CN104561175B - A kind of method of lipase-catalyzed online synthesis 1- (4- nitro-imidazols base)-ethyl acetate - Google Patents
A kind of method of lipase-catalyzed online synthesis 1- (4- nitro-imidazols base)-ethyl acetate Download PDFInfo
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Abstract
The invention discloses a kind of method of 1 (4 nitroimidazole base) ethyl acetate of lipase-catalyzed online synthesis, the method is：Using molar ratio as 1:1~8 4 nitroimidazoles are raw material with vinyl acetate, using 0.5~1.0g Lipozymes TLIM as catalyst, using DMSO solvents as reaction dissolvent, Lipozyme TLIM is uniformly filled in the reaction channel of microfluidic channel reactor, 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；Raw material and reaction dissolvent is made continuously to be passed through progress Markovnikov addition reaction in reaction channel, controlling reaction temperature is 40~55 DEG C, reaction time is 20~35min, collects reaction solution online, and reaction solution obtains 1 (4 nitroimidazole base) ethyl acetate through conventional post processing.The present invention has the advantages that short reaction time, high selectivity and yield are high.
Description
(1) technical field
The present invention relates to a kind of methods of lipase-catalyzed online synthesis 1- (4- nitro-imidazols base)-ethyl acetate.
(2) background technology
Markovnikov additions are one of important tools to form C-C, C-N, C-O, C-X key, be in organic synthesis very
Important a kind of addition reaction.Nitrogen heterocyclic is as addition substrate not only due to this kind of compound is good nucleophilic addition
Reagent, and imidazole derivative generally has higher pharmacological activity, is important pharmaceutical intermediate.
Chemical method Markovnikov addition General reactions are very fast, and conversion ratio is higher, but its harsh reaction condition can be made
Into certain environmental pollution and energy waste, while many side reactions of association, the yield and selectivity of addition are seriously affected.Enzymatic
The advantages that method is because of high selectivity, mild condition, very fast reaction speed is as one of effective tool of organic synthesis, nearly more than ten years
It is rapidly developed.Acylase is once used to catalysis Markovnikov addition reactions, but not only price is relatively more high for acylase
It is expensive, and this method generally requires the longer reaction time (48-96h), and conversion ratio is also to be improved.Therefore development is greener
Color effectively, with more highly selective new catalyst becomes the key of expansion Markovnikov addition application studies and chooses
War.
It is micro-fluidic learn (Microfluidics) be in the micron-scale in structure manipulation nanoliter to picoliters volume fluid technology with
Science 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 becoming entire 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 carries out synthetic reaction and has become micro-fluidic chip neck in the chips
One of the research 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；It needs reactant dosage little, can not only reduce the dosage of expensive, toxic adverse reaction object, the ring generated in reaction process
Border pollutant is also few, is a kind of environmental-friendly, study on the synthesis novel substance technology.
At present, have more domestic and foreign scholars to the Enzyme catalyzed synthesis of Markovnikov addition reactions in organic media into
Research is gone, but this method multiselect is catalyzed with acylase, generally requires the longer reaction time (24-96h), and react
Conversion ratio and selectivity it is not high, therefore we have studied in micro passage reaction it is lipase-catalyzed it is online synthesis 1- (4- nitros-
Imidazole radicals)-ethyl acetate method, it is intended to find a kind of the online of 1- of high-efficiency environment friendly (4- nitro-imidazols base)-ethyl acetate
Controllable method for selective synthesis.
(3) invention content
The technical problem to be solved in the present invention is to provide lipase-catalyzed online synthesis in a kind of microfluidic channel reactor
The new process of 1- (4- nitro-imidazols base)-ethyl acetate, has the advantages that the reaction time is short, yield is high.
