CN109321609A - A method of R-MA is prepared using microchannel reaction unit - Google Patents
A method of R-MA is prepared using microchannel reaction unit Download PDFInfo
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- CN109321609A CN109321609A CN201811272681.1A CN201811272681A CN109321609A CN 109321609 A CN109321609 A CN 109321609A CN 201811272681 A CN201811272681 A CN 201811272681A CN 109321609 A CN109321609 A CN 109321609A
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- 238000006243 chemical reaction Methods 0.000 title claims abstract description 138
- 238000000034 method Methods 0.000 title claims abstract description 26
- 239000011259 mixed solution Substances 0.000 claims abstract description 85
- 239000007788 liquid Substances 0.000 claims abstract description 47
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 39
- 239000003960 organic solvent Substances 0.000 claims abstract description 27
- 108090001060 Lipase Proteins 0.000 claims abstract description 25
- 102000004882 Lipase Human genes 0.000 claims abstract description 25
- 239000004367 Lipase Substances 0.000 claims abstract description 25
- 230000002255 enzymatic effect Effects 0.000 claims abstract description 25
- 235000019421 lipase Nutrition 0.000 claims abstract description 25
- 238000010931 ester hydrolysis Methods 0.000 claims abstract description 18
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 claims abstract description 15
- 238000000926 separation method Methods 0.000 claims abstract description 13
- 230000035484 reaction time Effects 0.000 claims abstract description 8
- 239000012093 phosphatic buffer solution Substances 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 48
- 239000007853 buffer solution Substances 0.000 claims description 46
- 238000002156 mixing Methods 0.000 claims description 33
- SAXHIDRUJXPDOD-UHFFFAOYSA-N ethyl hydroxy(phenyl)acetate Chemical compound CCOC(=O)C(O)C1=CC=CC=C1 SAXHIDRUJXPDOD-UHFFFAOYSA-N 0.000 claims description 26
- 108010084311 Novozyme 435 Proteins 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 18
- NHTMVDHEPJAVLT-UHFFFAOYSA-N Isooctane Chemical compound CC(C)CC(C)(C)C NHTMVDHEPJAVLT-UHFFFAOYSA-N 0.000 claims description 17
- 239000007836 KH2PO4 Substances 0.000 claims description 17
- JVSWJIKNEAIKJW-UHFFFAOYSA-N dimethyl-hexane Natural products CCCCCC(C)C JVSWJIKNEAIKJW-UHFFFAOYSA-N 0.000 claims description 17
- 229910000396 dipotassium phosphate Inorganic materials 0.000 claims description 17
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 17
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 claims description 17
- 102000004190 Enzymes Human genes 0.000 claims description 14
- 108090000790 Enzymes Proteins 0.000 claims description 14
- ITATYELQCJRCCK-UHFFFAOYSA-N Mandelic Acid, Methyl Ester Chemical group COC(=O)C(O)C1=CC=CC=C1 ITATYELQCJRCCK-UHFFFAOYSA-N 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 5
- 239000000243 solution Substances 0.000 claims description 4
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 3
- 229910000397 disodium phosphate Inorganic materials 0.000 claims description 3
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 3
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 abstract description 29
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 abstract description 28
- 229960002510 mandelic acid Drugs 0.000 abstract description 28
- 230000008901 benefit Effects 0.000 abstract description 5
- 230000003287 optical effect Effects 0.000 abstract description 4
- 230000008569 process Effects 0.000 abstract description 4
- 230000007062 hydrolysis Effects 0.000 abstract description 3
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 3
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 14
- -1 pH value are 7 or so Substances 0.000 description 14
- 239000007832 Na2SO4 Substances 0.000 description 12
- 229910052938 sodium sulfate Inorganic materials 0.000 description 12
- 238000010438 heat treatment Methods 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 2
- 239000004810 polytetrafluoroethylene Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 235000006041 Prunus persica f compressa Nutrition 0.000 description 1
- 240000006522 Prunus persica f. compressa Species 0.000 description 1
- 102000018120 Recombinases Human genes 0.000 description 1
- 108010091086 Recombinases Proteins 0.000 description 1
- AOWPVIWVMWUSBD-RNFRBKRXSA-N [(3r)-3-hydroxybutyl] (3r)-3-hydroxybutanoate Chemical compound C[C@@H](O)CCOC(=O)C[C@@H](C)O AOWPVIWVMWUSBD-RNFRBKRXSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000012069 chiral reagent Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 239000011943 nanocatalyst Substances 0.000 description 1
- ORMNNUPLFAPCFD-DVLYDCSHSA-M phenethicillin potassium Chemical compound [K+].N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C([O-])=O)=O)C(=O)C(C)OC1=CC=CC=C1 ORMNNUPLFAPCFD-DVLYDCSHSA-M 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 208000019206 urinary tract infection Diseases 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P7/00—Preparation of oxygen-containing organic compounds
