CN113801025B - Method for carrying out reductive amination reaction by adopting microchannel reaction device - Google Patents
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- 238000006243 chemical reaction Methods 0.000 title claims abstract description 44
- 238000000034 method Methods 0.000 title claims abstract description 30
- 238000006268 reductive amination reaction Methods 0.000 title claims abstract description 21
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims abstract description 28
- 235000019162 flavin adenine dinucleotide Nutrition 0.000 claims abstract description 28
- 239000011714 flavin adenine dinucleotide Substances 0.000 claims abstract description 28
- 239000012456 homogeneous solution Substances 0.000 claims abstract description 21
- 108010025188 Alcohol oxidase Proteins 0.000 claims abstract description 18
- 239000000203 mixture Substances 0.000 claims abstract description 18
- VWWQXMAJTJZDQX-UYBVJOGSSA-N flavin adenine dinucleotide Chemical compound C1=NC2=C(N)N=CN=C2N1[C@@H]([C@H](O)[C@@H]1O)O[C@@H]1CO[P@](O)(=O)O[P@@](O)(=O)OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C2=NC(=O)NC(=O)C2=NC2=C1C=C(C)C(C)=C2 VWWQXMAJTJZDQX-UYBVJOGSSA-N 0.000 claims abstract description 17
- 229940093632 flavin-adenine dinucleotide Drugs 0.000 claims abstract description 17
- 101000581498 Methylosinus trichosporium Methanobactin mb-OB3b Proteins 0.000 claims abstract description 16
- 238000002156 mixing Methods 0.000 claims abstract description 12
- -1 N-benzyl aniline compound Chemical class 0.000 claims abstract description 10
- 238000005086 pumping Methods 0.000 claims abstract description 7
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims abstract description 6
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 claims abstract description 4
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims description 60
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 48
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 33
- 235000019445 benzyl alcohol Nutrition 0.000 claims description 20
- 238000004440 column chromatography Methods 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 239000012295 chemical reaction liquid Substances 0.000 claims description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 3
- GTWJETSWSUWSEJ-UHFFFAOYSA-N n-benzylaniline Chemical compound C=1C=CC=CC=1CNC1=CC=CC=C1 GTWJETSWSUWSEJ-UHFFFAOYSA-N 0.000 claims description 3
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 239000012074 organic phase Substances 0.000 claims description 2
- IQHSSYROJYPFDV-UHFFFAOYSA-N 2-bromo-1,3-dichloro-5-(trifluoromethyl)benzene Chemical group FC(F)(F)C1=CC(Cl)=C(Br)C(Cl)=C1 IQHSSYROJYPFDV-UHFFFAOYSA-N 0.000 claims 1
- 230000003321 amplification Effects 0.000 abstract description 2
- 238000004140 cleaning Methods 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 238000003199 nucleic acid amplification method Methods 0.000 abstract description 2
- 239000007858 starting material Substances 0.000 abstract description 2
- 238000001308 synthesis method Methods 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 17
- 239000000047 product Substances 0.000 description 14
- 238000000605 extraction Methods 0.000 description 13
- 239000007864 aqueous solution Substances 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 11
- 239000012043 crude product Substances 0.000 description 11
- 238000001035 drying Methods 0.000 description 11
- 230000002829 reductive effect Effects 0.000 description 11
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 7
- 150000001412 amines Chemical class 0.000 description 4
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 3
- 238000006555 catalytic reaction Methods 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- RQJDUEKERVZLLU-UHFFFAOYSA-N 4-Hydroxybenzylamine Chemical compound NCC1=CC=C(O)C=C1 RQJDUEKERVZLLU-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 229910000510 noble metal Inorganic materials 0.000 description 2
- RNVCVTLRINQCPJ-UHFFFAOYSA-N o-toluidine Chemical compound CC1=CC=CC=C1N RNVCVTLRINQCPJ-UHFFFAOYSA-N 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- QKLXBIHSGMPUQS-FGZHOGPDSA-M (3r,5r)-7-[4-(4-fluorophenyl)-2,5-dimethyl-1-phenylpyrrol-3-yl]-3,5-dihydroxyheptanoate Chemical compound CC1=C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)C(C=2C=CC(F)=CC=2)=C(C)N1C1=CC=CC=C1 QKLXBIHSGMPUQS-FGZHOGPDSA-M 0.000 description 1
