CN104561174B - A kind of method of lipase-catalyzed online synthesis palmitic acid 1 (4 nitroimidazole base) ethyl ester - Google Patents
A kind of method of lipase-catalyzed online synthesis palmitic acid 1 (4 nitroimidazole base) ethyl ester Download PDFInfo
- Publication number
- CN104561174B CN104561174B CN201510018113.9A CN201510018113A CN104561174B CN 104561174 B CN104561174 B CN 104561174B CN 201510018113 A CN201510018113 A CN 201510018113A CN 104561174 B CN104561174 B CN 104561174B
- Authority
- CN
- China
- Prior art keywords
- reaction
- palmitic acid
- ethyl ester
- nitroimidazoles
- base
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 title claims abstract description 76
- 238000000034 method Methods 0.000 title claims abstract description 39
- 235000021314 Palmitic acid Nutrition 0.000 title claims abstract description 38
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 title claims abstract description 38
- 125000004494 ethyl ester group Chemical group 0.000 title claims abstract description 36
- VYDWQPKRHOGLPA-UHFFFAOYSA-N 5-nitroimidazole Chemical compound [O-][N+](=O)C1=CN=CN1 VYDWQPKRHOGLPA-UHFFFAOYSA-N 0.000 title claims abstract description 25
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 24
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 21
- 238000006243 chemical reaction Methods 0.000 claims abstract description 127
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims abstract description 57
- 150000004960 4-nitroimidazoles Chemical class 0.000 claims abstract description 32
- UJRIYYLGNDXVTA-UHFFFAOYSA-N ethenyl hexadecanoate Chemical compound CCCCCCCCCCCCCCCC(=O)OC=C UJRIYYLGNDXVTA-UHFFFAOYSA-N 0.000 claims abstract description 20
- 230000035484 reaction time Effects 0.000 claims abstract description 18
- 239000002994 raw material Substances 0.000 claims abstract description 13
- 238000007259 addition reaction Methods 0.000 claims abstract description 11
- 108010048733 Lipozyme Proteins 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
- 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
- 239000000463 material Substances 0.000 claims description 9
- 238000010828 elution Methods 0.000 claims description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims description 7
- 239000003480 eluent Substances 0.000 claims description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 5
- 239000000741 silica gel Substances 0.000 claims description 5
- 229910002027 silica gel Inorganic materials 0.000 claims description 5
- 239000006227 byproduct Substances 0.000 claims description 4
- 239000012043 crude product Substances 0.000 claims description 4
- -1 Alkene ester Chemical class 0.000 claims description 3
- 238000013459 approach Methods 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- 239000007787 solid Substances 0.000 claims description 3
- 230000001360 synchronised effect Effects 0.000 claims description 3
- WVCYWQSZHOVRTR-UHFFFAOYSA-N C(C)(=O)OC=C.C(CCCCCCCCCCCCCCC)(=O)O Chemical compound C(C)(=O)OC=C.C(CCCCCCCCCCCCCCC)(=O)O WVCYWQSZHOVRTR-UHFFFAOYSA-N 0.000 claims description 2
- 150000003851 azoles Chemical class 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 238000003860 storage Methods 0.000 claims description 2
- 238000004587 chromatography analysis Methods 0.000 claims 1
- 230000008901 benefit Effects 0.000 abstract description 4
- FCCDDURTIIUXBY-UHFFFAOYSA-N lipoamide Chemical compound NC(=O)CCCCC1CCSS1 FCCDDURTIIUXBY-UHFFFAOYSA-N 0.000 abstract description 4
- 239000000243 solution Substances 0.000 description 14
- 239000000376 reactant Substances 0.000 description 7
- 238000007792 addition Methods 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 239000000758 substrate Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- 230000008859 change Effects 0.000 description 3
- 208000012839 conversion disease Diseases 0.000 description 3
- 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
- 239000000126 substance Substances 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
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 235000019421 lipase Nutrition 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 241000223258 Thermomyces lanuginosus Species 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 230000003247 decreasing effect Effects 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
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 238000005935 nucleophilic addition reaction Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 230000007096 poisonous effect Effects 0.000 description 1
- 231100000719 pollutant Toxicity 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000036632 reaction speed Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Landscapes
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Apparatus Associated With Microorganisms And Enzymes (AREA)
Abstract
The invention discloses a kind of method of lipase-catalyzed online synthesis palmitic acid 1 (4 nitroimidazole base) ethyl ester, methods described is：Using mol ratio as 1:1~8 4 nitroimidazoles and vinyl palmitate are raw material, 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 set 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 palmitic acid 1 (4 nitroimidazole base) ethyl ester 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 synthesis palmitic acid 1- (4- nitroimidazoles base) ethyl 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 typically 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 had a strong impact on.Enzymatic
The advantages that method is because of selective height, 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 be catalyzed 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 also has much room for improvement.Therefore development is greener
Color, new catalyst effectively, with more high selectivity as the key for expanding Markovnikov addition application studies and are chosen
War.