In order to solve the above technical problems, the present invention adopts the following technical scheme that：
A kind of method of 1- (4- nitro-imidazols base)-ethyl acetate shown in lipase-catalyzed online synthesis Formulas I, it is described
Method uses microfluidic channel reactor, and the microfluidic channel reactor includes syringe pump, syringe, reaction channel and production
Object collector, the syringe are installed in syringe pump, are connected by first interface with the entrance of reaction channel, and the product is received
Storage is 0.8~2.4mm by second interface and the outlet of reaction channel, the reaction channel internal diameter, and reaction channel is long
For 0.5~1.0m；The method includes：The ratio between amount with substance is 1:1~8 4- nitro-imidazols are original with vinyl acetate
Material, using 0.5~1.0g Lipozymes TLIM as catalyst, with dimethyl sulfoxide (DMSO) for reaction dissolvent, by lipase
Lipozyme TLIM are uniformly filled in reaction channel, and raw material and reaction dissolvent are placed in syringe, and syringe is in syringe pump
Promotion under raw material and reaction dissolvent are continuously passed through in reaction channel carry out Markovnikov addition reaction (Markovnikov additions are anti-
Should), controlling reaction temperature is 40~55 DEG C, and the reaction time is 20~35min, and reaction solution is collected online by product collector,
1- (4- nitro-imidazols base)-ethyl acetate shown in the post-treated obtained Formulas I of reaction solution.
In the microfluidic channel reactor that the present invention uses, the syringe number can be one or more, depending on specific
Depending on reaction requirement.Reaction raw materials of the present invention be two kinds, it is preferable to use two syringes, specifically, two syringes are installed on
In syringe pump, it is connected by using T-shaped or Y types interface with the entrance of reaction channel, by raw material 4- nitro-imidazols and vinyl acetate
Ester is dissolved in reaction dissolvent respectively, and is respectively placed in two syringes, and syringe makes different under the synchronous promotion of syringe pump
Reactant is introduced from two entrances, and confluence enters public reaction channel, is contacted by the middle reactant molecule of microchannel with touching
Probability increase is hit, two bursts of reaction liquid streams is made to mix and be reacted in public reaction channel.
The microfluidic channel reactor further includes insulating box, and the reaction channel is placed in insulating box, can with this
With effective controlling reaction temperature.The insulating box can require voluntarily to select, such as constant temperature water box etc. according to reaction temperature.
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；Reaction
Channel is preferably shaped to shaped form, it is ensured that reaction solution stably passes through.
The present invention first can dissolve 4- nitro-imidazols in implementation process with DMSO, as long as dosage ensures 4- nitros-miaow
Azoles can fully dissolve, and loaded on spare in syringe；Then vinyl acetate is dissolved with DMSO, loaded in another syringe
It is spare；Then raw material and reaction dissolvent is made to be passed through reaction channel under the synchronous promotion of syringe pump (such as PHD2000 syringe pumps)
In reacted.
More preferred, method of the present invention includes the following steps：
4- nitro-imidazols first are dissolved with DMSO, the DMSO solution dissolved with 4- nitro-imidazols are obtained, loaded in syringe；With
DMSO dissolves vinyl acetate, the DMSO solution dissolved with vinyl acetate is obtained, loaded in another syringe；Two syringes lead to
Y types interface is crossed with the entrance of reaction channel to be connected, it then will be dissolved with 4- nitro-imidazols under the synchronous promotion of syringe pump
DMSO solution and DMSO solution dissolved with vinyl acetate are passed through progress Markovnikov addition reaction in reaction channel.
It is injected respectively to reaction channel dissolved with the DMSO solution of 4- nitro-imidazols and dissolved with second when using two syringes
During the DMSO solution of vinyl acetate, vinyl acetate is dissolved with being used for for dissolving the volumetric usage of the DMSO of 4- nitro-imidazols
DMSO volumetric usage be preferably it is equal, in order to ensure enter reaction channel when two kinds of material molar ratios consistency.
In the DMSO solution dissolved with 4- nitro-imidazols, the concentration of 4- nitro-imidazols is generally 0.1mmol/mL.
In the DMSO solution dissolved with vinyl acetate, the concentration of vinyl acetate is generally 0.1~0.8mmol/mL.
In the present invention, the Lipozyme TLIM believes the quotient of (novozymes) company production using Novi
Product, be it is a kind of prepared by microorganism, the system of 1,3 position-specifics, food-grade lipase (EC3.1.1.3) on particle silica gel
Agent.It is the lipase obtained from Thermomyces lanuginosus, is with a kind of gene-modified aspergillus oryzae
(Aspergillus oryzae) microorganism is by submerged fermentation production.
Lipozyme TLIM is uniformly filled in reaction channel by the method for the present invention, can be direct by mechanical means
Granular catalyst is uniformly fixed in reaction channel.
Further, the ratio between amount of substance of the 4- nitro-imidazols and vinyl acetate is preferably 1:6~8, most preferably
1:6。
Further, the Markovnikov addition reactions temperature is preferably 50~55 DEG C, most preferably 50 DEG C.
