WO2023206700A1 - Continuous amide hydrogenation reduction method - Google Patents

Continuous amide hydrogenation reduction method Download PDF

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WO2023206700A1
WO2023206700A1 PCT/CN2022/096391 CN2022096391W WO2023206700A1 WO 2023206700 A1 WO2023206700 A1 WO 2023206700A1 CN 2022096391 W CN2022096391 W CN 2022096391W WO 2023206700 A1 WO2023206700 A1 WO 2023206700A1
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amide
hydrogenation reduction
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mol
continuous
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PCT/CN2022/096391
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Chinese (zh)
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洪浩
詹姆斯•盖吉
肖毅
张欣
李敏亮
寇耀宗
唐维克
刘凯
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凯莱英医药集团（天津）股份有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B35/00—Reactions without formation or introduction of functional groups containing hetero atoms, involving a change in the type of bonding between two carbon atoms already directly linked
    • C07B35/02—Reduction
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/267—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/46—Iso-indoles; Hydrogenated iso-indoles with an oxygen atom in position 1
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/02—Preparation by ring-closure or hydrogenation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D211/74—Oxygen atoms
    • C07D211/76—Oxygen atoms attached in position 2 or 6
    • 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
    • Y02P20/584—Recycling of catalysts

Definitions

  • the invention relates to the field of pharmaceutical and chemical engineering, and specifically to a method for continuous hydrogenation and reduction of amide.
  • Amine compounds are widely found in biologically active natural products, drugs, and pesticide molecules. As universal building blocks in organic synthesis, amines can be easily used to construct some useful complex molecules. In addition, amines are also widely used as dyes, surfactants, preservatives, detergents, etc. in industrial production.
  • Amide reduction is an important method to generate amine compounds.
  • Traditional amide reduction mostly uses lithium aluminum tetrahydride, borane, and silane.
  • these reduction methods have problems such as complex post-processing, difficult filtration and extraction, and large amounts of waste in industrial production.
  • using hydrogen for catalytic reduction is an ideal method that can effectively avoid the above problems.
  • hydrogen is a flammable and explosive gas with a wide explosion limit, and its safe use has also received widespread attention, especially under high temperature and high pressure conditions. The larger the volume of the autoclave, the higher the risk. In order to avoid these risks, large technical and economic investments are usually required to ensure safe operation.
  • Unfortunately despite maximizing safety, several major accidents have occurred in high-pressure hydrogenation facilities, some of which even caused casualties.
  • homogeneous catalysts are used to catalyze the hydrogenation reduction of amides, all of which use autoclaves as reaction equipment, which require relatively high temperatures and pressures, relatively strict equipment requirements, high investment costs, and great safety risks; And most of them are limited to specific catalyst types, are expensive, and are not suitable for large-scale industrial production.
  • Continuous hydrogenation technology has many advantages over batch reactions, but it still faces many challenges, especially in the production process of amide reduction.
  • Heterogeneous catalysts are easily threatened by pipeline blockage, and homogeneous catalysts also lack suitable type.
  • the main purpose of the present invention is to provide a continuous amide hydrogenation reduction method to solve the problem in the prior art that amide hydrogenation reduction has strict equipment requirements, requires specific catalysts, and has high costs, making it difficult to achieve large-scale industrial production.
  • a continuous hydrogenation reduction method of amide which method includes the following steps: performing a continuous hydrogenation reduction reaction of amide and hydrogen in a solvent under the action of a homogeneous catalyst to obtain the amide Hydrogenation reduction product, wherein the temperature of the continuous hydrogenation reduction reaction is 100 to 350°C, and the amide has the structure shown in the following structural formula I:
  • the hydrogenation reduction product of amide has the structure shown in the following structural formula II:
  • n is any integer from 1 to 5, m is 0 or 1
  • R 1 , R 2 , R 3 , and R 4 are each independently hydrogen, a linear alkyl group of C 1 to C 18 , and C 3 to C 18 branched alkyl group, C 3 to C 18 cycloalkyl group, C 6 to C 20 aryl group, C 6 to C 20 aralkyl group, C 1 to C 18 alkoxy group, siloxy group ;
  • R 1 and R 3 , R 2 and R 4 can form a ring respectively, and the ring can be a three-membered ring, a four-membered ring, a five-membered ring, a six-membered ring or a seven-membered ring;
  • the hydrogen on the ring can be optionally substituted by the following substituents Substituted, the substituents include C 1 to C 18 linear alkyl, C 3 to C 18 branched alkyl, C 3 to C 18
  • n is any integer from 1 to 5
  • R 1 , R 2 , R 3 , and R 4 are each independently hydrogen, a linear alkyl group of C 1 to C 6 , or a branched chain of C 3 to C 6 Alkyl group, C 3 to C 6 cycloalkyl group, C 6 to C 10 aryl group, C 6 to C 12 aralkyl group, C 2 to C 5 alkoxy group, siloxy group; R 1 and R 3.
  • R 2 and R 4 can form a ring respectively, and the ring can be a three-membered ring, a four-membered ring, a five-membered ring, a six-membered ring or a seven-membered ring;
  • the hydrogen on the ring can be optionally substituted by the following substituents, and the substituents include C 1 to C 6 linear alkyl group, C 3 to C 6 branched alkyl group, C 3 to C 6 cycloalkyl group, C 6 to C 10 aryl group, C 6 to C 12 aralkyl group , C 2 ⁇ C 5 alkoxy group, siloxy group;
  • n is 1 or 2
  • R 1 , R 2 , R 3 , and R 4 are each independently hydrogen, a C 1 to C 3 linear alkyl group, a C 3 or C 4 branched alkyl group, or C 6 ⁇ C 10 aryl group, C 2 ⁇ C 5 alkoxy group, siloxy group;
  • R 1 and R 3 , or R 2 and R 4 can form a ring, and the ring is a three-membered ring, a four-membered ring or a six-membered ring ;
  • the hydrogen on the ring can be optionally substituted by the following substituents.
  • the substituents include C 1 to C 6 linear alkyl groups, C 3 to C 6 branched alkyl groups, C 3 to C 6 cycloalkyl groups, C Aryl groups from 6 to C 10 , aralkyl groups from C 6 to C 12 , alkoxy groups from C 2 to C 5 , and siloxy groups;
  • n is 1 or 2
  • R 1 , R 2 , R 3 and R 4 are each independently hydrogen, or R 1 and R 3 or R 2 and R 4 can form a ring, and the ring is a three-membered ring or a six-membered ring.
  • a membered ring, the hydrogen on the ring can be optionally substituted by one or more of methyl or ethyl.
  • the pressure of the hydrogenation reduction reaction is 3 to 10 MPa, preferably 5 to 8 MPa;
  • the temperature of the hydrogenation reduction reaction is preferably 150 to 250°C, and further preferably 200 to 250°C.
  • the homogeneous catalyst includes a metal complex and a ligand.
  • the metal complex is selected from any one or more of ruthenium complexes and cobalt complexes, preferably ruthenium acetylacetonate; the amount of the metal complex is 0.1 mol of the amide.