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, more domestic and foreign scholars enter the Enzyme catalyzed synthesis of Markovnikov addition reactions in organic media
Research is gone, but this method is catalyzed from acylase more, generally requires the longer reaction time (24-96h), and react
Conversion ratio and selectivity it is not high, therefore we have studied lipase-catalyzed online synthesis palmitic acid 1- in micro passage reaction
The method of (4- nitroimidazoles base) ethyl ester, it is intended to find a kind of palmitic acid 1- (4- nitroimidazoles base) ethyl ester of high-efficiency environment friendly
The controllable method for selective synthesis of line.
(3) content of the invention
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 technology of palmitic acid 1- (4- nitroimidazoles base) ethyl ester, there is the advantages of 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 palmitic acid 1- (4- nitroimidazoles base) ethyl ester shown in lipase-catalyzed online synthesis type I, it is described
Method uses microfluidic channel reactor, and described microfluidic channel reactor includes syringe pump, syringe, reaction channel and production
Thing collector, the syringe are installed in syringe pump, are connected by first interface with the entrance of reaction channel, and the product is received
For storage by second interface and the outlet of reaction channel, the reaction channel internal diameter is 0.8~2.4mm, and reaction channel is grown
For 0.5~1.0m；Methods described includes：The ratio between amount with material is 1:1~8 4- nitro-imidazols are with vinyl palmitate
Raw material, using 0.5~1.0g Lipozymes TLIM as catalyst, with dimethyl sulfoxide (DMSO) for reaction dissolvent, by fat
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 (Markovnikov additions in reaction channel under the promotion of pump
Reaction), controlling reaction temperature is 40~55 DEG C, and the reaction time is 20~35min, collects reaction online by product collector
Liquid, palmitic acid 1- (4- nitroimidazoles base) ethyl ester 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 are two kinds, preferably using 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 palmitic acid second
Alkene ester is dissolved in reaction dissolvent respectively, and is respectively placed in two syringes, and syringe makes difference under the synchronous promotion of syringe pump
Reactant introduced from two entrances, conflux into public reaction channel, by the middle reactant molecule contact of microchannel with
Collision probability increases, and 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, 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；Reaction
Passage 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 its dosage ensures 4- nitros-miaow
Azoles can fully dissolve, and loaded on standby in syringe；Then vinyl palmitate is dissolved with DMSO, loaded on another syringe
In it is standby；Then raw material and reaction dissolvent is made to be passed through in reaction channel under syringe pump (such as PHD2000 syringe pumps) promotion
Row reaction.
More preferable, method of the present invention comprises 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 palmitate, the DMSO solution dissolved with vinyl palmitate is obtained, loaded in another syringe；Two injections
Device is connected by Y types interface with the entrance of reaction channel, then will be dissolved with 4- nitro-imidazols under the synchronous promotion of syringe pump
DMSO solution and be passed through in reaction channel progress Markovnikov addition reaction dissolved with the DMSO solution of vinyl palmitate.
