CN109321609B - Method for preparing R-mandelic acid by using microchannel reaction device - Google Patents
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- 238000006243 chemical reaction Methods 0.000 title claims abstract description 81
- 238000000034 method Methods 0.000 title claims abstract description 20
- IWYDHOAUDWTVEP-SSDOTTSWSA-N (R)-mandelic acid Chemical compound OC(=O)[C@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-SSDOTTSWSA-N 0.000 title claims abstract description 12
- 239000011259 mixed solution Substances 0.000 claims abstract description 100
- 239000007788 liquid Substances 0.000 claims abstract description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 36
- 239000003960 organic solvent Substances 0.000 claims abstract description 29
- 108090001060 Lipase Proteins 0.000 claims abstract description 26
- 102000004882 Lipase Human genes 0.000 claims abstract description 26
- 239000004367 Lipase Substances 0.000 claims abstract description 26
- 235000019421 lipase Nutrition 0.000 claims abstract description 26
- 238000010931 ester hydrolysis Methods 0.000 claims abstract description 22
- 238000000605 extraction Methods 0.000 claims abstract description 20
- 238000002390 rotary evaporation Methods 0.000 claims abstract description 20
- 238000001035 drying Methods 0.000 claims abstract description 19
- 239000007832 Na2SO4 Substances 0.000 claims abstract description 18
- 229910052938 sodium sulfate Inorganic materials 0.000 claims abstract description 18
- 108090000790 Enzymes Proteins 0.000 claims abstract description 17
- 102000004190 Enzymes Human genes 0.000 claims abstract description 17
- 238000002156 mixing Methods 0.000 claims abstract description 15
- 238000005086 pumping Methods 0.000 claims abstract description 15
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 claims abstract description 7
- 239000008055 phosphate buffer solution Substances 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 48
- 239000007853 buffer solution Substances 0.000 claims description 35
- -1 mandelate ester Chemical class 0.000 claims description 27
- 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
- 229920001343 polytetrafluoroethylene Polymers 0.000 claims description 22
- 239000004810 polytetrafluoroethylene Substances 0.000 claims description 22
- 108010084311 Novozyme 435 Proteins 0.000 claims description 18
- 229910019142 PO4 Inorganic materials 0.000 claims description 18
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 18
- 239000010452 phosphate Substances 0.000 claims description 18
- NHTMVDHEPJAVLT-UHFFFAOYSA-N Isooctane Chemical group 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
- ITATYELQCJRCCK-UHFFFAOYSA-N Mandelic Acid, Methyl Ester Chemical compound 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
- 230000000694 effects Effects 0.000 claims description 4
- 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
- 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 26
- 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 26
- 229960002510 mandelic acid Drugs 0.000 abstract description 26
- 230000035484 reaction time Effects 0.000 abstract description 6
- 238000006555 catalytic reaction Methods 0.000 abstract description 4
- WZHCOOQXZCIUNC-UHFFFAOYSA-N cyclandelate Chemical compound C1C(C)(C)CC(C)CC1OC(=O)C(O)C1=CC=CC=C1 WZHCOOQXZCIUNC-UHFFFAOYSA-N 0.000 abstract description 4
- 230000003287 optical effect Effects 0.000 abstract description 4
- 239000000463 material Substances 0.000 abstract description 3
- 239000012071 phase Substances 0.000 description 32
- 239000000243 solution Substances 0.000 description 16
- 239000002904 solvent Substances 0.000 description 16
- 238000010438 heat treatment Methods 0.000 description 7
- 108010093096 Immobilized Enzymes Proteins 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 238000005034 decoration Methods 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- IWYDHOAUDWTVEP-ZETCQYMHSA-N (S)-mandelic acid Chemical compound OC(=O)[C@@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-ZETCQYMHSA-N 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000011943 nanocatalyst Substances 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 229910052697 platinum Inorganic materials 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
- 238000003756 stirring Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 208000019206 urinary tract infection Diseases 0.000 description 1
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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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- 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 method for preparing R-mandelic acid by using a microchannel reaction device, which comprises the steps of dissolving mandelate in a first organic solvent to obtain a mixed solution A; dissolving lipase in a phosphate buffer solution to obtain a mixed solution B; simultaneously pumping the mixed solution A and the mixed solution B into a mixer of the microchannel reaction device for mixing, and then entering a reactor of the microchannel reaction device for enzyme-catalyzed ester hydrolysis reaction; after the reaction is finished, collecting effluent liquid of the reactor, separating liquid, taking a lower-layer water phase, adding a second organic solvent into the water phase for extraction, and then using anhydrous Na2SO4Drying, and finally removing the organic solvent by rotary evaporation to obtain the R-mandelic acid. The method carries out enzyme catalysis mandelic ester hydrolysis by changing the residence time of reaction materials in the microchannel reaction device, can obtain mandelic acid with single isomer, accelerates the reaction rate, improves the optical selectivity of mandelic acid, and has the advantages of simple process, short reaction time and the like.
