CN107475330A - A kind of method of lipase-catalyzed online synthesis N (5 glucose ester valeryl) metoprolol - Google Patents
A kind of method of lipase-catalyzed online synthesis N (5 glucose ester valeryl) metoprolol Download PDFInfo
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Abstract
The invention discloses a kind of method of lipase-catalyzed online synthesis N (5 glucose ester valeryl) metoprolol：The ratio between amount with material is 1:1~10 N (5 vinyl acetate valeryl) metoprolols and glucose are raw material; dimethyl sulfoxide and tert-pentyl alcohol are reaction dissolvent; 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 ester exchange 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 esterification reaction temperature, and reaction time of esterification is 20~40min, collects reaction solution online by product collector, reaction solution obtains N (5 glucose ester valeryl) metoprolol 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 N- (5- glucose esters valeryl) Mei Tuoluo
Your method.
(2) background technology
Clinically commonly used medicine is using small-molecule drug as main flow at present, but small-molecule drug metabolism is fast, partly declines
Phase, short and obvious peak valley effect caused frequent drug administration, and small-molecule drug is prepared into new medicine by chemicobiological method
Thing derivative or the medicaments derivative containing sugar, and medicine Macromolecule Prodrug be it is a kind of effective improve controlled drug release and
The method of targeting.
At this stage, most drug is faced with the problem of fat-soluble too high or water-soluble poor, and these problems are deposited
Causing, the gastrointestinal absorption of medicine is bad, and oral administration biaavailability is poor.Therefore, researcher pass through it is water-soluble modified
Mode either forms the water solubility and its oral administration biaavailability of the increase medicine such as oil-in-water microemulsion system.And sugared graft,
If sugar esters compounds are a kind of good biocompatible compounds, have water-soluble well, and many medicines are being controlled
Sugar is dependent on during treatment in organism role.Therefore hydrophobic drug and sugar are combined to form into the medicine containing sugar
Derivative is possible to have above-mentioned property concurrently, this just for medicine especially amphiphilic drug development provide it is more wide before
Scape.
Metoprolol is beta-blockers, available for treatment hypertension, angina pectoris, myocardial infarction, hypertrophic cardiomyopathy,
The illnesss such as dissection of aorta, arrhythmia cordis, hyperthyroidism, cardiac neurosis.But shown in clinical process
Half-life short is, it is necessary to successive administration, and the limitations such as bioavilability is low.By enzymatic method to metoprolol with it is some other
Material (such as sugar and amino acid compound) with physiologically active either pharmacological activity carries out esterification, obtains beautiful containing sugar
The compound prodrugs of Tuo Luoer, it is of great significance for the pharmacological activity for improving medicine with function tool.In common chemistry
In method synthesis, multiple hydroxyls of saccharide compound are likely to participate in esterification, and product is the mixture of monoesters and polyester, thus is needed
Series of steps such as " protection and deprotections " through functional group could obtain single position esterification products.And lipase-catalyzed esterification reacts
Not only there is higher selectivity, and reaction condition is gentle so that it plays more and more important effect in prodrug derivatization.
It is micro-fluidic learn (Microfluidics) be in micron scale construction manipulation nanoliter to picoliters volume fluid technology with
Science, it is the new cross discipline to emerge rapidly nearly ten years.Currently, the development of micro-fluidic has surmounted originally main significantly
For the purpose of analytical chemistry service, and turn into whole chemistry subject, life science, instrumental science or even information science new one
Take turns the important technological platform of innovation research.
The text that a first piece synthesizes compound in micro-fluidic chip microreactor has been delivered from Harrison seminars in 1997
After offering, micro-fluidic chip reactor has been successfully used to a variety of organic synthesis, and illustrates the prospect of being widely applied.With
The development of microring array, micro-reacting tcchnology in micro-fluidic chip, synthetic reaction is carried out in the chips and has become micro-fluidic chip neck
One of the study hotspot in domain.
Compared with conventional chemical reactor, micro passage reaction, which not only has, makes the diffusion length between reactant contract significantly
It is short, and mass transfer velocity is fast；The easy control of reaction conditions such as reactant ratio, temperature, reaction time and flow velocity, side reaction compared with
It is few；Need reactant dosage little, can not only reduce the dosage of expensive, poisonous adverse reaction thing, caused ring in course of reaction
Border pollutant is also few, is a kind of environment-friendly, study on the synthesis novel substance technology.