Injected respectively to reaction channel dissolved with the DMSO solution of 4- nitro-imidazols and dissolved with palm fibre when using two syringes
During the DMSO solution of palmitic acid vinyl acetate, palmitic acid second is dissolved with being used for for dissolving the DMSO volumetric usage of 4- nitro-imidazols
The DMSO of alkene ester volumetric usage is preferably equal, and two kinds of material molar ratios is consistent during in order to ensure to enter reaction channel
Property.
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 palmitate, the concentration of vinyl palmitate is generally 0.1~
0.8mmol/mL。
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 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 inventive method, can be direct by mechanical means
Granular catalyst is uniformly fixed in reaction channel.
Further, the ratio between amount of material of the 4- nitro-imidazols and vinyl palmitate is preferably 1:6~8, most preferably
For 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., it is anti-
Between seasonable.
The reaction product of the present invention can collect online, and gained reaction solution can obtain palm by post-processing approach
Sour 1- (4- nitroimidazoles base) ethyl ester.The post-processing approach can be：Gained reaction solution, which is evaporated under reduced pressure, removes solvent, and gained is thick
Product separates through silica gel column chromatography, and with 200-300 mesh silica gel wet method dress posts, elution reagent is ethyl acetate, n-hexane 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 tracking elute into
Journey, the obtained eluent containing single product is merged and is evaporated, white solid, as palmitic acid 1- (4- nitros can be obtained
Imidazole radicals) 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 rate of flow of fluid 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 palmitic acid 1- (4- nitroimidazoles base) ethyl ester online, and the method not only significantly shortens the reaction time, and has
There is high conversion ratio；Utilize economic Lipozyme TLIM catalysis Markovnikov addition reactions, phase first simultaneously
Reaction cost is greatly reduced than the acylase used in prior art, the advantage with 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 structural reference Fig. 1 for the microfluidic channel reactor that the embodiment of the present invention uses, including a syringe pump (do not show
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 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 the reaction channel 3 is connected by second interface with product collector 4.
Embodiment 1：The synthesis of palmitic acid 1- (4- nitroimidazoles base) ethyl ester
Device is with reference to figure 1：4- nitro-imidazols (1.0mmol) are dissolved in 10mLDMSO, vinyl palmitate
(6.0mmol) is dissolved in 10mLDMSO, then respectively loaded on standby 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 is entered in reaction channel by Y types interface 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, is evaporated under reduced pressure and removes solvent, crude product is obtained, with 200-300 mesh
Silica gel wet method dress post, elution reagent are ethyl acetate：N-hexane volume ratio=1:5 mixed solvent, pillar height 35cm, column diameter
4.5cm, wet method upper prop after crude product is dissolved with a small amount of elution reagent, eluent collect flow velocity 2mLmin-1, while TLC is tracked
Elution process, the obtained eluent containing single product is merged and is evaporated, obtains white solid, obtains palmitic acid 1- (4- nitre
Base imidazole radicals) ethyl ester, HPLC detection 4- nitroimidazoles conversion ratio 75%, the selectivity of palmitic acid 1- (4- nitroimidazoles base) ethyl ester
100%.
Nuclear-magnetism characterization result is as follows：
1H NMR(DMSO-d6,500MHz,δ,ppm)；8.67 (s, 1H, N=CH-N), 8.10 (s, 1H, N-CH=C),
6.79 (q, 1H, J=6.15Hz, N-CH-O-C=O), 2.31 (t, 2H, J=7.20Hz, O=C-CH 2-CH2),1.77(d,3H,J
=6.15Hz, CH3- CH-), 1.48 (m, 2H, O=C-CH2-CH 2)1.20(m,24H,-CH2-(CH2)12-CH3),0.85(t,3H,
J=6.70Hz ,-CH2-CH3).
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
The result of table 1 shows, when flow velocity is 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 optimal, will now if continuing to heat up
The reduction of enzymatic activity can be caused, decreased so as to result in the conversion ratio of reaction, so micro-fluidic microchannel plate in the present invention
The optimal reaction temperature for answering palmitic acid 1- in device (4- nitroimidazoles base) ethyl ester is 50 DEG C.