  • the ligand is selected from any one or more of phosphine ligands, nitrogen ligands, and phosphine-nitrogen ligands, preferably It is 1,1,1-tris(diphenylphosphinemethyl)ethane; the amount of ligand is 0.1mol% to 50mol% of the amide; preferably 0.1mol% to 10mol%; further preferably 1mol% to 5mol% .
  • the solvent is any one or more of tetrahydrofuran, ethylene glycol dimethyl ether, 2-methyltetrahydrofuran, methyl tert-butyl ether, dioxane, toluene, xylene, and heptane, preferably Tetrahydrofuran and/or ethylene glycol dimethyl ether; the volume of the solvent is 5 to 50 times the volume of the amide.
  • the reaction system of the continuous hydrogenation reduction reaction also includes Lewis acid additives.
  • the Lewis acid additives are selected from boron trifluoride ether, gallium triflate, zinc triflate, and triflate. Any one or more of silver, cerium triflate, ytterbium triflate, triflate, and methanesulfonic acid; the preferred dosage of Lewis acid additives is 0.1 mol% to 200 mol of the amide. %; preferably 1 mol% to 50 mol%; further preferably 2 mol% to 10 mol%.
  • the continuous hydrogenation reduction method of amide includes: continuously transporting hydrogen gas and liquid phase components to a continuous reactor to perform a continuous hydrogenation reduction reaction, and controlling the flow rate of hydrogen gas and liquid phase components to ensure that the hydrogen gas and liquid phase components are at room temperature and normal pressure.
  • the volume ratio is 10-500:1, preferably 10-100:1, more preferably 25-100:1, and the liquid phase components include amide, catalyst, Lewis acid additives and solvent.
  • liquid phase components enter the continuous reactor together, or one or more of the liquid phase components enter the continuous reactor separately, and the catalyst is in the form of a catalyst solution and the Lewis acid additive is in the form of a solution of the Lewis acid additive. into the continuous reactor.
  • the continuous reactor is a coil reactor, and the inner diameter of the coil reactor is preferably 1 to 20 mm, and more preferably 2 to 8 mm.
  • a mixing device is provided in front of the continuous reactor to mix the catalyst solution, Lewis acid additive solution, amide and solvent entering the continuous reactor.
  • the homogeneous hydrogenation system only has two phases of gas/liquid, and the impact of mass transfer on the reaction is also greatly reduced; this method All catalysts in the application are soluble in solvents and are active sites, and their catalytic efficiency is significantly improved; and the catalysts used in this application can be purchased directly in the market from a wide range of sources, which reduces material costs; using continuous hydrogenation, the reactor is relatively It is simple, has low equipment cost, and occupies a small area. The reaction can be carried out continuously, the efficiency is improved, and the production capacity is increased. It is especially suitable for large-scale industrial production. In addition, the reaction space of the continuous hydrogenation reactor of the present application is dispersed in the pipeline. Compared with autoclaves, the safety performance has been greatly improved, especially under higher temperature and pressure conditions.
  • Figure 1 shows a schematic diagram of the reaction device of Example 1 of an amide continuous hydrogenation reduction method according to the present invention.
  • Container A 1. Container A; 2. Dosing pump; 3. Hydrogen storage tank; 4. Hydrogen cylinder; 5. Container B; 6. Coil reactor; 7. Gas-liquid separator; 8. Hydrogen outlet; 9. Sampling device ; 10. Receiving container.
  • a continuous hydrogenation reduction method of amide includes the following steps: making the amide and hydrogen carry out a continuous hydrogenation reduction reaction in a solvent under the action of a homogeneous catalyst to obtain a hydrogenation reduction product of the amide, wherein the hydrogenation reduction reaction of the amide is The temperature is 100 to 350°C.
  • the amide has the structure shown in the following structural formula I.
  • the hydrogenation reduction product of the amide has the structure shown in the following structural formula II:
  • n is any integer from 1 to 5, m is 0 or 1
  • R 1 , R 2 , R 3 , and R 4 are each independently hydrogen, a linear alkyl group of C 1 to C 18 , and C 3 to C 18 branched alkyl group, C 3 to C 18 cycloalkyl group, C 6 to C 20 aryl group, C 6 to C 20 aralkyl group, C 1 to C 18 alkoxy group, siloxy group ;
  • R 1 and R 3 , R 2 and R 4 can form a ring respectively, and the ring can be a three-membered ring, a four-membered ring, a five-membered ring, a six-membered ring or a seven-membered ring;
  • the hydrogen on the ring can be optionally substituted by the following substituents Substituted, the substituents include C 1 to C 18 linear alkyl, C 3 to C 18 branched alkyl, C 3 to C 18
  • This application uses hydrogen to hydrogenate and reduce amide to obtain a better yield.
  • post-processing operations such as quenching, filtration, and water washing are avoided.
  • the post-processing process is simple, the amount of waste is small, and more Suitable for industrial production.
  • the use of homogeneous catalysts for continuous hydrogenation reduction reactions avoids the problems of poor tolerance and selectivity of heterogeneous catalysts to functional groups.
  • the homogeneous hydrogenation system only has two phases of gas/liquid, and the impact of mass transfer on the reaction is also greatly reduced; this method All catalysts in the application are soluble in solvents and are active sites.
  • n is any integer from 1 to 5
  • R 1 , R 2 , R 3 , and R 4 are each independently hydrogen, a linear alkyl group of C 1 to C 6 , or a branched alkyl group of C 3 to C 6 , C 3 to C 6 cycloalkyl group, C 6 to C 10 aryl group, C 6 to C 12 aralkyl group, C 2 to C 5 alkoxy group, siloxy group;
  • R 1 and R 3 , R 2 and R 4 can form a ring respectively, and the ring can be a three-membered ring, a four-membered ring, a five-membered ring, a six-membered ring or a seven-membered ring; the hydrogen on the ring
  • R 1 and R 3 , or R 2 and R 4 can form a ring , the ring is a three-membered ring or a four-membered ring; the hydrogen on the ring can be optionally substituted by the following substituents.
  • the substituents include C 1 to C 6 straight chain alkyl groups, C 3 to C 6 branched chain alkyl groups, C 3 to C 6 cycloalkyl group, C 6 to C 10 aryl group, C 6 to C 12 aralkyl group, C 2 to C 5 alkoxy group, siloxy group; most preferably, n is 1 or 2.
  • R 1 , R 2 , R 3 and R 4 are each independently hydrogen, or R 1 and R 3 , or R 2 and R 4 can form a ring.
  • the ring is a three-membered ring or a six-membered ring, and the hydrogen on the ring Can be optionally substituted by one or more of methyl or ethyl.
  • the hydrogenation reduction reaction pressure of the above-mentioned amide can refer to the existing technology.
  • the preferred pressure of the hydrogenation reduction reaction is: 3 ⁇ 10MPa.
  • the further preferred pressure of the hydrogenation reduction reaction is 5 to 8 MPa, such as the pressure of the hydrogenation reduction reaction When it is 5MPa, 6MPa, 7MPa or 8MPa, a higher yield can be obtained in a shorter time.