- CWLKGDAVCFYWJK-UHFFFAOYSA-N 3-aminophenol Chemical compound NC1=CC=CC(O)=C1 CWLKGDAVCFYWJK-UHFFFAOYSA-N 0.000 description 1
- PNPCRKVUWYDDST-UHFFFAOYSA-N 3-chloroaniline Chemical compound NC1=CC=CC(Cl)=C1 PNPCRKVUWYDDST-UHFFFAOYSA-N 0.000 description 1
- 102000016938 Catalase Human genes 0.000 description 1
- 108010053835 Catalase Proteins 0.000 description 1
- CYSWUSAYJNCAKA-FYJFLYSWSA-N ClC1=C(C=CC=2N=C(SC=21)OCC)OC1=CC=C(C=N1)/C=C/[C@H](C)NC(C)=O Chemical compound ClC1=C(C=CC=2N=C(SC=21)OCC)OC1=CC=C(C=N1)/C=C/[C@H](C)NC(C)=O CYSWUSAYJNCAKA-FYJFLYSWSA-N 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 description 1
- 150000008365 aromatic ketones Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 208000012839 conversion disease Diseases 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 238000010667 large scale reaction Methods 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- QAPTWHXHEYAIKG-RCOXNQKVSA-N n-[(1r,2s,5r)-5-(tert-butylamino)-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 QAPTWHXHEYAIKG-RCOXNQKVSA-N 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 239000012321 sodium triacetoxyborohydride 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
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/0093—Microreactors, e.g. miniaturised or microfabricated reactors
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
The invention discloses a method for carrying out reductive amination reaction by adopting a micro-channel reaction device, wherein the micro-channel reaction device comprises a micro-reactor 1 and a micro-reactor 2 which are connected in series, and the method comprises the following steps: (1) Preparing a solution containing benzyl alcohol, alcohol oxidase, flavin adenine dinucleotide and hydrogen peroxide reductase as a first homogeneous solution; preparing a solution of aniline compound III as a second homogeneous solution; (2) Mixing the first homogeneous solution with air, and simultaneously pumping the mixture into the microreactor 1 for reaction; (3) And (3) mixing the reaction solution obtained in the step (2) with the second homogeneous solution, and simultaneously pumping the mixture into a microreactor 2 for reaction to obtain the N-benzyl aniline compound shown in the formula IV. The microreactor related in the invention has the characteristics of high reaction safety, convenient cleaning, easy amplification and the like. Meanwhile, compared with the prior art, the synthesis method has the advantages of simple, low-cost and easily available starting materials, simple operation and high reaction efficiency, and is expected to be applied to industrial production.
Description
Technical Field
The invention belongs to the technical field of reductive amination, and particularly relates to a method for carrying out reductive amination reaction by adopting a microchannel reaction device.
Background
Reductive amination, also known as Bao Ji reduction, is a simple method of converting an aldehyde ketone into an amine. Reductive amination plays an important role in organic synthesis, pharmaceutical chemistry, biochemistry and the like, is a key method for constructing C-N bonds, and is one of the most useful and important tools for synthesizing different kinds of amines. Currently, there are a number of reductive amination processes reported for different types of substrates. In practical applications, there are two most common: the first method is catalytic hydrogenation using platinum, palladium or nickel catalysts. This is a relatively economical reductive amination process, especially in large scale reactions. However, this reaction may produce more by-products and lower yields. The second method uses a hydride reducing agent, mainly sodium cyanoborohydride, for the reduction. This reaction may require up to five times excess amine, is generally slower for aromatic ketones and weakly basic amines, and may result in contamination of the product with cyanide. The reagent is extremely toxic and produces toxic byproducts such as HCN and NaCN upon treatment. Such agents also suffer from the disadvantage of being sensitive to water and air and releasing borane and hydrogen.