- C12P7/40—Preparation of oxygen-containing organic compounds containing a carboxyl group including Peroxycarboxylic acids
- C12P7/42—Hydroxy-carboxylic acids
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Zoology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Wood Science & Technology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Microbiology (AREA)
- General Chemical & Material Sciences (AREA)
- Biotechnology (AREA)
- Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Apparatus Associated With Microorganisms And Enzymes (AREA)
Abstract
The invention discloses a kind of methods for preparing R-MA using microchannel reaction unit, and mandelate is dissolved in the first organic solvent and obtains mixed solution A；Lipase is dissolved in phosphatic buffer solution and obtains mixed solution B；Mixed solution A and mixed solution B are pumped into the mixer of microchannel reaction unit simultaneously to be mixed, subsequently into progress enzymatic ester hydrolysis reaction in the reactor of microchannel reaction unit；After reaction, reactor efflux is collected, the second organic solvent is added in water phase and is extracted, anhydrous Na is then used for liquid separation Hou Qu lower layer water phase2SO4It is dried, finally revolving removes organic solvent and obtains R-MA.The present invention carries out the hydrolysis of enzymatic mandelate by changing residence time of the reaction mass in the reaction unit of microchannel, the mandelic acid of individual isomer can be obtained, accelerate reaction rate to improving mandelic acid optical selective, there are the advantages such as simple process, reaction time be short.
Description
Technical field
The present invention relates to the reactions of enzymatic mandelate hydrolysis, and in particular to is prepared using microchannel reaction unit
The method of R-MA.
Background technique
Mandelic acid also known as mandelic acid, Alpha-hydroxy phenylacetic acid.It is intermediate that chiral mandelic acid and its ester are important medicine synthesis
Body, and can be used as chiral reagent for splitting other chipal compounds.R-MA is that syncillin and cephalo series are anti-
The important intermediate of raw element, S-MA is the precursor raw material for treating the drug Ao Xibuning of urinary tract infections.Optics mapping
The targeting synthesis of body can improve the economic benefit of the technique of pharmaceutical industry, reduce the quantity of application, to reduce to environment
Adverse effect.
The mandelate of classical chemical synthesis process resolution of racemic mainly using chiral aminated compounds, passes through shape
Optical isomer is separated at diastereomer isomery salt fractional crystallization, but chiral resolving agent price is higher and has certain poison
Property.It also has been reported that the hydro-reduction that chiral platinum nano catalyst is applied to ketone ester prepares chiral mandelic acid in the recent period, obtains higher
Selectivity and yield, but catalyst it is expensive and production safety in terms of there is also certain defects.With it is classical organic
Chemical synthesising technology compares, and the reaction condition of enzymatic is mild, and stereoselectivity is preferable, therefore, currently, mostly using in the world
Lipase-catalyzed mandelate hydrolysis is to which to chiral mandelic acid is obtained, but there are the following problems: (1) being fixed using commercialization
Enzyme, expensive, the reaction time is too long, and selectivity is low；(2) using self-control enzyme, the technique of preparation and the modification of enzyme is cumbersome, reaction
Time is longer.
Summary of the invention
The technical problem to be solved by the present invention is in view of the deficiencies of the prior art, provide one kind to fill by microchannel plate
It sets enzymatic mandelate and hydrolyzes the method for obtaining individual isomer mandelic acid, deposited in the process to overcome and split mandelic acid at present
Reaction time is too long, low yield, the low technical problem of selectivity.
In order to solve the above-mentioned technical problem, the technical solution adopted by the present invention is as follows:
A method of R-MA being prepared using microchannel reaction unit, is included the following steps:
Step 1: mandelate is dissolved in the first organic solvent and obtains mixed solution A；Lipase is dissolved in phosphate
Buffer solution in obtain mixed solution B；
Step 2: by mixed solution A and mixed solution B that step 1 obtains while the mixing for being pumped into microchannel reaction unit
It is mixed in device, subsequently into progress enzymatic ester hydrolysis reaction in the reactor of microchannel reaction unit；
Step 3: after reaction, reactor efflux is collected, liquid separation Hou Qu lower layer water phase is added second in water phase
Organic solvent is extracted, and anhydrous Na is then used2SO4It is dried, finally revolving removes organic solvent and obtains R-MA.
