CN113072548B - Method for preparing 5, 8-dihydro-6H-isoquinoline [3, 2-alpha ] isoquinoline based on micro-reaction system - Google Patents
Method for preparing 5, 8-dihydro-6H-isoquinoline [3, 2-alpha ] isoquinoline based on micro-reaction system Download PDFInfo
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Abstract
The invention provides a method for preparing 5, 8-dihydro-6H-isoquinoline [3, 2-alpha ] isoquinoline based on a micro-reaction system. The first solution and the second solution are introduced into the first micromixer by a feed pump for mixing. The mixture of the arylethylamine solution and the aryl aldehyde solution is pumped into a first fixed bed reactor through a first micromixer to carry out dehydration condensation reaction. And introducing the mixture subjected to dehydration condensation reaction into a second fixed bed reactor through a second micromixer for catalytic hydrogenation. Introducing the mixed material subjected to catalytic hydrogenation and a methanol solution of saturated hydrochloric acid into a microchannel reactor through a third micro mixer for salt forming reaction, and carrying out reduced pressure concentration, pulping and purification to obtain secondary amine hydrochloride. In the presence of acid, dehydrating agent and additive, making secondary amine hydrochloride and glyoxal solution produce Pictet-Schpengler reaction, Friedel-crafts hydroxyalkylation and dehydration series reaction so as to obtain the 5, 8-dihydro-6H-isoquinoline [3, 2-alpha ] isoquinoline compound.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a method for continuously preparing 5, 8-dihydro-6H-isoquinoline [3, 2-alpha ] isoquinoline (I) by using a micro-reaction system.
Background
5, 8-dihydro-6H-isoquinoline [3, 2-alpha ] isoquinoline (I) is a key intermediate for synthesizing protoberberine and tetrahydroberberine such as berberine hydrochloride. Berberine hydrochloride is an isoquinoline alkaloid with numerous pharmacological activities extracted from rhizome of plants such as Coptidis rhizoma, cortex Phellodendri and radix Berberidis. Berberine hydrochloride is widely used in Chinese traditional Chinese patent medicine, and has the functions of clearing heat, detoxifying, purging fire and the like. It is used clinically for treating bacterial gastrointestinal tract inflammation, bacillary dysentery and other indications, and has also excellent curative effect on diarrhea caused by irritable bowel syndrome. In recent years, berberine hydrochloride is found to have the activities of regulating blood sugar and lipid metabolism, preventing atherosclerosis, resisting arrhythmia, inhibiting tumor cell proliferation, resisting virus and the like. Therefore, berberine becomes one of the research hotspots in the chemical field of natural medicines at home and abroad, and the development of the preparation method of the intermediate dihydroberberine is particularly important.
The existing method for preparing the dihydroberberine by applying a chemical synthesis strategy mainly comprises the following two methods:
in the first method, as shown in the following reaction scheme, tetrahydroisoquinoline, TMS-protected acetylene and bromobenzaldehyde are used as starting materials, and copper-catalyzed Redox-A is sequentially carried out3Reaction, palladium catalytic coupling reaction ring closing, Ley oxidation, decarboxylation and reduction, thereby obtaining the dihydroberberine. Berberine (Zhou, S.; Tong, R.chem. -Eur.J.2016, 22, 7084-.
In the second method, as shown in the following reaction scheme, phenethylamine and glyoxal monoalcohol are used as starting materials, and subjected to a cuter-spengler reaction, reductive amination, friedel-crafts hydroxyalkylation, and dehydration reaction in this order to produce dihydroberberine. Berberine can be further prepared by iodine oxidation of dihydroberberine (Mori-Quiroz, L.M.; Hedrick, S.L.; De Los Santos, A.R.; Clift, M.D. Org. Lett.2018, 20, 4281-one 4284.).
The above-described method has certain drawbacks. For example, the synthesis steps are relatively complicated and the operation is complex; the preparation process needs expensive transition metal and excessive acid catalysis, so the production energy is low and the cost is high.
Therefore, the development of a preparation method of 5, 8-dihydro-6H-isoquinoline [3, 2-alpha ] isoquinoline (I) with simple process, low cost and environmental friendliness is of great significance.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention provides a method for preparing 5, 8-dihydro-6H-isoquinoline [3, 2-alpha ] isoquinoline (I), which has the advantages of simple process, high efficiency, low cost and environmental protection.
In particular, the invention provides a method for preparing 5, 8-dihydro-6H-isoquinoline [3, 2-alpha ] isoquinoline with a formula (I) based on a micro-reaction system,
the micro-reaction system comprises a feeding pump, a first micro mixer, a first fixed bed reactor, a first back pressure valve, a gas mass flowmeter, a second micro mixer, a second fixed bed reactor, a condenser, a gas-liquid separator, a second back pressure valve, a third micro mixer, a micro-channel reactor and a third back pressure valve which are communicated; the method comprises the following steps:
(1) introducing the first solution and the second solution into a first micro mixer through a feeding pump to mix to obtain a mixed reaction material; introducing the mixed reaction material into a first fixed bed reactor filled with a dehydrating agent to carry out dehydration condensation reaction; applying backpressure to the mixed reaction materials in the first fixed bed reactor through the first backpressure valve to uniformly mix the materials; the first solution is a mixture of aryl ethylamine (IV) and an organic solvent, and the second solution is a mixture of aryl aldehyde (V) and an organic solvent;
(2) introducing the dehydrated and condensed mixed reaction material obtained in the step (1) and hydrogen into a second fixed bed reactor filled with a reducing agent through a second micro mixer so as to perform catalytic hydrogenation reaction; introducing the mixed reaction material subjected to catalytic hydrogenation reaction into a condenser for condensation, and separating gas components by a gas-liquid separator; applying back pressure to the mixed reaction materials in the gas-liquid separator through the second back pressure valve to uniformly mix the materials;
(3) introducing the mixed reaction material subjected to gas-liquid separation and obtained in the step (2) and a third solution into a microchannel reactor through a third micro mixer to perform salt forming reaction; carrying out reduced pressure concentration, pulping and purification on the mixed reaction material after the salt forming reaction to obtain secondary amine hydrochloride (II); applying back pressure to the mixed reaction materials in the microchannel reactor through the third back pressure valve to uniformly mix the materials; the third solution is a mixture of hydrochloric acid and an organic solvent; and
(4) subjecting the secondary amine hydrochloride (II) and the fourth solution to a Pictet-Schpendeller reaction, Friedel-crafts hydroxyalkylation, and dehydration cascade reaction in the presence of an acid, a dehydrating agent, and an additive to produce a 5, 8-dihydro-6H-isoquinolino [3, 2-alpha ] isoquinoline compound of formula (I); wherein the fourth solution is a mixture of glyoxal (III) and an organic solvent;
as shown in the following reaction scheme:
wherein:
x is mono-or di-substituted, and is positioned at any substitutable position on a benzene ring; x is hydrogen, straight or branched C1-C5Alkyl, straight or branched C1～C5Alkoxy or halogen; or two X substituents are linked together to form a ring;
y is mono-or di-substituted, and is positioned at any substitutable position on a benzene ring; y is hydrogen, straight or branched C1-C5Alkyl, straight or branched C1～C5Alkoxy or halogen; or two Y substituents may be joined together to form a ring.
In some embodiments, the molar ratio of arylethylamine (IV) to aryl aldehyde (V) in step (1) is 1: 1 to (1-10), preferably 1: 1.
In some embodiments, the organic solvent in step (1) is any one or more of methanol, ethanol, isopropanol, dimethyl sulfoxide, N-dimethylformamide, ethyl acetate, acetone, dichloromethane, chloroform, N-hexane, cyclohexane, petroleum ether, toluene and carbon tetrachloride, preferably dichloromethane.
In some embodiments, the concentration of the arylethylamine (IV) in the first solution in the step (1) is 0.01 to 10mol/L, preferably 0.8 mol/L; the concentration of the aryl aldehyde (V) in the second solution is 0.01-10 mol/L, preferably 0.8 mol/L.
In some embodiments, the reaction temperature in the first fixed bed reactor is-20 to 100 ℃, preferably 25 ℃.
In some embodiments, the residence time of the mixed reaction mass in the first fixed bed reactor in step (1) is 0.2 to 60 minutes, preferably 5 minutes.
