CN107384992A - A kind of method of lipase-catalyzed online synthesis 5 '-O- lauroyl -5-methyl-uridin - Google Patents
A kind of method of lipase-catalyzed online synthesis 5 '-O- lauroyl -5-methyl-uridin Download PDFInfo
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- CN107384992A CN107384992A CN201610327780.XA CN201610327780A CN107384992A CN 107384992 A CN107384992 A CN 107384992A CN 201610327780 A CN201610327780 A CN 201610327780A CN 107384992 A CN107384992 A CN 107384992A
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Abstract
The invention discloses a kind of method of the lipase-catalyzed online methyluridine of synthesis 5'O lauroyl 5.Methods described includes：Using volume ratio as 1:8~16 dimethyl sulfoxide and tert-pentyl alcohol is reaction dissolvent, using mol ratio as 1:5~13 5 methyluridines and vinyl laurate are raw material; using 0.5~1.0g Lipozymes TLIM as catalyst; raw material and reaction dissolvent are placed in syringe; Lipozyme TLIM is uniformly filled in the reaction channel of microfluidic channel reactor; raw material and reaction dissolvent is continuously passed through in reaction channel 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 15~50 DEG C to control esterification reaction temperature, and reaction time of esterification is 20~35min, collects reaction solution online by product collector, reaction solution obtains the methyluridine of 5'O lauroyl 5 through conventional post processing.The present invention has the advantages of reaction time is short, selectivity is high and yield is high.
Description
(1) technical field
The present invention relates to a kind of lipase-catalyzed online controllable selectivity synthesis 5'-O- lauroyl -5-methyl-uridin
Method
(2) background technology
Nucleoside medicine occupies an important position in the treatment of viral disease.Clinically use at present disease-resistant
In cytotoxic drug, nucleoside medicine proportion is up to more than 60%.Most nucleoside class compound is polyhydroxy chemical combination
Thing, has that polarity is higher, intestinal permeability is relatively low, and fat-soluble poor, toxic side effect is big and oral bioavailability
Spend the defects of relatively low.After nucleoside compound is by being esterified modification, its fat-soluble, raising pharmacological activity can be strengthened,
Improve its oral administration biaavailability.In common chemical method esterification process, multiple hydroxyls are likely to participate in ester
Change, product is the mixture of monoesters and polyester, thus needs through " radical protection --- esterification --- is deprotected group "
Three steps could obtain the product of single position esterification., can be with and enzyme has good selectivity and selectivity to substrate
Selectivity is esterified to some hydroxyl of nucleosides, and reaction selectivity is higher, reduces the tired of product later separation
Difficulty, therefore biocatalysis technology plays more and more important role in the esterification of nucleoside compound.
It is micro-fluidic learn (Microfluidics) be in micron scale construction manipulation nanoliter to picoliters volume fluid technology
It is the new cross discipline to emerge rapidly nearly ten years with science.Currently, the development of micro-fluidic surmounts significantly
The purpose of original predominantly analytical chemistry service, and turn into whole chemistry subject, life science, instrument
The important technological platform of device science or even information science new round innovation research.
A first piece, which has been delivered, from Harrison seminars in 1997 in micro-fluidic chip microreactor synthesizes compound
Document after, micro-fluidic chip reactor has been successfully used to a variety of organic synthesis, and illustrates extensive
Application prospect.With the development of microring array, micro-reacting tcchnology in micro-fluidic chip, carry out synthesizing instead in the chips
One of the study hotspot in micro-fluidic chip field should be had become.
Compared with conventional chemical reactor, micro passage reaction not only has and makes diffusion length between reactant significantly
Shorten, and mass transfer velocity is fast；The reaction conditions such as reactant ratio, temperature, reaction time and flow velocity are easily controlled
System, side reaction are less；Need reactant dosage little, can not only reduce expensive, poisonous, adverse reaction thing
Dosage, caused environmental contaminants are also few in course of reaction, are a kind of environment-friendly, study on the synthesis novel substances
Technology.