At present, concern is compared in the enzyme' s catalysis research both at home and abroad to the analog derivative containing osamine, especially for containing sugared U.S. support
The synthesis exploitation of Luo Er combination drugs, improves its pharmacological activity, solves the half-life period showed during its Clinical practice
It is short, it is necessary to successive administration, the limitations such as bioavilability is low.It has been reported that enzymatic synthesis method generally require longer reaction
Time (12-24h), and the conversion ratio reacted and selectivity be not high, therefore it is we have discovered that fatty in micro passage reaction
The method that enzymatic synthesizes N- (5- glucose esters valeryl) metoprolol online, it is intended to find a kind of N- (5- of high-efficiency environment friendly
Glucose ester valeryl) metoprolol online controllable method for selective synthesis.
(3) content of the invention
To solve the problems, such as that prior art is present, it is an object of the invention to provide fat in a kind of microfluidic channel reactor
Fat enzymatic synthesizes the new technology of N- (5- glucose esters valeryl) metoprolol online, with the reaction time is short, yield is high, choosing
The advantages of selecting property is good.
The present invention adopts the following technical scheme that：
A kind of method of lipase-catalyzed online synthesis N- (5- glucose esters valeryl) metoprolol, methods described use
Microfluidic channel reactor, described microfluidic channel reactor include be sequentially connected syringe, with temperature control equipment
Reaction channel and product collector, the syringe be installed in syringe pump, described syringe passes through the first connecting pipe
It is connected with reaction channel entrance, the product collector is connected by the second connecting pipe 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：With N- (5- vinyl acetates valeryl)
Metoprolol and glucose are raw material, using the mixed solvent of dimethyl sulfoxide and tert-pentyl alcohol as reaction dissolvent, with lipase
Lipozyme TL IM are catalyst, and described raw material and described reaction dissolvent are placed in syringe, by lipase
Lipozyme TL IM are uniformly filled in reaction channel, make described raw material and described reaction molten under the promotion of syringe pump
Agent, which is continuously passed through in reaction channel device, carries out esterification, controlling reaction temperature be 20~60 DEG C, the reaction time be 20~
40min, reaction solution is collected by product collector online, described reaction solution is post-treated to obtain N- (5- glucose esters valeryl)
Metoprolol；The ratio between described N- (5- vinyl acetates valeryl) metoprolols and the amount of material of glucose are 1:1~10；It is described
Reaction dissolvent in, the volume fraction of dimethyl sulfoxide is 1~20%, and surplus is tert-pentyl alcohol；The addition of described catalyst with
The volume of described reaction dissolvent is calculated as 0.025~0.05g/mL.
Further, in the microfluidic channel reactor that the present invention uses, the syringe number can be one or more,
Depending on specific reaction requirement.Reaction raw materials of the present invention are two kinds, preferably using two syringes, specifically, described injection
Device is the first syringe and the second syringe respectively, and the first described connecting pipe is Y types or T-shaped pipeline, described syringe
Connected again with described reaction channel by described Y types or T-shaped pipeline parallel connection, by the contact of the reactant molecule of microchannel with
Collision probability increases, and two bursts of reaction liquid streams is mixed and is reacted in public reaction channel.
Further, more specifically, method of the present invention comprises the following steps：
The ratio between amount with material is 1:1~10 N- (5- vinyl acetates valeryl) metoprolols and glucose is raw material, with
Lipozyme TLIM is catalyst, using the mixed solvent of dimethyl sulfoxide and tert-pentyl alcohol as reaction dissolvent, by lipase
Lipozyme TLIM are uniformly filled in reaction channel, first dissolve N- (5- vinyl acetates valeryl) metoprolol with dimethyl sulfoxide,
Tert-pentyl alcohol is added, mixed liquor A is obtained, loaded in the first syringe；Glucose is dissolved with dimethyl sulfoxide, tert-pentyl alcohol is added, obtains
Mixed liquid B, loaded in the second syringe；Two syringes are connected by Y types interface with the entrance of reaction channel, are then being noted
Penetrate under the synchronous promotion of pump mixed liquor A and mixed liquid B being passed through in reaction channel and reacted, controlling reaction temperature is 20~60
DEG C, the reaction time is 20~40min, collects reaction solution online by product collector, described reaction solution is post-treated to be made
N- (5- glucose esters valeryl) metoprolol；The addition of described catalyst is calculated as with the volume of described reaction dissolvent
0.025~0.05g/mL.