Further, the Markovnikov addition reactions time is preferably 25~35min, most preferably 30min.It can lead to
Overregulate syringe pump to adjust the flow velocity of fluid in reaction channel and then adjust residence time of the raw material in reaction channel, i.e., instead
Between seasonable.
The reaction product of the present invention can collect online, and gained reaction solution can be obtained by conventional post-processing approach
1- (4- nitro-imidazols base)-ethyl acetate.It is described routine post-processing approach can be：The vacuum distillation of gained reaction solution removes molten
Agent, gained crude on silica gel column chromatography for separation, with 200-300 mesh silica gel wet method dress posts, elution reagent is ethyl acetate, just oneself
Alkane volume ratio 1:5 mixed solvent, crude product with a small amount of elution reagent dissolve after wet method upper prop, collect eluent, while TLC with
Track elutes process, and the obtained merging of the eluent containing single product is evaporated, can obtain the crystal of white, as 1- (4-
Nitro-imidazol base)-ethyl acetate.
The reaction channel internal diameter that the embodiment of the present invention uses is 2mm, a length of 1.0m of reaction channel.Reaction channel internal diameter and length
Degree can influence the fluid flow rate in reaction channel and residence time, but reaction is not caused in itself to directly affect.
Compared with prior art, beneficial effects of the present invention are：The present invention utilizes fat in microfluidic channel reactor
Enzymatic synthesizes 1- (4- nitro-imidazols base)-ethyl acetate online, which not only significantly shortens the reaction time, but also has
There is high conversion ratio；Utilize economic Lipozyme TLIM catalysis Markovnikov addition reactions, phase for the first time simultaneously
Reaction cost is greatly reduced than the acylase used in the prior art, the advantage with economical and efficient.
(4) it illustrates
Fig. 1 is the structure diagram of microfluidic channel reactor used in the embodiment of the present invention.
(5) specific embodiment
Protection scope of the present invention is described further with specific embodiment below, but protection scope of the present invention is unlimited
In this：
The structural reference Fig. 1 for the microfluidic channel reactor that the embodiment of the present invention uses (is not shown including a syringe pump
Show), two syringes 1, reaction channel 3, constant temperature water box (5, only show its floor map) and product collector 4；Two
Syringe 1 is installed in syringe pump, is connected by a Y types interface with the entrance of reaction channel 3, the reaction channel 3 is placed in
In constant temperature water box 5, by 5 controlling reaction temperature of constant temperature water box, the internal diameter 2.0mm of the reaction channel 3, pipe range 1m,
The outlet of the reaction channel 3 is connected by second interface with product collector 4.
Embodiment 1：The synthesis of 1- (4- nitro-imidazols base)-ethyl acetate
Device is with reference to figure 1：4- nitro-imidazols (1.0mmol) are dissolved in 10mLDMSO, vinyl acetate
(6.0mmol) is dissolved in 10mLDMSO, then spare in the syringe respectively loaded on 2 10mL.0.87g lipase
Lipozyme TLIM are uniformly filled in reaction channel, and under the promotion of PHD2000 syringe pumps, two-way reaction solution is respectively with 10.4 μ
L·min-1Flow velocity entered in reaction channel by Y-shaped interface and reacted, temperature of reactor is controlled by constant temperature water box
At 50 DEG C, reaction solution continuous flowing reactive 30min, reaction result in reaction channel pass through thin-layer chromatography TLC tracing detections.
Reaction solution is collected by product collector online, vacuum distillation removes solvent, crude product obtained, with 200-300 mesh
Silica gel wet method dress post, elution reagent are ethyl acetate：N-hexane volume ratio=1:5, pillar height 35cm, column diameter 4.5cm, crude product
Wet method upper prop after being dissolved with a small amount of elution reagent, eluent collect flow velocity 2mLmin-1, while TLC tracking elution processes, will
To containing single product eluent merging be evaporated, obtain white crystal, obtain 1- (4- nitro-imidazols base)-acetic acid second
Ester, HPLC detection 4- nitro-imidazols conversion ratio 92%, the selectivity 100% of 1- (4- nitro-imidazols base)-ethyl acetate.