Embodiment 5-8
It is 1 to change the substrate mol ratio of vinyl palmitate and 4- nitro-imidazols in micro-fluidic micro passage reaction:1 is (real
Apply 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 for becoming vinyl palmitate is changed to 1.0mmol (embodiment 5), 2.0mmol (embodiment 6), 4.0mmol (embodiments respectively
7), 8.0mmol (embodiment 8), is dissolved in 10mLDMSO respectively, and other are with embodiment 1, as a result as shown in table 2.
Table 2:4- nitro-imidazols and influence of the vinyl palmitate substrate mol ratio to reaction
The result of table 2 shows, with the increase of reactant vinyl palmitate, the conversion ratio of reaction also increases as, when
Substrate ratio is 6:When 1, the conversion ratio of reaction is optimal, 4- nitro-imidazols substantially Quantitative yield for palmitic acid 1- (4- nitros
Imidazole radicals) ethyl ester.Now if continuing to increase the dosage of reactant vinyl palmitate, it will cause the conversion ratio drop of reaction
It is low, thus, the optimal substrate ratio of the reaction is 6:1, under the reaction conditions, 4- nitro-imidazols have been substantially transitioned to palmitic acid
1- (4- nitroimidazoles base) ethyl ester.
Embodiment 9-11
Change in micro-fluidic micro passage reaction the reaction time be 20min (embodiment 9), 25min (embodiment 10),
35min (embodiment 11), other are with embodiment 1, as a result as shown in table 3.
Table 3:Influence of the reaction time to reaction conversion ratio
| Embodiment | Reaction time [min] | Conversion ratio [%] |
| 9 | 20 | 40 |
| 10 | 25 | 68 |
| 1 | 30 | 75 |
| 11 | 35 | 68 |
The result of table 3 shows that reaction carries out palmitic acid 1- (4- nitroimidazoles base) ethyl ester that 25min is available 68%,
4- nitro-imidazols are substantially fully converted to palmitic acid 1- (4- nitroimidazoles base) ethyl ester.With the increase in reaction time, reaction
Conversion ratio gradually increase, when reaction carry out 30min when, the conversion ratio of palmitic acid 1- (4- nitroimidazoles base) ethyl ester can reach
75%, now if continuing to extend the reaction time, the reduction of reaction conversion ratio can be caused on the contrary, thus, microfluidic channel reaction
The Best Times that palmitic acid 1- (4- nitroimidazoles base) ethyl ester synthesizes in device are 30min.
Claims (10)
1. a kind of method of palmitic acid 1- (4- nitroimidazoles base) ethyl ester shown in lipase-catalyzed online synthesis type I, its feature
It is that methods described uses microfluidic channel reactor, described microfluidic channel reactor includes syringe pump, syringe, reaction
Passage 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 0.5~1.0 m of passage；Methods described includes：The ratio between amount with material is 1:1~8 4- nitro-imidazols and palmitic acid
Vinyl acetate is raw material, using 0.5~1.0g Lipozymes TLIM as catalyst, using dimethyl sulfoxide as reaction dissolvent, by fat
Fat enzyme Lipozyme TLIM are uniformly filled in reaction channel, raw material and reaction dissolvent are placed in syringe, syringe is being noted
Penetrate that raw material and reaction dissolvent are continuously passed through in reaction channel under the promotion of pump and carry out Markovnikov addition reaction, controlling reaction temperature is
40~55 DEG C, the reaction time is 20~35min, collects reaction solution online by product collector, reaction solution is post-treated to be made
Palmitic acid 1- (4- nitroimidazoles base) ethyl ester shown in Formulas I；
2. the method for lipase-catalyzed online synthesis palmitic acid 1- (4- nitroimidazoles base) ethyl ester as claimed in claim 1, its
It is characterised by that described method comprises the following steps：The ratio between amount with material is 1:1~8 4- nitro-imidazols and palmitic acid second
Alkene ester is raw material, using 0.5~1.0g Lipozymes TLIM as catalyst, using dimethyl sulfoxide as reaction dissolvent, by fat
Enzyme Lipozyme TLIM are uniformly filled in reaction channel, are first dissolved 4- nitro-imidazols with DMSO, are obtained dissolved with 4- nitros-miaow
The DMSO solution of azoles, loaded in syringe；Vinyl palmitate is dissolved with DMSO, the DMSO obtained dissolved with vinyl palmitate is molten
Liquid, loaded in another syringe；Two syringes are connected by Y types interface with the entrance of reaction channel, then in syringe pump
It is synchronous promote under the DMSO solution dissolved with 4- nitro-imidazols and the DMSO solution dissolved with vinyl palmitate be passed through reaction
Markovnikov addition reaction is carried out in passage, controlling reaction temperature is 40~55 DEG C, and the reaction time is 20~35min, is received by product
Storage collects reaction solution online, palmitic acid 1- (4- nitroimidazoles base) ethyl ester shown in the post-treated obtained Formulas I of reaction solution.