Description
Technical Field
The invention relates to a reaction for catalyzing hydrolysis of mandelate by enzyme, in particular to a method for preparing R-mandelic acid by using a microchannel reaction device.
Background
The R-mandelic acid is an important intermediate for synthesizing penicillin and cephalosporin antibiotics, and the S-mandelic acid is a precursor raw material of oxibunin serving as a medicament for treating urinary tract infection.
The classical chemical synthesis method is mainly used for resolving racemic mandelic acid ester, and optical isomers are separated by forming diastereoisomer salt fractional crystallization by using chiral amine compounds, but chiral resolving agents are high in price and have certain toxicity. Recently, the chiral platinum nano-catalyst is also reported to be applied to hydrogenation reduction of ketoester to prepare chiral mandelic acid, so that higher selectivity and yield are obtained, but the catalyst is expensive and has certain defects in production safety. Compared with the classical organic chemical synthesis technology, the reaction condition of enzyme catalysis is mild, and the stereoselectivity is good, so that currently, the chiral mandelic acid is obtained by catalyzing mandelic ester hydrolysis with lipase internationally, but the following problems exist: (1) the use of commercial immobilized enzyme has high price, overlong reaction time and low selectivity; (2) the self-made enzyme is used, the preparation and modification processes of the enzyme are complicated, and the reaction time is long.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a method for obtaining single isomer mandelic acid by catalyzing mandelic ester hydrolysis with micro-channel reaction device, aiming at the defects of the prior art, thereby overcoming the technical problems of overlong reaction time, low yield, low selectivity and the like in the prior process of splitting mandelic acid.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows:
a method for preparing R-mandelic acid by using a microchannel reaction device comprises the following steps:
the method comprises the following steps: dissolving mandelate in a first organic solvent to obtain a mixed solution A; dissolving lipase in a phosphate buffer solution to obtain a mixed solution B;
step two: simultaneously pumping the mixed solution A and the mixed solution B obtained in the step one into a mixer of a microchannel reaction device for mixing, and then entering a reactor of the microchannel reaction device for enzyme-catalyzed ester hydrolysis reaction;
step three: after the reaction is finished, collecting effluent liquid of the reactor, separating liquid, taking a lower-layer water phase, adding a second organic solvent into the water phase for extraction, and then using anhydrous Na2SO4Drying, and finally removing the organic solvent by rotary evaporation to obtain the R-mandelic acid.
Preferably, in the first step, the mandelic ester is any one of methyl mandelate and ethyl mandelate.
The first organic solvent is any one or a mixture of more than two of isooctane, normal hexane and cyclohexane, and preferably isooctane.
The concentration of the mandelate in the mixed solution A is 5 mmol-L-1～30mmol·L-1Preferably 5 to 10 mmol/L-1。
The lipase is liquid Novozyme435, and the enzyme activity value is more than or equal to 5000 u.g-1The concentration of lipase in the mixed solution B was 0.5 mg/ml-1～5mg·ml-1Preferably 1 mg/ml-1～2mg·ml-1。
The enzyme activity of lipase is defined as: 1g of solid enzyme powder or 1ml of liquid enzyme, under the condition of certain pH value and temperature, the enzyme quantity required for 1 mu mol of substrate to be converted in 1min is one enzyme activity unit in u.g-1Or u.ml-1And (4) showing.