Preferably, in step 1, the mandelate is methyl mandelate, any one in ethyl mandelate.
First organic solvent is any one or two or more mixing in isooctane, n-hexane and hexamethylene
Object, preferably isooctane.
Concentration of the mandelate in mixed solution A is 5mmolL-1~30mmolL-1, preferably 5~
10mmol·L-1。
The lipase is the Novozyme435 of liquid, enzyme activity force value >=5000ug-1, lipase is in mixed solution B
Concentration be 0.5mgml-1~5mgml-1, preferably 1mgml-1~2mgml-1。
The enzyme activity of lipase is defined as: 1g solid enzyme powder or 1ml liquid enzymes, under the conditions of the pH of certain temperature, 1min turns
Enzyme amount needed for changing 1 μm of ol substrate, as an enzyme activity unit, with ug-1Or uml-1It indicates.
The phosphatic buffer solution is KH2PO4/K2HPO4Or NaH2PO4/Na2HPO4, pH value is 6~8, preferable ph
It is 7；Phosphatic total concentration is 0.05mmolL in buffer solution-1~0.2mmolL-1, preferably 0.05mmolL-1。
In step 2, mixed solution A and mixed solution B's is pumped into microchannel plate than 1: 2~2: 1 according to flow volume and should fill
In setting.
Reaction temperature in the reactor is 40~70 DEG C, preferably 50 DEG C~60 DEG C；Reaction time be 40~
100min, preferably 50~60min.
The microchannel reaction unit includes the mixer and reactor being sequentially connected in series by connecting tube, the charging of mixer
Mouth connection first charging aperture and second charging aperture；Pipeline in reactor is polyfluortetraethylene pipe, and internal diameter is that 0.5~1mm is preferred
0.5mm, conduit volume are 5~10ml, preferably 5~6ml.
In step 3, second organic solvent is any one in methylene chloride, tetrahydrofuran or acetonitrile.
The temperature of the revolving is 40 DEG C.
The utility model has the advantages that
It is mostly high using business immobilised enzymes or self-control enzyme, business immobilised enzymes price in the existing technology for splitting mandelic acid
It is expensive, and make that enzyme preparation process is complicated, and lipase used in the present invention is resolvase by oneself, it is cheap, it is easy to use, have compared with
Good catalytic effect.Enzymatic mandelate water is carried out by changing residence time of the reaction mass in the reaction unit of microchannel
Solution, can be obtained the mandelic acid of individual isomer.For mandelic acid and its derivative, the microchannel reaction unit that the present invention uses can
Accelerate reaction rate to improving its optical selective, there are the advantages such as simple process, reaction time be short.
Detailed description of the invention
The present invention is done with reference to the accompanying drawings and detailed description and is further illustrated, of the invention is above-mentioned
And/or otherwise advantage will become apparent.
Fig. 1 is the process schematic that the present invention prepares R-MA using microchannel reaction unit.
Specific embodiment
According to following embodiments, the present invention may be better understood.
As shown in Figure 1, microchannel reaction unit includes the 1 (slitplate of micro-mixer being sequentially connected in series by connecting tube
Mixer LH25Hastelloy C) and micro passage reaction 2, wherein micro-mixer is connected with first charging aperture 3 and the second charging
Mouth 4.Pipeline in micro passage reaction 2 is polyfluortetraethylene pipe, and internal diameter is 0.5~1mm, and conduit volume is 5~10ml.
