CN107384781A - A kind of method of lipase-catalyzed online synthesis 5 '-O- ethene adipyls -5-methyl-uridin - Google Patents
A kind of method of lipase-catalyzed online synthesis 5 '-O- ethene adipyls -5-methyl-uridin Download PDFInfo
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Abstract
The invention discloses a kind of method of the lipase-catalyzed online methyluridine of synthesis 5'O ethene adipyl 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 hexanediacetate 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 acylation reaction temperature, and the acylation reaction time is 20~35min, collects reaction solution online by product collector, reaction solution obtains the methyluridine of 5'O ethene adipyl 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- ethene adipyl -5- methyl urine
The method of glycosides.
(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- ethene adipyl -5-methyl-uridin, it is intended to find a kind of high-efficiency environment friendly 5'-O- ethene oneself
The online controllable method for selective synthesis of two acyls -5-methyl-uridin.
(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- ethene adipyl -5-methyl-uridin is synthesized, with the reaction time is short, yield is high, selectivity
The advantages of 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 5'-O- ethene adipyl -5-methyl-uridin, methods described are adopted
With microfluidic channel reactor, described microfluidic channel reactor includes syringe pump, syringe, reaction channel
And product collector, the syringe are installed in syringe pump, it is connected by an interface with reaction channel entrance,
The product collector is connected by an interface 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；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 oneself
Diacid divinyl ester is raw material, using 0.5~1.0g Lipozymes TLIM as catalyst, by raw material and
Reaction dissolvent is placed in syringe, and Lipozyme TLIM is uniformly filled in reaction channel,
Raw material and reaction dissolvent is continuously passed through in reaction channel device under the promotion of syringe pump and carry out acylation reaction, make reaction
The concentration of 5-methyl-uridin is 0.03~0.07mmol/mL in system (being made up of raw material and reaction dissolvent), control
Acylation reaction temperature processed is 15~50 DEG C, and the acylation reaction time is 20~35min, online by product collector
Reaction solution is collected, reaction solution obtains 5'-O- ethene adipyl -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 hexanediacetate is dissolved to certain volume, dress with tert-pentyl alcohol
It is standby in another syringe；Finally make raw material and anti-under syringe pump (such as the syringe pumps of PD 1200) promotion
Answer solvent to be 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 hexanediacetate is preferably 1:7~13, it is more excellent
Select 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- ethene adipyl -5-methyl-uridin.The conventional post-processing approach can be：Gained reaction solution subtracts
Solvent is distilled off in pressure, and with 200-300 mesh silica gel wet method dress posts, elution reagent is ethyl acetate:Methanol=40:1,
Wet method upper prop after sample is dissolved with a small amount of elution reagent, eluent, while TLC tracking elution processes are collected,
The obtained eluent containing single product is merged and is evaporated, white solid, as 5'-O- ethene can be obtained
Adipyl -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- ethene adipyl -5-methyl-uridin, the method not only significantly shorten reaction
Time, and there is high conversion ratio and selectivity；Utilize economic Lipozyme first simultaneously
TLIM is catalyzed nucleosides esterification, reduces reaction cost, has the advantage of 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- ethene adipyl -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 hexanediacetate (9.0mmol) is dissolved in 10mL tert-pentyl alcohols, is then loaded on respectively
It is standby in 10mL syringes.0.87g Lipozymes TLIM is uniformly filled in reaction channel, in PD
Under 1200 syringe pumps promote, two-way reaction solution is respectively with 10.4 μ Lmin-1Flow velocity entered by " Y " joint it is anti-
Answer in passage and reacted, controlling temperature of reactor by constant temperature water box, reaction solution is in reaction channel at 30 DEG C
Interior 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 5'-O- second
Alkene adipyl -5-methyl-uridin, HPLC detection 5-methyl-uridins conversion ratio 94%, selectivity 99%.
Nuclear-magnetism characterization result is as follows：
1H-NMR(DMSO-d6,δ,ppm)：11.36(s,H3), 7.43 (d, J=1Hz, H6), 7.22 (dd, 1H, J=
6.5Hz, J=13Hz ,=CH-O), 5.77 (d, 1H, J=5Hz, H1'), 5.43 (d, 1H, J=5.5Hz,
3'-OH), 5.27 (d, 1H, J=5.5Hz, 2'-OH), 4.90 (dd, 1H, J=1.5Hz, J=14Hz,
), CH=C-O 4.65 (dd, 1H, J=1.5Hz, J=6Hz, CH=C-O), 4.24 (m, 2H, H2'+H3'),
4.09(m,1H,H4'),3.96(m,2H,H5'), 2.44 (t, 2H, J=7Hz, H2”), 2.38 (t, 2H, J=7Hz,
H5”), 1.79 (d, 3H, J=0.5Hz, 5-CH 3),1.57(m,4H,H4”+H3”).