The phosphate buffer solution is KH2PO4/K2HPO4Or NaH2PO4/Na2HPO4The pH value is 6-8, the preferable pH value is 7, and the total concentration of phosphate in the buffer solution is 0.05 mmol-L-1～0.2mmol·L-1Preferably 0.05 mmol/L-1。
And in the second step, pumping the mixed solution A and the mixed solution B into a microchannel reaction device according to the flow volume ratio of 1: 2-2: 1.
The reaction temperature in the reactor is 40-70 ℃, preferably 50-60 ℃; the reaction residence time is 40-100 min, preferably 50-60 min.
The microchannel reaction device comprises a mixer and a reactor which are sequentially connected in series through a connecting pipe, wherein a feed inlet of the mixer is connected with a first feed inlet and a second feed inlet; the pipeline in the reactor is a polytetrafluoroethylene pipe, the inner diameter of the polytetrafluoroethylene pipe is 0.5-1 mm, preferably 0.5mm, and the volume of the pipeline is 5-10 ml, preferably 5-6 ml.
In the third step, the second organic solvent is any one of dichloromethane, tetrahydrofuran or acetonitrile.
The temperature of the rotary evaporation is 40 ℃.
Has the advantages that:
in the existing technology for splitting mandelic acid, commercial immobilized enzyme or self-made enzyme is mostly used, the commercial immobilized enzyme is expensive, the preparation process of the self-made enzyme is complex, and the lipase used in the method is free enzyme, is low in cost and convenient to use, and has a good catalytic effect. The mandelic acid with single isomer can be obtained by changing the residence time of the reaction materials in the microchannel reaction device to carry out enzyme catalysis mandelic ester hydrolysis. For mandelic acid and derivatives thereof, the microchannel reaction device adopted by the invention can accelerate the reaction rate so as to improve the optical selectivity, and has the advantages of simple process, short reaction time and the like.
Drawings
The foregoing and/or other advantages of the invention will become further apparent from the following detailed description of the invention when taken in conjunction with the accompanying drawings.
FIG. 1 is a schematic diagram of the process for preparing R-mandelic acid by using a microchannel reaction apparatus according to the present invention.
Detailed Description
The invention will be better understood from the following examples.
As shown in figure 1, the microchannel reactor device comprises a micromixer 1 (slitplacemixer L H25Hastelloy C) and a microchannel reactor 2 which are sequentially connected in series through connecting pipes, wherein the micromixer is connected with a first feed inlet 3 and a second feed inlet 4, a pipeline in the microchannel reactor 2 is a polytetrafluoroethylene pipe, the inner diameter of the polytetrafluoroethylene pipe is 0.5-1 mm, and the volume of the pipeline is 5-10 ml.
Example 1
Dissolving ethyl mandelate in isooctane solvent to obtain ethyl mandelate solution with concentration of 10 mmol-L-1Obtaining a mixed solution A; the liquid Novozyme435 is soluble in KH2PO4/K2HPO4In a buffer solution (buffer solution, pH 7, total phosphate concentration of 0.05 mmol. multidot. L-1) Obtaining a mixed solution B in which the concentration of the lipase in the mixed solution B is 2 mg/ml-1. Pumping the mixed solution A and the mixed solution B into a microchannel reaction device according to the flow volume ratio of 1: 1, mixing by a T-shaped mixer, then entering a microchannel reactor for enzyme-catalyzed ester hydrolysis reaction, allowing polytetrafluoroethylene tubes in the microchannel reactor to have an inner diameter of 0.5mm and a volume of 5ml, standing at 50 ℃ for reaction for 50min, collecting effluent of the microchannel reactor, separating liquid, taking a lower-layer water phase, adding dichloromethane into the water phase for extraction, and then extracting by using anhydrous Na2SO4Drying, and finally removing the organic solvent by rotary evaporation to obtain the R-type mandelic acid, wherein the yield is 99.9 percent, and the enantiomeric excess value is 99.9 percent.