At present, more domestic and foreign scholars carry out the Enzyme catalyzed synthesis of nucleosides acylation reaction in organic media
Research, but this method is catalyzed from acylase more, generally requires the longer reaction time (12-24h),
And the conversion ratio of reaction and selectivity be not high, therefore we have studied lipase-catalyzed online in micro passage reaction
The method for synthesizing 5'-O- lauroyl -5-methyl-uridin, it is intended to find a kind of 5'-O- lauroyl -5- of high-efficiency environment friendly
The online controllable method for selective synthesis of methyluridine.
(3) content of the invention
The technical problem to be solved in the present invention is to provide lipase-catalyzed online in a kind of microfluidic channel reactor
The new technology of 5'-O- lauroyl -5-methyl-uridin is synthesized, 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 5'-O- lauroyl -5-methyl-uridin, methods described is using micro-
Stream control channel reactor, described microfluidic channel reactor include syringe pump, syringe, reaction channel and production
Thing collector, the syringe are installed in syringe pump, are connected by an interface with reaction channel entrance, institute
State product collector to connect by an interface and reaction channel outlet, the reaction channel internal diameter is
0.8~2.4mm, a length of 0.5~1.0m of reaction channel；Methods described includes：Using volume ratio as 1:The two of 8~16
First sulfoxide (DMSO) and tert-pentyl alcohol are reaction dissolvent, using mol ratio as 1:5~13 5-methyl-uridin and the moon
Laurate is raw material, using 0.5~1.0g Lipozymes TLIM as catalyst, by raw material and instead
Answer solvent to be placed in syringe, Lipozyme TLIM is uniformly filled in reaction channel, noting
Penetrating under the promotion of pump, which makes raw material and reaction dissolvent continuously be passed through in reaction channel, carries out acylation reaction, makes reaction system
The concentration of 5-methyl-uridin is 0.03~0.07mmol/mL in (raw material+reaction dissolvent), controls acylation reaction temperature
To spend for 15~50 DEG C, the acylation reaction time is 20~35min, and reaction solution is collected online by product collector,
Reaction solution obtains 5'-O- lauroyl -5-methyl-uridin through conventional post processing.
In the microfluidic channel reactor that the present invention uses, the syringe number can be one or more, depending on
Depending on specific reaction requirement.For example when using two syringes, T-shaped or Y type interfaces can be used to make not
Same reactant introduces from two entrances, confluxes into public reaction channel, passes through the middle reactant of microchannel
Molecule contacts increase with collision probability, two bursts of reaction liquid streams is mixed and is reacted in public reaction channel.
Described microfluidic channel reactor also includes insulating box, and described reaction channel is placed in insulating box, with
This can effective controlling reaction temperature.Described insulating box can voluntarily select according to reaction temperature requirement, such as
Constant temperature water box 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；
Shape for reaction channel is preferably shaped form, it is ensured that reaction solution stably passes through.
The present invention first dissolves 5-methyl-uridin in implementation process with DMSO, is further continued for adding tert-pentyl alcohol to one
Volume is determined, loaded on standby in syringe；Then vinyl laurate is dissolved to certain volume with tert-pentyl alcohol, be loaded on
It is standby in another syringe；Finally make raw material and reaction under syringe pump (such as the syringe pumps of PD 1200) promotion
Solvent, which is passed through in reaction channel, to be reacted.
In the present invention, described Lipozyme TLIM is given birth to using letter (Novozymes) company of Novi
The commodity of production, it is a kind of 1,3 position-specifics prepared by microorganism, food-grade lipase (EC3.1.1.3)
Preparation on particle silica gel.It is being obtained from Thermomyceslanuginosus, gene-modified with one kind
Aspergillus oryzae (Aspergillusoryzae) microorganism is by submerged fermentation production.
Further, the volume ratio of dimethyl sulfoxide and tert-pentyl alcohol is preferably 1 in the reaction dissolvent:12~1:16, preferably
For 1:14.