Further, described temperature control equipment is insulating box, and described reaction channel is placed in insulating box, can with this
With 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；For
The shape of reaction channel is preferably shaped form, it is ensured that reaction solution stably passes through.
In the present invention, described Lipozyme TLIM believes 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 volume ratio of preferably described dimethyl sulfoxide and reaction dissolvent is 0.01~0.1:1, more preferably
0.07:1。
Further, the ratio between amount of material of preferably described N- (5- vinyl acetates valeryl) metoprolols and glucose is 1:1
~7, most preferably 1:5.
Further, the esterification reaction temperature is preferably 25~55 DEG C, most preferably 35 DEG C.
Further, the reaction time of esterification is preferably 20~35min, most preferably 30min.
The reaction product of the present invention can be collected online, and gained reaction solution be able to can be obtained by conventional post-processing approach
N- (5- glucose esters valeryl) metoprolol.The conventional post-processing approach can be：Gained reaction solution, which is evaporated under reduced pressure, to be removed
Solvent, gained crude on silica gel column chromatography for separation, with 200-300 mesh silica gel wet method dress posts, elution reagent is ethyl acetate:First
Alcohol:Water=6:0.4:0.1 mixed solvent, wet method upper prop after crude product is dissolved with a small amount of elution reagent, eluent is collected, simultaneously
TLC tracks elution process, and the obtained eluent containing single product is merged and is evaporated, obtains transparent oily liquid, as N-
(5- glucose esters valeryl) metoprolol.
Compared with prior art, beneficial effects of the present invention are：
The present invention utilizes lipase-catalyzed online synthesis N- (5- glucose esters valeryl) in microfluidic channel reactor
Metoprolol, the method not only significantly shortens the reaction time, and has high conversion ratio and selectivity；Utilize first simultaneously
Economic Lipozyme TLIM catalysis N- (5- vinyl acetates valeryl) metoprolols and the esterification of glucose, drop
Low reaction cost, there is 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 is unlimited
In this：
The apparatus structure for the microfluidic channel reactor that the embodiment of the present invention uses is with reference to figure 1, including a syringe pump is (not
Display), two syringes 1 and 2, reaction channel 3, constant temperature water box (5, only show its floor map) and product collector 4；
Two syringes 1 and 2 are installed in syringe pump, are connected by a Y types interface with the entrance of reaction channel 3, the reaction channel 3
It is placed in constant temperature water box 5, by the controlling reaction temperature of constant temperature water box 5, the internal diameter 2.0mm of described reaction channel 3, pipe range
1m, the outlet of reaction channel 3 are connected by the second connecting pipe with product collector 4.
Embodiment 1：The synthesis of N- (5- glucose esters valeryl) metoprolol
N- (5- vinyl acetates valeryl) metoprolol (0.1mmol) is dissolved in 0.70mL DMSO and 9.30mL tert-pentyl alcohols
In, glucose (0.5mmol) is dissolved in 0.70mL DMSO and 9.30mL tert-pentyl alcohols, is then loaded on 10mL syringes respectively
In it is standby.0.87g Lipozyme TL IM are uniformly filled in reaction channel, under the promotion of the syringe pumps of PD 1200, two
Road reaction solution is respectively with 10.4 μ Lmin-1Flow velocity entered by " Y " joint in reaction channel and reacted, it is permanent to pass through water-bath
Incubator controls temperature of reactor, and at 35 DEG C, reaction solution continuous flowing reactive 30min, reaction result in reaction channel pass through thin layer
Chromatogram TLC tracing detections.
Reaction solution is collected by product collector online, is evaporated under reduced pressure and removes solvent, is filled with 200-300 mesh silica gel wet method
Post, elution reagent are ethyl acetate:Methanol:Water=6:0.4:0.1, pillar height 35cm, column diameter 4.5cm, a small amount of elution of sample
Wet method upper prop after reagent dissolving, eluent collect flow velocity 2mLmin-1, while TLC tracking elution processes, it will obtain containing single
The eluent of one product, which merges, to be evaporated, and is obtained transparent oily liquid, is obtained N- (5- glucose esters valeryl) metoprolol, HPLC
Detect N- (5- vinyl acetates valeryl) metoprolol conversion ratio 85%, selectivity 98%.