Example 2
Dissolving methyl mandelate in isooctane solvent to obtain methyl mandelate solution with concentration of 5 mmol-L-1Obtaining a mixed solution A; novozyme435 in liquid form dissolved in NaH2PO4/Na2HPO4In a buffer solution (buffer solution, pH 7, total phosphate concentration of 0.05 mmol. multidot. L-1) Obtaining a mixed solution B in which the concentration of the lipase in the mixed solution B is 1 mg/ml-1. The mixed solution A and the mixed solution B are pumped into a microchannel reaction device according to the flow volume ratio of 1: 1, mixed by a T-shaped mixer and then enter a microchannel reactor for enzyme catalysis ester hydrolysis reactionThe inner diameter of a polytetrafluoroethylene tube in the microchannel reactor is 0.5mm, the volume is 6ml, the polytetrafluoroethylene tube stays at the temperature of 60 ℃ for reaction for 60min, effluent of the microchannel reactor is collected, liquid is separated, a lower-layer water phase is taken out, tetrahydrofuran is added into the water phase for extraction, and then anhydrous Na is used for extraction2SO4Drying, and finally removing the organic solvent by rotary evaporation to obtain the R-type mandelic acid, wherein the yield is 99.9 percent, and the enantiomeric excess value is 99.9 percent.
Example 3
Dissolving methyl mandelate in isooctane solvent to obtain methyl mandelate solution with concentration of 7.5 mmol-L-1Obtaining a mixed solution A; the liquid Novozyme435 is soluble in KH2PO4/K2HPO4In a buffer solution (buffer solution, pH 7, total phosphate concentration of 0.05 mmol. multidot. L-1) Obtaining a mixed solution B in which the concentration of the lipase in the mixed solution B is 1.5 mg/ml-1. Pumping the mixed solution A and the mixed solution B into a microchannel reaction device according to the flow volume ratio of 1: 1, mixing by a T-shaped mixer, then entering a microchannel reactor for enzyme-catalyzed ester hydrolysis reaction, allowing polytetrafluoroethylene tubes in the microchannel reactor to have an inner diameter of 0.5mm and a volume of 5.5ml, standing at 55 ℃ for reaction for 55min, collecting effluent of the microchannel reactor, separating liquid, taking a lower-layer water phase, adding acetonitrile into the water phase for extraction, and extracting by using anhydrous Na2SO4Drying, and finally removing the organic solvent by rotary evaporation to obtain the R-type mandelic acid, wherein the yield is 99.9 percent, and the enantiomeric excess value is 99.9 percent.
Example 4
Dissolving ethyl mandelate in isooctane solvent to obtain ethyl mandelate solution with concentration of 10 mmol-L-1Obtaining a mixed solution A; the liquid Novozyme435 is soluble in KH2PO4/K2HPO4In the buffer solution (pH of the buffer solution is about 7, and the total concentration of phosphate in the buffer solution is 0.05 mmol. multidot. L-1) Obtaining a mixed solution B in which the concentration of the lipase in the mixed solution B is 2 mg/ml-1. The mixed solution A and the mixed solution B are pumped into a microchannel reactor according to the flow volume ratio of 1: 1, mixed by a T-shaped mixer and then enter a microchannel reactorPerforming enzyme-catalyzed ester hydrolysis reaction, allowing polytetrafluoroethylene tube with inner diameter of 0.5mm and volume of 6ml in microchannel reactor to stay at 50 deg.C for 40min, collecting effluent of microchannel reactor, separating, collecting lower water phase, adding dichloromethane into the water phase for extraction, and extracting with anhydrous Na2SO4Drying, and finally removing the organic solvent by rotary evaporation to obtain the R-type mandelic acid, wherein the yield is 86.4 percent, and the enantiomeric excess value is 85.7 percent.
Example 5
Dissolving methyl mandelate in isooctane solvent to obtain methyl mandelate solution with concentration of 10 mmol-L-1Obtaining a mixed solution A; the liquid Novozyme435 is soluble in KH2PO4/K2HPO4In a buffer solution (buffer solution, pH 7, total phosphate concentration of 0.05 mmol. multidot. L-1) Obtaining a mixed solution B in which the concentration of the lipase in the mixed solution B is 2 mg/ml-1. Pumping the mixed solution A and the mixed solution B into a microchannel reaction device according to the flow volume ratio of 1: 1, mixing by a T-shaped mixer, then feeding into a microchannel reactor for enzyme-catalyzed ester hydrolysis reaction, allowing polytetrafluoroethylene tubes in the microchannel reactor to have an inner diameter of 0.5mm and a volume of 6ml, standing at a heating temperature of 50 ℃ for reaction for 100min, collecting effluent of the microchannel reactor, separating liquid, taking a lower-layer water phase, adding dichloromethane into the water phase for extraction, and extracting by using anhydrous Na2SO4Drying, and finally removing the organic solvent by rotary evaporation to obtain the R-type mandelic acid, wherein the yield is 70.9 percent, and the enantiomeric excess value is 51.3 percent.