13C NMR(DMSO-d6,ppm)：172.24(C1”),170.27(C6”),163.63(C4),150.60(C2),
141.24 (C=C-O),140.76(C6),102.02(C5),98.09(C=C-O), 88.76 (C1'),81.04(C4'),
72.70(C3'),69.77(C2'),63.51(C5'),32.93(C5”),32.61(C2”),23.67(C4”),23.39(C3”),
12.05(5-CH3).
Embodiment 2-6
Change organic solvent DMSO in microfluidic channel reactor:Tert-pentyl alcohol volume ratio, it is 50 DEG C to control temperature,
, with embodiment 1, reaction result is as shown in table 1 for other：
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 hexanediacetate mol ratio are 1:9, in reaction system
When 5-methyl-uridin concentration is 0.05mmol/mL, conversion ratio is with organic solvent volume in reactor than increase
And increase, work as DMSO:Tert-pentyl alcohol volume ratio reaches 1:Reach optimal when 14, being further continued for increase volume ratio will
Reactant dissolving is caused not exclusively to reduce conversion ratio.It is so optimal in micro-fluidic micro passage reaction in the present invention
Organic solvent volume ratio is 1:14.
Embodiment 7-11
Change the substrate mol ratio of 5-methyl-uridin and vinyl hexanediacetate in micro-fluidic micro passage reaction, control
Temperature 50 C processed, other are with embodiment 1, as a result as shown in table 2：
Table 2:5-methyl-uridin and influence of the vinyl hexanediacetate 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 hexanediacetate, reaction
Conversion ratio also increase as, work as 5-methyl-uridin:Vinyl hexanediacetate substrate mol ratio is 1:When 9, instead
The conversion ratio answered 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:Vinyl hexanediacetate rubs
Your ratio is 1:9, when 5-methyl-uridin concentration is 0.05mmol/mL in reaction system, work as reaction temperature
In 30 DEG C when, the conversion ratio of reaction is optimal, temperature or Tai Gao or the too low activity that will all influence enzyme.So
Optimum temperature is 30 DEG C in micro-fluidic micro passage reaction in the present 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
Answer thing 5-methyl-uridin:Vinyl hexanediacetate mol ratio is 1:9, reaction temperature is 30 DEG C, reactant
When 5-methyl-uridin concentration is 0.05mmol/mL in system, when reacted between when be 30min, reaction
High conversion rate is up to 94%, so optimum reacting time is 30min in micro-fluidic micro passage reaction in the present invention.
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
Answer thing 5-methyl-uridin:Vinyl hexanediacetate mol ratio is 1:9, reaction temperature is 30 DEG C, reaction
Time is 30min, and when 5-methyl-uridin concentration is 0.05mmol/mL in reaction system, reaction turns
Rate is up to 94%, so optimum response thing concentration is in micro-fluidic micro passage reaction in the present invention
0.05mmol/mL。
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- ethene adipyl -5-methyl-uridin is 48%.And utilize Bacillus subtilis alkaline
The albumen enzymatic reaction, the conversion ratio of 5'-O- ethene adipyl -5-methyl-uridin is only 9%.From the knot of table 6
Fruit sees, for the regioselectivity esterification of enzymatic 5-methyl-uridin in microfluidic channel reactor, most
Effective catalyst is Lipozyme TLIM, and the conversion ratio of 5-methyl-uridin is 94%, is selectively
99%.
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, for the regioselectivity of enzymatic nucleoside compound in microfluidic channel reactor
For esterification, different nucleoside compounds has different reaction results.3'- BrdUs are same
Under reaction condition, conversion ratio is only 25%, and reaction is relatively difficult.The reaction result of guanosine is also undesirable, conversion
Rate is only 33%.In terms of the result of table 7, for the area of enzymatic nucleoside compound in microfluidic channel reactor
For field selectivity esterification, 5-methyl-uridin can obtain more satisfactory reaction result, the conversion of reaction
Rate can reach 94%, and selectivity is 99%.