3. the method for lipase-catalyzed online synthesis palmitic acid 1- (4- nitroimidazoles base) ethyl ester 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 palmitic acid 1- (4- nitroimidazoles base) ethyl ester 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. lipase-catalyzed online synthesis palmitic acid 1- (4- nitroimidazoles base) ethyl ester as described in one of Claims 1 to 4
Method, it is characterised in that：The ratio between amount of material of the 4- nitro-imidazols and vinyl palmitate is 1:6~8.
6. lipase-catalyzed online synthesis palmitic acid 1- (4- nitroimidazoles base) ethyl ester 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 palmitic acid 1- (4- nitroimidazoles base) ethyl ester 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 palmitic acid 1- (4- nitroimidazoles base) ethyl ester as described in one of Claims 1 to 4
Method, it is characterised in that：The ratio between amount of material of the 4- nitro-imidazols and vinyl palmitate is 1:6.
9. lipase-catalyzed online synthesis palmitic acid 1- (4- nitroimidazoles base) ethyl ester 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 palmitic acid 1- (4- nitroimidazoles base) ethyl ester as described in one of Claims 1 to 4
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 post
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, eluent, while TLC tracking elution processes are collected, by what is obtained
Eluent containing single product, which merges, to be evaporated, and obtains white solid, as palmitic acid 1- (4- nitroimidazoles base) ethyl ester.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510018113.9A CN104561174B (en) | 2015-01-14 | 2015-01-14 | A kind of method of lipase-catalyzed online synthesis palmitic acid 1 (4 nitroimidazole base) ethyl ester |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510018113.9A CN104561174B (en) | 2015-01-14 | 2015-01-14 | A kind of method of lipase-catalyzed online synthesis palmitic acid 1 (4 nitroimidazole base) ethyl ester |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104561174A CN104561174A (en) | 2015-04-29 |
| CN104561174B true CN104561174B (en) | 2017-12-05 |
Family
ID=53078250
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510018113.9A Active CN104561174B (en) | 2015-01-14 | 2015-01-14 | A kind of method of lipase-catalyzed online synthesis palmitic acid 1 (4 nitroimidazole base) ethyl ester |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104561174B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN109706198A (en) * | 2018-12-24 | 2019-05-03 | 浙江工业大学 | A kind of method that online enzyme process closes nitro imidazole derivatives |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103184252A (en) * | 2011-12-31 | 2013-07-03 | 浙江工业大学 | Method of using lipase to catalyze and synthesize glucose-6-laurate on line |
| CN103184249A (en) * | 2011-12-31 | 2013-07-03 | 浙江工业大学 | Method for on-line synthesizing glucose-6-palmitate by lipase catalysis |
-
2015
- 2015-01-14 CN CN201510018113.9A patent/CN104561174B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103184252A (en) * | 2011-12-31 | 2013-07-03 | 浙江工业大学 | Method of using lipase to catalyze and synthesize glucose-6-laurate on line |
| CN103184249A (en) * | 2011-12-31 | 2013-07-03 | 浙江工业大学 | Method for on-line synthesizing glucose-6-palmitate by lipase catalysis |
Non-Patent Citations (1)