Example 6
Dissolving ethyl mandelate in isooctane solvent to obtain ethyl mandelate solution with concentration of 10 mmol-L-1Obtaining a mixed solution A; the liquid Novozyme435 is soluble in KH2PO4/K2HPO4In a buffer solution (buffer solution, pH 7, total phosphate concentration of 0.05 mmol. multidot. L-1) Obtaining a mixed solution B in which the concentration of the lipase in the mixed solution B is 2 mg/ml-1. The mixed solution A and the mixed solution B are pumped into a microchannel reaction device according to the flow volume ratio of 1: 1 and are mixed by a T-shaped mixerMixing in a mixer, allowing to enter a microchannel reactor for enzyme-catalyzed ester hydrolysis reaction, allowing polytetrafluoroethylene tube with inner diameter of 0.5mm and volume of 6ml to stay at 40 deg.C for 50min, collecting effluent of the microchannel reactor, separating, collecting lower water phase, adding dichloromethane into the water phase for extraction, and extracting with anhydrous Na2SO4Drying, and finally removing the organic solvent by rotary evaporation to obtain the R-type mandelic acid, wherein the yield is 83.5 percent, and the enantiomeric excess value is 79.0 percent.
Example 7
Dissolving ethyl mandelate in isooctane solvent to obtain ethyl mandelate solution with concentration of 10 mmol-L-1Obtaining a mixed solution A; the liquid Novozyme435 is soluble in KH2PO4/K2HPO4In a buffer solution (buffer solution, pH 7, total phosphate concentration of 0.05 mmol. multidot. L-1) Obtaining a mixed solution B in which the concentration of the lipase in the mixed solution B is 2 mg/ml-1. Pumping the mixed solution A and the mixed solution B into a microchannel reaction device according to the flow volume ratio of 1: 1, mixing by a T-shaped mixer, then entering a microchannel reactor for enzyme-catalyzed ester hydrolysis reaction, allowing polytetrafluoroethylene tubes in the microchannel reactor to have an inner diameter of 0.5mm and a volume of 6ml, standing at 70 ℃ for reaction for 50min, collecting effluent of the microchannel reactor, separating liquid, taking a lower-layer water phase, adding dichloromethane into the water phase for extraction, and then extracting by using anhydrous Na2SO4Drying, and finally removing the organic solvent by rotary evaporation to obtain the R-type mandelic acid, wherein the yield is 81.6 percent, and the enantiomeric excess value is 77.8 percent.
Example 8
Dissolving ethyl mandelate in isooctane solvent to obtain ethyl mandelate solution with concentration of 30 mmol-L-1Obtaining a mixed solution A; the liquid Novozyme435 is soluble in KH2PO4/K2HPO4In a buffer solution (buffer solution, pH 8, total phosphate concentration of 0.2 mmol. multidot. L-1) Obtaining a mixed solution B in which the concentration of the lipase in the mixed solution B is 5 mg/ml-1. The mixed solution A and the mixed solution B are pumped into a micro-channel according to the flow volume ratio of 1: 1In the channel reaction device, mixing the materials by a T-shaped mixer, allowing the mixture to enter a microchannel reactor for enzyme-catalyzed ester hydrolysis reaction, allowing the polytetrafluoroethylene tube in the microchannel reactor to have an inner diameter of 0.5mm and a volume of 6ml, standing at 50 ℃ for reaction for 50min, collecting the effluent of the microchannel reactor, separating the effluent, taking the lower aqueous phase, adding dichloromethane into the aqueous phase for extraction, and extracting with anhydrous Na2SO4Drying, and rotary evaporating to remove organic solvent to obtain R-type mandelic acid with yield of 77.1% and enantiomeric excess of 81.0%.