Claims (7)
1. a kind of method of lipase-catalyzed online synthesis 5'-O- ethene adipyl -5-methyl-uridin, its feature exist
In：Methods described uses microfluidic channel reactor, and described microfluidic channel reactor includes syringe pump, note
Emitter, reaction channel and product collector, the syringe are installed in syringe pump, by an interface and instead
Feeder connection is answered to connect, the product collector is connected 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
1:8~16 dimethyl sulfoxide and tert-pentyl alcohol is reaction dissolvent, using mol ratio as 1:5~13 5-methyl-uridin with
Vinyl hexanediacetate is raw material, using 0.5~1.0g Lipozymes TLIM as catalyst, by raw material
It is placed in reaction dissolvent in syringe, Lipozyme TLIM is uniformly filled in reaction channel,
Raw material and reaction dissolvent is continuously passed through in reaction channel under the promotion of syringe pump and carry out acylation reaction, make reaction
The concentration of 5-methyl-uridin is 0.03~0.07mmol/mL in system, and it is 15~50 DEG C to control acylation reaction temperature,
The acylation reaction time is 20~35min, collects reaction solution online by product collector, reaction solution is post-treated
5'-O- ethene adipyl -5-methyl-uridin can be obtained.
2. lipase-catalyzed online synthesis 5'-O- ethene adipyl -5-methyl-uridin as claimed in claim 1
Method, it is characterised in that：Described method comprises the following steps：5-methyl-uridin first is dissolved with dimethyl sulfoxide,
Again plus tert-pentyl alcohol is to certain volume, loaded on standby in syringe；Vinyl hexanediacetate is dissolved to one with tert-pentyl alcohol
Volume is determined, loaded on standby in another syringe；Then raw material and reaction dissolvent is made to be passed through instead under syringe pump promotion
Answer in passage and reacted.
3. lipase-catalyzed online synthesis 5'-O- ethene adipyl -5-methyl-uridin as claimed in claim 1
Method, it is characterised in that：The microfluidic channel reactor includes insulating box, and the reaction channel is placed in constant temperature
In case.
4. lipase-catalyzed online synthesis 5'-O- ethene adipyl -5-methyl-uridin as claimed in claim 2
Method, it is characterised in that：The microfluidic channel reactor includes insulating box, and the reaction channel is placed in constant temperature
In case.
5. the lipase-catalyzed online synthesis 5'-O- ethene adipyl -5- methyl as described in one of Claims 1 to 4
The method of uridine, it is characterised in that：The volume ratio of organic solvent dimethyl sulfoxide and tert-pentyl alcohol in the reaction system
For 1:12~16, the mol ratio of the 5-methyl-uridin and vinyl hexanediacetate is 1:7~13, in reaction system
The concentration of 5-methyl-uridin is 0.04~0.06mmol/mL, and the acylation reaction temperature is 20~40 DEG C, described
The acylation reaction time is 25~35min.
6. lipase-catalyzed online synthesis 5'-O- ethene adipyl -5-methyl-uridin as claimed in claim 5
Method, it is characterised in that：The mol ratio of the 5-methyl-uridin and vinyl hexanediacetate is 1:9~11.
7. lipase-catalyzed online synthesis 5'-O- ethene adipyl -5-methyl-uridin as claimed in claim 6
Method, it is characterised in that：The volume ratio of organic solvent dimethyl sulfoxide and tert-pentyl alcohol is 1 in the reaction system:14,
The mol ratio of the 5-methyl-uridin and vinyl hexanediacetate is 1:9,5-methyl-uridin is dense in reaction system
It is 30 DEG C to spend for 0.05mmol/mL, the acylation reaction temperature, and the acylation reaction time is 30min.
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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 |
| CN108060183A (en) * | 2017-12-21 | 2018-05-22 | 浙江工业大学 | A kind of lipase-catalyzed online synthesis 6-（Benzylthio）The method of -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 |
| CN108060185A (en) * | 2017-12-21 | 2018-05-22 | 浙江工业大学 | A kind of method of lipase-catalyzed online synthesis S- (4- methylbenzyls) thiacetate |
| CN108070625A (en) * | 2017-12-21 | 2018-05-25 | 浙江工业大学 | A kind of lipase-catalyzed online synthesis S-（4- methylbenzyls）The method of palmitic acid thioesters |
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