  • the hydrogen used in this application can be directly provided by a hydrogen cylinder, or a hydrogen gas storage tank can be installed behind the hydrogen cylinder, and a pressure reducing valve can be installed behind the hydrogen cylinder or gas storage tank to provide the pressure of the reaction system. It can also be installed in a continuous reactor A back pressure valve is set up to maintain the reaction pressure. This application does not limit the hydrogen supply method and pressure maintenance method.
  • the preferred reaction temperature is 150 to 250°C, and more preferably 200 to 250°C.
  • Heating can use an oil bath, electric heating, or any other heating method, which is not limited in this application.
  • the homogeneous catalyst used in the above amide hydrogenation reduction reaction can be selected from the existing homogeneous catalysts used for catalytic hydrogenation reduction.
  • the homogeneous catalyst includes metal complexes and ligands.
  • the metal complex is selected from any one or more of ruthenium complexes and cobalt complexes, preferably ruthenium acetylacetonate (Ru(acac) 3 ), which has good catalytic selectivity and is relatively economical in source.
  • the amount of metal complex used is 0.1 mol% to 50 mol% of the amide, preferably 0.1 mol% to 10 mol%, more preferably 1 mol% to 5 mol%, such as 1 mol%, 2 mol%, 3 mol%, 4 mol%, 5 mol%; ligand Any one or more selected from phosphine ligands, nitrogen ligands, and phosphine-nitrogen ligands, preferably 1,1,1-tris(diphenylphosphinemethyl)ethane (Triphos); ligand dosage It is 0.1 mol% to 50 mol% of the amide; preferably 0.1 mol% to 10 mol%; more preferably 1 mol% to 5 mol%, such as 1 mol%, 2 mol%, 3 mol%, 4 mol%, and 5 mol%.
  • the type and amount of solvent in the above-mentioned amide hydrogenation reduction reaction can be selected from the existing technology, as long as it can dissolve the above-mentioned amide and the homogeneous catalyst, such as tetrahydrofuran (THF), ethylene glycol dimethyl ether, 2-methyltetrahydrofuran , any one or more of methyl tert-butyl ether, dioxane, toluene, xylene, and heptane, among which tetrahydrofuran and/or ethylene glycol dimethyl ether are preferred, both of which are effective for the above reduction substrate and
  • the catalyst has good solubility, which is more conducive to improving the yield of the reaction and facilitating product analysis, separation and purification.
  • the volume of the solvent is 5 to 50 times the volume of the amide, preferably 15 to 30 times, taking into account the ability to completely dissolve the raw materials and catalyst, and to ensure the concentration of the substrate and reduce waste. Before the above solvent is used in this reaction, it is preferred to carry out oxygen removal and drying to avoid affecting the reduction reaction.
  • the above reaction system also includes Lewis acid additives, which can complex with the oxygen of the amide carbonyl group and activate the carbonyl group.
  • Lewis acid additives are selected from boron trifluoride ether (BF 3 .Et 2 O), gallium triflate, zinc triflate, silver triflate, cerium triflate, and trifluoromethanesulfonate.
  • the dosage of the above-mentioned homogeneous catalyst and Lewis acid additive will affect the product composition of the amide hydrogenation reduction.
  • the smaller dosage of the homogeneous catalyst and Lewis acid additive will only reduce one of the carbon-oxygen double bonds.
  • Increasing the dosage can reduce the two carbon-oxygen double bonds. All oxygen double bonds are hydrogenated and reduced, so different reduction products can be prepared by adjusting the dosage of the above-mentioned homogeneous catalyst and Lewis acid additive.
  • the continuous hydrogenation reduction method of amide includes: continuously transporting hydrogen gas and liquid phase components into a continuous reactor to perform a continuous hydrogenation reduction reaction, wherein the liquid phase components include amide, catalyst, Lewis acid additives and solvents .
  • the volume ratio of hydrogen and liquid components at normal temperature and pressure is 10 to 500:1. Maintaining this volume ratio can maintain the fluid flow pattern of the reaction system in the continuous reactor: On the one hand, it avoids the influence of the fluid flow pattern due to hydrogen being consumed during the reaction; on the other hand, keeping the volume ratio within a certain range can keep the fluid in a certain flow pattern and avoid liquid aggregation, which affects the mass transfer effect.
  • the volume ratio of hydrogen gas and liquid phase components at normal temperature and pressure is preferably 10 to 100:1, and further preferably 25 to 100:1, so as to make the flow pattern of the reaction system better and achieve better efficiency in the continuous hydrogenation and reduction of amide. .
  • the flow of hydrogen or liquid phase components can be detected by setting up a flow measuring device in the input pipeline, for example, setting up a hydrogen mass flow meter after the hydrogen cylinder and/or gas storage tank to control the hydrogen flow; it can also be achieved through a dosing pump. Control of liquid component flow.
  • the above-mentioned liquid phase components in the reaction system enter the continuous reactor together, or one or more of the liquid phase components enter the continuous reactor separately, and the catalyst is used as a catalyst solution, Lewis acid
  • the additives enter the continuous reactor in the form of a solution of Lewis acid additives.
  • the liquid phase components in the latter reaction system are divided into multiple channels and enter the continuous reactor to facilitate the control and monitoring of the substances therein.
  • the solutions of the amide and Lewis acid additives are divided into one channel, and the solutions of the metal complex and the ligand are divided into one channel, and are simultaneously transported to the continuous reactor, which is beneficial to improving the yield of the product.
  • the above-mentioned continuous reactor can be selected from reactors in the existing technology that can meet the above reaction conditions.
  • the continuous reactor adopts a coil reactor, a column reactor, a continuous reactor, etc., especially a coil reactor.
  • its structure is relatively simple, heat energy can be fully utilized, and production capacity can be greatly increased, especially suitable for large-scale industrial production.
  • the inner diameter of the coil reactor is preferably 1 to 20 mm, more preferably 2 to 8 mm, and even more preferably 2 to 4 mm.
  • the residence time of the liquid and gas in the coil is 10 min to 5 h, preferably 30 min to 2 h.
  • the device shown in Figure 1 is used to perform the hydrogenation reduction reaction of the amide.
  • the amide used is 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione.
  • the reduction product is 6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-one.
  • the preparation method is as follows:
  • Solution A Under nitrogen protection, add the above amide to container 1 of A, then add the pre-deoxygenated solvent THF, the amount of THF added is 15 times the volume of the amide, then add 2.2 mol% of amide BF 3 .Et 2 O, After mixing evenly, protect with nitrogen and set aside;
  • Solution B Under nitrogen protection, add 1 mol% of amide Ru(acac) 3 to B container 5, then add 1.1 mol% of amide in Triphos, and 15 times the volume of amide in THF. After mixing evenly, protect with nitrogen and set aside.
  • Example 1 The difference from Example 1 is that: the amount of Ru(acac) 3 is 4 mol% of the amide, the amount of Triphos is 8 mol% of the amide, and the amount of BF 3.Et 2 O is 8 mol% of the amide; coil reactor The temperature of the external bath is controlled at (150 ⁇ 5)°C; the flow rate of hydrogen is 10mL/min; the flow rate of solution A is 0.1mL/min, and the flow rate of solution B is 0.1mL/min.