Further, the mol ratio of the 5-methyl-uridin and vinyl laurate is preferably 1:7~13, more preferably
1:9~11, most preferably 1:9.
Further, the concentration of 5-methyl-uridin is preferably 0.04~0.06mmol/mL in reaction system, most preferably
For 0.05mmol/mL.
Further, the acylation reaction temperature is preferably 20~40 DEG C, most preferably 30 DEG C.
Further, the acylation reaction time is preferably 25~35min, most preferably 30min.
The reaction product of the present invention can collect online, and gained reaction solution can pass through conventional post-processing approach
Obtain 5'-O- lauroyl -5-methyl-uridin.The conventional 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 ethyl acetate:Methanol=40:1, sample
Wet method upper prop after product are dissolved with a small amount of elution reagent, eluent, while TLC tracking elution processes are collected, will
The obtained eluent containing single product, which merges, to be evaporated, and can obtain white solid, as 5'-O- lauroyl
- 5-methyl-uridin.
Compared with prior art, beneficial effects of the present invention are：The present invention utilizes in microfluidic channel reactor
Lipase-catalyzed online synthesis 5'-O- lauroyl -5-methyl-uridin, the method not only significantly shorten the reaction time,
And there is high conversion ratio and selectivity；Urged first using the Lipozyme TLIM of economy simultaneously
Change nucleosides esterification, reduce reaction cost, the advantage with economical and efficient.
(4) illustrate
Fig. 1 is the structural representation 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
Not limited to this：
The structural reference Fig. 1 for the microfluidic channel reactor that the embodiment of the present invention uses, including a syringe pump
(not shown), two syringes 1 and 2, reaction channel 3, constant temperature water box (5, only show that its plane is shown
It is intended to) and product collector 4；Two syringes 1 and 2 are installed in syringe pump, pass through a Y type interface
It is connected with the entrance of reaction channel 3, the reaction channel 3 is placed in constant temperature water box 5, passes through constant temperature water box
5 controlling reaction temperatures, the internal diameter 2.0mm of described reaction channel 3, pipe range 1m, the reaction channel 3
Outlet is connected by an interface with product collector 4.
Embodiment 1：The synthesis of 5'-O- lauroyl -5-methyl-uridin
Device is with reference to figure 1：5-methyl-uridin (1.0mmol) is dissolved in 1.33mLDMSO and 8.67mL uncles
In amylalcohol, vinyl laurate (9.0mmol) is dissolved in 10mL tert-pentyl alcohols, is then loaded on 10mL respectively
It is standby in syringe.0.87g Lipozymes TLIM is uniformly filled in reaction channel, in PD 1200
Under syringe pump promotes, two-way reaction solution is respectively with 10.4 μ Lmin-1Flow velocity by " Y " joint to enter reaction logical
Reacted in road, controlling temperature of reactor by constant temperature water box, reaction solution connects in reaction channel at 30 DEG C
Continuous flowing reactive 30min, reaction result pass through thin-layer chromatography TLC tracing detections.
Reaction solution is collected by product collector online, is evaporated under reduced pressure and removes solvent, it is wet with 200-300 mesh silica gel
Method fills post, and elution reagent is ethyl acetate:Methanol=40:1, pillar height 35cm, column diameter 4.5cm, sample is with less
Wet method upper prop after elution reagent dissolves is measured, eluent collects flow velocity 2mLmin-1, while TLC tracking elutions
Process, the obtained eluent containing single product is merged and is evaporated, obtains white solid, obtains the 5'-O- months
Osmanthus acyl -5-methyl-uridin, HPLC detection 5-methyl-uridins conversion ratio 97%, selectivity 100%.
Nuclear-magnetism characterization result is as follows：
1H-NMR(DMSO-d6,δ,ppm)：11.36(s,H3), 7.43 (d, J=1Hz, H6), 5.77 (d, 1H, J=5
Hz,H1'), 5.43 (d, 1H, J=5.5Hz, 3'-OH), 5.27 (d, 1H, J=5.5Hz, 2'-OH), 4.23 (m, 2H,
H2'+H3'),4.07(m,1H,H4'),3.96(m,2H,H5'), 2.33 (t, 2H, J=7Hz, H2”),1.79(d,3H,
J=0.5Hz, 5-CH 3),1.53(m,2H,H3”),1.23(br,16H,H4”+H5”+H6”+H7”+H8”+H9”
+H10”+H11”), 0.85 (t, 3H, J=7Hz, H12”).