Nuclear-magnetism characterization result is as follows：
1H NMR(DMSO-d6,500MHz,δ,ppm)；8.66 (s, 1H, N=CH-N), 8.10 (s, 1H, N-CH=C),
6.77 (q, 1H, J=6.25Hz, N-CH-O-C=O), 2.06 (s, 3H, O=C-CH3), 1.78 (d, 3H, J=6.25Hz ,-CH-
CH3).13C NMR(DMSO-d6,125MHz,δ,ppm):169.78(-O-C=O), 147.80 (C4), 137.24 (C2),
120.13(C5),77.34(-N-C), H-O-C=O 21.13 (O=C-CH3),20.18(O-CH-CH3).HRMS.m/z for[M+
Na]+C7H9N3O4Na222.0485,found 222.0476.
Embodiment 2-4
Change the temperature of microfluidic channel reactor, with embodiment 1, reaction result is as shown in table 1 for other：
Table 1:Influence of the temperature to reaction
Table 1 the result shows that, when flow velocity be 10.4 μ Lmin-1, when the reaction time is 30min, react the liter with temperature
Height, conversion ratio is also significantly raised, and when reaction temperature reaches 50 DEG C, the conversion ratio of reaction is best, will at this time if continuing to heat up
The reduction of enzymatic activity can be caused, the conversion ratio so as to cause reaction decreases, so micro-fluidic microchannel plate in the present invention
The optimal reaction temperature for answering 1- in device (4- nitro-imidazols base)-ethyl acetate is 50 DEG C.
Embodiment 5-8
It is 1 to change the substrate molar ratio of vinyl acetate and 4- nitro-imidazols in micro-fluidic micro passage reaction:1 (implements
Example 5), 2:1 (embodiment 6), 4:1 (embodiment 7), 8:1 (embodiment 8), the dosage 1.0mmol of 4- nitro-imidazols is constant, changes
The dosage of vinyl acetate be changed to respectively 1.0mmol (embodiment 5), 2.0mmol (embodiment 6), 4.0mmol (embodiment 7),
8.0mmol (embodiment 8), is dissolved in 10mLDMSO respectively, other are with embodiment 1, and the results are shown in Table 2.
Table 2:4- nitro-imidazols and influence of the vinyl acetate substrate molar ratio to reacting
Table 2 the result shows that, with the increase of reactant vinyl acetate, the conversion ratio of reaction also increases as, and works as bottom
Object ratio is 6:When 1, the conversion ratio of reaction is optimal, and 4- nitro-imidazols have quantitatively been fully converted to 1- (4- nitros-miaow substantially
Oxazolyl)-ethyl acetate.At this time if continuing the dosage of increase reactant vinyl acetate, it will lead to the conversion ratio drop of reaction
It is low, thus, the best substrate ratio of the reaction is 6:1, under the reaction conditions, 4- nitro-imidazol basal rations are fully converted to
1- (4- nitro-imidazols base)-ethyl acetate.
Embodiment 9-11
Change in micro-fluidic micro passage reaction the reaction time for 20min (embodiment 9), 25min (embodiment 10),
35min (embodiment 11), other are with embodiment 1, and the results are shown in Table 3.
Table 3:Influence of the reaction time to reaction conversion ratio
| Embodiment | Reaction time [min] | Conversion ratio [%] |
| 9 | 20 | 50 |
| 10 | 25 | 80 |
| 1 | 30 | 92 |
| 11 | 35 | 82 |
Table 3 the result shows that, reaction carries out 1- (4- nitro-imidazols base)-ethyl acetate that 25min is available 80%,
4- nitro-imidazols are substantially fully converted to 1- (4- nitro-imidazols base)-ethyl acetate.With the increase in reaction time, reaction
Conversion ratio gradually increase, when reaction carry out 30min when, the conversion ratio of 1- (4- nitro-imidazols base)-ethyl acetate can reach
92%, at this time if continuing to extend the reaction time, the reduction of reaction conversion ratio can be caused instead, thus, microfluidic channel reaction
The Best Times of 1- (4- nitro-imidazols base)-Synthesis Diethyl ether are 30min in device.