  • Example 1 The difference from Example 1 is that: the amount of Ru(acac) 3 is 2 mol% of the amide, the amount of Triphos is 4 mol% of the amide, and the amount of BF 3.Et 2 O is 4 mol% of the amide; coil reactor The temperature of the external bath is controlled at (200 ⁇ 5)°C; the flow rate of hydrogen is 10mL/min; the flow rate of solution A is 0.1mL/min, and the flow rate of solution B is 0.1mL/min.
  • Example 1 The difference from Example 1 is that: the amount of Ru(acac) 3 is 2 mol% of the amide, the amount of Triphos is 4 mol% of the amide, and the amount of BF 3.Et 2 O is 4 mol% of the amide; coil reactor The temperature of the external bath is controlled at (200 ⁇ 5)°C.
  • Example 1 The difference from Example 1 is that: the amount of Ru(acac) 3 is 2 mol% of the amide, the amount of Triphos is 4 mol% of the amide, and the amount of BF 3.Et 2 O is 4 mol% of the amide; coil reactor The temperature of the external bath is controlled at (200 ⁇ 5)°C; the flow rate of hydrogen is 30mL/min.
  • Example 2 The difference from Example 1 is that: the amount of Ru(acac) 3 is 1 mol% of the amide, the amount of Triphos is 2 mol% of the amide, and the amount of BF 3 .Et 2 O is 2 mol% of the amide.
  • Example 1 The difference from Example 1 is that: the amount of Ru(acac) 3 is 1 mol% of the amide, the amount of Triphos is 2 mol% of the amide, the amount of BF 3.Et 2 O is 2 mol% of the amide; the flow rate of hydrogen is 30mL/min, the sum of the volumes of solvent THF in solution A and solution B is 20 times the volume of the amide.
  • Example 1 The difference from Example 1 is that: the amount of Ru(acac) 3 is 1 mol% of the amide, the amount of Triphos is 2 mol% of the amide, the amount of BF 3.Et 2 O is 2 mol% of the amide; the flow rate of hydrogen is 45mL/min, the sum of the volumes of solvent THF in solution A and solution B is 10 times the volume of the amide.
  • Example 1 The difference from Example 1 is that: the amount of Ru(acac) 3 is 1 mol% of the amide, the amount of Triphos is 2 mol% of the amide, the amount of BF 3.Et 2 O is 2 mol% of the amide; the flow rate of hydrogen is 20mL/min; the flow rate of solution A is 0.21mL/min, and the flow rate of solution B is 0.2mL/min.
  • Example 1 The difference from Example 1 is that: the amount of Ru(acac) 3 is 1 mol% of the amide, the amount of Triphos is 2 mol% of the amide, the amount of BF 3.Et 2 O is 2 mol% of the amide; the flow rate of hydrogen is 25mL/min; the flow rate of solution A is 0.27mL/min, and the flow rate of solution B is 0.25mL/min.
  • Example 2 The difference from Example 1 is that: the amount of Ru(acac) 3 is 1 mol% of the amide, the amount of Triphos is 1.1 mol% of the amide, and the amount of BF 3 .Et 2 O is 1.1 mol% of the amide.
  • Example 2 The difference from Example 1 is that: the amount of Ru(acac) 3 is 1 mol% of the amide, the amount of Triphos is 1.1 mol% of the amide, and the amount of BF 3 .Et 2 O is 5 mol% of the amide.
  • Solution A Under nitrogen protection, add the same type of amide as in Example 1 to container A, and then add the pre-deoxygenated solvent THF. The amount of THF added is 15 times the volume of the amide, and then add 2.2 mol% of BF 3 of the amide. .Et 2 O, after mixing evenly, protect it with nitrogen and set aside;
  • Solution B Under nitrogen protection, add 1 mol% of amide Ru(acac) 3 to container B, then add 1.1 mol% of amide Triphos, and 15 times the volume of amide in THF. After mixing evenly, protect with nitrogen and set aside;
  • Adjust the back pressure valve gradually reduce the system pressure, discharge the reaction system pressure to 0 through the hydrogen outlet, then replace it with nitrogen, increase the pressure to 0.4 ⁇ 0.5MPa, and then release the pressure to 0 ⁇ 0.05MPa, repeat 3 times .
  • Solution A Under nitrogen protection, add the same type of amide as in Example 1 to container A, then add pre-deoxygenated solvent THF, the amount of THF added is 15 times the volume of the amide, and then add 2.2 mol% of amide BF 3 . Et 2 O, mix evenly, protect with nitrogen, and set aside;
  • Solution B Under nitrogen protection, add 1 mol% of amide Ru(acac) 3 to container B, then add 1.1 mol% of amide in Triphos, and 15 times the volume of amide in THF. After mixing evenly, protect with nitrogen and set aside;
  • Adjust the back pressure valve gradually reduce the system pressure, discharge the reaction system pressure to 0 through the hydrogen outlet, then replace it with nitrogen, increase the pressure to 0.4 ⁇ 0.5MPa, and then release the pressure to 0 ⁇ 0.05MPa, repeat 3 times .
  • Adjust the back pressure valve gradually reduce the system pressure, discharge the reaction system pressure to 0 through the hydrogen outlet, then replace it with nitrogen, increase the pressure to 0.4 ⁇ 0.5MPa, and then release the pressure to 0 ⁇ 0.05MPa, repeat 3 times .
  • Example 1 The difference from Example 1 is that: the reduction product is 6,6-dimethyl-3-azabicyclo[3.1.0]hexane; the amount of Ru(acac) 3 is 4 mol% of the amide, and the amount of Triphos The dosage of BF 3.Et 2 O is 5 mol% of the amide, and the dosage of BF 3.Et 2 O is 200 mol% of the amide.
  • Example 1 The difference from Example 1 is that the reduced amide is 2,6-piperidinedione, and the reduction product is piperidin-2-one.
  • Example 1 The difference from Example 1 is that the reduced amide is succinimide and the reduction product is 2-pyrrolidone.
  • Example 1 The difference from Example 1 is that the reduced amide is phthalimide and the reduction product is 1-isoindolinone.
  • Example 4 The difference from Example 4 is that the pressure of hydrogen in the system is 3MPa.
  • Example 4 The difference from Example 4 is that the pressure of hydrogen in the system is 5MPa.
  • Example 4 The difference from Example 4 is that the pressure of hydrogen in the system is 10 MPa.
  • Example 4 The difference from Example 4 is that the temperature of the outer bath of the coil reactor is controlled at (100 ⁇ 5)°C.
  • Example 4 The difference from Example 4 is that the temperature of the outer bath of the coil reactor is controlled at (350 ⁇ 5)°C.
  • Example 2 The difference from Example 1 is that the amount of Ru(acac) 3 is 0.1 mol% of the amide, and the amount of Triphos is 0.1 mol% of the amide.
  • Example 16 The difference from Example 16 is that the amount of Ru(acac) 3 is 10 mol% of the amide, and the amount of Triphos is 10 mol% of the amide.