Example 9
Dissolving ethyl mandelate in isooctane solvent to obtain ethyl mandelate solution with concentration of 10 mmol-L-1Obtaining a mixed solution A; the liquid Novozyme435 is soluble in KH2PO4/K2HPO4In a buffer solution (buffer solution, pH 7, total phosphate concentration of 0.05 mmol. multidot. L-1) Obtaining a mixed solution B in which the concentration of the lipase in the mixed solution B is 2 mg/ml-1. Pumping the mixed solution A and the mixed solution B into a microchannel reaction device according to the flow volume ratio of 1: 2, mixing by a T-shaped mixer, then feeding into a microchannel reactor for enzyme-catalyzed ester hydrolysis reaction, allowing polytetrafluoroethylene tubes in the microchannel reactor to have an inner diameter of 0.5mm and a volume of 6ml, standing at a heating temperature of 50 ℃ for reaction for 50min, collecting effluent of the microchannel reactor, separating liquid, taking a lower-layer water phase, adding dichloromethane into the water phase for extraction, and extracting by using anhydrous Na2SO4Drying, and finally removing the organic solvent by rotary evaporation to obtain the R-type mandelic acid, wherein the yield is 73.8 percent, and the enantiomeric excess value is 80.8 percent.
Example 10
Dissolving ethyl mandelate in isooctane solvent to obtain ethyl mandelate solution with concentration of 10 mmol-L-1Obtaining a mixed solution A; the liquid Novozyme435 is soluble in KH2PO4/K2HPO4In a buffer solution (buffer solution, pH 7, total phosphate concentration of 0.05 mmol. multidot. L-1) Obtaining a mixed solution B in which the concentration of the lipase in the mixed solution B is 2 mg/ml-1. Mixed solution A and mixed solutionPumping the solution B into a microchannel reactor according to the flow volume ratio of 2:1, mixing by a T-shaped mixer, allowing the mixture to enter a microchannel reactor for enzyme-catalyzed ester hydrolysis reaction, allowing the inner diameter of a polytetrafluoroethylene tube in the microchannel reactor to be 0.5mm and the volume of the polytetrafluoroethylene tube to be 6ml, standing at a heating temperature of 50 ℃ for reaction for 50min, collecting effluent of the microchannel reactor, separating, taking a lower-layer water phase, adding dichloromethane into the water phase for extraction, and extracting by using anhydrous Na2SO4Drying, and finally removing the organic solvent by rotary evaporation to obtain the R-type mandelic acid, wherein the yield is 66.6 percent, and the enantiomeric excess value is 70.3 percent.
Example 11
Dissolving ethyl mandelate in isooctane solvent to obtain ethyl mandelate solution with concentration of 10 mmol-L-1Obtaining a mixed solution A; the liquid Novozyme435 is soluble in KH2PO4/K2HPO4In a buffer solution (buffer solution, pH 6, total phosphate concentration of 0.05 mmol. multidot. L-1) Obtaining a mixed solution B in which the concentration of the lipase in the mixed solution B is 2 mg/ml-1. Pumping the mixed solution A and the mixed solution B into a microchannel reaction device according to the flow volume ratio of 1: 1, mixing by a T-shaped mixer, then feeding into a microchannel reactor for enzyme-catalyzed ester hydrolysis reaction, allowing polytetrafluoroethylene tubes with the inner diameter of 1mm and the volume of 10ml in the microchannel reactor to stay at the heating temperature of 50 ℃ for reaction for 50min, collecting effluent of the microchannel reactor, separating liquid, taking a lower-layer water phase, adding dichloromethane into the water phase for extraction, and then extracting by using anhydrous Na2SO4Drying, and finally removing the organic solvent by rotary evaporation to obtain the R-type mandelic acid, wherein the yield is 90.2 percent, and the enantiomeric excess value is 88.3 percent.
