CN107384994A - A kind of method of lipase-catalyzed online synthesis 5 '-O- acetyl -5-FUD - Google Patents
A kind of method of lipase-catalyzed online synthesis 5 '-O- acetyl -5-FUD Download PDFInfo
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- CN107384994A CN107384994A CN201610328944.0A CN201610328944A CN107384994A CN 107384994 A CN107384994 A CN 107384994A CN 201610328944 A CN201610328944 A CN 201610328944A CN 107384994 A CN107384994 A CN 107384994A
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Abstract
The invention discloses a kind of method of the lipase-catalyzed online floxuridine of synthesis 5'O acetyl 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 floxuridines and vinyl acetate 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 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 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 floxuridine of 5'O acetyl 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 method of lipase-catalyzed online controllable selectivity synthesis 5'-O- acetyl -5-FUD
(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- acetyl -5-FUD, it is intended to find a kind of 5'-O- acetyl -5-FUD of high-efficiency environment friendly
Online controllable method for selective synthesis.
(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- acetyl -5-FUD is synthesized, there is the advantages of 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 5'-O- acetyl -5-FUD, methods described is using micro-fluidic
Channel reactor, described microfluidic channel reactor include syringe pump, syringe, reaction channel and product and received
Storage, the syringe are installed in syringe pump, are connected by an interface with reaction channel entrance, the production
Thing 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~the 1.0m of reaction channel；Methods described includes：Using volume ratio as 1:8~16 dimethyl sulfoxide (DMSO)
It is reaction dissolvent with tert-pentyl alcohol, using mol ratio as 1:5~13 5-FUD and vinyl acetate are raw material, with
0.5~1.0g Lipozymes TLIM is catalyst, and raw material and reaction dissolvent are placed in syringe, will
Lipozyme TLIM is uniformly filled in reaction channel, and raw material and anti-is made under the promotion of syringe pump
Answer solvent to be continuously passed through in reaction channel and carry out acylation reaction, make 5- in reaction system (raw material+reaction dissolvent)
The concentration of floxuridine is 0.03~0.07mmol/mL, and it is 15~50 DEG C to control acylation reaction temperature, during acylation reaction
Between be 20~35min, reaction solution is collected by product collector online, reaction solution obtains 5'-O- through conventional post processing
Acetyl -5-FUD.
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-FUD in implementation process with DMSO, is further continued for plus tert-pentyl alcohol is to certain
Volume, loaded on standby in syringe；Then vinyl acetate is dissolved to certain volume with tert-pentyl alcohol, loaded on another
It is standby in syringe；Finally make raw material and reaction dissolvent under syringe pump (such as PD1200 syringe pumps) promotion
It is passed through in reaction channel and is 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 by microorganism preparation, 1,3 position-specifics, 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-FUD and vinyl acetate is preferably 1:9~11, most preferably 1:9.
Further, the concentration of 5-FUD is preferably 0.04~0.06mmol/mL in reaction system, is most preferably
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- acetyl -5-FUD.The conventional post-processing approach can be：Gained reaction solution is evaporated under reduced pressure and removed
Solvent is removed, with 200-300 mesh silica gel wet method dress posts, elution reagent is ethyl acetate:Methanol=20:1, sample is used
Wet method upper prop after a small amount of elution reagent dissolving, eluent, while TLC tracking elution processes are collected, will be obtained
Eluent containing single product merge and be evaporated, white solid can be obtained, as 5'-O- acetyl -5- fluorine is urinated
Glycosides.
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- acetyl -5-FUD, the method not only significantly shorten the reaction time, and
And there is high conversion ratio and selectivity；Utilize economic Lipozyme TLIM catalysis first simultaneously
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- acetyl -5-FUD
Device is with reference to figure 1：5-FUD (1.0mmol) is dissolved in 1.33mLDMSO and 8.67mL uncles penta
In alcohol, vinyl acetate (9.0mmol) is dissolved in 10mL tert-pentyl alcohols, is then noted respectively loaded on 10mL
It is standby in emitter.0.87g Lipozymes TLIM is uniformly filled in reaction channel, in the notes of PD 1200
Penetrate under pump promotion, two-way reaction solution is respectively with 10.4 μ Lmin-1Flow velocity reaction channel is entered by " Y " joint
In reacted, controlling temperature of reactor by constant temperature water box, reaction solution is continuous in reaction channel at 30 DEG C
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=20:1, 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
Acyl -5-FUD, HPLC detection 5-FUDs conversion ratio 82%, selectivity 98%.