  • Example 16 The difference from Example 16 is that the amount of Ru(acac) 3 is 50 mol% of the amide, and the amount of Triphos is 50 mol% of the amide.
  • Example 1 The difference from Example 1 is that the amount of BF 3 .Et 2 O is 0.1 mol% of the amide.
  • Example 1 The difference from Example 1 is that the amount of BF 3 .Et 2 O is 50 mol% of the amide.
  • Example 1 The difference from Example 1 is that: the internal diameter of the coil reactor is 1mm, the flow rate of solution A is 0.04mL/min, the flow rate of solution B is 0.04mL/min, adjust the hydrogen mass flow meter at the inlet end to the flow rate is 4mL/min.
  • Example 1 The difference from Example 1 is that: the internal diameter of the coil reactor is 20mm, the flow rate of solution A is 16mL/min, the flow rate of solution B is 15mL/min, and the hydrogen mass flow meter at the inlet end is adjusted to a flow rate of 1500mL. /min.
  • Example 1 The difference from Example 1 is that the flow rate of hydrogen is 8 mL/min.
  • Example 1 The difference from Example 1 is that the flow rate of hydrogen is 3 mL/min.
  • Example 1 The difference from Example 1 is that the flow rate of hydrogen is 150 mL/min.
  • the product obtained in the receiving container in the above embodiment was analyzed by gas chromatography (GC) or liquid chromatography (HPLC), and the corresponding reduction product yield was calculated, as shown in Table 1 below.
  • the reaction material in the receiving container is recrystallized or distilled to obtain a purified reduction product.
  • Example 1 Group Yield (%) Example 1 85.4 Example 2 50.2 Example 3 92.7 Example 4 93.5 Example 5 93.5 Example 6 91.5 Example 7 76.6 Example 8 69.1 Example 9 84.0 Example 10 83.3 Example 11 81.4 Example 12 81.5 Example 13 86.2 Example 14 79.1 Example 15 83.6 Example 16 62.5 Example 17 83.1 Example 18 78.0 Example 19 86.9 Example 20 51.2 Example 21 68.3 Example 22 93.5 Example 23 34.3 Example 24 60.2 Example 25 36.8 Example 26 95.1 Example 27 95.4 Example 28 60.3 Example 29 84.5 Example 30 86.4 Example 31 30.5 Example 32 42.3 Example 33 25.6 Example 34 66.8 Comparative example 1 8.2
  • the present application uses hydrogen to hydrogenate and reduce amide to obtain a better yield.
  • reducing agents such as lithium aluminum tetrahydride
  • post-processing operations such as quenching, filtration, and water washing are avoided.
  • the post-processing process is simple and the amount of waste is small, making it more suitable for industrial production.
  • the use of homogeneous catalysts for continuous hydrogenation reduction reactions avoids the problems of poor tolerance and selectivity of heterogeneous catalysts to functional groups.
  • the homogeneous hydrogenation system only has two phases of gas/liquid, and the impact of mass transfer on the reaction is also greatly reduced; this method All catalysts in the application are soluble in solvents and are active sites.

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Abstract

A continuous amide hydrogenation reduction method. The method comprises the following steps: under the action of a homogeneous catalyst, performing a continuous hydrogenation reduction reaction on an amide and hydrogen in a solvent to obtain a hydrogenation reduction product of the amide, wherein the temperature of the continuous hydrogenation reduction reaction is 100-350 °C, the structural formula of the amide is aa, and the structural formula of the hydrogenation reduction product of the amide is bb.

Description

一种酰胺连续氢化还原方法A kind of amide continuous hydrogenation reduction method 技术领域Technical field
本发明涉及医药化工领域，具体而言，涉及一种酰胺连续氢化还原方法。The invention relates to the field of pharmaceutical and chemical engineering, and specifically to a method for continuous hydrogenation and reduction of amide.
背景技术Background technique
胺类化合物广泛地存在于有生物活性的天然产物、药物、和农药分子中。胺作为有机合成中的通用构件，可以很容易地用于构筑一些有用的复杂分子。此外，胺类在工业生产中也广泛用作染料、表面活性剂、防腐剂、洗涤剂等。Amine compounds are widely found in biologically active natural products, drugs, and pesticide molecules. As universal building blocks in organic synthesis, amines can be easily used to construct some useful complex molecules. In addition, amines are also widely used as dyes, surfactants, preservatives, detergents, etc. in industrial production.
酰胺还原，是生成胺类化合物的重要方法。传统的酰胺还原大多采用四氢铝锂、硼烷，以及硅烷等，但是这些还原方式在工业化生产中都存在后处理复杂、过滤以及萃取困难、三废量大等问题。相比较而言，利用氢气进行催化还原则是一种比较理想的方式，能够有效的避免上述问题。但是，氢气是一种易燃易爆的气体，其爆炸极限范围宽，其安全使用问题也受到广泛关注，尤其是在高温高压条件下，高压釜的体积越大，其风险也相应更高。而为了避免这些风险，通常需要大量的技术和经济投资来确保安全操作，然而不幸的是，尽管已经最大限度地提高安全性，但高压加氢设施依然发生了几次重大事故，其中一些甚至造成了人员伤亡。Amide reduction is an important method to generate amine compounds. Traditional amide reduction mostly uses lithium aluminum tetrahydride, borane, and silane. However, these reduction methods have problems such as complex post-processing, difficult filtration and extraction, and large amounts of waste in industrial production. In comparison, using hydrogen for catalytic reduction is an ideal method that can effectively avoid the above problems. However, hydrogen is a flammable and explosive gas with a wide explosion limit, and its safe use has also received widespread attention, especially under high temperature and high pressure conditions. The larger the volume of the autoclave, the higher the risk. In order to avoid these risks, large technical and economic investments are usually required to ensure safe operation. Unfortunately, despite maximizing safety, several major accidents have occurred in high-pressure hydrogenation facilities, some of which even caused casualties.
另一方面，由于酰胺稳定性较高，同时存在脱氧氢化(C-O裂解)和脱氨氢化(C-N裂解)的选择性问题，因此，酰胺的氢化具有较大的挑战性。目前，已经有一些非均相催化剂已经被用于酰胺的氢化，但是这些催化通常需要很高的温度和压力，对设备要求较高，同时，非均相催化剂在催化还原过程中，对官能团的耐受性较差，选择性也较低，使用寿命较短，导致难以满足大规模生产的要求。同时由于非均相氢化还原过程中存在气/液/固三相，传质难度大，还可能存在催化剂溶出的问题，最后导致固体沉积，堵塞管路，使得其应用于工业化生产也变得愈加困难。On the other hand, due to the high stability of amides and the selectivity issues of deoxyhydrogenation (C-O cleavage) and deamination hydrogenation (C-N cleavage), the hydrogenation of amides is quite challenging. At present, some heterogeneous catalysts have been used for the hydrogenation of amides, but these catalysis usually require high temperatures and pressures, and have high requirements on equipment. At the same time, heterogeneous catalysts have a negative impact on the functional groups during the catalytic reduction process. It has poor tolerance, low selectivity and short service life, making it difficult to meet the requirements of mass production. At the same time, due to the existence of gas/liquid/solid three phases in the heterogeneous hydrogenation reduction process, mass transfer is difficult, and there may also be problems with catalyst dissolution, which ultimately leads to solid deposition and blockage of pipelines, making its application in industrial production increasingly difficult. difficulty.