Embodiment 1
Ethyl mandelate is dissolved in iso-octane solvent, the concentration of ethyl mandelate is 10mmolL-1It obtains mixing molten
Liquid A；The Novozyme435 of liquid is dissolved in KH2PO4/K2HPO4(buffer solution, pH value are 7 or so, buffer solution in buffer solution
In phosphatic total concentration be 0.05mmolL-1), mixed solution B is obtained, wherein concentration of the lipase in mixed solution B is
2mg·ml-1.Mixed solution A and mixed solution B are pumped into the reaction unit of microchannel according to flow volume ratio for 1: 1, mixed through T-type
Enter after clutch mixing and carry out enzymatic ester hydrolysis reaction in micro passage reaction, in micro passage reaction in polyfluortetraethylene pipe
Diameter is 0.5mm, volume 5ml, and reaction 50min is stopped under temperature 50 C, micro passage reaction efflux is collected, takes after liquid separation
Lower layer's water phase is added methylene chloride in water phase and is extracted, then uses anhydrous Na2SO4It is dried, finally revolving removes and has
Solvent obtains the mandelic acid of R type, yield 99.9%, enantiomeric excess value 99.9%.
Embodiment 2
Methyl mandelate is dissolved in iso-octane solvent, the concentration of methyl mandelate is 5mmolL-1It obtains mixing molten
Liquid A；The Novozyme435 of liquid is dissolved in NaH2PO4/Na2HPO4(buffer solution, pH value are 7 or so, are buffered molten in buffer solution
Phosphatic total concentration is 0.05mmolL in liquid-1), mixed solution B is obtained, wherein concentration of the lipase in mixed solution B
For 1mgml-1.Mixed solution A and mixed solution B are pumped into the reaction unit of microchannel according to flow volume ratio for 1: 1, through T-type
Enter after mixer mixing and carries out enzymatic ester hydrolysis reaction in micro passage reaction, polyfluortetraethylene pipe in micro passage reaction
Internal diameter is 0.5mm, volume 6ml, stops reaction 60min at being 60 DEG C in temperature, collects micro passage reaction efflux, liquid separation
Hou Qu lower layer water phase is added tetrahydrofuran in water phase and is extracted, then uses anhydrous Na2SO4It is dried, finally revolving is removed
Organic solvent is gone to obtain the mandelic acid of R type, yield 99.9%, enantiomeric excess value 99.9%.
Embodiment 3
Methyl mandelate is dissolved in iso-octane solvent, the concentration of methyl mandelate is 7.5mmolL-1It is mixed
Solution A；The Novozyme435 of liquid is dissolved in KH2PO4/K2HPO4(buffer solution, pH value are 7 or so, are buffered molten in buffer solution
Phosphatic total concentration is 0.05mmolL in liquid-1), mixed solution B is obtained, wherein concentration of the lipase in mixed solution B
For 1.5mgml-1.Mixed solution A and mixed solution B are pumped into the reaction unit of microchannel according to flow volume ratio for 1: 1, through T
Enter after the mixing of type mixer and carries out enzymatic ester hydrolysis reaction in micro passage reaction, polytetrafluoroethylene (PTFE) in micro passage reaction
Bore is 0.5mm, volume 5.5ml, stops reaction 55min at being 55 DEG C in temperature, collects micro passage reaction efflux,
Liquid separation Hou Qu lower layer water phase is added acetonitrile in water phase and is extracted, then uses anhydrous Na2SO4It is dried, finally revolving is removed
Organic solvent is gone to obtain the mandelic acid of R type, yield 99.9%, enantiomeric excess value 99.9%.
Embodiment 4
Ethyl mandelate is dissolved in iso-octane solvent, the concentration of ethyl mandelate is 10mmolL-1It obtains mixing molten
Liquid A；The Novozyme435 of liquid is dissolved in KH2PO4/K2HPO4In buffer solution, (buffer solution, pH value are 7 or so, are buffered molten
Phosphatic total concentration is 0.05mmolL in liquid-1), mixed solution B is obtained, wherein concentration of the lipase in mixed solution B
For 2mgml-1.Mixed solution A and mixed solution B are pumped into the reaction unit of microchannel according to flow volume ratio for 1: 1, through T-type
Enter after mixer mixing and carries out enzymatic ester hydrolysis reaction in micro passage reaction, polyfluortetraethylene pipe in micro passage reaction
Internal diameter is 0.5mm, volume 6ml, stops reaction 40min at being 50 DEG C in temperature, collects micro passage reaction efflux, liquid separation
Hou Qu lower layer water phase is added methylene chloride in water phase and is extracted, then uses anhydrous Na2SO4It is dried, finally revolving is removed
Organic solvent is gone to obtain the mandelic acid of R type, yield 86.4%, enantiomeric excess value 85.7%.