Nuclear-magnetism characterization result is as follows：
1H NMR(DMSO-d6,δ,ppm):7.14 (t, 2H, J=7.8Hz, Ar-H), 6.84 (dd, 2H, J=8.4Hz, J=
16.8Hz,Ar-H),5.22(s,1H,CHOH),5.13(s,1H,C1-H of D-glucose),4.90(s,1H,C4-OH of
D-glucose),4.78(s,1H,C2-OH of D-glucose),4.66(m,2H,CHOH and C3-OH of D-
glucose),4.34(s,1H,C1-OH of D-glucose),4.31(m,2H,C6-H2of D-glucose),4.28-4.07
(d, J=6.6Hz, 2H, OCH 2CH),4.12(s,1H,C5-H of D-glucose),3.85(s,1H,NCH),3.78(m,2H,
C3-H and C2-H of D-glucose),3.48(m,3H,OCH 2CH2 and C4-H of D-glucose),3.58-3.33
(s,2H,NCH2),3.19(s,3H,CH3), O 2.89-2.67 (q, 2H, J=6.6Hz, Ar-CH2),2.60-2.18(s,4H,
COCH2), 1.52-1.46 (t, 4H, J=9.2Hz ,-COCH2CH 2CH 2CH2), CO 1.16 (d, 3H, J=6.4Hz, CH3),1.00
(d, 3H, J=7.6Hz, CH3).
13C NMR(DMSO-d6,ppm):174.36,172.52 (C=O), 156.11,130.75,129.80,114.23
(Ar-C,metoprolol),98.94,74.05,72.87,72.23,70.60(C of D-glucose),75.14,74.69,
46.31,34.49,33.40,24.05,24.04(CH2),68.75,48.59(CH),57.80,21.44,19,59(CH3).
Embodiment 2-7
Change the content of DMSO in reaction medium (DMSO/ tert-pentyl alcohols) in microfluidic channel reactor, it is 35 to control temperature
DEG C, with embodiment 1, reaction result is as shown in table 1 for other：
Table 1:Influence of the DMSO amounts to reaction in reaction medium
| Embodiment | DMSO (%) | Conversion ratio [%] | Selectivity [%] |
| 2 | 1 | 51 | 97 |
| 3 | 3 | 63 | 98 |
| 4 | 5 | 70 | 99 |
| 1 | 7 | 85 | 98 |
| 5 | 9 | 79 | 96 |
| 6 | 11 | 65 | 91 |
| 7 | 20 | 22 | 90 |
The result of table 1 shows, when flow velocity is 10.4 μ Lmin-1, the reaction time is 30min, and reaction temperature is 35
DEG C, the ratio between amount of reactant N- (5- vinyl acetates valeryl) metoprolols and glucose substance is 1:5, conversion ratio is with reactant
System (DMSO/ tert-pentyl alcohols) in DMSO volume ratios increase and increase, when DMSO the amount of DMSO and tert-pentyl alcohol in the mixed solvent be 7%
When reach optimal, be further continued for increasing in the mixed solvent DMSO amount, it will influence enzymatic activity and influence conversion ratio and the choosing of reaction
Selecting property.So optimum response medium is 7% in micro-fluidic micro passage reaction in the present invention DMSO and tert-pentyl alcohol blending agent
System.
Embodiment 8-13
Change the substrate materials of (the 5- vinyl acetates valeryl) metoprolols of N- in micro-fluidic micro passage reaction and glucose
The ratio between amount, control 35 DEG C of temperature, other are with embodiment 1, as a result as shown in table 2：
Table 2:N- (5- vinyl acetates valeryl) metoprolols and the influence for comparing reaction of the amount of glucose substrate material
The result of table 2 shows, when flow velocity is 10.4 μ Lmin-1, the reaction time is 30min, and reaction temperature is 35
DEG C, when reaction medium DMSO contents are 7%, with the increase of reactant glucose amount, the conversion ratio of reaction also increases as, when
The ratio between amount of substrate materials is 1:When 5, the conversion ratio of reaction is optimal, so optimal in micro-fluidic micro passage reaction in the present invention
The ratio between amount of substrate materials is 1:5.