Disclosure of Invention
The invention aims to: the invention provides a method for carrying out reductive amination reaction by adopting a microchannel reaction device, which is environment-friendly, short in reaction time and high in yield.
The technical scheme is as follows: in order to achieve the aim of the invention, the invention adopts the following technical scheme:
a method for performing a reductive amination reaction using a microchannel reaction apparatus comprising a microreactor 1 and a microreactor 2 in series, the method comprising the steps of:
(1) Preparing a solution containing benzyl alcohol, alcohol oxidase, flavin adenine dinucleotide and hydrogen peroxide reductase as a first homogeneous solution; preparing a solution of an aniline compound III as a second homogeneous solution;
(2) Mixing the first homogeneous solution with air, and simultaneously pumping the mixture into the microreactor 1 for reaction;
(3) Mixing the reaction solution obtained in the step (2) with a second homogeneous solution, and simultaneously pumping the mixture into a microreactor 2 for reaction to obtain an N-benzyl aniline compound shown in a formula IV;
wherein R is selected from one or more of hydrogen, hydroxyl, C1-C3 alkyl and halogen.
As preferable:
and R is any one of hydrogen, 2-methyl, 3-chlorine, 2-hydroxy or 4-bromine.
In the step (1), the solvent of the first homogeneous solution is water; the solvent of the second homogeneous solution is any one or a combination of a plurality of acetonitrile, ethyl acetate and dichloromethane, and acetonitrile is preferred.
In the step (1), in the first homogeneous phase solution, the molar ratio of benzyl alcohol to flavin adenine dinucleotide is (150-170): 1, preferably 160:1, a step of; the dosage ratio of benzyl alcohol to alcohol oxidase to hydrogen peroxide reductase is 1 mol-500-900U to 1-7mg calculated by mol-u.
In step (2), the flow rate in the microreactor 1 is 40 to 72.5. Mu.L min -1 Preferably 56.25. Mu.L min -1 The method comprises the steps of carrying out a first treatment on the surface of the The reaction temperature is 30-50 ℃, preferably 40 ℃; the reaction residence time is 20 to 30min, preferably 25min.
In the step (3), the molar ratio of the aniline compound III to the benzyl alcohol is 1-2 based on the amount of the benzyl alcohol in the first homogeneous solution: 1.
in step (3), the flow rate in the microreactor 2 is 50 to 60. Mu.L min -1 Preferably 56.25. Mu.L min -1 The method comprises the steps of carrying out a first treatment on the surface of the The reaction temperature is 20-40 ℃, preferably 30 ℃; the reaction residence time is 5 to 10min, preferably 8min.
The volume of the microreactor 1 is 1-2mL, preferably 1.4mL, and the volume of the microreactor 2 is 0.5-1.5mL, preferably 0.9mL.
The micro-channel reaction device further comprises a pump 1, a pump 2, a pump 3, a micro-mixer 1 and a micro-mixer 2, wherein the pump 1 and the pump 2 are arranged in parallel and are connected to the micro-mixer 1, and the micro-mixer 1 is connected with the micro-reactor 1; the pump 3 and the microreactor 1 are arranged in parallel and are each connected to a micromixer 2, the micromixer 2 being connected to the microreactor 2.
The reaction liquid in the micro-reactor 2 is subjected to organic phase acquisition, concentration and column chromatography to obtain the pure product of the N-benzyl aniline compound IV. Preferably, the extraction is extraction of the reaction solution by ethyl acetate and aqueous solution. The eluent for column chromatography is a mixed solvent of ethyl acetate and petroleum ether according to the volume ratio of 1:5-1:20.