现有技术中采用均相催化剂催化酰胺的氢化还原都是使用高压釜作为反应设备，需要的温度和压力都较高，对设备要求比较严苛，投资成本大，且具有极大的安全风险；并且大部分也都限于特定的催化剂种类，价格昂贵，不适用于大规模的工业生产。连续氢化技术相对于批次反应有着较多的优点，但是仍面临很多挑战，尤其是在酰胺还原的生产过程中，对于非均相催化剂，易受管道堵塞威胁，而均相催化剂也缺少适宜的种类。In the existing technology, homogeneous catalysts are used to catalyze the hydrogenation reduction of amides, all of which use autoclaves as reaction equipment, which require relatively high temperatures and pressures, relatively strict equipment requirements, high investment costs, and great safety risks; And most of them are limited to specific catalyst types, are expensive, and are not suitable for large-scale industrial production. Continuous hydrogenation technology has many advantages over batch reactions, but it still faces many challenges, especially in the production process of amide reduction. Heterogeneous catalysts are easily threatened by pipeline blockage, and homogeneous catalysts also lack suitable type.
发明内容Contents of the invention
本发明的主要目的在于提供一种酰胺连续氢化还原方法，以解决现有技术中酰胺氢化还原对设备要求严苛，且需要特定的催化剂，成本较高，导致难以实现大规模工业生产的问题。The main purpose of the present invention is to provide a continuous amide hydrogenation reduction method to solve the problem in the prior art that amide hydrogenation reduction has strict equipment requirements, requires specific catalysts, and has high costs, making it difficult to achieve large-scale industrial production.
为了实现上述目的，根据本发明的一个方面，提供了一种酰胺连续氢化还原方法，该方法包括以下步骤：在均相催化剂作用下使酰胺和氢气在溶剂中进行连续氢化还原反应，得到酰胺的氢化还原产物，其中，连续氢化还原反应的温度为100～350℃，酰胺具有以下结构式I所示结构：In order to achieve the above object, according to one aspect of the present invention, a continuous hydrogenation reduction method of amide is provided, which method includes the following steps: performing a continuous hydrogenation reduction reaction of amide and hydrogen in a solvent under the action of a homogeneous catalyst to obtain the amide Hydrogenation reduction product, wherein the temperature of the continuous hydrogenation reduction reaction is 100 to 350°C, and the amide has the structure shown in the following structural formula I:
Figure PCTCN2022096391-appb-000001
Figure PCTCN2022096391-appb-000001
酰胺的氢化还原产物具有以下结构式II所示结构：The hydrogenation reduction product of amide has the structure shown in the following structural formula II:
Figure PCTCN2022096391-appb-000002
Figure PCTCN2022096391-appb-000002
其中，n为1～5中的任意一个整数，m为0或1，R 1、R 2、R 3、R 4各自独立的为氢、C 1～C 18的直链烷基、C 3～C 18的支链烷基、C 3～C 18的环烷基、C 6～C 20的芳基、C 6～C 20的芳烷基、C 1～C 18的烷氧基、硅氧基；R 1和R 3、R 2和R 4可以分别成环，环是三元环、四元环、五元环、六元环或七元环；环上的氢可以被以下取代基任意的取代，取代基包括C 1～C 18的直链烷基、C 3～C 18的支链烷基、C 3～C 18的环烷基、C 6～C 20的芳基、C 6～C 20的芳烷基、C 1～C 18的烷氧基、硅氧基。 Among them, n is any integer from 1 to 5, m is 0 or 1, R 1 , R 2 , R 3 , and R 4 are each independently hydrogen, a linear alkyl group of C 1 to C 18 , and C 3 to C 18 branched alkyl group, C 3 to C 18 cycloalkyl group, C 6 to C 20 aryl group, C 6 to C 20 aralkyl group, C 1 to C 18 alkoxy group, siloxy group ; R 1 and R 3 , R 2 and R 4 can form a ring respectively, and the ring can be a three-membered ring, a four-membered ring, a five-membered ring, a six-membered ring or a seven-membered ring; the hydrogen on the ring can be optionally substituted by the following substituents Substituted, the substituents include C 1 to C 18 linear alkyl, C 3 to C 18 branched alkyl, C 3 to C 18 cycloalkyl, C 6 to C 20 aryl, C 6 to C 20 aralkyl group, C 1 to C 18 alkoxy group, and siloxy group.
进一步地，n为1～5中的任意一个整数，R 1、R 2、R 3、R 4各自独立的为氢、C 1～C 6的直链烷基、C 3～C 6的支链烷基、C 3～C 6的环烷基、C 6～C 10的芳基、C 6～C 12的芳烷基、C 2～C 5的烷氧基、硅氧基；R 1和R 3、R 2和R 4可以分别成环，环是三元环、四元环、五元环、六元环或七元环；环上的氢可以被以下取代基任意的取代，取代基包括C 1～C 6的直链烷基、C 3～C 6的支链烷基、C 3～C 6的环烷基、C 6～C 10的芳基、C 6～C 12的芳烷基、C 2～C 5的烷氧基、硅氧基； Further, n is any integer from 1 to 5, and R 1 , R 2 , R 3 , and R 4 are each independently hydrogen, a linear alkyl group of C 1 to C 6 , or a branched chain of C 3 to C 6 Alkyl group, C 3 to C 6 cycloalkyl group, C 6 to C 10 aryl group, C 6 to C 12 aralkyl group, C 2 to C 5 alkoxy group, siloxy group; R 1 and R 3. R 2 and R 4 can form a ring respectively, and the ring can be a three-membered ring, a four-membered ring, a five-membered ring, a six-membered ring or a seven-membered ring; the hydrogen on the ring can be optionally substituted by the following substituents, and the substituents include C 1 to C 6 linear alkyl group, C 3 to C 6 branched alkyl group, C 3 to C 6 cycloalkyl group, C 6 to C 10 aryl group, C 6 to C 12 aralkyl group , C 2 ~ C 5 alkoxy group, siloxy group;
进一步地，n为1或2，R 1、R 2、R 3、R 4各自独立的为氢、C 1～C 3的直链烷基、C 3或C 4的支链烷基、C 6～C 10的芳基、C 2～C 5的烷氧基、硅氧基；R 1和R 3、或者R 2和R 4可以成环，环是三元环、四元环或六元环；环上的氢可以被以下取代基任意的取代，取代基包括C 1～C 6的直链烷基、C 3～C 6的支链烷基、C 3～C 6的环烷基、C 6～C 10的芳基、C 6～C 12的芳烷基、C 2～C 5的烷氧基、硅氧基； Further, n is 1 or 2, and R 1 , R 2 , R 3 , and R 4 are each independently hydrogen, a C 1 to C 3 linear alkyl group, a C 3 or C 4 branched alkyl group, or C 6 ~C 10 aryl group, C 2 ~C 5 alkoxy group, siloxy group; R 1 and R 3 , or R 2 and R 4 can form a ring, and the ring is a three-membered ring, a four-membered ring or a six-membered ring ; The hydrogen on the ring can be optionally substituted by the following substituents. The substituents include C 1 to C 6 linear alkyl groups, C 3 to C 6 branched alkyl groups, C 3 to C 6 cycloalkyl groups, C Aryl groups from 6 to C 10 , aralkyl groups from C 6 to C 12 , alkoxy groups from C 2 to C 5 , and siloxy groups;
进一步地，n为1或2，R 1、R 2、R 3、R 4各自独立的为氢，或者R 1和R 3、或者R 2和R 4可以成环，环是三元环或者六元环，环上的氢可以被甲基或乙基中的一种或者多种任意的取代。 Further, n is 1 or 2, R 1 , R 2 , R 3 and R 4 are each independently hydrogen, or R 1 and R 3 or R 2 and R 4 can form a ring, and the ring is a three-membered ring or a six-membered ring. A membered ring, the hydrogen on the ring can be optionally substituted by one or more of methyl or ethyl.