Embodiment 5
Methyl mandelate is dissolved in iso-octane solvent, the concentration of methyl mandelate is 10mmolL-1It obtains mixing molten
Liquid A；The Novozyme435 of liquid is dissolved in KH2PO4/K2HPO4(buffer solution, pH value are 7 or so, buffer solution in buffer solution
In phosphatic total concentration be 0.05mmolL-1), mixed solution B is obtained, wherein concentration of the lipase in mixed solution B is
2mg·ml-1.Mixed solution A and mixed solution B are pumped into the reaction unit of microchannel according to flow volume ratio for 1: 1, mixed through T-type
Enter after clutch mixing and carry out enzymatic ester hydrolysis reaction in micro passage reaction, in micro passage reaction in polyfluortetraethylene pipe
Diameter is 0.5mm, volume 6ml, stops reaction 100min at being 50 DEG C in heating temperature, collects micro passage reaction efflux,
Liquid separation Hou Qu lower layer water phase is added methylene chloride in water phase and is extracted, then uses anhydrous Na2SO4It is dried, most back spin
The mandelic acid that organic solvent obtains R type, yield 70.9%, enantiomeric excess value 51.3% is evaporated off.
Embodiment 6
Ethyl mandelate is dissolved in iso-octane solvent, the concentration of ethyl mandelate is 10mmolL-1It obtains mixing molten
Liquid A；The Novozyme435 of liquid is dissolved in KH2PO4/K2HPO4(buffer solution, pH value are 7 or so, buffer solution in buffer solution
In phosphatic total concentration be 0.05mmolL-1), mixed solution B is obtained, wherein concentration of the lipase in mixed solution B is
2mg·ml-1.Mixed solution A and mixed solution B are pumped into the reaction unit of microchannel according to flow volume ratio for 1: 1, mixed through T-type
Enter after clutch mixing and carry out enzymatic ester hydrolysis reaction in micro passage reaction, in micro passage reaction in polyfluortetraethylene pipe
Diameter is 0.5mm, volume 6ml, stops reaction 50min at being 40 DEG C in temperature, micro passage reaction efflux is collected, after liquid separation
Lower layer's water phase is taken, methylene chloride is added in water phase and is extracted, anhydrous Na is then used2SO4It is dried, finally revolving removes
Organic solvent obtains the mandelic acid of R type, yield 83.5%, enantiomeric excess value 79.0%.
Embodiment 7
Ethyl mandelate is dissolved in iso-octane solvent, the concentration of ethyl mandelate is 10mmolL-1It obtains mixing molten
Liquid A；The Novozyme435 of liquid is dissolved in KH2PO4/K2HPO4(buffer solution, pH value are 7 or so, buffer solution in buffer solution
In phosphatic total concentration be 0.05mmolL-1), mixed solution B is obtained, wherein concentration of the lipase in mixed solution B is
2mg·ml-1.Mixed solution A and mixed solution B are pumped into the reaction unit of microchannel according to flow volume ratio for 1: 1, mixed through T-type
Enter after clutch mixing and carry out enzymatic ester hydrolysis reaction in micro passage reaction, in micro passage reaction in polyfluortetraethylene pipe
Diameter is 0.5mm, volume 6ml, stops reaction 50min at being 70 DEG C in temperature, micro passage reaction efflux is collected, after liquid separation
Lower layer's water phase is taken, methylene chloride is added in water phase and is extracted, anhydrous Na is then used2SO4It is dried, finally revolving removes
Organic solvent obtains the mandelic acid of R type, yield 81.6%, enantiomeric excess value 77.8%.
Embodiment 8
Ethyl mandelate is dissolved in iso-octane solvent, the concentration of ethyl mandelate is 30mmolL-1It obtains mixing molten
Liquid A；The Novozyme435 of liquid is dissolved in KH2PO4/K2HPO4(buffer solution, pH value are 8 or so, buffer solution in buffer solution
In phosphatic total concentration be 0.2mmolL-1), mixed solution B is obtained, wherein concentration of the lipase in mixed solution B is
5mg·ml-1.Mixed solution A and mixed solution B are pumped into the reaction unit of microchannel according to flow volume ratio for 1: 1, mixed through T-type
Enter after clutch mixing and carry out enzymatic ester hydrolysis reaction in micro passage reaction, in micro passage reaction in polyfluortetraethylene pipe
Diameter is 0.5mm, volume 6ml, stops reaction 50min at being 50 DEG C in heating temperature, collects micro passage reaction efflux, point
Ye Houqu lower layer water phase is added methylene chloride in water phase and is extracted, then uses anhydrous Na2SO4It is dried, finally rotates
Remove the mandelic acid that organic solvent obtains R type, yield 77.1%, enantiomeric excess value 81.0%.