According to the method, benzyl alcohol (I) is used as a starting raw material in a novel microchannel reactor through two continuous flows, benzaldehyde (II) is obtained through catalysis of alcohol oxidase, condensation reaction is carried out on II and aniline (III), and N-benzyl aniline compound (IV) is obtained through reduction of sodium triacetoxyborohydride. The microreactor related in the invention has the characteristics of high reaction safety, convenient cleaning, easy amplification and the like. Meanwhile, compared with the prior art, the synthesis method has the advantages of simple, low-cost and easily available starting materials, simple operation and high reaction efficiency, and is expected to be applied to industrial production.
The beneficial effects are that: compared with the prior art, the invention has the following advantages:
the method has the advantages of short reaction time, high reaction conversion rate, less side reaction, low toxicity and pollution, low production cost, good product quality and the like, does not use noble metal for catalysis in the reaction process, is environment-friendly, energy-saving and efficient, is suitable for popularization and application, and solves the problems of long reaction time, harsh reaction conditions and the need of noble metal catalysis catalysts in the prior art.
Drawings
FIG. 1 shows the N-benzylaniline compound according to the examples of the present invention 1 H NMR spectrum.
FIG. 2 shows the N-benzylaniline compound according to the example of the present invention 13 C NMR spectrum.
FIG. 3 is a schematic illustration of a reaction apparatus and flow scheme of the present invention.
Detailed Description
The following describes in further detail the embodiments of the present invention with reference to the drawings and examples. The following examples are illustrative of the invention and are not intended to limit the scope of the invention.
The structure of the micro-channel reaction device used in the invention is shown in fig. 3, and the micro-channel reaction device comprises a pump 1, a pump 2, a pump 3, a micro-mixer 1, a micro-mixer 2, and a micro-reactor 1 and a micro-reactor 2 which are connected in series, wherein the pump 1 and the pump 2 are arranged in parallel and are connected to the micro-mixer 1, and the micro-mixer 1 is connected with the micro-reactor 1; the pump 3 and the microreactor 1 are arranged in parallel and are each connected to a micromixer 2, the micromixer 2 being connected to the microreactor 2. Pump 1, pump 2, and pump 3 pump the first homogeneous solution, air, and the second homogeneous solution, respectively.
In the following examples, aniline represented by compound III and N-benzylaniline represented by compound IV are shown in tables 1 and 2, respectively.
Table 1 reactants: aniline
TABLE 2N-benzyl anilines
Example 1: synthesis of Compound 2a
10mL of an aqueous solution containing 1mmol of benzyl alcohol (I), alcohol oxidase (. About.700 u), flavin adenine dinucleotide (FAD, 6. Mu. Mol,5 mg) and hydrogen peroxide reductase (0.02. Mu. Mol,4 mg) was injected into syringe A, air was sucked into syringe B, and both sample flow rates were set at 56.25. Mu.L min -1 Pumping into a micro mixer 1 for mixing, and then entering the micro reactor 1 for reaction at 40 ℃ for 25min. An acetonitrile solution of aniline (1 mmol,0.1 m) injected into the syringe C was mixed with the effluent of the microreactor 1 by the micromixer 2, and then reacted at 30 ℃ for 8min in the microreactor 2. Adding a proper amount of water and ethyl acetate into the collected reaction liquid for extraction, drying by anhydrous sodium sulfate, concentrating under reduced pressure to obtain a crude product, and separating by column chromatography to obtain a target product 2a with the yield of 75%. The nuclear magnetic diagram is shown in figures 1 and 2, 1 H NMR(400MHz,DMSO-d 6 )δ7.43–7.27(m,4H),7.23(t,J＝7.2Hz,1H),7.05(dd,J＝8.4,7.4Hz,2H),6.59(d,J＝7.7Hz,2H),6.52(t,J＝7.3Hz,1H),6.23(t,J＝6.0Hz,1H),4.27(d,J＝6.1Hz,2H). 13 C NMR(101MHz,DMSO-d 6 )δ149.15,140.79,129.28,128.73,127.64,127.06,116.20,112.75,46.95.