In some embodiments, the backpressure of the first backpressure valve in the step (1) is 0.1-100 bar, preferably 7 bar.
In some embodiments, the first micromixer in step (1) is any one of a static mixer, a T-type micromixer, a Y-type micromixer, a coaxial flow micromixer, and a flow focusing micromixer, preferably a T-type micromixer.
In some embodiments, the first fixed bed reactor in the step (1) further comprises silicon dioxide, and the mass ratio of the silicon dioxide to the dehydrating agent is (0.1-100) to 1, preferably 10 to 1.
In some embodiments, the dehydrating agent in step (1) is
Molecular sieve,
Molecular sieve,
Any one or more of molecular sieve, 13X molecular sieve, XH molecular sieve, anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous calcium chloride and anhydrous potassium carbonate, preferably
And (3) a molecular sieve.
In some embodiments, the feed pump comprises a first feed pump and a second feed pump, one inlet of the first micromixer is connected with the first feed pump, the other inlet of the first micromixer is connected with the second feed pump, the first solution and the second solution are respectively introduced into the first micromixer through the first feed pump and the second feed pump for mixing, the outlet of the first micromixer is connected with the inlet of the first fixed bed reactor, and the outlet of the first fixed bed reactor is connected with the first backpressure valve.
In some embodiments, in step (2), the flow ratio of the dehydrated and condensed mixed reaction material to hydrogen is adjusted so that the molar ratio of the arylethylamine (IV) to the hydrogen in the mixed reaction material is 1: (0.95-1.5) in the second fixed bed reactor.
In some embodiments, the reaction temperature in the second fixed bed reactor in the step (2) is-20 to 120 ℃, preferably 60 ℃.
In some embodiments, the residence time of the mixed reaction mass in the second fixed bed reactor in step (2) is 0.2 to 60 minutes, preferably 5 minutes.
In some embodiments, the backpressure of the second backpressure valve in the step (2) is 0.1-120 bar, preferably 30 bar.
In some embodiments, the second micromixer in step (2) is any one of a static mixer, a T-type micromixer, a Y-type micromixer, a coaxial flow micromixer, and a flow focusing micromixer, preferably a T-type micromixer.
In some embodiments, the second fixed bed reactor further comprises silicon dioxide, and the mass ratio of the silicon dioxide to the reducing agent is (0.1-100) to 1, preferably 10 to 1.
In some embodiments, the packing of the second fixed bed reactor in step (2) is 1 to 50 wt% Pd/C, 1 to 50 wt% Pd (OH)21 to 50 wt% of Pt/C and 1 to 50 wt% of PtO2Preferably 10 wt% Pd (OH)2/C。
In some embodiments, one inlet of the second micro mixer is connected with an outlet of the first backpressure valve, the other inlet of the second micro mixer is connected with the gas mass flow meter, an outlet of the second micro mixer is connected with an inlet of the second fixed bed reactor, an outlet of the second fixed bed reactor is connected with an inlet of the condenser, an outlet of the condenser is connected with a first top interface of the gas-liquid separator, nitrogen is connected through a second top interface of the gas-liquid separator and is used for providing pressure for the gas-liquid separator, the pressure of the connected nitrogen is 0.3-120 bar, and the second backpressure valve is connected with a third top interface of the gas-liquid separator.
In some embodiments, in step (3), the flow ratio of the gas-liquid separated mixed reaction material to the third solution is adjusted so that the molar ratio of the arylethylamine (IV) to the hydrochloric acid in the mixed reaction material in the third micromixer is 1: 1 (1-20), preferably 1: 1.5.
In some embodiments, the organic solvent in step (3) is any one or more of methanol, ethanol, isopropanol, dimethyl sulfoxide, N-dimethylformamide, ethyl acetate, acetone, dichloromethane, chloroform, N-hexane, cyclohexane, petroleum ether, toluene and carbon tetrachloride, preferably methanol.
In some embodiments, the concentration of hydrochloric acid in the third solution in the step (3) is 0.01-15 mol/L, and a saturated solution is preferred.
In some embodiments, the reaction temperature in the microchannel reactor in the step (3) is-20 to 100 ℃, preferably 25 ℃.
In some embodiments, the residence time of the mixed reaction mass in step (3) in the microchannel reactor is 0.2 to 60 minutes, preferably 5 minutes.
In some embodiments, the back pressure of the third back pressure valve in step (3) is 0.1 to 100bar, preferably 7 bar.
In some embodiments, the third micromixer in step (3) is any one of a static mixer, a T-type micromixer, a Y-type micromixer, a coaxial flow micromixer, and a flow focusing micromixer, preferably a T-type micromixer.
In some embodiments, the microchannel reactor in step (3) is a tubular microchannel reactor or a plate microchannel reactor; the inner diameter of the tubular micro-channel reactor is 0.1-50 mm; or the hydraulic diameter of a reaction fluid channel of the plate-type microchannel reactor is 0.1-50 mm; preferably a tubular microchannel reactor with the inner diameter of 0.12-5.35 mm.
In some embodiments, the feed pump comprises a third feed pump and a fourth feed pump, an inlet of the third feed pump is connected with the bottom outlet of the gas-liquid separator, an outlet of the third feed pump is connected with one inlet of a third micromixer, another inlet of the third micromixer is connected with the fourth feed pump, an outlet of the third micromixer is connected with an inlet of the microchannel reactor, and an outlet of the microchannel reactor is connected with a third back pressure valve.
In some embodiments, the organic solvent used for pulping in step (3) is any one or more of ethyl acetate, acetone, dichloromethane, chloroform, n-hexane, cyclohexane, petroleum ether, toluene, carbon tetrachloride, diethyl ether and methyl tert-butyl ether, preferably ethyl acetate.
In some embodiments, the concentration of the organic solvent used for pulping in step (3) is 1-10 g/mL, preferably 1-5 g/mL.
In some embodiments, the dehydrating agent in step (4) is any one or more of trimethyl orthoformate, 3A molecular sieve, 4A molecular sieve, 5A molecular sieve, 13X molecular sieve, XH molecular sieve, anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous calcium chloride, and anhydrous potassium carbonate, preferably anhydrous magnesium sulfate.
In some embodiments, the acid used in step (4) is any one or more of formic acid, acetic acid, trifluoroacetic acid, oxalic acid, p-toluenesulfonic acid, methanesulfonic acid, benzoic acid, succinic acid, citric acid, tartaric acid, camphorsulfonic acid, and boric acid, preferably formic acid.
In some embodiments, the additive used in step (4) is any one or more of sodium fluoride, potassium fluoride, magnesium fluoride, lithium chloride, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, barium chloride, aluminum chloride, lithium bromide, sodium bromide, potassium bromide, magnesium bromide, calcium bromide, barium bromide, lithium iodide, sodium iodide, potassium iodide, magnesium iodide, and calcium iodide; sodium chloride is preferred.
In some embodiments, in the step (4), the molar ratio of the secondary amine hydrochloride (II), the glyoxal, the dehydrating agent, the acid and the additive is 1: 1-100: 0.1-20: 1-1000: 0.1-20, preferably 1: 20: 2.2: 250: 3.5.
In some embodiments, the organic solvent used in step (4) is any one or more of methanol, ethanol, ethyl acetate, acetone, dichloromethane, chloroform, n-hexane, cyclohexane, petroleum ether, toluene, carbon tetrachloride, diethyl ether, and methyl tert-butyl ether.
The method has the advantages of mild reaction conditions, simple and convenient operation, high chemical yield, high optical purity and good diastereoselectivity, can continuously prepare the 5, 8-dihydro-6H-isoquinoline [3, 2-alpha ] isoquinoline (I), can prepare the 5, 8-dihydro-6H-isoquinoline [3, 2-alpha ] isoquinoline compound with the yield of more than 90 percent, and is suitable for amplification application.
Drawings
FIG. 1 is a schematic structural diagram of a micro-reaction system according to an embodiment of the present invention.
In the figure: 1-a feeding pump I; 2-a first micromixer; 3-a second feeding pump; 4-a first fixed bed reactor; 5-dehydrating agent and silica filler; 6-first back pressure valve; 7-hydrogen passage; 8-gas mass flow meter; 9-a second micromixer; 10-a second fixed bed reactor; 11-reducing agent and silica filler; 12-a condenser; 13-nitrogen gas passage; 14-a gas-liquid separator; 15-second back pressure valve; 16-charge pump three; 17-a third micromixer; 18-charge pump four; 19-microchannel reactor, 20-third backpressure valve; 21-a first interface; 22-a second interface; 23-third interface.