Claims (10)
1. a kind of method of 1- (4- nitro-imidazols base)-ethyl acetate shown in lipase-catalyzed online synthesis Formulas I, feature
It is the method using microfluidic channel reactor, the microfluidic channel reactor includes syringe pump, syringe, reaction
Channel and product collector, the syringe are installed in syringe pump, are connected by first interface with the entrance of reaction channel, institute
Product collector is stated by second interface and the outlet of reaction channel, the reaction channel internal diameter is 0.8~2.4mm, instead
Answer a length of 0.5~1.0m of channel；The method includes：The ratio between amount with substance is 1:1~8 4- nitro-imidazols and acetic acid second
Enester is raw material,, will be fatty using dimethyl sulfoxide as reaction dissolvent using 0.5~1.0g Lipozymes TLIM as catalyst
Enzyme Lipozyme TLIM are uniformly filled in reaction channel, and raw material and reaction dissolvent are placed in syringe, and syringe is being injected
Raw material and reaction dissolvent are continuously passed through progress Markovnikov addition reaction, controlling reaction temperature 40 in reaction channel under the promotion of pump
~55 DEG C, the reaction time is 20~35min, and reaction solution, the post-treated obtained Formulas I of reaction solution are collected online by product collector
Shown 1- (4- nitro-imidazols base)-ethyl acetate；
2. the method for lipase-catalyzed online synthesis 1- (4- nitro-imidazols base)-ethyl acetate as described in claim 1,
It is characterized in that the method includes the following steps：
The ratio between amount with substance is 1:1~8 4- nitro-imidazols are raw material with vinyl acetate, with 0.5~1.0g lipase
Lipozyme TLIM are catalyst, and using dimethyl sulfoxide as reaction dissolvent, Lipozyme TLIM is uniformly filled in instead
It answers in channel, first dissolves 4- nitro-imidazols with DMSO, the DMSO solution dissolved with 4- nitro-imidazols is obtained, loaded in syringe；
Vinyl acetate is dissolved with DMSO, the DMSO solution dissolved with vinyl acetate is obtained, loaded in another syringe；Two syringes
It is connected by Y types interface with the entrance of reaction channel, it then will be dissolved with 4- nitro-imidazols under the synchronous promotion of syringe pump
DMSO solution and DMSO solution dissolved with vinyl acetate are passed through progress Markovnikov addition reaction in reaction channel, control reaction temperature
It is 40~55 DEG C to spend, and the reaction time is 20~35min, collects reaction solution online by product collector, reaction solution is post-treated
1- (4- nitro-imidazols base)-ethyl acetate is made.
3. the method for lipase-catalyzed online synthesis 1- (4- nitro-imidazols base)-ethyl acetate as described 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 1- (4- nitro-imidazols base)-ethyl acetate 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 1- (4- nitro-imidazols base)-ethyl acetate as described in one of Claims 1 to 4
Method, it is characterised in that：The ratio between amount of substance of the 4- nitro-imidazols and vinyl acetate is 1:6~8.
6. lipase-catalyzed online synthesis 1- (4- nitro-imidazols base)-ethyl acetate as described in one of Claims 1 to 4
Method, it is characterised in that the reaction temperature is 50~55 DEG C.
7. lipase-catalyzed online synthesis 1- (4- nitro-imidazols base)-ethyl acetate as described in one of Claims 1 to 4
Method, it is characterised in that the reaction time is 25~35min.
8. lipase-catalyzed online synthesis 1- (4- nitro-imidazols base)-ethyl acetate as described in one of Claims 1 to 4
Method, it is characterised in that：The ratio between amount of substance of the 4- nitro-imidazols and vinyl acetate is 1:6.
9. lipase-catalyzed online synthesis 1- (4- nitro-imidazols base)-ethyl acetate as described in one of Claims 1 to 4
Method, it is characterised in that the reaction temperature is 50 DEG C, and the reaction time is 30min.
10. lipase-catalyzed online synthesis 1- (4- nitro-imidazols base)-ethyl acetate as described in one of Claims 1 to 4
Method, it is characterised in that the post-processing approach is：The vacuum distillation of gained reaction solution removes solvent, gained crude on silica gel column
Chromatography, with 200-300 mesh silica gel wet method dress posts, elution reagent is ethyl acetate, n-hexane volume ratio 1:5 mixing is molten
Agent, wet method upper prop after crude product is dissolved with a small amount of elution reagent collect eluent, while TLC tracking elution processes, by what is obtained
Eluent merging containing single product is evaporated, and obtains the crystal of white, as 1- (4- nitro-imidazols base)-ethyl acetate.
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| Two lipase-catalyzed sequential synthesis of drug derivatives in organic media;Bokai Liu et al.;《Enzyme and Microbial Technology》;20081006;第43卷(第4-5期);第376页Scheme 1、第3.1-3.4节 * |
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