Embodiment 14-18
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, reaction medium DMSO contents
For 7% when, the ratio between amount of reactant N- (5- vinyl acetates valeryl) metoprolols and glucose substance is 1:5, when reaction temperature
When degree is in 35 DEG C, the conversion ratio of reaction is optimal, temperature or the Tai Gao or too low activity that will all influence enzyme.It is so micro- in the present invention
Optimum temperature is 35 DEG C in stream control micro passage reaction.
Embodiment 19-22
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
| Embodiment | Time [min] | Conversion ratio [%] | Selectivity [%] |
| 19 | 20 | 64 | 99 |
| 20 | 25 | 73 | 98 |
| 1 | 30 | 85 | 98 |
| 21 | 35 | 78 | 99 |
| 22 | 40 | 75 | 97 |
The result of table 4 shows, when reaction medium DMSO contents are 7%, reactant N- (5- vinyl acetates valeryl) Mei Tuoluo
The ratio between amount of that and glucose substance is 1:5, reaction temperature is 35 DEG C, when reacted between when be 30min, reaction turns
Rate is 85%, reaches optimal.So optimum reacting time is 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 5
Show.
Table 5：Influence of the different enzymes to reaction conversion ratio and selectivity
The result of table 5 shows, for the region of enzymatic N- in micro-fluidic reactor (5- vinyl acetates valeryl) metoprolol
For selective esterification reaction, different enzymes has fairly obvious influence to reaction.It is anti-using porcine pancreatic lipase PPL catalysis
Should, the conversion ratio of N- (5- vinyl acetates valeryl) metoprolol is 37%.And it is anti-to be catalyzed this using bacillus alkaline protease
Should, the conversion ratio of N- (5- vinyl acetates valeryl) metoprolol is only 14%.In terms of the result of table 5, for micro-fluidic reactor
For the regioselectivity esterification of middle enzymatic N- (5- vinyl acetates valeryl) metoprolol, maximally effective catalyst is fat
The conversion ratio of enzyme Lipozyme TL IM, N- (5- vinyl acetates valeryl) metoprolol is 85%, and selectivity is 98%.
Claims (10)
- A kind of 1. method of lipase-catalyzed online synthesis N- (5- glucose esters valeryl) metoprolol, it is characterised in that described Method uses microfluidic channel reactor, syringe that described microfluidic channel reactor includes being sequentially connected, with temperature The reaction channel and product collector of control device, the syringe are installed in syringe pump, and described syringe passes through first Connecting pipe is connected with reaction channel entrance, and the product collector is connected by the second connecting pipe 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：With N- (5- vinyl acetates Valeryl) metoprolol and glucose is raw material, using the mixed solvent of dimethyl sulfoxide and tert-pentyl alcohol as reaction dissolvent, with lipase Lipozyme TL IM are catalyst, and described raw material and described reaction dissolvent are placed in syringe, by lipase Lipozyme TL IM are uniformly filled in reaction channel, make described raw material and described reaction molten under the promotion of syringe pump Agent, which is continuously passed through in reaction channel device, carries out esterification, controlling reaction temperature be 20~60 DEG C, the reaction time be 20~ 40min, reaction solution is collected by product collector online, described reaction solution is post-treated to obtain N- (5- glucose esters valeryl) Metoprolol；The ratio between described N- (5- vinyl acetates valeryl) metoprolols and the amount of material of glucose are 1:1~10；It is described Reaction dissolvent in, the volume fraction of dimethyl sulfoxide is 1~20%, and surplus is tert-pentyl alcohol；The addition of described catalyst with The volume of described reaction dissolvent is calculated as 0.025~0.05g/mL.
- 2. the method for lipase-catalyzed online synthesis N- (5- glucose esters valeryl) metoprolol as claimed in claim 1, It is characterized in that：Described syringe has two, is the first syringe and the second syringe respectively, the first described connecting pipe For Y types or T-shaped pipeline, described syringe is connected with described reaction channel again by described Y types or T-shaped pipeline parallel connection.