Detailed Description
Herein, the term "alkyl group" may represent a straight or branched alkyl group having a carbon number of 1 to 50, preferably 1 to 10, more preferably 1 to 5, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, etc.; the alkyl group may also represent a halogenated linear or branched alkyl group having 1 to 10 carbon atoms, preferably 1 to 5 carbon atoms, such as trifluoromethyl, trifluoroethyl, hexafluoroisopropyl, and the like; the alkyl group may also represent a C3-30 monocyclic, polycyclic or fused cyclic alkyl group, preferably C3-10 cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
As used herein, the term "aryl" refers to a C6-36, preferably C6-14, monocyclic, polycyclic or fused ring aryl group, such as phenyl, naphthyl, anthryl, phenanthryl, biphenyl, binaphthyl, and the like.
As used herein, the term "aralkyl group" refers to a group in which at least one hydrogen atom in an alkyl group is substituted with an aryl group, preferably an aralkyl group having 7 to 15 carbon atoms, such as benzyl, 1-phenylethyl, 2-phenylethyl, 1-phenylpropyl, 3-naphthylpropyl, and the like.
As used herein, the term "alkoxy" refers to an unprotected hydroxyl group, and may also refer to an alkoxy group formed from a straight or linear alkyl group having 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, and more preferably 1 to 5 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like.
As used herein, the term "aryloxy group" refers to an aryloxy group formed from a C6-36, preferably C6-14, monocyclic, polycyclic or fused ring aryl group, such as phenoxy, tolyloxy, xylyloxy, naphthyloxy, and the like.
As used herein, the term "halogen" refers to fluorine, chlorine, bromine or iodine.
As used herein, the term "imine" refers to a species formed by substituting an oxygen atom on a carbonyl group (aldehyde carbonyl or ketone carbonyl) with a nitrogen atom in a mixed reaction mass.
Compounds that may be prepared by a microreaction system-based process for the preparation of 5, 8-dihydro-6H-isoquinolin [3, 2-alpha ] isoquinoline herein may include dihydroberberine, dihydropalmatine, dihydroepiberberine, and dihydropseudopalmatine, among others.
As shown in fig. 1, the first solution and the second solution are introduced into a first micromixer 2 by a feed pump to obtain a mixed reaction material; the mixed reaction mass is introduced into the first fixed bed reactor 4. Applying backpressure to the mixed reaction materials in the first fixed bed reactor 4 through a first backpressure valve 6 to uniformly mix the materials; the first solution is a mixture of the aryl ethylamine (IV) and an organic solvent, and the second solution is a mixture of the aryl aldehyde (V) and an organic solvent.
Introducing the dehydrated and condensed mixed reaction material and hydrogen into a second fixed bed reactor 10 filled with a reducing agent through a second micromixer 9 to perform a catalytic hydrogenation reaction; introducing the mixed reaction material after the catalytic hydrogenation reaction into a condenser 12 for condensation, and separating gas components through a gas-liquid separator 14; applying back pressure to the mixed reaction materials in the gas-liquid separator 14 through a second back pressure valve 15 to uniformly mix the materials;
introducing the gas-liquid separated mixed reaction material and the third solution into a microchannel reactor 19 through a third micro mixer 17 to perform a salt forming reaction; carrying out reduced pressure concentration, pulping and purification on the mixed reaction material after the salt forming reaction to obtain secondary amine hydrochloride (II); applying back pressure to the mixed reaction materials in the micro-channel reactor 19 through a third back pressure valve 20 to uniformly mix the materials; the third solution is a mixture of hydrochloric acid and an organic solvent.
Subjecting the secondary amine hydrochloride (II) and the fourth solution to a Pictet-Schpendeller reaction, Friedel-crafts hydroxyalkylation, and dehydration cascade reaction in the presence of an acid, a dehydrating agent, and an additive to produce a 5, 8-dihydro-6H-isoquinolino [3, 2-alpha ] isoquinoline compound of formula (I); the fourth solution is a mixture of glyoxal (III) and an organic solvent.
As shown in the following reaction scheme:
x is mono-or di-substituted, and is positioned at any substitutable position on a benzene ring; x is hydrogen, straight or branched C1-C5Alkyl, straight or branched C1～C5Alkoxy or halogen; or two X substituents are linked together to form a ring;
y is mono-substituted or di-substituted and is positioned at any substitutable position on a benzene ring; y is hydrogen, straight or branched C1-C5Alkyl, straight or branched C1～C5Alkoxy or halogen; or two Y substituents may be joined together to form a ring.
In some embodiments, the organic solvent mixed with the arylethylamine (IV), the organic solvent mixed with the arylaldehyde (V) may each independently be any one or more of methanol, ethanol, isopropanol, dimethyl sulfoxide, N-dimethylformamide, ethyl acetate, acetone, dichloromethane, chloroform, N-hexane, cyclohexane, petroleum ether, toluene, and carbon tetrachloride.
As a specific example, the first solution herein may be a mixed solution of arylethylamine (IV) and dichloromethane; the second solution may be a mixed solution of the aryl aldehyde (V) and dichloromethane.
In some embodiments, the concentration of the arylethylamine (IV) is 0.01 to 10mol/L, preferably 0.8 mol/L. The concentration of the arylaldehyde (V) is 0.01 to 10mol/L, preferably 0.8mol/L, after mixing the arylaldehyde (V) with the organic solvent.
In some embodiments, when the concentration of one of the arylethylamine (IV) solution and the aryl aldehyde (V) solution is determined, the concentration of the other solution may be such that the molar ratio of arylethylamine (IV) to aryl aldehyde (V) is 1: 1 to 10, preferably 1: 1.
In some embodiments, the arylethylamine (IV) solution and the aryl aldehyde (V) solution can be pumped into the first micromixer 2 by feed pumps one 1 and two 3, respectively, to control the flow rates of the arylethylamine (IV) solution and the aryl aldehyde (V) solution. For example, as shown in fig. 1, an arylethylamine (IV) solution may be pumped into a first micromixer 2 by a feed pump one 1; the aryl aldehyde (V) solution is pumped into the first micromixer 2 by means of the feed pump two 3. Alternatively, the aryl aldehyde (V) solution may be pumped into the first micromixer 2 by the feed pump one 1; the arylethylamine (IV) solution is pumped into the first micromixer 2 by means of the feed pump two 3.
Herein, the arylethylamine (IV) solution and the aryl aldehyde (V) solution are introduced into the first fixed reaction bed through the first micromixer 2. In some embodiments, the first micromixer 2 may be any one of a static mixer, a T-type micromixer, a Y-type micromixer, a coaxial flow micromixer, and a flow focusing micromixer. For example, the arylethylamine (IV) solution and the arylaldehyde (V) solution may be introduced into the first fixed reaction bed through a T-type micromixer.
The first fixed bed reactor 4 may include a dehydrating agent and a silica filler 5 in a mass ratio of 1: (0.1-100). The dehydrating agent can be
Molecular sieve,
Molecular sieve,
Any one or more of molecular sieve, 13X molecular sieve, XH molecular sieve, anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous calcium chloride and anhydrous potassium carbonate.
In some embodiments, the method can be used for
Any one of the molecular sieve, 13X molecular sieve or XH molecular sieve is dispersed in silica to form the packing in the first fixed bed reactor 4.
In some embodiments, the dehydrating agent may be 20 to 40 mesh, and the silica particle size may be 0.5mm to 1.0 mm.
Specifically, in the first fixed bed reactor 4, the reaction temperature for dehydration condensation is-20 to 100 ℃, and preferably 60 ℃.
In some embodiments, the residence time of the mixed reaction mass in the first fixed bed reactor 4 is between 0.2 and 60 minutes, preferably 5 minutes.
In some embodiments, the first back pressure valve 6 applies 0.1 to 120bar of pressure to the mixed reaction materials in the first fixed bed reactor 4 to uniformly mix the materials.
Here, the dehydrated mixed reaction mass may be introduced into the second fixed bed reactor 10 through the second micromixer 9. Hydrogen is likewise introduced into the second fixed-bed reactor 10 via the second micromixer 9. In the second fixed bed reactor 10, the mixed reaction mass and hydrogen undergo a catalytic hydrogenation reaction.