example 2: synthesis of Compound 2b
10mL of an aqueous solution containing 1mmol of benzyl alcohol (I), alcohol oxidase (. About.700 u), flavin adenine dinucleotide (FAD, 6. Mu. Mol,5 mg) and hydrogen peroxide reductase (0.02. Mu. Mol,4 mg) was injected into syringe A, air was sucked into syringe B, and both sample flow rates were set at 56.25. Mu.L min -1 After being mixed by the micro mixer 1, the mixture enters the micro reactor 1 to react for 25min at 40 ℃. An acetonitrile solution of 2-methylaniline (1 mmol, 0.1M) injected into the syringe C was mixed with the effluent of the microreactor 1 by the micromixer 2, and then reacted at 30℃for 8 minutes in the microreactor 2. Adding a proper amount of water and ethyl acetate into the collected reaction liquid for extraction, drying by anhydrous sodium sulfate, concentrating under reduced pressure to obtain a crude product, and separating by column chromatography to obtain a target product 2b with the yield of 76%.
Example 3: synthesis of Compound 2c
10mL of an aqueous solution containing 1mmol of benzyl alcohol (I), alcohol oxidase (. About.700 u), flavin adenine dinucleotide (FAD, 6. Mu. Mol,5 mg) and hydrogen peroxide reductase (0.02. Mu. Mol,4 mg) was injected into syringe A, air was sucked into syringe B, and both sample flow rates were set at 56.25. Mu.L min -1 After being mixed by the micro mixer 1, the mixture enters the micro reactor 1 to react for 25min at 40 ℃. An acetonitrile solution of 3-chloroaniline (1 mmol, 0.1M) injected into the syringe C was mixed with the effluent of the microreactor 1 by the micromixer 2, and then reacted at 30℃for 8 minutes in the microreactor 2. Adding a proper amount of water and ethyl acetate into the collected reaction liquid for extraction, drying by anhydrous sodium sulfate, concentrating under reduced pressure to obtain a crude product, and separating by column chromatography to obtain a target product 2c with the yield of 71%.
Example 4: synthesis of Compound 2d
10mL of an aqueous solution containing 1mmol of benzyl alcohol (I), alcohol oxidase (. About.700 u), flavin adenine dinucleotide (FAD, 6. Mu. Mol,5 mg) and hydrogen peroxide reductase (0.02. Mu. Mol,4 mg) was injected into syringe A, air was sucked into syringe B, and both sample flow rates were set at 56.25. Mu.L min -1 After being mixed by the micro mixer 1, the mixture enters the micro reactor 1 to react for 25min at 40 ℃. An acetonitrile solution of 3-hydroxyaniline (1 mmol, 0.1M) injected into the syringe C was mixed with the effluent of the microreactor 1 by the micromixer 2, and then reacted at 30℃for 8 minutes in the microreactor 2. Adding a proper amount of water and ethyl acetate into the collected reaction liquid for extraction, drying by anhydrous sodium sulfate, concentrating under reduced pressure to obtain a crude product, and separating by column chromatography to obtain a target product 2d with the yield of 73%.
Example 5: synthesis of Compound 2e
10mL of an aqueous solution containing 1mmol of benzyl alcohol (I), alcohol oxidase (. About.700 u), flavin adenine dinucleotide (FAD, 6. Mu. Mol,5 mg) and hydrogen peroxide reductase (0.02. Mu. Mol,4 mg) was injected into syringe A, air was sucked into syringe B, and both sample flow rates were set at 56.25. Mu.L min -1 After being mixed by the micro mixer 1, the mixture enters the micro reactor 1 to react for 25min at 40 ℃. An acetonitrile solution of 4-hydroxybenzylamine (1 mmol, 0.1M) injected into the syringe C was mixed with the effluent of the microreactor 1 by the micromixer 2, and then reacted at 30℃for 8 minutes in the microreactor 2. Adding a proper amount of water and ethyl acetate into the collected reaction liquid for extraction, drying by anhydrous sodium sulfate, concentrating under reduced pressure to obtain a crude product, and separating by column chromatography to obtain a target product 2e with the yield of 68%.