- 3. the method for lipase-catalyzed online synthesis N- (5- glucose esters valeryl) metoprolol as claimed in claim 2, It is characterized in that：Described method comprises the following steps：The ratio between amount with material is 1:1~10 N- (5- vinyl acetates valeryl) Metoprolol and glucose are raw material, using Lipozyme TLIM as catalyst, with the mixing of dimethyl sulfoxide and tert-pentyl alcohol Solvent is reaction dissolvent, and Lipozyme TLIM is uniformly filled in reaction channel, first dissolves N- with dimethyl sulfoxide (5- vinyl acetates valeryl) metoprolol, tert-pentyl alcohol is added, mixed liquor A is obtained, loaded in the first syringe；It is molten with dimethyl sulfoxide Glucose is solved, tert-pentyl alcohol is added, mixed liquid B is obtained, loaded in the second syringe；Two syringes pass through Y types interface and reaction The entrance of passage is connected, and then mixed liquor A and mixed liquid B are passed through in reaction channel under the synchronous promotion of syringe pump and carried out 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 N- (the 5- glucose esters valeryl) metoprolol of described reaction solution；The addition of described catalyst is with institute The volume for the reaction dissolvent stated is calculated as 0.025~0.05g/mL.
- 4. the method for lipase-catalyzed online synthesis N- (5- glucose esters valeryl) metoprolol as claimed in claim 1, It is characterized in that：Described temperature control equipment is insulating box, and the reaction channel is placed in insulating box.
- 5. the method for lipase-catalyzed online synthesis N- (5- glucose esters valeryl) metoprolol as claimed in claim 3, It is characterized in that：Described temperature control equipment is insulating box, and the reaction channel is placed in insulating box.
- 6. lipase-catalyzed online synthesis N- (5- glucose esters valeryl) metoprolol as described in one of Claims 1 to 5 Method, it is characterised in that：The ratio between amount of material of N- (the 5- vinyl acetates valeryl) metoprolols and glucose is 1:1~ 7。
- 7. lipase-catalyzed online synthesis N- (5- glucose esters valeryl) metoprolol as described in one of Claims 1 to 5 Method, it is characterised in that：The esterification reaction temperature is 25~50 DEG C, and the reaction time is 20~35min.
- 8. lipase-catalyzed online synthesis N- (5- glucose esters valeryl) metoprolol as described in one of Claims 1 to 5 Method, it is characterised in that：The ratio between amount of material of N- (the 5- vinyl acetates valeryl) metoprolols and glucose is 1:5.
- 9. lipase-catalyzed online synthesis N- (5- glucose esters valeryl) metoprolol as described in one of Claims 1 to 5 Method, it is characterised in that：The volume ratio of dimethyl sulfoxide and reaction dissolvent described in the reaction system is 0.07:1.
- 10. lipase-catalyzed online synthesis N- (5- glucose esters valeryl) metoprolol as described in one of Claims 1 to 5 Method, it is characterised in that the post-processing approach is：Gained reaction solution, which is evaporated under reduced pressure, removes solvent, gained crude on silica gel Column chromatography for separation, with 200-300 mesh silica gel wet method dress posts, elution reagent is ethyl acetate:Methanol:Water=6:0.4:0.1 it is mixed Bonding solvent, wet method upper prop after crude product is dissolved with a small amount of elution reagent, eluent, while TLC tracking elution processes are collected, will To eluent containing single product merge and be evaporated, obtain transparent oily liquid, as N- (5- glucose esters valeryl) is beautiful Tuo Luoer.
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| 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 |
| 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 |
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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 |
| CN107955824A (en) * | 2017-12-21 | 2018-04-24 | 浙江工业大学 | A kind of lipase-catalyzed online synthesis S-（4- chlorobenzyls）The method of laurate thioesters |
| CN107988278A (en) * | 2017-12-21 | 2018-05-04 | 浙江农林大学 | A kind of method of lipase-catalyzed online synthesis S- benzyl laurate thioesters |
| 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 |
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| 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 |
| 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 |
| CN107988278B (en) * | 2017-12-21 | 2021-06-04 | 浙江农林大学 | Method for synthesizing S-benzyl lauric acid thioester on line by lipase catalysis |
| CN107988277B (en) * | 2017-12-21 | 2021-06-08 | 浙江农林大学 | Method for synthesizing S-benzylpalmitic acid thioester on line under catalysis of lipase |
| CN111560408A (en) * | 2020-02-29 | 2020-08-21 | 浙江工业大学 | Method for synthesizing coumarin-3-carboxylic acid sugar ester derivative on line based on flow chemistry enzymatic catalysis |
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