In some embodiments, the second micromixer 9 may be any one of a static mixer, a T-type micromixer, a Y-type micromixer, a coaxial flow micromixer, and a flow focusing micromixer. For example, the mixed reaction mass and hydrogen can be introduced into the second fixed reaction bed through a T-type micromixer.
In some embodiments, the reaction temperature in the second fixed bed reactor 10 is-20 to 120 ℃, preferably 60 ℃.
In some embodiments, the residence time of the dehydrated mixed reaction mass in the second fixed bed reactor 10 is 0.2 to 60 minutes, preferably 5 minutes.
In some embodiments, the first backpressure valve 6 applies a pressure of 0.1 to 120bar, preferably 10 to 50bar, to the mixed reactant stream in the second fixed bed reactor 10.
In some embodiments, the flow ratio of the dehydrated and condensed mixed reaction material to hydrogen can be adjusted to make the molar ratio of the aryl ethylamine (IV) to the hydrogen be 1: 0.95-1.5. For example, as shown in FIG. 1, the flow rate of hydrogen can be controlled by the gas mass flow meter 8 so that the molar ratio of arylethylamine (IV) to hydrogen is in the range of 1: (0.95-1.5) in the second fixed bed reactor 10.
In some embodiments, hydrogen may be provided by the hydrogen passage 7 to which the second micromixer 9 is connected.
The second fixed bed reactor 10 may include a reducing agent and a silica filler 11 in a mass ratio of 1: (0.1-100). The reducing agent may be 1 to 50 wt% Pd/C, 1 to 50 wt% Pd (OH)21 to 50 wt% of Pt/C and 1 to 50 wt% of PtO2Any one or more of them.
In some embodiments, 1 to 50 wt% Pd (OH)2dispersing/C in silica to form a filler; or dispersing 1-50 wt% of Pt/C in the silicon dioxide to form the filler. Preferably, 10 wt% Pd (OH)2C or 10 wt% PtO2Dispersed in silicaTo form the packing in the second fixed bed reactor 10.
In some embodiments, the dehydrating agent may be 20 to 40 mesh, and the silica particle size may be 0.5mm to 1.0 mm.
Herein, the mixed reaction material after the reaction may be introduced into a condenser 14 to be condensed, and the gas component may be separated by a gas-liquid separator 14.
The top of the gas-liquid separator 14 may have a first port 21, a second port 22, and a third port 23 in some embodiments, the first port 21 being connected with the outlet of the condenser 12; the second port 22 is connected to the nitrogen gas passage 13 to introduce nitrogen gas; the third port 23 is connected to the second back pressure valve 15. The gas-liquid separator 14 also has an outlet which is connected to a third micromixer 17.
In some embodiments, the second back pressure valve 15 pressurizes the mixed reactant material in the gas-liquid separator 14 by 0.1 to 120bar, preferably 30 bar.
Herein, the mixed reaction material may be pumped into the third micromixer 17 by the feed pump three 16, and the third solution may be pumped into the third micromixer 17 by the feed pump four 18, to control the flow rates of the third solution and the mixed reaction material. For example, the flow rate of the mixed reaction mass can be controlled to 0.16mL/min by the feed pump III 16; the flow rate of the third solution was controlled to 0.04mL/min by feed pump four 18.
Herein, the third solution is a mixed solution of hydrochloric acid and an organic solvent, and the organic solvent may be any one or more of methanol, ethanol, isopropanol, dimethyl sulfoxide, N-dimethylformamide, ethyl acetate, acetone, dichloromethane, chloroform, N-hexane, cyclohexane, petroleum ether, toluene, and carbon tetrachloride. For example, methanol and hydrochloric acid may be mixed, and a methanol solution of hydrochloric acid and a mixed reaction material subjected to gas-liquid separation may be introduced into the microchannel reactor 19 through the third micromixer 17.
In some embodiments, the concentration of hydrochloric acid in the methanol solution of hydrochloric acid is 0.01-15 mol/L, and a saturated solution is preferred. That is, a methanol solution of saturated hydrochloric acid may be mixed with the mixed reaction material by the third micro-mixer 17 and introduced into the microchannel reactor 19.
In some embodiments, for the third micromixer 17, the third micromixer 17 herein may be any one of a static mixer, a T-type micromixer, a Y-type micromixer, a coaxial flow micromixer, and a flow focusing micromixer, preferably a T-type micromixer.
In a specific embodiment, the T-type micromixer has two inlets and one outlet, and the gas-liquid separator 14 is connected to one of the inlets by the feed pump iii 16, so that the mixed reaction material in the gas-liquid separator 14 is pumped into the microchannel reactor 19 by the feed pump iii 16; the feed pump four 18 is connected to the other inlet of the T-type micromixer to pump the methanolic solution of saturated hydrochloric acid into the T-type micromixer by the feed pump four 18. The outlet of the T-shaped micro mixer is connected with the micro-channel reactor 19, so that the mixed solution of the methanol solution of saturated hydrochloric acid and the mixed reaction material enters the micro-channel reactor to carry out salt-forming reaction, and secondary amine hydrochloride (II) is obtained by carrying out reduced pressure concentration, pulping and purification.
In some embodiments, the third backpressure valve 20 applies 0.1-100 bar, preferably 7bar, to the mixed reaction materials in the microchannel reactor 19 to uniformly mix the materials.
In some embodiments, the residence time of the mixed reaction mass in the microchannel reactor 19 is from 0.2 to 60 minutes, preferably 5 minutes. The reaction temperature in the microchannel reactor 19 is-20 to 100 ℃, and preferably 25 ℃.
In some embodiments, the microchannel reactor 19 is a tubular microchannel reactor 19 or a plate microchannel reactor 19; the inner diameter of the tubular micro-channel reactor 19 is 0.1-50 mm; or the hydraulic diameter of the reaction fluid channel of the plate-type microchannel reactor 19 is 0.1-50 mm; preferably a tubular microchannel reactor 19 with an inner diameter of 0.12-5.35 mm.
In some embodiments, the organic solvent used for pulping may be any one or more of ethyl acetate, acetone, dichloromethane, chloroform, n-hexane, cyclohexane, petroleum ether, toluene, carbon tetrachloride, diethyl ether, and methyl tert-butyl ether. For example, the mixed reaction mass after the salt formation reaction may be slurried with ethyl acetate.
In some embodiments, the concentration of the organic solvent used for pulping may be 1-10 g/mL, preferably 1-5 g/mL.
In some embodiments, the reactants used to prepare the 5, 8-dihydro-6H-isoquinoline [3,2- α ] isoquinoline herein include a secondary amine hydrochloride (II), glyoxal, a dehydrating agent, an acid, and an additive in a molar ratio of 1: 1 to 100: 0.1 to 20: 1 to 1000: 0.1 to 20.
For example, in some embodiments, the mole ratio of secondary amine hydrochloride (II), glyoxal, dehydrating agent, acid, additive is 1: 20: 2.2: 250: 3.5, and in the case of the dehydrating agent, acid, additive being in this ratio, the secondary amine hydrochloride (II) and glyoxal solution in this ratio undergo a picket-spengler reaction, friedel-crafts hydroxyalkylation, and dehydration tandem reaction to produce the 5, 8-dihydro-6H-isoquinolin [3, 2-a ] isoquinoline compound of formula (I).
In some embodiments, the glyoxal solution (fourth solution) herein is a mixed solution of glyoxal and an organic solvent, and the organic solvent may be one or more of methanol, ethanol, formic acid, ethyl acetate, acetone, dichloromethane, chloroform, n-hexane, cyclohexane, petroleum ether, toluene, carbon tetrachloride, diethyl ether, and methyl t-butyl ether. Such as glyoxal in formic acid.
In some embodiments, the acid herein may be any one or more of formic acid, acetic acid, trifluoroacetic acid, oxalic acid, p-toluenesulfonic acid, methanesulfonic acid, benzoic acid, succinic acid, citric acid, tartaric acid, camphorsulfonic acid, and boric acid, preferably formic acid.
In some embodiments, the additive may be any one or more of sodium fluoride, potassium fluoride, magnesium fluoride, lithium chloride, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, barium chloride, aluminum chloride, lithium bromide, sodium bromide, potassium bromide, magnesium bromide, calcium bromide, barium bromide, lithium iodide, sodium iodide, potassium iodide, magnesium iodide, and calcium iodide; sodium chloride is preferred.