Nuclear-magnetism characterization result is as follows：
1H-NMR(DMSO-d6,δ,ppm)：11.90(s,H3), 7.97 (d, J=7Hz, H6), 7.62 (d, J=9Hz,
H6), 5.72 (d, 1H, J=4.5Hz, H1'), 5.67 (d, 1H, J=9Hz, H5), 5.49 (d, 1H, J=5.5Hz,
3'-OH), 5.28 (d, 1H, J=5.5Hz, 2'-OH), 4.24 (m, 2H, H2'+H3'),4.10(m,1H,H4'),
3.98(m,2H,H5'),2.06(s,3H,H2”).
13C NMR(DMSO-d6,ppm)：170.14(C1”),156.93(C4),149.25(C2),139.18(C6),
125.05(C5),89.11(C1'),81.10(C4'),72.68(C3'),69.46(C2'),63.51(C5'),20.58(C2”).
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 volume 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-FUD and vinyl acetate mol ratio are 1:9,5-FUD in reaction system
Concentration when being 0.05mmol/mL, conversion ratio increases and increased with tert-pentyl alcohol content in reactor, works as body
Product ratio reaches 1:Reach optimal when 14, being further continued for increase tert-pentyl alcohol content will cause reactant dissolving incomplete
And reduce conversion ratio.So optimal DMSO in micro-fluidic micro passage reaction in the present invention:Tert-pentyl alcohol volume ratio
For 1:14.
Embodiment 7-11
Change the substrate mol ratio of 5-FUD and vinyl acetate in micro-fluidic micro passage reaction, control temperature
50 DEG C, other are with embodiment 1, as a result as shown in table 2：
Table 2:5-FUD and influence of the vinyl acetate 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, DMSO:Tert-pentyl alcohol volume ratio is 1:14, the concentration of 5-FUD is in reaction system
During 0.05mmol/mL, with the increase of reactant vinyl acetate, the conversion ratio of reaction also increases as, when
5-FUD is 1 with vinyl acetate substrate mol ratio:When 9, the conversion ratio of reaction is optimal, so in the present invention
Optimal substrate mol ratio is 1 in micro-fluidic micro passage reaction: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
DMSO:Tert-pentyl alcohol volume ratio is 1:14, reactant 5-FUD and vinyl acetate mol ratio are 1:9,
When the concentration of 5-FUD is 0.05mmol/mL in reaction system, when reaction temperature is in 30 DEG C, instead
The conversion ratio answered is optimal, temperature or the Tai Gao or too low activity that will all influence enzyme.It is so micro-fluidic micro- in the present invention
Optimum temperature is 30 DEG C in channel reactor.
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-FUD and vinyl acetate mol ratio:9, reaction temperature is 30 DEG C, in reaction system
When the concentration of 5-FUD is 0.05mmol/mL, when reacted between when be 30min, reaction conversion
Rate reaches 82%.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
It is 1 to answer thing 5-FUD and vinyl acetate mol ratio:9, reaction temperature is 30 DEG C, and the reaction time is equal
For 30min, when 5-FUD concentration is 0.05mmol/mL in reaction system, reaction conversion ratio is up to
82%, so optimum response thing 5-FUD 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, is esterified for the regioselectivity of enzymatic 5-FUD in microfluidic channel reactor
For reaction, different enzymes has fairly obvious influence to reaction.Utilize Lipozyme RMIM
Catalytic reaction, the conversion ratio of 5'-O- acetyl -5-FUD is 40%.And urged using bacillus alkaline protease
Change the reaction, the conversion ratio of 5'-O- acetyl -5-FUD is only 5%.In terms of the result of table 6, for micro-fluidic
In channel reactor for the regioselectivity esterification of enzymatic 5-FUD, maximally effective catalyst is fat
Enzyme Lipozyme TLIM, the conversion ratio of 5-FUD is 82%, and selectivity is 98%.
