CN104561171B - A kind of method of lipase-catalyzed online synthesizing adipic acid vinyl list 1- (6- nitrobenzimidazoles base) ethyl ester - Google Patents
A kind of method of lipase-catalyzed online synthesizing adipic acid vinyl list 1- (6- nitrobenzimidazoles base) ethyl ester Download PDFInfo
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- CN104561171B CN104561171B CN201510018032.9A CN201510018032A CN104561171B CN 104561171 B CN104561171 B CN 104561171B CN 201510018032 A CN201510018032 A CN 201510018032A CN 104561171 B CN104561171 B CN 104561171B
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- 229920002554 vinyl polymer Polymers 0.000 title claims abstract description 59
- 238000000034 method Methods 0.000 title claims abstract description 41
- 235000011037 adipic acid Nutrition 0.000 title claims abstract description 33
- WNLRTRBMVRJNCN-UHFFFAOYSA-N hexanedioic acid Natural products OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 title claims abstract description 33
- 125000004494 ethyl ester group Chemical group 0.000 title claims abstract description 32
- XPAZGLFMMUODDK-UHFFFAOYSA-N 6-nitro-1h-benzimidazole Chemical class [O-][N+](=O)C1=CC=C2N=CNC2=C1 XPAZGLFMMUODDK-UHFFFAOYSA-N 0.000 title claims abstract description 28
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 15
- 239000001361 adipic acid Substances 0.000 title claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 124
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims abstract description 55
- 229960000250 adipic acid Drugs 0.000 claims abstract description 32
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims abstract description 28
- 230000035484 reaction time Effects 0.000 claims abstract description 18
- 239000002994 raw material Substances 0.000 claims abstract description 14
- 238000007259 addition reaction Methods 0.000 claims abstract description 9
- 108010048733 Lipozyme Proteins 0.000 claims abstract description 7
- FCCDDURTIIUXBY-UHFFFAOYSA-N lipoamide Chemical compound NC(=O)CCCCC1CCSS1 FCCDDURTIIUXBY-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000003054 catalyst Substances 0.000 claims abstract description 6
- 238000012805 post-processing Methods 0.000 claims abstract description 4
- 239000002904 solvent Substances 0.000 claims abstract description 4
- 238000003786 synthesis reaction Methods 0.000 claims description 11
- 239000000047 product Substances 0.000 claims description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- 238000010828 elution Methods 0.000 claims description 9
- 239000000126 substance Substances 0.000 claims description 9
- 230000015572 biosynthetic process Effects 0.000 claims description 8
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims description 7
- 239000003480 eluent Substances 0.000 claims description 6
- 125000002971 oxazolyl group Chemical group 0.000 claims description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
- 229940049706 benzodiazepine Drugs 0.000 claims description 4
- 239000012043 crude product Substances 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 4
- 239000000741 silica gel Substances 0.000 claims description 4
- 229910002027 silica gel Inorganic materials 0.000 claims description 4
- -1 Imidazole radicals Chemical class 0.000 claims description 3
- 238000013459 approach Methods 0.000 claims description 3
- 239000006227 byproduct Substances 0.000 claims description 3
- 150000002460 imidazoles Chemical class 0.000 claims description 3
- 230000001360 synchronised effect Effects 0.000 claims description 3
- 238000005292 vacuum distillation Methods 0.000 claims description 3
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- 238000010898 silica gel chromatography Methods 0.000 claims description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 1
- 150000003457 sulfones Chemical class 0.000 claims 1
- KRTDQDCPEZRVGC-UHFFFAOYSA-N 2-nitro-1h-benzimidazole Chemical class C1=CC=C2NC([N+](=O)[O-])=NC2=C1 KRTDQDCPEZRVGC-UHFFFAOYSA-N 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 15
- 239000000376 reactant Substances 0.000 description 7
- 238000007792 addition Methods 0.000 description 6
- 239000000758 substrate Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 238000004809 thin layer chromatography Methods 0.000 description 4
- 238000011161 development Methods 0.000 description 3
- 230000002255 enzymatic effect Effects 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 240000006439 Aspergillus oryzae Species 0.000 description 2
- 235000002247 Aspergillus oryzae Nutrition 0.000 description 2
- 108090001060 Lipase Proteins 0.000 description 2
- 239000004367 Lipase Substances 0.000 description 2