In some embodiments, the dehydrating agent may be any one or more of trimethyl orthoformate, 3A molecular sieve, 4A molecular sieve, 5A molecular sieve, 13X molecular sieve, XH molecular sieve, anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous calcium chloride, and anhydrous potassium carbonate, preferably anhydrous magnesium sulfate.
The present invention is described in further detail below with reference to specific examples, but the scope of the present invention is not limited thereto.
Example 1
This example provides a method for preparing 5, 8-dihydro-6H-isoquinolin [3, 2-a ] isoquinoline using a microreaction system. As shown in fig. 1, the micro-reaction system includes a feed pump 1, a first micro mixer 2, a feed pump two 3, a first fixed bed reactor 4, a dehydrating agent and silica packing 5, a first back pressure valve 6, a hydrogen passage 7, a gas mass flow meter 8, a second micro mixer 9, a second fixed bed reactor 10, a reducing agent and silica packing 11, a condenser 12, a nitrogen passage 13, a gas-liquid separator 14, a second back pressure valve 15, a feed pump three 16, a third micro mixer 17, a feed pump four 18, a microchannel reactor 19, a third back pressure valve 20, a first interface 21, a second interface 22 and a third interface 23, which are connected in this order.
Preparation of the first fixed bed reactor
Mixing 2g of
The molecular sieve (20-40 mesh) is dispersed in 20g of silica (particle size 0.5 mm-1.0 mm), and the formed dehydrating agent and silica filler 5 are filled in the first fixed bed reactor 4. The first fixed bed reactor 4 may be a tubular microchannel reactor, which may have a length of 20cm and an inner diameter of 1 cm.
Preparation of the second fixed bed reactor
2gPd (OH)2the/C (10% by weight) is dispersed in 20g of silica (particle size 0.5mm to 1.0mm), and the resulting reducing agent and silica filler 11 are packed in the second fixed-bed reactor 10. The second fixed bed reactor 10 may be a tubular microchannel reactor, which may have a length of 20cm and an internal diameter of 1 cm.
Preparation of dihydroberberine
(1) As shown in fig. 1, two inlets of the first micromixer are respectively connected with a feed pump i 1 and a feed pump ii 3, and a mixed solution of piperonylethylamine (6mmol) and methanol (100mL), and a mixed solution of veratraldehyde (6mmol) and dichloromethane (100mL) are respectively pumped into the first micromixer 2 through the feed pump i 1 and the feed pump ii 3 to be mixed. The mixture of piperonylethylamine and methanol was pumped into the first micro-mixer 2 at a flow rate of 0.2mL/min, the mixture of veratraldehyde and dichloromethane was pumped into the first micro-mixer 2 at a flow rate of 0.2mL/min, and the molar ratio of piperonylethylamine to veratraldehyde in the mixed reaction mass was 1: 1.
(2) The mixed reaction mass flowing out of the first micromixer 2 is introduced into an MF-200 first fixed-bed reactor 4 (filler content 10% by weight)
Molecular sieves and SiO2) The dehydration condensation reaction is carried out. The residence time of the mixed reaction mass in the first fixed bed reactor 4 was 5 minutes, the reaction temperature was 25 ℃, and 7bar of pressure was applied to the mixed reaction mass in the first fixed bed reactor 4 through the first back pressure valve 6.
(3) The dehydrated mixed reaction material is introduced into the second micromixer 9, and the hydrogen gas of the hydrogen passage 7 is sent to the second micromixer 9. The hydrogen gas was passed through a gas mass flow meter 8 to adjust the molar ratio of imine to hydrogen in the dehydrated mixed reaction mass to 1: 1.1.
(4) Introducing the mixed reaction mass obtained in step (3) and hydrogen into a second fixed bed reactor 10 (packing of 10 wt% Pd (OH))2C and SiO2) Carrying out catalytic hydrogenation reaction. The residence time of the mixed reaction mass in the second fixed bed reactor 10 was 5 minutes, the reaction temperature was 60 ℃, and 30bar of pressure was applied to the mixed reaction mass in the second fixed bed reactor 10 through the first back pressure valve 6. Introducing the mixed reaction material after catalytic hydrogenation into a condenser12, and is introduced into the gas-liquid separator 14 from a first port 21 of the gas-liquid separator 14, the nitrogen gas in the nitrogen gas passage 13 is introduced into the gas-liquid separator 14 from a second port 22 of the gas-liquid separator 14, and the second back pressure valve 15 is connected to the gas-liquid separator 14 through a third port 23. The mixed reaction mass and nitrogen in the gas-liquid separator 14 were pressurized by 30bar through the second back pressure valve 15. After separating the gas components in the mixed reaction mass, the mixed reaction mass is collected by a product liquid collection tank (not shown in the figure).
(5) Pumping the mixed reaction material obtained in the step (4) into a third micro-mixer 17 through a third feeding pump 16, and pumping a methanol solution of saturated hydrochloric acid into the third micro-mixer 17 through a fourth feeding pump 18 to uniformly mix the materials. Pumping the mixed reaction material obtained in the step (4) into a third micro mixer 17 at a flow rate of 0.16mL/min, and pumping a saturated hydrochloric acid methanol solution into the third micro mixer 17 at a flow rate of 0.04mL/min so that the molar ratio of the mixed reaction material to hydrochloric acid is 1: 1.5.
(6) And introducing the mixed reaction material and a saturated hydrochloric acid methanol solution into a micro-channel reactor 19 from a third micro-mixer 17 for salt forming reaction. It was allowed to stay in the microchannel reactor 19 for 5 minutes at a reaction temperature of 25 c and the mixed reaction mass in the microchannel reactor 19 was pressurized to 7bar through the third back pressure valve 20.
(7) And (3) concentrating the salified mixed reaction material in the step (6), pulping with ethyl acetate, filtering and drying to obtain yellow solid 2- (3, 4-dioxyphenyl) -N- (2, 3-dimethoxy benzyl) ethylamine hydrochloride (space-time yield is 505mg/h, and yield is 94%).
(8) 2- (3, 4-Dioxyphenyl) -N- (2, 3-dimethoxybenzyl) ethylamine hydrochloride (70.3mg, 0.2mmol), boric acid (24.7mg, 0.4mmol) and sodium chloride (40.9mg, 0.7mmol) were added to the vial. In a sealed tube, degassed glyoxalic formic acid solution (2mL, 2M formic acid solution) was added for dispersion, and anhydrous magnesium sulfate (140mg, 200 wt%) was added and stirred at 80 ℃ for 12 hours. In a sealed tube, 2M sodium hydroxide solution (20mL) was added for quenching, pH was adjusted to 10, dichloromethane was added for extraction, the organic layer was collected, dried over anhydrous sodium sulfate, and concentrated to give dihydroberberine (tan solid, 47mg, 71% yield, melting point: 150.4-152.8 ℃ C.).
1H NMR (600MHz, chloroform-d) δ 7.17(s, 1H), 6.74(d, J ═ 9.0Hz, 2H), 6.58(s, 1H), 5.95(s, 1H), 5.94(s, 2H), 4.32(s, 2H), 3.84(s, 6H), 3.13(t, J ═ 6.0Hz, 2H), 2.87(t, J ═ 6.0Hz, 2H).13C NMR (150MHz, chloroform-d) delta 150.5, 147.4, 146.8, 144.6, 141.8, 128.9, 128.7, 124.7, 122.3, 118.9, 111.6, 108.0, 103.9, 101.1, 96.5, 60.9, 56.1, 49.5, 49.2, 30.0.IR (neat)2932.1, 2833.1, 1596.5, 1478.7, 1452.1, 1346, 1267.4, 1225.1, 1082.1, 1028, 815.3, 737.4, 646.5, 443.6cm-1。
Example 2
Preparation of the first fixed bed reactor
0.2g of
The molecular sieve (20-40 mesh) is dispersed in 20g of silica (particle size 0.5 mm-1.0 mm), and the formed dehydrating agent and silica filler 5 are filled in the first fixed bed reactor 4. The first fixed bed reactor 4 may be a tubular microchannel reactor, which may have a length of 20cm and an inner diameter of 1 cm.