Comparative example 4-5
Change different types of uridine compound in micro-fluidic micro passage reaction, by the 5-FUD of embodiment 1
1mmol be changed to respectively guanosine 1mmol (comparative example 4), 3'- BrdUs 1mmol (comparative example 5), other
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 17%, and reaction is relatively difficult.The reaction result of guanosine is also undesirable, conversion
Rate is only 23%.In terms of the result of table 7, for the area of enzymatic nucleoside compound in microfluidic channel reactor
For field selectivity esterification, 5-FUD can obtain more satisfactory reaction result, the conversion ratio of reaction
82% can be reached, selectivity is 98%.
Claims (6)
- A kind of 1. method of lipase-catalyzed online synthesis 5'-O- acetyl -5-FUD, it is characterised in that the side Method uses microfluidic channel reactor, and described microfluidic channel reactor includes syringe pump, syringe, reaction Passage and product collector, the syringe are installed in syringe pump, pass through an interface and reaction channel entrance Connection, the product collector are 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 and tert-pentyl alcohol are reaction dissolvent, using mol ratio as 1:5~13 5-FUD is original with vinyl acetate Material, using 0.5~1.0g Lipozymes TLIM as catalyst, injection is placed in by raw material and reaction dissolvent In device, Lipozyme TLIM is uniformly filled in reaction channel, made under the promotion of syringe pump Raw material and reaction dissolvent, which are continuously passed through in reaction channel, carries out acylation reaction, makes the dense of 5-FUD in reaction system Spend for 0.03~0.07mmol/mL, it is 15~50 DEG C to control acylation reaction temperature, and the acylation reaction time is 20~35 Min, reaction solution is collected by product collector online, reaction solution is post-treated to obtain 5'-O- acetyl -5-FUD.
- 2. the method for lipase-catalyzed online synthesis 5'-O- acetyl -5-FUD as claimed in claim 1, its It is characterised by：Described method comprises the following steps：5-FUD first is dissolved with a certain amount of dimethyl sulfoxide, then Add tert-pentyl alcohol to certain volume, loaded on standby in syringe；Vinyl acetate is dissolved to certain volume with tert-pentyl alcohol, Loaded on standby in another syringe；Then raw material and reaction dissolvent is made to be passed through in reaction channel under syringe pump promotion Reacted.
- 3. the method for lipase-catalyzed online synthesis 5'-O- acetyl -5-FUD as claimed in claim 1, its It is characterised by：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- acetyl -5-FUD as claimed in claim 2, its It is characterised by：The microfluidic channel reactor includes insulating box, and the reaction channel is placed in insulating box.
- 5. the side of lipase-catalyzed online synthesis 5'-O- acetyl -5-FUD 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 dissolvent:12~16, it is described The mol ratio of 5-FUD and vinyl acetate is 1:9~11, the concentration of 5-FUD is in reaction system 0.04~0.06mmol/mL, the acylation reaction temperature are 20~40 DEG C, and the acylation reaction time is 25~35 min。
- 6. the side of lipase-catalyzed online synthesis 5'-O- acetyl -5-FUD 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 dissolvent:14, the 5- The mol ratio of floxuridine and vinyl acetate is 1:9, the concentration of 5-FUD 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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Cited By (1)
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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 |
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| CN103184257A (en) * | 2011-12-31 | 2013-07-03 | 浙江工业大学 | Method for on-line synthesizing sucrose-6-acetate catalyzed by lipase |
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- 2016-05-17 CN CN201610328944.0A patent/CN107384994A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103184257A (en) * | 2011-12-31 | 2013-07-03 | 浙江工业大学 | Method for on-line synthesizing sucrose-6-acetate catalyzed by lipase |
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| HUAI WANG等: "Novel and highly regioselective route for synthesis of 5-fluorouridine lipophilic ester derivatives by lipozyme TL IM", 《JOURNAL OF BIOTECHNOLOGY》 * |
| 董辉等: "去氧氟尿苷合成工艺改进", 《中国医药工业杂志》 * |
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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 |
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