Example 6: synthesis of Compound 2a
10mL of an aqueous solution containing 1mmol of benzyl alcohol (I), alcohol oxidase (. About.700 u), flavin adenine dinucleotide (FAD, 6. Mu. Mol,5 mg) and hydrogen peroxide reductase (0.02. Mu. Mol,4 mg) was injected into syringe A, air was sucked into syringe B, and both sample flow rates were set at 56.25. Mu.L min -1 After being mixed by the micro mixer 1, the mixture enters the micro reactor 1 to react for 25min at 30 ℃. An acetonitrile solution of aniline (1 mmol,0.1 m) injected into the syringe C was mixed with the effluent of the microreactor 1 by the micromixer 2, and then reacted at 30 ℃ for 8min in the microreactor 2. Adding a proper amount of water and ethyl acetate into the collected reaction liquid for extraction, drying by anhydrous sodium sulfate, concentrating under reduced pressure to obtain a crude product, and separating by column chromatography to obtain a target product 2a with the yield of 64%.
Example 7: synthesis of Compound 2a
10mL of an aqueous solution containing 1mmol of benzyl alcohol (I), alcohol oxidase (. About.700 u), flavin adenine dinucleotide (FAD, 6. Mu. Mol,5 mg) and hydrogen peroxide reductase (0.02. Mu. Mol,4 mg) was injected into syringe A, air was sucked into syringe B, and both sample flow rates were set at 56.25. Mu.L min -1 After mixing by the micro mixer 1, the mixture was introduced into the micro reactor 1 and reacted at 40℃for 25 minutes. After mixing the methylene chloride solution of aniline (1 mmol, 0.1M) injected into the syringe C with the effluent of the microreactor 1 through the micromixer 2, the mixture was introduced into the microreactor 2 and reacted at 30℃for 8 minutes. Adding a proper amount of water and ethyl acetate into the collected reaction liquid for extraction, drying by anhydrous sodium sulfate, concentrating under reduced pressure to obtain a crude product, and separating by column chromatography to obtain a target product 2a with the yield of 56%.
Example 8: synthesis of Compound 2a
10mL of an aqueous solution containing 1mmol of benzyl alcohol (I), alcohol oxidase (. About.700 u), flavin adenine dinucleotide (FAD, 6. Mu. Mol,5 mg) and hydrogen peroxide reductase (0.02. Mu. Mol,4 mg) was injected into syringe A, air was sucked into syringe B, and both sample flow rates were set at 56.25. Mu.L min -1 After being mixed by the micro mixer 1, the mixture enters the micro reactor 1 to react for 25min at 40 ℃. An ethyl acetate solution of aniline (1 mmol,0.1 m) injected into the syringe C was mixed with the effluent of the microreactor 1 by the micromixer 2, and then reacted at 30 ℃ for 8min in the microreactor 2. Adding a proper amount of water and ethyl acetate into the collected reaction liquid for extraction, drying by anhydrous sodium sulfate, concentrating under reduced pressure to obtain a crude product, and separating by column chromatography to obtain a target product 2a with the yield of 61%.