13C NMR(DMSO-d6,ppm)：172.74(C1”),163.63(C4),150.66(C2),136.15(C6),
109.67(C5),88.21(C1'),81.04(C4'),72.47(C3'),69.81(C2'),63.06(C5'),33.37(C2”),
31.26(C10”),28.37-28.93(C4”+C5”+C6”+C7”+C8”+C9”),24.37(C3”),22.06(C11”),
13.94(C12”),12.05(5-CH3).
Embodiment 2-6
Change organic solvent volume ratio in microfluidic channel reactor, it is 50 DEG C to control temperature, and other are the same as implementation
Example 1, reaction result is as shown in table 1：
Table 1:Organic solvent compares the influence of reaction
The result of table 1 shows, when flow velocity is 10.4 μ Lmin-1, the reaction time is 30min, reaction temperature
It it is 50 DEG C, reactant 5-methyl-uridin and vinyl laurate mol ratio are 1:9,5- in reaction system
When methyluridine concentration is 0.05mmol/mL, conversion ratio with reactor organic solvent volume than increase and
Increase, works as DMSO:Tert-pentyl alcohol volume ratio reaches 1:Reach optimal when 14, being further continued for increase volume ratio will lead
Reactant dissolving is caused not exclusively to reduce conversion ratio.So most preferably have in micro-fluidic micro passage reaction in the present invention
Solvent volume ratio is 1:14.
Embodiment 7-11
Change the substrate mol ratio of 5-methyl-uridin and vinyl laurate in micro-fluidic micro passage reaction, control
Temperature 50 C, other are with embodiment 1, as a result as shown in table 2：
Table 2:5-methyl-uridin and influence of the vinyl laurate substrate mol ratio to reaction
The result of table 2 shows, when flow velocity is 10.4 μ Lmin-1, the reaction time is 30min, reaction temperature
It is 50 DEG C, organic solvent DMSO in reactor:Tert-pentyl alcohol volume ratio is 1:14,5- in reaction system
When methyluridine concentration is 0.05mmol/mL, with the increase of reactant vinyl laurate, reaction
Conversion ratio also increases as, when 5-methyl-uridin and vinyl laurate substrate mol ratio are 1:When 9, reaction
Conversion ratio is optimal, so optimal substrate mol ratio is 1 in micro-fluidic micro passage reaction in the present invention:9.
Embodiment 12-15
Change the temperature of microfluidic channel reactor, with embodiment 1, reaction result is as shown in table 3 for other：
Table 3：Influence of the temperature to reaction
The result of table 3 shows, when flow velocity is 10.4 μ Lmin-1, the reaction time is 30min, in reactor
Organic solvent DMSO:Tert-pentyl alcohol volume ratio is 1:14, reactant 5-methyl-uridin rubs with vinyl laurate
Your ratio is 1:9, when 5-methyl-uridin concentration is 0.05mmol/mL in reaction system, at reaction temperature
When 30 DEG C, the conversion ratio of reaction is optimal, temperature or the Tai Gao or too low activity that will all influence enzyme.So this
Optimum temperature is 30 DEG C in micro-fluidic micro passage reaction in invention.
Embodiment 16-18
Change the reaction time of microfluidic channel reactor, with embodiment 1, reaction result is as shown in table 4 for other：
Table 4：Influence of the reaction time to reaction
The result of table 4 shows, as organic solvent DMSO in reactor:Tert-pentyl alcohol volume ratio is 1:14, instead
It is 1 to answer thing 5-methyl-uridin and vinyl laurate mol ratio:9, reaction temperature is 30 DEG C, reaction system
When middle 5-methyl-uridin concentration is 0.05mmol/mL, when reacted between when be 30min, reaction turns
Rate is up to 97%, almost conversion completely.So in the present invention in micro-fluidic micro passage reaction during optimum response
Between be 30min.