Embodiment 9
Ethyl mandelate is dissolved in iso-octane solvent, the concentration of ethyl mandelate is 10mmolL-1It obtains mixing molten
Liquid A；The Novozyme435 of liquid is dissolved in KH2PO4/K2HPO4(buffer solution, pH value are 7 or so, buffer solution in buffer solution
In phosphatic total concentration be 0.05mmolL-1), mixed solution B is obtained, wherein concentration of the lipase in mixed solution B is
2mg·ml-1.Mixed solution A and mixed solution B are pumped into the reaction unit of microchannel according to flow volume ratio for 1: 2, mixed through T-type
Enter after clutch mixing and carry out enzymatic ester hydrolysis reaction in micro passage reaction, in micro passage reaction in polyfluortetraethylene pipe
Diameter is 0.5mm, volume 6ml, stops reaction 50min at being 50 DEG C in heating temperature, collects micro passage reaction efflux, point
Ye Houqu lower layer water phase is added methylene chloride in water phase and is extracted, then uses anhydrous Na2SO4It is dried, finally rotates
Remove the mandelic acid that organic solvent obtains R type, yield 73.8%, enantiomeric excess value 80.8%.
Embodiment 10
Ethyl mandelate is dissolved in iso-octane solvent, the concentration of ethyl mandelate is 10mmolL-1It obtains mixing molten
Liquid A；The Novozyme435 of liquid is dissolved in KH2PO4/K2HPO4(buffer solution, pH value are 7 or so, buffer solution in buffer solution
In phosphatic total concentration be 0.05mmolL-1), mixed solution B is obtained, wherein concentration of the lipase in mixed solution B is
2mg·ml-1.Mixed solution A and mixed solution B are pumped into the reaction unit of microchannel according to flow volume ratio for 2: 1, mixed through T-type
Enter after clutch mixing and carry out enzymatic ester hydrolysis reaction in micro passage reaction, in micro passage reaction in polyfluortetraethylene pipe
Diameter is 0.5mm, volume 6ml, stops reaction 50min at being 50 DEG C in heating temperature, collects micro passage reaction efflux, point
Ye Houqu lower layer water phase is added methylene chloride in water phase and is extracted, then uses anhydrous Na2SO4It is dried, finally rotates
Remove the mandelic acid that organic solvent obtains R type, yield 66.6%, enantiomeric excess value 70.3%.
Embodiment 11
Ethyl mandelate is dissolved in iso-octane solvent, the concentration of ethyl mandelate is 10mmolL-1It obtains mixing molten
Liquid A；The Novozyme435 of liquid is dissolved in KH2PO4/K2HPO4(buffer solution, pH value are 6 or so, buffer solution in buffer solution
In phosphatic total concentration be 0.05mmolL-1), mixed solution B is obtained, wherein concentration of the lipase in mixed solution B is
2mg·ml-1.Mixed solution A and mixed solution B are pumped into the reaction unit of microchannel according to flow volume ratio for 1: 1, mixed through T-type
Enter after clutch mixing and carry out enzymatic ester hydrolysis reaction in micro passage reaction, in micro passage reaction in polyfluortetraethylene pipe
Diameter is 1mm, volume 10ml, stops reaction 50min at being 50 DEG C in heating temperature, collects micro passage reaction efflux, point
Ye Houqu lower layer water phase is added methylene chloride in water phase and is extracted, then uses anhydrous Na2SO4It is dried, finally rotates
Remove the mandelic acid that organic solvent obtains R type, yield 90.2%, enantiomeric excess value 88.3%.