- 102000004882 Lipase Human genes 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 208000012839 conversion disease Diseases 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 235000019421 lipase Nutrition 0.000 description 2
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- 229910052757 nitrogen Inorganic materials 0.000 description 2
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- 206010067484 Adverse reaction Diseases 0.000 description 1
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- 230000006838 adverse reaction Effects 0.000 description 1
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- 238000012512 characterization method Methods 0.000 description 1
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- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000003344 environmental pollutant Substances 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- UVSDPQBAKJACCV-UHFFFAOYSA-N ethene;hexanedioic acid Chemical group C=C.OC(=O)CCCCC(O)=O UVSDPQBAKJACCV-UHFFFAOYSA-N 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical class [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses a kind of method of lipase-catalyzed online synthesizing adipic acid vinyl list 1 (6 nitrobenzimidazole base) ethyl ester, the method is：Using molar ratio as 1:1~8 6 nitrobenzimidazoles are raw material with vinyl hexanediacetate, 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 hexanedioic acid vinyl base list 1 (6 nitrobenzimidazole base) ethyl ester 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 lipase-catalyzed online synthesizing adipic acid vinyl list 1- (6- nitrobenzimidazoles base) second
The method of ester.
(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 online synthesizing adipic acid ethylene lipase-catalyzed in micro passage reaction
The method of base list 1- (6- nitrobenzimidazoles base) ethyl ester, it is intended to find a kind of hexanedioic acid vinyl base list 1- (6- of high-efficiency environment friendly
Nitrobenzimidazole base) ethyl ester online 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 hexanedioic acid vinyl base list 1- (6- nitrobenzimidazoles base) ethyl ester, 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 hexanedioic acid vinyl base list 1- (6- nitrobenzimidazoles base) ethyl ester shown in lipase-catalyzed online synthesis Formulas I
Method, the method use microfluidic channel reactor, the microfluidic channel reactor include syringe pump, syringe,
Reaction channel and product collector, the syringe are installed in syringe pump, are connected by the entrance of first interface and reaction channel
It is logical, the product collector by second interface and the outlet of reaction channel, the reaction channel internal diameter for 0.8~
2.4mm, a length of 0.5~1.0m of reaction channel；The method includes：The ratio between amount with substance is 1:1~8 6- nitros-benzo
Imidazoles is raw material with vinyl hexanediacetate, using 0.5~1.0g Lipozymes TLIM as catalyst, with dimethyl sulfoxide
(DMSO) it is reaction dissolvent, Lipozyme TLIM is uniformly filled in reaction channel, raw material and reaction dissolvent are put
In syringe, raw material and reaction dissolvent are continuously passed through progress geneva in reaction channel under the promotion of syringe pump and added by syringe
Into reaction (Markovnikov addition reactions), controlling reaction temperature is 40~55 DEG C, and the reaction time is 20~35min, passes through production
Object collector collects reaction solution online, hexanedioic acid vinyl base list 1- (the 6- nitro benzos shown in the post-treated obtained Formulas I of reaction solution
Imidazole radicals) ethyl ester.
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, be connected by using T-shaped or Y types interface with the entrance of reaction channel, by raw material 6- nitros-benzimidazole and oneself two
Sour diethyl enester is dissolved in reaction dissolvent respectively, and is respectively placed in two syringes, and syringe is under the synchronous promotion of syringe pump
Different reactants is made to be introduced from two entrances, confluence enters public reaction channel, passes through the middle reactant molecule of microchannel
Contact increases with collision probability, and 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 6- nitros-benzimidazole in implementation process with DMSO, as long as dosage ensures 6- nitre
Base-benzimidazole can fully dissolve, and loaded on spare in syringe；Then vinyl hexanediacetate, dress are dissolved with DMSO
It is spare in another syringe；Then it is passed through raw material and reaction dissolvent under syringe pump (such as PHD2000 syringe pumps) promotion
It is reacted in reaction channel.
More preferred, method of the present invention includes the following steps：
First with DMSO dissolving 6- nitros-benzimidazole, the DMSO solution dissolved with 6- nitros-benzimidazole is obtained, loaded on note
In emitter；Vinyl hexanediacetate is dissolved with DMSO, the DMSO solution dissolved with vinyl hexanediacetate is obtained, loaded on another injection
In device；Two syringes are connected by Y types interface with the entrance of reaction channel, then will be molten under the synchronous promotion of syringe pump
There is the DMSO solution of 6- nitros-benzimidazole and be passed through in reaction channel and carry out dissolved with the DMSO solution of vinyl hexanediacetate
Markovnikov addition reacts.
When using two syringes respectively to reaction channel injection dissolved with the DMSO solution of 6- nitros-benzimidazole and molten
When having the DMSO solution of vinyl hexanediacetate, for dissolve the volumetric usage of the DMSO of 6- nitros-benzimidazole with for molten
Solve vinyl hexanediacetate DMSO volumetric usage be preferably it is equal, in order to ensure enter reaction channel when two kinds of raw materials
The consistency of molar ratio.
In the DMSO solution dissolved with 6- nitros-benzimidazole, the concentration of 6- nitros-benzimidazole is generally
0.1mmol/mL。
In the DMSO solution dissolved with vinyl hexanediacetate, the concentration of vinyl hexanediacetate 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 6- nitros-benzimidazole and vinyl hexanediacetate 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 obtain oneself two by post-processing approach
Sour vinyl list 1- (6- nitrobenzimidazoles base) ethyl ester.The post-processing approach can be：The vacuum distillation of gained reaction solution removes
Remove 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,
N-hexane volume ratio 1:5 mixed solvent, wet method upper prop after crude product is dissolved with a small amount of elution reagent collect eluent, simultaneously
TLC tracks elution process, and the obtained merging of the eluent containing single product is evaporated, can obtain yellow oily liquid, i.e.,
For hexanedioic acid vinyl base list 1- (6- nitrobenzimidazoles base) ethyl ester.
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
The online synthesizing adipic acid vinyl list 1- of enzymatic (6- nitrobenzimidazoles base) ethyl ester, the method not only significantly shorten reaction
Time, and with high conversion ratio；Utilize economic Lipozyme TLIM catalysis Markovnikov for the first time simultaneously
Addition reaction, compared with prior art acylase used greatly reduce reaction cost, have economical and efficient advantage.
(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 hexanedioic acid vinyl base list 1- (6- nitrobenzimidazoles base) ethyl ester
Device is with reference to figure 1：6- nitros-benzimidazole (1.0mmol) is dissolved in 10mLDMSO, vinyl hexanediacetate
(6.0mmol) is dissolved in 10mLDMSO, then respectively loaded on spare in 2 10mL syringes.0.87g Lipozymes
TLIM is uniformly filled in reaction channel, and under the promotion of PHD2000 syringe pumps, two-way reaction solution is respectively with 10.4 μ Lmin-1's
Flow velocity, which is entered by Y type interfaces in reaction channel, to be reacted, and controls temperature of reactor at 50 DEG C by constant temperature water box, reaction
Liquid 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 the merging of the eluent containing single product be evaporated, obtain yellow oily liquids, obtain hexanedioic acid vinyl base list 1- (6- nitros
Benzimidazolyl) ethyl ester, HPLC detection 6- nitrobenzimidazoles conversion ratio 92%, hexanedioic acid vinyl base list 1- (6- nitro benzos
Imidazole radicals) ethyl ester selectivity 100%.
Nuclear-magnetism characterization result is as follows：
1H NMR(DMSO-d6,500MHz,δ,ppm):8.84 (s, 1H, C5-H, 6- nitrobenzimidazoles), 8.57 (d, 1H,
J=1.95Hz, C2-H, 6- nitrobenzimidazole), 8.23 (dd, 1H, J1=2.00Hz, J2=10.95Hz, C7-H, 6- nitrobenzenes
And imidazoles), 7.94 (d, 1H, J=9.0Hz, C8-H, 6- nitrobenzimidazoles), 7.24 (m, 1H, O-CH=CH2),7.15(q,
1H, J=6.20Hz, N-CH-O-C=O), 4.86,4.63 (m, 2H, O-CH=CH2), 2.36-2.34 (m, 4H, O=C-CH2 -
CH2-CH2-CH2 - C=O), 1.92 (d, 3H, J=3.30Hz ,-CH-CH3), 1.46 (m, 4H, O=C-CH2-CH2 -CH2 -CH2-C
=O)
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 hexanedioic acid vinyl base list 1- in device (6- nitrobenzimidazoles base) ethyl ester is 50 DEG C.
Embodiment 5-8
The substrate molar ratio for changing vinyl hexanediacetate and 6- nitros-benzimidazole in micro-fluidic micro passage reaction is
1:1 (embodiment 5), 2:1 (embodiment 6), 4:1 (embodiment 7), 8:1 (embodiment 8), the dosage of 6- nitros-benzimidazole
1.0mmo is constant, change vinyl hexanediacetate dosage be changed to respectively 1.0mmol (embodiment 5), 2.0mmol (embodiment 6),
4.0mmol (embodiment 7), 8.0mmol (embodiment 8), are dissolved in 10mLDMSO respectively, other are with embodiment 1, as a result such as table
Shown in 2.
Table 2:6- nitros-benzimidazole and influence of the vinyl hexanediacetate substrate molar ratio to reacting
Table 2 the result shows that, with the increase of reactant vinyl hexanediacetate, the conversion ratio of reaction also increases as,
When substrate ratio is 6:When 1, the conversion ratio of reaction is optimal, and 6- nitros-benzimidazole has quantitatively been fully converted to oneself two substantially
Sour vinyl list 1- (6- nitrobenzimidazoles base) ethyl ester.At this time if continuing the use of increase reactant vinyl hexanediacetate
Amount, it will lead to the conversion ratio of reaction to reduce, thus, the best substrate ratio of the reaction is 6:1, under the reaction conditions, 6- nitre
Base-benzimidazole has quantitatively been fully converted to hexanedioic acid vinyl base list 1- (6- nitrobenzimidazoles base) ethyl ester substantially.
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 | 55 |
| 10 | 25 | 82 |
| 1 | 30 | 92 |
| 11 | 35 | 84 |
Table 3 the result shows that, reaction carries out hexanedioic acid vinyl base list 1- (the 6- nitro benzos that 25min is available 82%
Imidazole radicals) ethyl ester, 6- nitros-benzimidazole is to be fully converted to hexanedioic acid vinyl base list 1- (6- nitrobenzimidazoles base) substantially
Ethyl ester.With the increase in reaction time, the conversion ratio of reaction gradually increases, when reaction carries out 30min, hexanedioic acid vinyl base list
The conversion ratio of 1- (6- nitrobenzimidazoles base) ethyl ester can reach 92%, at this time if continuing to extend the reaction time, instead can
Lead to the reduction of reaction conversion ratio, thus, hexanedioic acid vinyl base list 1- (6- nitrobenzimidazoles in microfluidic channel reactor
Base) ethyl ester synthesis Best Times be 30min.
Claims (10)
1. a kind of hexanedioic acid vinyl base list 1- (6- nitrobenzimidazoles base) ethyl ester shown in lipase-catalyzed online synthesis Formulas I
Method, it is characterised in that the method use microfluidic channel reactor, the microfluidic channel reactor include syringe pump,
Syringe, reaction channel and product collector, the syringe are installed in syringe pump, pass through first interface and reaction channel
Entrance connects, and for the product collector by second interface and the outlet of reaction channel, the reaction channel internal diameter is 0.8
~2.4mm, a length of 0.5~1.0m of reaction channel；The method includes：The ratio between amount with substance is 1:1~8 6- nitros-benzene
And imidazoles and vinyl hexanediacetate are raw material, using 0.5~1.0g Lipozymes TLIM as catalyst, with diformazan Asia
Sulfone is reaction dissolvent, and Lipozyme TLIM is uniformly filled in reaction channel, and raw material and reaction dissolvent are placed in note
In emitter, it is anti-that raw material and reaction dissolvent are continuously passed through progress Markovnikov addition in reaction channel by syringe under the promotion of syringe pump
Should, controlling reaction temperature is 40~55 DEG C, and the reaction time is 20~35min, collects reaction solution online by product collector, instead
Answer hexanedioic acid vinyl base list 1- (6- nitrobenzimidazoles base) ethyl ester shown in the post-treated obtained Formulas I of liquid；
2. lipase-catalyzed online synthesizing adipic acid vinyl list 1- (6- nitrobenzimidazoles base) second as described in claim 1
The method of ester, it is characterised in that the method includes the following steps：The ratio between amount with substance is 1:1~8 6- nitros-benzo
Imidazoles is raw material with vinyl hexanediacetate, using 0.5~1.0g Lipozymes TLIM as catalyst, with dimethyl sulfoxide
For reaction dissolvent, Lipozyme TLIM is uniformly filled in reaction channel, first with DMSO dissolving 6- nitros-benzo
Imidazoles obtains the DMSO solution dissolved with 6- nitros-benzimidazole, loaded in syringe；Vinyl hexanediacetate is dissolved with DMSO,
The DMSO solution dissolved with vinyl hexanediacetate is obtained, loaded in another syringe；Two syringes are by Y type interfaces with reacting
The entrance of channel is connected, then syringe pump it is synchronous push under by dissolved with the DMSO solution of 6- nitros-benzimidazole and
Be passed through in reaction channel progress Markovnikov addition reaction dissolved with the DMSO solution of vinyl hexanediacetate, controlling reaction temperature for 40~
55 DEG C, the reaction time is 20~35min, and reaction solution, the post-treated obtained Formulas I institute of reaction solution are collected online by product collector
Hexanedioic acid vinyl base list 1- (the 6- nitrobenzimidazoles base) ethyl ester shown.
3. lipase-catalyzed online synthesizing adipic acid vinyl list 1- (6- nitrobenzimidazoles base) second as described in claim 1
The method of ester, it is characterised in that：The microfluidic channel reactor includes insulating box, and the reaction channel is placed in insulating box.
4. lipase-catalyzed online synthesizing adipic acid vinyl list 1- (6- nitrobenzimidazoles base) second as claimed in claim 2
The method of ester, it is characterised in that：The microfluidic channel reactor includes insulating box, and the reaction channel is placed in insulating box.
5. lipase-catalyzed online synthesizing adipic acid vinyl list 1- (the 6- nitro benzo miaows as described in one of Claims 1 to 4
Oxazolyl) ethyl ester method, it is characterised in that：The ratio between amount of substance of the 6- nitros-benzimidazole and vinyl hexanediacetate
It is 1:6~8.
6. lipase-catalyzed online synthesizing adipic acid vinyl list 1- (the 6- nitro benzo miaows as described in one of Claims 1 to 4
Oxazolyl) ethyl ester method, it is characterised in that the reaction temperature be 50~55 DEG C.
7. lipase-catalyzed online synthesizing adipic acid vinyl list 1- (the 6- nitro benzo miaows as described in one of Claims 1 to 4
Oxazolyl) ethyl ester method, it is characterised in that the reaction time be 25~35min.
8. lipase-catalyzed online synthesizing adipic acid vinyl list 1- (the 6- nitro benzo miaows as described in one of Claims 1 to 4
Oxazolyl) ethyl ester method, it is characterised in that：The ratio between amount of substance of the 6- nitros-benzimidazole and vinyl hexanediacetate
It is 1:6.
9. lipase-catalyzed online synthesizing adipic acid vinyl list 1- (the 6- nitro benzo miaows as described in one of Claims 1 to 4
Oxazolyl) ethyl ester method, it is characterised in that the reaction temperature be 50 DEG C, the reaction time be 30min.
10. lipase-catalyzed online synthesizing adipic acid vinyl list 1- (the 6- nitro benzos as described in one of Claims 1 to 4
Imidazole radicals) ethyl ester 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 for separation, with 200-300 mesh silica gel wet method dress posts, elution reagent is ethyl acetate, n-hexane volume
Than 1:5 mixed solvent, wet method upper prop after crude product is dissolved with a small amount of elution reagent collect eluent, while TLC tracking elutions
The obtained merging of the eluent containing single product is evaporated, obtains yellow oily liquid, as hexanedioic acid vinyl base list by process
1- (6- nitrobenzimidazoles base) ethyl ester.
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| Regioselective acylation of flavonoids catalyzed by lipase in low toxicity media;Athina Kontogianni et al.;《Eur. J. Lipid Sci. Technol.》;20011031;第103卷(第10期);第655–660页 * |
| 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2.1、2.3、3.1-3.4节，反应式2 * |
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