Example 12
Dissolving ethyl mandelate in n-hexane solvent, wherein the concentration of ethyl mandelate is 10 mmol-L-1Obtaining a mixed solution A; the liquid Novozyme435 is soluble in KH2PO4/K2HPO4In a buffer solution (buffer solution, pH 7, total phosphate concentration of 0.05 mmol. multidot. L-1) Obtaining a mixed solution B, wherein the concentration of the lipase in the mixed solution B is 2mg·ml-1. Pumping the mixed solution A and the mixed solution B into a microchannel reaction device according to the flow volume ratio of 1: 1, mixing by a T-shaped mixer, then entering a microchannel reactor for enzyme-catalyzed ester hydrolysis reaction, allowing polytetrafluoroethylene tubes in the microchannel reactor to have an inner diameter of 0.5mm and a volume of 6ml, standing at 50 ℃ for reaction for 50min, collecting effluent of the microchannel reactor, separating liquid, taking a lower-layer water phase, adding dichloromethane into the water phase for extraction, and extracting by using anhydrous Na2SO4Drying, and finally removing the organic solvent by rotary evaporation to obtain the R-type mandelic acid, wherein the yield is 75.3%, and the enantiomeric excess value is 71.2%.
Example 13
Dissolving ethyl mandelate in cyclohexane solvent to obtain ethyl mandelate solution with concentration of 10 mmol-L-1Obtaining a mixed solution A; the liquid Novozyme435 is soluble in KH2PO4/K2HPO4In a buffer solution (buffer solution, pH 7, total phosphate concentration of 0.05 mmol. multidot. L-1) Obtaining a mixed solution B in which the concentration of the lipase in the mixed solution B is 2 mg/ml-1. Pumping the mixed solution A and the mixed solution B into a microchannel reaction device according to the flow volume ratio of 1: 1, mixing by a T-shaped mixer, then entering a microchannel reactor for enzyme-catalyzed ester hydrolysis reaction, allowing polytetrafluoroethylene tubes in the microchannel reactor to have an inner diameter of 0.5mm and a volume of 6ml, standing at 50 ℃ for reaction for 50min, collecting effluent of the microchannel reactor, separating liquid, taking a lower-layer water phase, adding dichloromethane into the water phase for extraction, and extracting by using anhydrous Na2SO4Drying, and finally removing the organic solvent by rotary evaporation to obtain the R-type mandelic acid, wherein the yield is 73.1 percent, and the enantiomeric excess value is 70.8 percent.
Comparative example 1
Dissolving ethyl mandelate in isooctane solvent to obtain ethyl mandelate solution with concentration of 10 mmol-L-1Obtaining a mixed solution A; the liquid Novozyme435 is soluble in KH2PO4/K2HPO4In a buffer solution (buffer solution, pH 7, total phosphate concentration of 0.05 mmol. multidot. L-1) Obtaining a mixed solution B in which the lipase is mixedThe concentration of the mixed solution B is 2 mg/ml-1. Pumping the mixed solution A and the mixed solution B into a microchannel reaction device according to the flow volume ratio of 1: 1, mixing by a T-shaped mixer, then feeding into a microchannel reactor for enzyme-catalyzed ester hydrolysis reaction, allowing polytetrafluoroethylene tubes in the microchannel reactor to have an inner diameter of 0.5mm and a volume of 5ml, standing at a heating temperature of 50 ℃ for reaction for 30min, collecting effluent of the microchannel reactor, separating liquid, taking a lower-layer water phase, adding dichloromethane into the water phase for extraction, and extracting by using anhydrous Na2SO4Drying, and finally removing the organic solvent by rotary evaporation to obtain the R-type mandelic acid, wherein the yield is 62.2 percent, and the enantiomeric excess value is 61.3 percent.
Comparative example 2
Dissolving ethyl mandelate in isooctane solvent to obtain ethyl mandelate solution with concentration of 10 mmol-L-1Obtaining a mixed solution A; the liquid Novozyme435 is soluble in KH2PO4/K2HPO4In a buffer solution (buffer solution, pH 7, total phosphate concentration of 0.05 mmol. multidot. L-1) Obtaining a mixed solution B in which the concentration of the lipase in the mixed solution B is 2 mg/ml-1. Pumping the mixed solution A and the mixed solution B into a microchannel reaction device according to the flow volume ratio of 1: 1, mixing by a T-shaped mixer, then feeding into a microchannel reactor for enzyme-catalyzed ester hydrolysis reaction, allowing polytetrafluoroethylene tubes in the microchannel reactor to have an inner diameter of 0.5mm and a volume of 1.5ml, standing at a heating temperature of 50 ℃ for reaction for 15min, collecting effluent of the microchannel reactor, separating liquid, taking a lower-layer water phase, adding dichloromethane into the water phase for extraction, and then extracting by using anhydrous Na2SO4Drying, and finally removing the organic solvent by rotary evaporation to obtain the R-type mandelic acid, wherein the yield is 50.8 percent, and the enantiomeric excess value is 45.6 percent.