进一步地，氢化还原反应的压力为3～10MPa，优选为5～8MPa；优选氢化还原反应的温度为150～250℃，进一步优选为200～250℃。Further, the pressure of the hydrogenation reduction reaction is 3 to 10 MPa, preferably 5 to 8 MPa; the temperature of the hydrogenation reduction reaction is preferably 150 to 250°C, and further preferably 200 to 250°C.
进一步地，均相催化剂包括金属配合物和配体，金属配合物选自钌配合物、钴配合物中的任意一种或者多种，优选为乙酰丙酮钌；金属配合物用量为酰胺的0.1mol％～50mol％，优选为0.1mol％～10mol％，进一步优选为1mol％～5mol％；配体选自膦配体、氮配体、膦-氮配体中的任意一种或者多种，优选为1,1,1-三(二苯基膦甲基)乙烷；配体的用量为酰胺的0.1mol％～50mol％；优选为0.1mol％～10mol％；进一步优选为1mol％～5mol％。Further, the homogeneous catalyst includes a metal complex and a ligand. The metal complex is selected from any one or more of ruthenium complexes and cobalt complexes, preferably ruthenium acetylacetonate; the amount of the metal complex is 0.1 mol of the amide. % to 50 mol%, preferably 0.1 mol% to 10 mol%, further preferably 1 mol% to 5 mol%; the ligand is selected from any one or more of phosphine ligands, nitrogen ligands, and phosphine-nitrogen ligands, preferably It is 1,1,1-tris(diphenylphosphinemethyl)ethane; the amount of ligand is 0.1mol% to 50mol% of the amide; preferably 0.1mol% to 10mol%; further preferably 1mol% to 5mol% .
进一步地，溶剂为四氢呋喃、乙二醇二甲醚、2-甲基四氢呋喃、甲基叔丁基醚、二氧六环、甲苯、二甲苯、庚烷中的任意一种或者多种，优选为四氢呋喃和/或乙二醇二甲醚；溶剂的体积为酰胺体积的5～50倍。Further, the solvent is any one or more of tetrahydrofuran, ethylene glycol dimethyl ether, 2-methyltetrahydrofuran, methyl tert-butyl ether, dioxane, toluene, xylene, and heptane, preferably Tetrahydrofuran and/or ethylene glycol dimethyl ether; the volume of the solvent is 5 to 50 times the volume of the amide.
进一步地，连续氢化还原反应的反应体系中还包括路易斯酸类添加剂，优选路易斯酸类添加剂选自三氟化硼乙醚、三氟甲磺酸镓、三氟甲磺酸锌、三氟甲磺酸银、三氟甲磺酸铈、三氟甲磺酸镱、三氟甲磺酸、甲基磺酸中的任意一种或者多种；优选路易斯酸类添加剂的用量为酰胺的0.1mol％～200mol％；优选为1mol％～50mol％；进一步优选为2mol％～10mol％。Further, the reaction system of the continuous hydrogenation reduction reaction also includes Lewis acid additives. Preferably, the Lewis acid additives are selected from boron trifluoride ether, gallium triflate, zinc triflate, and triflate. Any one or more of silver, cerium triflate, ytterbium triflate, triflate, and methanesulfonic acid; the preferred dosage of Lewis acid additives is 0.1 mol% to 200 mol of the amide. %; preferably 1 mol% to 50 mol%; further preferably 2 mol% to 10 mol%.
进一步地，酰胺连续氢化还原方法包括：将氢气和液相成分连续输送至连续反应器中进行连续氢化还原反应，通过控制氢气和液相成分的流速使氢气和液相成分在常温常压下的体积比为10～500:1，优选为10～100:1，进一步优选为25～100:1，的液相成分包括酰胺、催化剂、路易斯酸类添加剂和溶剂。Further, the continuous hydrogenation reduction method of amide includes: continuously transporting hydrogen gas and liquid phase components to a continuous reactor to perform a continuous hydrogenation reduction reaction, and controlling the flow rate of hydrogen gas and liquid phase components to ensure that the hydrogen gas and liquid phase components are at room temperature and normal pressure. The volume ratio is 10-500:1, preferably 10-100:1, more preferably 25-100:1, and the liquid phase components include amide, catalyst, Lewis acid additives and solvent.
进一步地，液相成分共同进入连续反应器中，或者，液相成分中的一种或者多种分别进入连续反应器中，且催化剂以催化剂溶液、路易斯酸类添加剂以路易斯酸类添加剂的溶液形式进入连续反应器中。Further, the liquid phase components enter the continuous reactor together, or one or more of the liquid phase components enter the continuous reactor separately, and the catalyst is in the form of a catalyst solution and the Lewis acid additive is in the form of a solution of the Lewis acid additive. into the continuous reactor.
进一步地，连续反应器为盘管反应器，优选盘管反应器的内径为1～20mm，进一步优选为2～8mm。Furthermore, the continuous reactor is a coil reactor, and the inner diameter of the coil reactor is preferably 1 to 20 mm, and more preferably 2 to 8 mm.
进一步地，连续反应器前设置混合装置，以将进入连续反应器的催化剂溶液、路易斯酸类添加剂溶液与酰胺及溶剂混合。Further, a mixing device is provided in front of the continuous reactor to mix the catalyst solution, Lewis acid additive solution, amide and solvent entering the continuous reactor.