Preparation of the second fixed bed reactor
0.2gPd (OH)2the/C (10 wt%) is dispersed in 20g of silica (particle size 0.5mm to 1.0mm), and the formed reducing agent and silica filler 11 are packed in the second fixed bed reactor 10. The second fixed bed reactor 10 may be a tubular microchannel reactor, which may have a length of 20cm and an internal diameter of 1 cm.
Preparation of dihydroberberine
(1) As shown in fig. 1, two inlets of the first micro-mixer are respectively connected with a first feeding pump 1 and a second feeding pump 3, and a solution obtained by uniformly mixing piperonylethylamine (6mmol) and methanol (100mL) and a solution obtained by uniformly mixing veratraldehyde (12mmol) and dichloromethane (100mL) are respectively pumped into the first micro-mixer 2 through the first feeding pump 1 and the second feeding pump 3 to be mixed, so as to obtain a mixed reaction material. Pumping the mixed solution of piperonylethylamine and methanol into a first micro mixer 2 at the flow rate of 0.2mL/min, pumping the mixed solution of veratraldehyde and dichloromethane into the first micro mixer 2 at the flow rate of 0.2mL/min, wherein the molar ratio of the piperonylethylamine to the veratraldehyde in the mixed reaction material is 1: 2.
(2) The mixed reaction mass flowing out of the first micromixer 2 is introduced into an MF-200 first fixed-bed reactor 4 (filler content 10% by weight)
Molecular sieves and SiO2) Dehydration condensation reaction is carried out. The residence time of the mixed reaction mass in the first fixed bed reactor 4 was 5 minutes, the reaction temperature was 25 ℃, and 1bar of pressure was applied to the mixed reaction mass in the first fixed bed reactor 4 through the first back pressure valve 6.
(3) The dehydrated mixed reaction material is introduced into the second micromixer 9, and the hydrogen gas of the hydrogen passage 7 is sent to the second micromixer 9. The hydrogen gas was passed through a gas mass flow meter 8 to adjust the molar ratio of imine to hydrogen in the dehydrated mixed reaction mass to 1: 1.0.
(4) Introducing the mixed reaction mass obtained in step (3) and hydrogen into a second fixed bed reactor 10 (packing of 10 wt% Pd (OH))2C and SiO2) Carrying out catalytic hydrogenation reaction. The residence time of the mixed reaction mass in the second fixed bed reactor 10 was 60 minutes, the reaction temperature was 20 ℃, and 10bar of pressure was applied to the mixed reaction mass in the second fixed bed reactor 10 through the first back pressure valve 6. The mixed reaction material after catalytic hydrogenation is introduced into the condenser 12 for condensation, and is introduced into the gas-liquid separator 14 from the first interface 21 of the gas-liquid separator 14, the nitrogen gas of the nitrogen gas passage 13 is introduced into the gas-liquid separator 14 from the second interface 22 of the gas-liquid separator 14, and the second back pressure valve 15 is connected with the gas-liquid separator 14 through the third interface 23. Mixing into the gas-liquid separator 14 by the second back pressure valve 15The reaction mass was combined and pressurized with nitrogen at 30 bar. After the separation of the gas components in the mixed reaction mass, the mixed reaction mass is collected by a product liquid collection tank (not shown in the figure).
(5) Pumping the mixed reaction material obtained in the step (4) into a third micro mixer 17 through a third feeding pump 16, and pumping the methanol solution of saturated hydrochloric acid into the third micro mixer 17 through a fourth feeding pump 18 to uniformly mix the materials. Pumping the mixed reaction material obtained in the step (4) into a third micro mixer 17 at a flow rate of 0.16mL/min, and pumping a methanol solution of saturated hydrochloric acid into the third micro mixer 17 at a flow rate of 0.06mL/min so that the molar ratio of the mixed reaction material to the hydrochloric acid is 1: 1.0.
(6) And introducing the mixed reaction material and a methanol solution of saturated hydrochloric acid into a microchannel reactor 19 from a third micro mixer 17 for salt forming reaction. It was allowed to stay in the microchannel reactor 19 for 5 minutes at a reaction temperature of 25 deg.c and 7bar of pressure was applied to the mixed reaction mass in the microchannel reactor 19 through the third back pressure valve 20.
(7) And (3) concentrating the salified mixed reaction material obtained in the step (6), pulping with ethyl acetate, filtering and drying to obtain yellow solid 2- (3, 4-dioxyphenyl) -N- (2, 3-dimethoxy benzyl) ethylamine hydrochloride (space-time yield is 505mg/h, and yield is 92%).
(8) 2- (3, 4-Dioxyphenyl) -N- (2, 3-dimethoxybenzyl) ethylamine hydrochloride (70.3mg, 0.2mmol), boric acid (24.7mg, 0.6mmol) and sodium chloride (40.9mg, 0.8mmol) were added to the vial. In a sealed tube, degassed glyoxalic formic acid solution (2mL, 2M formic acid solution) was added for dispersion, and anhydrous magnesium sulfate (300mg, 200 wt%) was added and stirred at 80 ℃ for 12 hours. In a sealed tube, 2M sodium hydroxide solution (20mL) was added for quenching, pH was adjusted to 10, dichloromethane was added for extraction, the organic layer was collected, dried over anhydrous sodium sulfate, and concentrated to give dihydroberberine (tan solid, 44mg, 66% yield, melting point: 151.1-152.5 ℃ C.).
1H NMR (600MHz, chloroform-d) δ 7.17(s, 1H), 6.74(d, J ═ 9.0Hz, 2H), 6.58(s, 1H), 5.95(s, 1H), 5.94(s, 2H), 4.32(s, 2H), 3.84(s, 6H), 3.13(t, J ═ 6.0 Hz)，2H)， 2.87(t，J＝6.0Hz，2H).
Example 3
Preparation of the first fixed bed reactor
Mixing 7g of
The molecular sieve (20-40 mesh) is dispersed in 0.7g of silica (particle size 0.5-1.0 mm), and the formed dehydrating agent and silica filler 5 are filled in the first fixed bed reactor 4. The first fixed bed reactor 4 may be a tubular microchannel reactor, which may have a length of 20cm and an inner diameter of 1 cm.
Preparation of the second fixed bed reactor
20g of Pd (OH)2the/C (10 wt%) is dispersed in 2g of silica (particle size 0.5mm to 1.0mm), and the formed reducing agent and silica filler 11 are packed in the second fixed bed reactor 10. The second fixed bed reactor 10 may be a tubular microchannel reactor, which may have a length of 20cm and an internal diameter of 1 cm.
Preparation of dihydroberberine
(1) As shown in fig. 1, two inlets of the first micro-mixer are respectively connected with a first feeding pump 1 and a second feeding pump 3, and a solution obtained by uniformly mixing piperonylethylamine (6mmol) and methanol (100mL) and a solution obtained by uniformly mixing veratraldehyde (60mmol) and dichloromethane (100mL) are respectively pumped into the first micro-mixer 2 through the first feeding pump 1 and the second feeding pump 3 to be mixed, so as to obtain a mixed reaction material. Pumping the mixed solution of piperonylethylamine and methanol into the first micro mixer 2 at the flow rate of 0.2mL/min, and pumping the mixed solution of veratraldehyde and dichloromethane into the first micro mixer 2 at the flow rate of 0.2mL/min, so that the molar ratio of the piperonylethylamine to the veratraldehyde in the mixed reaction material is 1: 10.
(2) The mixed reaction mass flowing out of the first micromixer 2 is introduced into an MF-200 first fixed-bed reactor 4 (filler content 10% by weight)
Molecular sieves and SiO2) The dehydration condensation reaction is carried out. The residence time of the mixed reaction mass in the first fixed bed reactor 4 was 60 minutes, the reaction temperature was 25 ℃, and 10bar of pressure was applied to the mixed reaction mass in the first fixed bed reactor 4 through the first back pressure valve 6.
(3) The dehydrated mixed reaction material is sent to the second micromixer 9, and the hydrogen gas of the hydrogen passage 7 is sent to the second micromixer 9. The hydrogen gas was passed through a gas mass flow meter 8 to adjust the molar ratio of imine to hydrogen in the dehydrated mixed reaction mass to 1: 1.5.