Example 9: synthesis of Compound 2a
10mL of an aqueous solution containing 1mmol of benzyl alcohol (I), alcohol oxidase (. About.700 u), flavin adenine dinucleotide (FAD, 6. Mu. Mol,5 mg) and hydrogen peroxide reductase (0.02. Mu. Mol,4 mg) was injected into syringe A, air was sucked into syringe B, and both sample flow rates were set at 56.25. Mu.L min -1 After being mixed by the micro mixer 1, the mixture enters the micro reactor 1 to react for 25min at 40 ℃. The flow of the methylene chloride solution, into which aniline (1 mmol, 0.1M) was injected in syringe C, was then carried out with the effluent of microreactor 1After mixing in the micro mixer 2, the mixture enters the micro reactor 2 to react for 5min at 30 ℃. Adding a proper amount of water and ethyl acetate into the collected reaction liquid for extraction, drying by anhydrous sodium sulfate, concentrating under reduced pressure to obtain a crude product, and separating by column chromatography to obtain a target product 2a with the yield of 62%.
Example 10: synthesis of Compound 2a
10mL of an aqueous solution containing 1mmol of benzyl alcohol (I), alcohol oxidase (. About.700 u), flavin adenine dinucleotide (FAD, 6. Mu. Mol,5 mg) and hydrogen peroxide reductase (0.02. Mu. Mol,4 mg) was injected into syringe A, air was sucked into syringe B, and both sample flow rates were set at 56.25. Mu.L min -1 After mixing by the micro mixer 1, the mixture was introduced into the micro reactor 1 and reacted at 40℃for 25 minutes. An acetonitrile solution of aniline (0.5 mmol,0.1 m) injected into the syringe C was mixed with the effluent of the microreactor 1 by the micromixer 2, and then reacted at 30 ℃ for 10min in the microreactor 2. Adding a proper amount of water and ethyl acetate into the collected reaction liquid for extraction, drying by anhydrous sodium sulfate, concentrating under reduced pressure to obtain a crude product, and separating by column chromatography to obtain a target product 2a with the yield of 72%.
Example 11: synthesis of Compound 2a
10mL of an aqueous solution containing 1mmol of benzyl alcohol (I), alcohol oxidase (. About.700 u), flavin adenine dinucleotide (FAD, 6. Mu. Mol,5 mg) and hydrogen peroxide reductase (0.02. Mu. Mol,4 mg) was injected into syringe A, air was sucked into syringe B, and both sample flow rates were set at 56.25. Mu.L min -1 After mixing by the micro mixer 1, the mixture was introduced into the micro reactor 1 and reacted at 40℃for 25 minutes. An acetonitrile solution of benzylamine (1.5 mmol, 0.1M) injected into the syringe C was mixed with the effluent of the microreactor 1 by the micromixer 2, and then reacted at 40℃for 8 minutes in the microreactor 2. Adding a proper amount of water and ethyl acetate into the collected reaction liquid for extraction, drying by anhydrous sodium sulfate, concentrating under reduced pressure to obtain a crude product, and separating by column chromatography to obtain a target product 2a with the yield of 63%.
Comparative example 1
A50 mL reaction flask was taken, and 0.5mmol of benzyl alcohol, alcohol oxidase (. About.700 u), flavin adenine dinucleotide (3. Mu. Mol,2.5 mg) and catalase (0.01. Mu. Mol,1 mg) were added,with 5mL H 2 O is dissolved. After stirring for 8h at 40℃aniline (0.5 mmol) and 2.5mL CH 3 CN was added to the above solution. Then, the reaction mixture was stirred at 30℃for 2 hours, and the reaction was completed. The yield was 52%.
The above examples illustrate only a few embodiments of the invention, which are described in detail and are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.
Claims (10)
1. A method for carrying out reductive amination reaction by adopting a microchannel reaction device, which is characterized in that the microchannel reaction device comprises a microreactor 1 and a microreactor 2 which are connected in series, and the method comprises the following steps:
(1) Preparing a solution containing benzyl alcohol, alcohol oxidase, flavin adenine dinucleotide and hydrogen peroxide reductase as a first homogeneous solution; preparing a solution of an aniline compound III as a second homogeneous solution;
(2) Mixing the first homogeneous solution with air, and simultaneously pumping the mixture into the microreactor 1 for reaction;
(3) Mixing the reaction solution obtained in the step (2) with a second homogeneous solution, and simultaneously pumping the mixture into a microreactor 2 for reaction to obtain an N-benzyl aniline compound shown in a formula IV;
wherein R is selected from one or more of hydrogen, hydroxyl, C1-C3 alkyl and halogen.