Embodiment 12
Ethyl mandelate is dissolved in n-hexane solvent, the concentration of ethyl mandelate is 10mmolL-1It obtains mixing molten
Liquid A；The Novozyme435 of liquid is dissolved in KH2PO4/K2HPO4(buffer solution, pH value are 7 or so, buffer solution in buffer solution
In phosphatic total concentration be 0.05mmolL-1), mixed solution B is obtained, wherein concentration of the lipase in mixed solution B is
2mg·ml-1.Mixed solution A and mixed solution B are pumped into the reaction unit of microchannel according to flow volume ratio for 1: 1, mixed through T-type
Enter after clutch mixing and carry out enzymatic ester hydrolysis reaction in micro passage reaction, in micro passage reaction in polyfluortetraethylene pipe
Diameter is 0.5mm, volume 6ml, stops reaction 50min at being 50 DEG C in temperature, micro passage reaction efflux is collected, after liquid separation
Lower layer's water phase is taken, methylene chloride is added in water phase and is extracted, anhydrous Na is then used2SO4It is dried, finally revolving removes
Organic solvent obtains the mandelic acid of R type, yield 75.3%, enantiomeric excess value 71.2%.
Embodiment 13
Ethyl mandelate is dissolved in cyclohexane solvent, the concentration of ethyl mandelate is 10mmolL-1It obtains mixing molten
Liquid A；The Novozyme435 of liquid is dissolved in KH2PO4/K2HPO4(buffer solution, pH value are 7 or so, buffer solution in buffer solution
In phosphatic total concentration be 0.05mmolL-1) mixed solution B is obtained, wherein concentration of the lipase in mixed solution B is
2mg·ml-1.Mixed solution A and mixed solution B are pumped into the reaction unit of microchannel according to flow volume ratio for 1: 1, mixed through T-type
Enter after clutch mixing and carry out enzymatic ester hydrolysis reaction in micro passage reaction, in micro passage reaction in polyfluortetraethylene pipe
Diameter is 0.5mm, volume 6ml, stops reaction 50min at being 50 DEG C in temperature, micro passage reaction efflux is collected, after liquid separation
Lower layer's water phase is taken, methylene chloride is added in water phase and is extracted, anhydrous Na is then used2SO4It is dried, finally revolving removes
Organic solvent obtains the mandelic acid of R type, yield 73.1%, enantiomeric excess value 70.8%.
Comparative example 1
Ethyl mandelate is dissolved in iso-octane solvent, the concentration of ethyl mandelate is 10mmolL-1It obtains mixing molten
Liquid A；The Novozyme435 of liquid is dissolved in KH2PO4/K2HPO4(buffer solution, pH value are 7 or so, buffer solution in buffer solution
In phosphatic total concentration be 0.05mmolL-1), mixed solution B is obtained, wherein concentration of the lipase in mixed solution B is
2mg·ml-1.Mixed solution A and mixed solution B are pumped into the reaction unit of microchannel according to flow volume ratio for 1: 1, mixed through T-type
Enter after clutch mixing and carry out enzymatic ester hydrolysis reaction in micro passage reaction, in micro passage reaction in polyfluortetraethylene pipe
Diameter is 0.5mm, volume 5ml, stops reaction 30min at being 50 DEG C in heating temperature, collects micro passage reaction efflux, point
Ye Houqu lower layer water phase is added methylene chloride in water phase and is extracted, then uses anhydrous Na2SO4It is dried, finally rotates
Remove the mandelic acid that organic solvent obtains R type, yield 62.2%, enantiomeric excess value 61.3%.
Comparative example 2
Ethyl mandelate is dissolved in iso-octane solvent, the concentration of ethyl mandelate is 10mmolL-1It obtains mixing molten
Liquid A；The Novozyme435 of liquid is dissolved in KH2PO4/K2HPO4(buffer solution, pH value are 7 or so, buffer solution in buffer solution
In phosphatic total concentration be 0.05mmolL-1), mixed solution B is obtained, wherein concentration of the lipase in mixed solution B is
2mg·ml-1.Mixed solution A and mixed solution B are pumped into the reaction unit of microchannel according to flow volume ratio for 1: 1, mixed through T-type
Enter after clutch mixing and carry out enzymatic ester hydrolysis reaction in micro passage reaction, in micro passage reaction in polyfluortetraethylene pipe
Diameter is 0.5mm, volume 1.5ml, stops reaction 15min at being 50 DEG C in heating temperature, collects micro passage reaction efflux,
Liquid separation Hou Qu lower layer water phase is added methylene chloride in water phase and is extracted, then uses anhydrous Na2SO4It is dried, most back spin
The mandelic acid that organic solvent obtains R type, yield 50.8%, enantiomeric excess value 45.6% is evaporated off.
Comparative example 3
Methyl mandelate is dissolved in iso-octane solvent, the concentration of methyl mandelate is 10mmolL-1It obtains mixing molten
Liquid A；The Novozyme435 of liquid is dissolved in KH2PO4/K2HPO4(buffer solution, pH value are 7 or so, buffer solution in buffer solution
In phosphatic total concentration be 0.05mmolL-1), mixed solution B is obtained, wherein concentration of the lipase in mixed solution B is
2mg·ml-1.Mixed solution B is added into mixed solution A, heating stirring reacts 3.5h in reaction flask at 55 DEG C of temperature, static
Hou Qu lower layer water phase is added methylene chloride in water phase and is extracted, then uses anhydrous Na2SO4It is dried, finally revolving is removed
Organic solvent is gone to obtain the mandelic acid of R type, yield 55.1%, enantiomeric excess value 66.5%.
The experimental results showed that hydrolyzing to obtain optical purity using microchannel reaction unit enzymatic mandelate higher flat
Peach acid, the reaction time is short, selectivity is excellent.Therefore proposed by the present invention to be hydrolyzed using microchannel reaction unit enzymatic mandelate
There is very big application value in pharmaceutical synthesis.
The present invention provides the thinkings and method of a kind of method that R-MA is prepared using microchannel reaction unit, specifically
Realize that there are many method and the approach of the technical solution, the above is only a preferred embodiment of the present invention, it is noted that for
For those skilled in the art, without departing from the principle of the present invention, can also make it is several improvement and
Retouching, these modifications and embellishments should also be considered as the scope of protection of the present invention.Each component part being not known in the present embodiment
It is realized with the prior art.
Claims (10)
1. a kind of method for preparing R-MA using microchannel reaction unit, which comprises the steps of:
Step 1: mandelate is dissolved in the first organic solvent and obtains mixed solution A；Lipase is dissolved in phosphatic slow
It rushes in solution and obtains mixed solution B；
Step 2: it by mixed solution A and mixed solution B that step 1 obtains while being pumped into the mixer of microchannel reaction unit
Mixing, subsequently into progress enzymatic ester hydrolysis reaction in the reactor of microchannel reaction unit；
Step 3: after reaction, reactor efflux is collected, it is organic to be added second in water phase for liquid separation Hou Qu lower layer water phase
Solvent is extracted, and anhydrous Na is then used2SO4It is dried, finally revolving removes organic solvent and obtains R-MA.
2. the method according to claim 1 for preparing R-MA using microchannel reaction unit, which is characterized in that step
In one, the mandelate is methyl mandelate, any one in ethyl mandelate.
3. the method according to claim 1 for preparing R-MA using microchannel reaction unit, which is characterized in that step
In one, first organic solvent is any one or two or more mixtures in isooctane, n-hexane and hexamethylene.
4. the method according to claim 1 for preparing R-MA using microchannel reaction unit, which is characterized in that step
In one, concentration of the mandelate in mixed solution A is 5mmolL-1~30mmolL-1。
5. the method according to claim 1 for preparing R-MA using microchannel reaction unit, which is characterized in that step
In one, the lipase is the Novozyme435 of liquid, enzyme activity force value >=5000ug-1, lipase is in mixed solution B
Concentration is 0.5mgml-1~5mgml-1。
6. the method according to claim 1 for preparing R-MA using microchannel reaction unit, which is characterized in that step
In one, the phosphatic buffer solution is KH2PO4/K2HPO4Or NaH2PO4/Na2HPO4, pH value is 6~8, in buffer solution
Phosphatic total concentration is 0.05mmolL-1~0.2mmolL-1。
7. the method according to claim 1 for preparing R-MA using microchannel reaction unit, which is characterized in that step
In two, mixed solution A and mixed solution B's is pumped into the reaction unit of microchannel according to flow volume than 1~2: 1~2.
8. the method according to claim 1 for preparing R-MA using microchannel reaction unit, which is characterized in that step
In two, the reaction temperature in the reactor is 40 DEG C~70 DEG C, and reaction time is 40~100min, the pipe in reactor
Road is polyfluortetraethylene pipe, and internal diameter is 0.5~1mm, and conduit volume is 5~10ml.
9. the method according to claim 1 for preparing R-MA using microchannel reaction unit, which is characterized in that step
In three, second organic solvent is any one in methylene chloride, tetrahydrofuran or acetonitrile.
10. the method according to claim 1 for preparing R-MA using microchannel reaction unit, which is characterized in that step
In rapid three, the temperature of the revolving is 40 DEG C.
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