(4) Introducing the mixed reaction mass obtained in step (3) and hydrogen into a second fixed bed reactor 10 (packing of 10 wt% Pd (OH))2C and SiO2) Carrying out catalytic hydrogenation reaction. The residence time of the mixed reaction mass in the second fixed bed reactor 10 was 30 minutes, the reaction temperature was 60 ℃, and 50bar pressure was applied to the mixed reaction mass in the second fixed bed reactor 10 through the first backpressure valve 6. The mixed reaction material after catalytic hydrogenation is introduced into the condenser 12 for condensation, and is introduced into the gas-liquid separator 14 from the first interface 21 of the gas-liquid separator 14, the nitrogen gas of the nitrogen gas passage 13 is introduced into the gas-liquid separator 14 from the second interface 22 of the gas-liquid separator 14, and the second back pressure valve 15 is connected with the gas-liquid separator 14 through the third interface 23. The mixed reaction mass and nitrogen in the gas-liquid separator 14 were pressurized by 30bar through the second back pressure valve 15. After the separation of the gas components in the mixed reaction mass, the mixed reaction mass is collected by a product liquid collection tank (not shown in the figure).
(5) Pumping the mixed reaction material obtained in the step (4) into a third micro mixer 17 through a third feeding pump 16, and pumping the methanol solution of saturated hydrochloric acid into the third micro mixer 17 through a fourth feeding pump 18 to uniformly mix the materials. Pumping the mixed reaction material obtained in the step (4) into a third micro mixer 17 at a flow rate of 0.16mL/min, and pumping a methanol solution of saturated hydrochloric acid into the third micro mixer 17 at a flow rate of 0.04mL/min so that the molar ratio of the mixed reaction material to the hydrochloric acid is 1: 1.5.
(6) The mixed reaction material and the methanol solution of saturated hydrochloric acid are introduced into a microchannel reactor 19 from a third micro mixer 17 to carry out salt-forming reaction. It was allowed to stay in the microchannel reactor 19 for 5 minutes at a reaction temperature of 25 c and the mixed reaction mass in the microchannel reactor 19 was pressurized to 7bar through the third back pressure valve 20.
(7) And (3) concentrating the salified mixed reactant liquid obtained in the step (6), pulping with ethyl acetate, filtering and drying to obtain yellow solid 2- (3, 4-dioxyphenyl) -N- (2, 3-dimethoxy benzyl) ethylamine hydrochloride (space-time yield is 505mg/h, and yield is 90%).
(8) 2- (3, 4-Dioxyphenyl) -N- (2, 3-dimethoxybenzyl) ethylamine hydrochloride (70.3mg, 0.2mmol), boric acid (24.7mg, 0.6mmol) and sodium chloride (40.9mg, 0.8mmol) were added to the vial. In a sealed tube, degassed glyoxalic formic acid solution (2mL, 2M formic acid solution) was added for dispersion, and anhydrous magnesium sulfate (300mg, 200 wt%) was added and stirred at 80 ℃ for 12 hours. In a sealed tube, 2M sodium hydroxide solution (20mL) was added for quenching, pH was adjusted to 10, dichloromethane was added for extraction, the organic layer was collected, dried over anhydrous sodium sulfate, and concentrated to give dihydroberberine (tan solid, 45mg, 68% yield, melting point: 150.5-151.9 ℃ C.).
1H NMR (600MHz, chloroform-d) δ 7.17(s, 1H), 6.74(d, J ═ 9.0Hz, 2H), 6.58(s, 1H), 5.95(s, 1H), 5.94(s, 2H), 4.32(s, 2H), 3.84(s, 6H), 3.13(t, J ═ 6.0Hz, 2H), 2.87(t, J ═ 6.0Hz, 2H).
Example 4
Preparation of dihydroberberine
The scheme of this example is substantially the same as that of example 1, except that in the first fixed bed reactor in this example, 0.2g of 13X molecular sieve (20-40 mesh) is dispersed in 20g of silica (particle size 0.5 mm-1.0 mm). The product was dihydroberberine (brown yellow solid, 42mg, 63% yield, melting point: 151.5-152.6 ℃ C.).
Example 5
Preparation of dihydroberberine
The scheme of this example is substantially the same as that of example 1, except that in the first fixed bed reactor in this example, the dehydrating agent is 0.2gXH molecular sieve (20-40 mesh) dispersed in 20g of silica (particle size 0.5 mm-1.0 mm). The product was dihydroberberine (tan solid, 46mg, 69% yield, melting point: 150.5-152.2 ℃ C.).
Example 6
Preparation of dihydroberberine
This example is substantially the same as example 1, except that in the second fixed bed reactor of this example, the reducing agent was 2gPtO2(10 wt%) was dispersed in 20g of silica (particle size 0.5mm to 1.0 mm). The product was dihydroberberine (tan solid, 48mg, 71% yield, melting point: 151.7-152.5 ℃ C.).
Example 7
Preparation of dihydropalmatine
This example is essentially the same as example 1 except that in this example the starting substrates are 3, 4-dimethoxyphenethylamine and veratraldehyde and the product is dihydropalmatine (yellow solid, 68% yield, melting point: 96.2-98.4 ℃).
1H NMR (600MHz, chloroform-d) Δ 7.18(s, 1H), 6.75(s, 2H), 6.60(s, 1H), 5.99(s, 1H), 4.33(s, 2H), 3.94(s, 3H), 3.89(s, 3H), 3.85(s, 3H), 3.84(s, 3H)H)，3.15(t，J＝6.0 Hz，2H)，2.90(t，J＝6.0Hz，2H).13C NMR (150MHz, chloroform-d) delta 150.5, 149.1, 147.9, 144.7, 141.8, 128.8, 127.5, 123.3, 122.2, 118.8, 111.6, 110.7, 106.8, 96.0, 60.9, 56.2, 56.1, 56.0, 49.6, 49.3, 29.5.IR (neat)2998, 2953.2, 1602.6, 1506.4, 1450.2, 1362.9, 1271.5, 1184.7, 1107.4, 1019.4, 862.4, 809.9, 649.9, 585.2, 406.1cm-1。
Example 8
Preparation of dihydro-epiberberine
This example is essentially the same as example 1, except that in this example the starting substrates are 3, 4-dimethoxyphenethylamine and 1, 3-benzodioxy-4-carbaldehyde and the product is dihydroepiberberine (dark yellow solid, 69% yield, m.p.: 162.8-164.7 ℃ C.).
1H NMR (400MHz, chloroform-d) δ 7.17(s, 1H), 6.65(d, J ═ 8.0Hz, 1H), 6.60(s, 1H), 6.52(d, J ═ 8.0Hz, 1H), 6.02(s, 1H), 5.93(s, 2H), 4.25(s, 2H), 3.94(s, 3H), 3.89(s, 3H), 3.14(t, J ═ 5.6Hz, 2H), 2.90(t, J ═ 5.6Hz, 2H).13C NMR (100MHz, chloroform-d) delta 149.1, 147.9, 145.4, 142.8, 141.5, 129.6, 127.5, 123.3, 116.1, 110.7, 110.0, 107.5, 106.7, 101.0, 96.6, 56.2, 56.0, 49.3, 49.0, 29.5.IR (neat)2925.9, 2831.7, 1509.9, 1455.3, 1373.8, 1216.3, 1157, 1062.3, 1016.8, 852.9, 810, 775.4, 481.6cm-1。
Example 9
Preparation of dihydropseudopalmatine
This example is essentially the same as example 1 except that in this example the starting substrates are 3, 4-dimethoxyphenethylamine and veratraldehyde and the product is dihydropseudopalmatine (pale yellow solid, 70% yield, m.p.: 182.3-184.5 ℃ C.).
1H NMR (400MHz, chloroform-d) δ 7.19(s, 1H), 6.63(s, 1H), 6.62(s, 1H), 6.60(s, 1H), 6.02(s, 1H), 4.19(s, 2H), 3.94(s, 3H), 3.89(s, 3H), 3.87(s, 3H), 3.86(s, 3H), 3.13(t, J ═ 6.0Hz, 2H), 2.90(t, J ═ 6.0Hz, 2H).13C NMR (100MHz, chloroform-d) delta 149.1, 148.7, 147.9, 146.8, 142.1, 127.8, 127.4, 123.2, 120.1, 110.7, 109.3, 107.1, 106.7, 96.3, 56.4, 56.1, 56.1, 56.0, 55.1, 49.4, 29.5.IR (neat)2997.4, 2929.1, 2833.9, 1610.1, 1512.4, 1461.8, 1346.9, 1256.8, 1141.5, 1100.1, 1022.3, 855.6, 730.1, 562.8 cm-1。
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art can easily think of many variations or alternatives within the technical scope of the present invention, and they should be covered within the scope of the present invention. Therefore, the protection scope of the present invention should be subject to the protection scope of the claims.