| Title |
|---|
| 水解酶催化多功能性与串联反应及其调控研究;刘博凯;《中国博士学位论文全文数据库工程科技I辑》;20120115;摘要，第51页第3.2.3节，第3.2.4节（3a），第53页第3.3.1节，第68页第3.5.1节，表3-10 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104561174A (en) | 2015-04-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107488683A (en) | A kind of lipase-catalyzed online synthesis N（5 vinyl acetate valeryls）The method of mexiletine | |
| CN105838600B (en) | A kind of method of 5 ' O palmityl uridines of lipase-catalyzed online synthesis | |
| CN103667402B (en) | A kind of lipase-catalyzed online synthesis 6 " method of-O-lauroyl-naringin ester | |
| CN107475330A (en) | A kind of method of lipase-catalyzed online synthesis N (5 glucose ester valeryl) metoprolol | |
| CN103184253A (en) | Method of using lipase to catalyze and synthesize mannose-6-laurate on line | |
| CN109593804B (en) | Method for quickly synthesizing nitrobenzimidazole derivative through enzyme catalysis | |
| CN109735582B (en) | Method for synthesizing cyclohexanol beta-amino alcohol derivatives on line by lipase catalysis | |
| CN103184255A (en) | Method of using lipase to catalyze and synthesize galactose-6-acetate on line | |
| CN107988277B (en) | Method for synthesizing S-benzylpalmitic acid thioester on line under catalysis of lipase | |
| CN107384782A (en) | A kind of method of lipase-catalyzed online synthesis 5 '-O- ethene adipyls -5-FUD | |
| CN104561170B (en) | A kind of method of lipase-catalyzed online synthesis of acetic acid 1 (6 nitrobenzimidazole base) ethyl ester | |
| CN107488690A (en) | A kind of method of lipase-catalyzed online synthesis N (5 glucose ester valeryl) mexiletine | |
| CN107475329A (en) | A kind of method of lipase-catalyzed online synthesis N (5 sucrose ester valeryl) mexiletine | |
| CN104561174B (en) | A kind of method of lipase-catalyzed online synthesis palmitic acid 1 (4 nitroimidazole base) ethyl ester | |
| CN107488691A (en) | A kind of method of lipase-catalyzed online synthesis N (5 lauroyl mannoses valeryl) metoprolol | |
| CN103667400B (en) | A kind of lipase-catalyzed online synthesis 6 " method of-O-palmityl-naringin ester | |
| CN104561172B (en) | A kind of method of lipase-catalyzed online synthesis laurate 1 (4 nitroimidazole base) ethyl ester | |
| CN104561175B (en) | A kind of method of lipase-catalyzed online synthesis 1- (4- nitro-imidazols base)-ethyl acetate | |
| CN104611388B (en) | A kind of method of lipase-catalyzed online synthesizing adipic acid vinyl list 1- (4- nitroimidazoles base) ethyl ester | |
| CN104561169B (en) | A kind of method of lipase-catalyzed online synthesis laurate 1 (6 nitrobenzimidazole base) ethyl ester | |
| CN104561173B (en) | A kind of method of lipase-catalyzed online synthesis palmitic acid 1- (6- nitrobenzimidazoles base) ethyl ester | |
| CN104561171B (en) | A kind of method of lipase-catalyzed online synthesizing adipic acid vinyl list 1- (6- nitrobenzimidazoles base) ethyl ester | |
| CN109706194A (en) | A method of phenylethanol beta-alkamine derivative is synthesized online based on chemical enzymatic aminolysis reaction is flowed | |
| CN109988787A (en) | A kind of method of lipase-catalyzed online synthesis 2- phenylamino cyclohexanol | |
| CN107418989A (en) | A kind of method of lipase-catalyzed online synthesis N (5 sucrose ester valeryl) metoprolol |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |