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