Claims (12)
1. A method for preparing 5, 8-dihydro-6H-isoquinoline [3, 2-alpha ] isoquinoline (I) based on a micro-reaction system,
the method is characterized in that:
the micro-reaction system comprises a feeding pump, a first micro mixer, a first fixed bed reactor, a first back pressure valve, a gas mass flowmeter, a second micro mixer, a second fixed bed reactor, a condenser, a gas-liquid separator, a second back pressure valve, a third micro mixer, a micro-channel reactor and a third back pressure valve which are communicated; the method comprises the following steps:
(1) introducing the first solution and the second solution into a first micro mixer through a feeding pump to mix to obtain a mixed reaction material; introducing the mixed reaction material into a first fixed bed reactor filled with a dehydrating agent to carry out dehydration condensation reaction; applying backpressure to the mixed reaction materials in the first fixed bed reactor through the first backpressure valve to uniformly mix the materials; the first solution is a mixture of aryl ethylamine (IV) and an organic solvent, and the second solution is a mixture of aryl aldehyde (V) and an organic solvent;
(2) introducing the dehydrated and condensed mixed reaction material obtained in the step (1) and hydrogen into a second fixed bed reactor filled with a reducing agent through a second micro mixer so as to perform catalytic hydrogenation reaction; introducing the mixed reaction material subjected to catalytic hydrogenation reaction into a condenser for condensation, and separating gas components by a gas-liquid separator; applying back pressure to the mixed reaction materials in the gas-liquid separator through the second back pressure valve to uniformly mix the materials;
(3) introducing the mixed reaction material subjected to gas-liquid separation and obtained in the step (2) and a third solution into a microchannel reactor through a third micro mixer to perform salt forming reaction; carrying out reduced pressure concentration, pulping and purification on the mixed reaction material after the salt forming reaction to obtain secondary amine hydrochloride (II); applying back pressure to the mixed reaction materials in the microchannel reactor through the third back pressure valve to uniformly mix the materials; the third solution is a mixture of hydrochloric acid and an organic solvent; and
(4) subjecting the secondary amine hydrochloride (II) and the fourth solution to a Pictet-Schpendeller reaction, Friedel-crafts hydroxyalkylation, and dehydration cascade reaction in the presence of an acid, a dehydrating agent, and an additive to produce a 5, 8-dihydro-6H-isoquinolino [3, 2-alpha ] isoquinoline compound of formula (I); wherein the fourth solution is a mixture of glyoxal (III) and an organic solvent;
as shown in the following reaction scheme:
x is mono-or di-substitutedAt any substitutable position on the benzene ring; x is hydrogen, straight or branched C1-C5Alkyl, straight or branched C1～C5Alkoxy or halogen; or two X substituents are linked together to form a ring;
y is mono-or di-substituted, and is positioned at any substitutable position on a benzene ring; y is hydrogen, straight or branched C1-C5Alkyl, straight or branched C1～C5Alkoxy or halogen; or two Y substituents are linked together to form a ring;
the first fixed bed reactor also comprises silicon dioxide, and the mass ratio of the silicon dioxide to the dehydrating agent is (0.1-100): 1;
the dehydrating agent in the step (1) is
Molecular sieve,
Molecular sieve,
Any one or more of molecular sieve, 13X molecular sieve, XH molecular sieve, anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous calcium chloride and anhydrous potassium carbonate;
the feeding pump comprises a first feeding pump and a second feeding pump, one inlet of the first micro mixer is connected with the first feeding pump, and the other inlet of the first micro mixer is connected with the second feeding pump; introducing the first solution and the second solution into the first micromixer through the first feeding pump and the second feeding pump respectively for mixing; the outlet of the first micro mixer is connected with the inlet of the first fixed bed reactor, and the outlet of the first fixed bed reactor is connected with the first backpressure valve;
the second fixed bed reactor also comprises silicon dioxide, and the mass ratio of the silicon dioxide to the reducing agent is (0.1-100): 1;
in the step (2), the reducing agent is any one or more of 1-50 wt% of Pd/C, 1-50 wt% of Pd (OH)2/C, 1-50 wt% of Pt/C and 1-50 wt% of PtO 2;
one inlet of the second micro mixer is connected with an outlet of the first backpressure valve, the other inlet of the second micro mixer is connected with the gas mass flow meter, an outlet of the second micro mixer is connected with an inlet of the second fixed bed reactor, an outlet of the second fixed bed reactor is connected with an inlet of the condenser, an outlet of the condenser is connected with a first interface at the top of the gas-liquid separator, nitrogen is accessed through a second interface at the top of the gas-liquid separator and is used for providing pressure for the gas-liquid separator, the pressure of the accessed nitrogen is 0.3-120 bar, and the second backpressure valve is connected with a third interface at the top of the gas-liquid separator;
the microchannel reactor in the step (3) is a tubular microchannel reactor or a plate microchannel reactor;
the inner diameter of the tubular microchannel reactor is 0.1-50 mm; or
The hydraulic diameter of a reaction fluid channel of the plate-type microchannel reactor is 0.1-50 mm;
the inlet of the third feeding pump is connected with the bottom outlet of the gas-liquid separator, the outlet of the third feeding pump is connected with one inlet of the third micro mixer, the other inlet of the third micro mixer is connected with the fourth feeding pump, the outlet of the third micro mixer is connected with the inlet of the microchannel reactor, and the outlet of the microchannel reactor is connected with the third back pressure valve.
2. The method of claim 1, wherein the molar ratio of the arylethylamine (IV) to the aryl aldehyde (V) in step (1) is 1 (1-10).
3. The method according to claim 1, wherein the organic solvent in step (1) is any one or more of methanol, ethanol, isopropanol, dimethylsulfoxide, N-dimethylformamide, ethyl acetate, acetone, dichloromethane, chloroform, N-hexane, cyclohexane, petroleum ether, toluene and carbon tetrachloride.
4. The method of claim 1, wherein the concentration of the arylethylamine (IV) in the first solution in step (1) is 0.01 to 10 mol/L; the concentration of the aryl aldehyde (V) in the second solution is 0.01-10 mol/L.
5. The method of claim 1, wherein the first back pressure valve has a back pressure of 0.1 to 100 bar.
6. The method of claim 1, wherein the first micromixer is any one of a static mixer, a T-type micromixer, a Y-type micromixer, a coaxial flow micromixer, and a flow focusing micromixer.
7. The method according to claim 1, wherein in the step (2), the flow ratio of the dehydrated and condensed mixed reaction material to hydrogen is adjusted so that the molar ratio of the arylethylamine (IV) to hydrogen in the mixed reaction material in the second fixed bed reactor is 1 (0.95-1.5).
8. The method of claim 1, wherein in the step (3), the flow ratio of the gas-liquid separated mixed reaction material to the third solution is adjusted so that the molar ratio of the arylethylamine (IV) to the hydrochloric acid in the mixed reaction material in the third micromixer is 1 (1-20).
9. The method according to claim 1, wherein in the step (3), the organic solvent used for the beating is any one or more of ethyl acetate, acetone, dichloromethane, chloroform, n-hexane, cyclohexane, petroleum ether, toluene, carbon tetrachloride, diethyl ether and methyl t-butyl ether.
10. The method of claim 1, wherein the acid in step (4) is any one or more of formic acid, acetic acid, trifluoroacetic acid, oxalic acid, p-toluenesulfonic acid, methanesulfonic acid, benzoic acid, succinic acid, citric acid, tartaric acid, camphorsulfonic acid, and boric acid.
11. The method of claim 1, wherein the additive in step (4) is any one or more of sodium fluoride, potassium fluoride, magnesium fluoride, lithium chloride, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, barium chloride, aluminum chloride, lithium bromide, sodium bromide, potassium bromide, magnesium bromide, calcium bromide, barium bromide, lithium iodide, sodium iodide, potassium iodide, magnesium iodide, and calcium iodide.
12. The method of claim 1, wherein the molar ratio of the secondary amine hydrochloride (II), the glyoxal, the dehydrating agent, the acid and the additive in the step (4) is 1 (1-100): 0.1-20): 1-1000: 0.1-20.
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