Comparative example 3
Dissolving methyl mandelate in isooctane solvent to obtain methyl mandelate solution with concentration of 10 mmol-L-1Obtaining a mixed solution A; the liquid Novozyme435 is soluble in KH2PO4/K2HPO4In a buffer solution (buffer solution, pH 7, total phosphate concentration of 0.05 mmol. multidot. L-1) Obtaining a mixed solution B in which the concentration of the lipase in the mixed solution B is 2 mg/ml-1. Adding the mixed solution B into the mixed solution A, heating and stirring the mixed solution B in a reaction bottle at the temperature of 55 ℃ for reaction for 3.5 hours, taking a lower-layer water phase after standing, adding dichloromethane into the water phase for extraction, and then using anhydrous Na2SO4Drying, and finally removing the organic solvent by rotary evaporation to obtain the R-type mandelic acid, wherein the yield is 55.1 percent, and the enantiomeric excess value is 66.5 percent.
Experimental results show that mandelic acid with higher optical purity is obtained by catalyzing mandelic ester to hydrolyze by using a microchannel reaction device, and the method has short reaction time and excellent selectivity. Therefore, the method for catalyzing mandelate hydrolysis by using the microchannel reaction device has great application value in drug synthesis.
The present invention provides a method and a concept for preparing R-mandelic acid using a microchannel reaction apparatus, and a method and a way for implementing the technical scheme are many, and the above description is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, several modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention. All the components not specified in the present embodiment can be realized by the prior art.
Claims (1)
1. A method for preparing R-mandelic acid by using a microchannel reaction device is characterized by comprising the following steps:
the method comprises the following steps: dissolving mandelate in a first organic solvent to obtain a mixed solution A; dissolving lipase in a phosphate buffer solution to obtain a mixed solution B;
step two: simultaneously pumping the mixed solution A and the mixed solution B obtained in the step one into a mixer of a microchannel reaction device for mixing, and then entering a reactor of the microchannel reaction device for enzyme-catalyzed ester hydrolysis reaction;
step three: after the reaction is finished, collecting effluent liquid of the reactor, separating liquid, taking a lower-layer water phase, adding a second organic solvent into the water phase for extraction, and then using anhydrous Na2SO4Drying, and finally performing rotary evaporation to remove the organic solvent to obtain R-mandelic acid;
in the first step, the first organic solvent is isooctane; in the third step, the second organic solvent is any one of dichloromethane, tetrahydrofuran or acetonitrile;
in the first step, the mandelate ester is any one of methyl mandelate and ethyl mandelate;
in the first step, the concentration of the mandelate in the mixed solution A is 5 mmol-L-1～30 mmol·L-1；
In the first step, the lipase is liquid Novozyme435, and the enzyme activity value is more than or equal to 5000 u.g-1The concentration of lipase in the mixed solution B was 0.5 mg/ml-1～5mg·ml-1；
In the first step, the phosphate buffer solution is KH2PO4/K2HPO4Or NaH2PO4/Na2HPO4The pH value is 6-8, and the total concentration of phosphate in the buffer solution is 0.05 mmol-L-1～0.2 mmol·L-1；
Pumping the mixed solution A and the mixed solution B into a microchannel reaction device according to the flow volume ratio of 1-2: 1-2;
in the second step, the reaction temperature in the reactor is 40-70 ℃, the reaction residence time is 40-100 min, the pipeline in the reactor is a polytetrafluoroethylene pipe, the inner diameter is 0.5-1 mm, and the volume of the pipeline is 5-10 ml;
in the third step, the temperature of the rotary evaporation is 40 ℃.
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