Embodiment 19-22
Change the concentration of microfluidic channel reactant, with embodiment 1, reaction result is as shown in table 5 for other：
Table 5：Influence of the reactant concentration to reaction
The result of table 5 shows, as organic solvent DMSO in reactor:Tert-pentyl alcohol volume ratio is 1:14, instead
It is 1 to answer thing 5-methyl-uridin and vinyl laurate mol ratio:9, reaction temperature is 30 DEG C, during reaction
Between be 30min, when 5-methyl-uridin concentration is 0.05mmol/mL, reaction conversion ratio is up to 97%,
So optimum response thing concentration is 0.05mmol/mL in micro-fluidic micro passage reaction in the present invention.
Comparative example 1-3
Change the catalyst in micro-fluidic micro passage reaction, it is (right to be changed to Lipozyme RM IM respectively
Ratio 1), lipase Novozym 435 (comparative example 2), bacillus alkaline protease (comparative example 3),
Other are with embodiment 1, as a result as shown in table 6.
Table 6：Influence of the different enzymes to reaction conversion ratio and selectivity
The result of table 6 shows, for the regioselectivity ester of enzymatic 5-methyl-uridin in microfluidic channel reactor
For changing reaction, different enzymes has fairly obvious influence to reaction.Utilize Lipozyme RMIM
Catalytic reaction, the conversion ratio of 5'-O- lauroyl -5-methyl-uridin is 50%.And utilize Bacillus subtilis alkaline albumen
The enzymatic reaction, the conversion ratio of 5'-O- lauroyl -5-methyl-uridin is only 12%.In terms of the result of table 6,
It is maximally effective for the regioselectivity esterification of enzymatic 5-methyl-uridin in microfluidic channel reactor
Catalyst is Lipozyme TLIM, and the conversion ratio of 5-methyl-uridin is 97%, and selectivity is 100%.
Comparative example 4-5
Change different types of uridine compound in micro-fluidic micro passage reaction, the 5- methyl of embodiment 1 is urinated
Glycosides 1mmol be changed to respectively guanosine 1mmol (comparative example 4), 3'- BrdUs 1mmol (comparative example 5), its
He is with embodiment 1, as a result as shown in table 7.
Table 7：Influence of the different nucleoside compounds to reaction
The result of table 7 shows, is esterified for the regioselectivity of enzymatic nucleoside compound in microfluidic channel reactor
For reaction, different nucleoside compounds has different reaction results.3'- BrdUs are in same reaction
Under the conditions of, conversion ratio is only 25%, and reaction is relatively difficult.The reaction result of guanosine is also undesirable, and conversion ratio is only
For 35%.In terms of the result of table 7, selected for the region of enzymatic nucleoside compound in microfluidic channel reactor
For selecting property esterification, 5-methyl-uridin can obtain more satisfactory reaction result, and the conversion ratio of reaction can
To reach 97%, selectivity is 100%.
Claims (7)
- A kind of 1. method of lipase-catalyzed online synthesis 5'-O- lauroyl -5-methyl-uridin, it is characterised in that： Methods described uses microfluidic channel reactor, described microfluidic channel reactor include syringe pump, syringe, Reaction channel and product collector, the syringe are installed in syringe pump, pass through an interface and reaction channel Entrance is connected, and the product collector is connected by an interface and reaction channel outlet, in the reaction channel Footpath is 0.8~2.4mm, a length of 0.5~1.0m of reaction channel；Methods described includes：Using volume ratio as 1:8~16 Dimethyl sulfoxide and tert-pentyl alcohol be reaction dissolvent, using mol ratio as 1:5~13 5-methyl-uridin and laurate second Alkene ester is raw material, using 0.5~1.0g Lipozymes TLIM as catalyst, by raw material and reaction dissolvent It is placed in syringe, Lipozyme TLIM is uniformly filled in reaction channel, in syringe pump Raw material and reaction dissolvent is continuously passed through in reaction channel under promotion and carry out acylation reaction, make 5- in reaction system The concentration of methyluridine is 0.03~0.07mmol/mL, and it is 15~50 DEG C to control acylation reaction temperature, acylated anti- It is 20~35min between seasonable, reaction solution is collected by product collector online, reaction solution is post-treated to obtain 5'-O- Lauroyl -5-methyl-uridin.
- 2. the method for lipase-catalyzed online synthesis 5'-O- lauroyl -5-methyl-uridin as claimed in claim 1, It is characterized in that：Described method comprises the following steps：5-methyl-uridin first is dissolved with a certain amount of dimethyl sulfoxide, Again plus tert-pentyl alcohol is to certain volume, loaded on standby in syringe；Vinyl laurate is dissolved to certain with tert-pentyl alcohol Volume, loaded on standby in another syringe；Then raw material and reaction dissolvent is made to be passed through reaction under syringe pump promotion Reacted in passage.
- 3. the method for lipase-catalyzed online synthesis 5'-O- lauroyl -5-methyl-uridin as claimed in claim 1, It is characterized in that：The microfluidic channel reactor includes insulating box, and the reaction channel is placed in insulating box.
- 4. the method for lipase-catalyzed online synthesis 5'-O- lauroyl -5-methyl-uridin as claimed in claim 2, It is characterized in that：The microfluidic channel reactor includes insulating box, and the reaction channel is placed in insulating box.
- 5. lipase-catalyzed online synthesis 5'-O- lauroyl -5-methyl-uridin as described in one of Claims 1 to 4 Method, it is characterised in that：The volume ratio of dimethyl sulfoxide and tert-pentyl alcohol is 1 in the reaction system:12~16, The mol ratio of the 5-methyl-uridin and vinyl laurate is 1:7~13,5-methyl-uridin in reaction system Concentration is 0.04~0.06mmol/mL, and the acylation reaction temperature is 20~40 DEG C, and the acylation reaction time is 25~35min.
- 6. the method for lipase-catalyzed online synthesis 5'-O- lauroyl -5-methyl-uridin as claimed in claim 5, It is characterized in that：The mol ratio of the 5-methyl-uridin and vinyl laurate is 1:9~11.
- 7. the method for lipase-catalyzed online synthesis 5'-O- lauroyl -5-methyl-uridin as claimed in claim 6, It is characterized in that：The volume ratio of dimethyl sulfoxide and tert-pentyl alcohol is 1 in the reaction system:14, the 5- methyl The mol ratio of uridine and vinyl laurate is 1:9, the concentration of 5-methyl-uridin is in reaction system 0.05mmol/mL, the acylation reaction temperature are 30 DEG C, and the acylation reaction time is 30min.
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| CN107955822A (en) * | 2017-12-21 | 2018-04-24 | 浙江工业大学 | A kind of lipase-catalyzed online synthesis S-（4- methyl-benzyls）The method of laurate thioesters |
| CN107955823A (en) * | 2017-12-21 | 2018-04-24 | 浙江工业大学 | A kind of method of lipase-catalyzed online synthesis 6- ((4- methyl-benzyls) sulfenyl) -6- oxo vinyl caproates |
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| CN107955823A (en) * | 2017-12-21 | 2018-04-24 | 浙江工业大学 | A kind of method of lipase-catalyzed online synthesis 6- ((4- methyl-benzyls) sulfenyl) -6- oxo vinyl caproates |
| CN107988279A (en) * | 2017-12-21 | 2018-05-04 | 浙江工业大学 | A kind of method of lipase-catalyzed online synthesis 6- ((4- chlorobenzyls) sulfenyl) -6- oxo vinyl caproates |
| CN108060184A (en) * | 2017-12-21 | 2018-05-22 | 浙江工业大学 | A kind of method of lipase-catalyzed online synthesis S- thioacetic acid benzyl esters |
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