2. The method for performing reductive amination using a microchannel reactor according to claim 1, wherein R is any one of hydrogen, 2-methyl, 3-chloro, 2-hydroxy or 4-bromo.
3. The method for performing reductive amination using a microchannel reactor according to claim 1, wherein in step (1), the solvent of the first homogeneous solution is water; the solvent of the second homogeneous solution is any one or a combination of a plurality of acetonitrile, ethyl acetate and dichloromethane.
4. The method for carrying out reductive amination according to claim 1, wherein in step (1), the molar ratio of benzyl alcohol to flavin adenine dinucleotide in the first homogeneous solution is (150-170): 1, calculated by mol:u, the dosage ratio of benzyl alcohol to alcohol oxidase and hydrogen peroxide reductase is 1 mol:500-900 U:1-7mg.
5. The method for reductive amination using a microchannel reactor according to claim 1, wherein in step (2), the flow rate in the microreactor 1 is 40 to 72.5 μlmin -1 The reaction temperature is 30-50 ℃; the reaction residence time is 20-30min.
6. The method for carrying out reductive amination according to claim 1, wherein in step (3), the molar ratio of the aniline compound III to benzyl alcohol is 1-2, based on the amount of benzyl alcohol in the first homogeneous solution: 1.
7. the method for reductive amination using a microchannel reactor according to claim 1, wherein in step (3), the flow rate in the microreactor 2 is 50 to 60 μl min -1 The method comprises the steps of carrying out a first treatment on the surface of the The reaction temperature is 20-40 ℃; the reaction residence time is 5-10min.
8. The method for carrying out reductive amination using a microchannel reactor according to claim 1, wherein the volume of the microreactor 1 is 1-2mL and the volume of the microreactor 2 is 0.5-1.5mL.
9. The method for carrying out reductive amination using a microchannel reaction device according to claim 1, wherein the microchannel reaction device further comprises a pump 1, a pump 2, a pump 3, a micromixer 1 and a micromixer 2, the pumps 1, 2 being arranged in parallel and each being connected to the micromixer 1, the micromixer 1 being connected to the micromixer 1; the pump 3 and the microreactor 1 are arranged in parallel and are each connected to a micromixer 2, the micromixer 2 being connected to the microreactor 2.
10. The method for carrying out reductive amination reaction by adopting a microchannel reactor as claimed in claim 1, wherein in the step (3), the reaction liquid in the microreactor 2 is subjected to organic phase acquisition, concentration and column chromatography to obtain a pure product of the N-benzyl aniline compound IV.
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| CN108872205A (en) * | 2018-06-19 | 2018-11-23 | 深圳上泰生物工程有限公司 | The application of object detection method of content and detection reagent in the detection method |
| CN111116398A (en) * | 2020-01-13 | 2020-05-08 | 肥城岳海化工有限公司 | Method for preparing naphthol AS-LC by micro-channel continuous method |
| CN113444752A (en) * | 2021-07-15 | 2021-09-28 | 南京工业大学 | Method for continuously preparing 2-benzyl isoindolinone compound by adopting microchannel reactor |
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| CN108872205A (en) * | 2018-06-19 | 2018-11-23 | 深圳上泰生物工程有限公司 | The application of object detection method of content and detection reagent in the detection method |
| CN111116398A (en) * | 2020-01-13 | 2020-05-08 | 肥城岳海化工有限公司 | Method for preparing naphthol AS-LC by micro-channel continuous method |
| CN113444752A (en) * | 2021-07-15 | 2021-09-28 | 南京工业大学 | Method for continuously preparing 2-benzyl isoindolinone compound by adopting microchannel reactor |
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