应用本发明的技术方案，利用氢气氢化还原酰胺能够获得较好的收率，相对于使用四氢铝锂等还原剂还原，避免了淬灭、过滤、水洗等后处理操作，后处理过程简单，三废量小，更适合工业化生产。采用均相催化剂进行连续的氢化还原反应，避免了非均相催化剂对官能团耐受性和选择性差的问题，均相氢化体系只有气/液两相，传质对反应的影响也大大降低；本申请中所有催化剂都溶于溶剂中，都是活性位点，其催化效率显著提高；而且本申请采用的催化剂可在市场直接购买，来源广泛，降低了物料成本；使用连续氢化方式，反应器较为简单，设备成本低，占地面积小，可以不间断的进行反应，效率得到提升，产能提高，尤其适用于大规模工业生产；另外，本申请的连续氢化反应器的反应空间分散在管道中，与高压釜相比，安全性能得到大幅提升，尤其是在较高的温度和压力条件下更为安全。By applying the technical solution of the present invention, a better yield can be obtained by hydrogenating and reducing the amide with hydrogen. Compared with reduction using reducing agents such as lithium aluminum tetrahydrogen, post-processing operations such as quenching, filtration, and water washing are avoided, and the post-processing process is simple. The amount of three wastes is small, which is more suitable for industrial production. The use of homogeneous catalysts for continuous hydrogenation reduction reactions avoids the problems of poor tolerance and selectivity of heterogeneous catalysts to functional groups. The homogeneous hydrogenation system only has two phases of gas/liquid, and the impact of mass transfer on the reaction is also greatly reduced; this method All catalysts in the application are soluble in solvents and are active sites, and their catalytic efficiency is significantly improved; and the catalysts used in this application can be purchased directly in the market from a wide range of sources, which reduces material costs; using continuous hydrogenation, the reactor is relatively It is simple, has low equipment cost, and occupies a small area. The reaction can be carried out continuously, the efficiency is improved, and the production capacity is increased. It is especially suitable for large-scale industrial production. In addition, the reaction space of the continuous hydrogenation reactor of the present application is dispersed in the pipeline. Compared with autoclaves, the safety performance has been greatly improved, especially under higher temperature and pressure conditions.
附图说明Description of the drawings
构成本申请的一部分的说明书附图用来提供对本发明的进一步理解，本发明的示意性实施例及其说明用于解释本发明，并不构成对本发明的不当限定。在附图中：The description and drawings that constitute a part of this application are used to provide a further understanding of the present invention. The illustrative embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute an improper limitation of the present invention. In the attached picture:
图1示出了根据本发明的一种酰胺连续氢化还原方法的实施例1的反应装置示意图。Figure 1 shows a schematic diagram of the reaction device of Example 1 of an amide continuous hydrogenation reduction method according to the present invention.
其中，上述附图包括以下附图标记：Among them, the above-mentioned drawings include the following reference signs:
1、A容器；2、打料泵；3、氢气储罐；4、氢气钢瓶；5、B容器；6、盘管反应器；7、气液分离器；8、氢气出口；9、取样装置；10、接收容器。1. Container A; 2. Dosing pump; 3. Hydrogen storage tank; 4. Hydrogen cylinder; 5. Container B; 6. Coil reactor; 7. Gas-liquid separator; 8. Hydrogen outlet; 9. Sampling device ; 10. Receiving container.
具体实施方式Detailed ways
需要说明的是，在不冲突的情况下，本申请中的实施例及实施例中的特征可以相互组合。下面将参考附图并结合实施例来详细说明本发明。It should be noted that, as long as there is no conflict, the embodiments and features in the embodiments of this application can be combined with each other. The present invention will be described in detail below with reference to the accompanying drawings and embodiments.
如本申请背景技术所分析的，现有技术中采用氢气氢化还原酰胺时，反应的压力和温度较高，同时采用特定的催化剂，成本昂贵，导致难以实现大规模的工业生产，为了解决该技术问题，提供了一种酰胺连续氢化还原方法，该方法包括以下步骤：在均相催化剂作用下使酰胺和氢气在溶剂中进行连续氢化还原反应，得到酰胺的氢化还原产物，其中，氢化还原反应的温度为100～350℃，酰胺具有以下结构式I所示结构，酰胺的氢化还原产物具有以下结构式II所示结构：As analyzed in the background technology of this application, when using hydrogen to reduce amide in the prior art, the pressure and temperature of the reaction are relatively high, and a specific catalyst is used, which is expensive, making it difficult to achieve large-scale industrial production. In order to solve this technology To solve the problem, a continuous hydrogenation reduction method of amide is provided. The method includes the following steps: making the amide and hydrogen carry out a continuous hydrogenation reduction reaction in a solvent under the action of a homogeneous catalyst to obtain a hydrogenation reduction product of the amide, wherein the hydrogenation reduction reaction of the amide is The temperature is 100 to 350°C. The amide has the structure shown in the following structural formula I. The hydrogenation reduction product of the amide has the structure shown in the following structural formula II:
Figure PCTCN2022096391-appb-000003
Figure PCTCN2022096391-appb-000003
其中，n为1～5中的任意一个整数，m为0或1，R 1、R 2、R 3、R 4各自独立的为氢、C 1～C 18的直链烷基、C 3～C 18的支链烷基、C 3～C 18的环烷基、C 6～C 20的芳基、C 6～C 20的芳烷基、C 1～C 18的烷氧基、硅氧基；R 1和R 3、R 2和R 4可以分别成环，环是三元环、四元环、五元环、六元环或七元环；环上的氢可以被以下取代基任意的取代，取代基包括C 1～C 18的直链烷基、C 3～C 18的支链烷基、C 3～C 18的环烷基、C 6～C 20的芳基、C 6～C 20的芳烷基、C 1～C 18的烷氧基、硅氧基。 Among them, n is any integer from 1 to 5, m is 0 or 1, R 1 , R 2 , R 3 , and R 4 are each independently hydrogen, a linear alkyl group of C 1 to C 18 , and C 3 to C 18 branched alkyl group, C 3 to C 18 cycloalkyl group, C 6 to C 20 aryl group, C 6 to C 20 aralkyl group, C 1 to C 18 alkoxy group, siloxy group ; R 1 and R 3 , R 2 and R 4 can form a ring respectively, and the ring can be a three-membered ring, a four-membered ring, a five-membered ring, a six-membered ring or a seven-membered ring; the hydrogen on the ring can be optionally substituted by the following substituents Substituted, the substituents include C 1 to C 18 linear alkyl, C 3 to C 18 branched alkyl, C 3 to C 18 cycloalkyl, C 6 to C 20 aryl, C 6 to C 20 aralkyl group, C 1 to C 18 alkoxy group, and siloxy group.
本申请利用氢气氢化还原酰胺能够获得较好的收率，相对于使用四氢铝锂等还原剂还原，避免了淬灭、过滤、水洗等后处理操作，后处理过程简单，三废量小，更适合工业化生产。采用均相催化剂进行连续的氢化还原反应，避免了非均相催化剂对官能团耐受性和选择性差的问题，均相氢化体系只有气/液两相，传质对反应的影响也大大降低；本申请所有催化剂都溶于溶剂中，都是活性位点，相对于非均相氢化，其催化效率显著提高；而且本申请采用的催化剂可在市场直接购买，来源广泛，降低了物料成本；使用连续氢化方式，反应器较为简单，设备成本低，占地面积小，可以不间断的进行反应，效率得到提升，产能提高，尤其适 用于大规模工业生产；另外，本申请的连续氢化反应器的反应空间分散在管道中，与高压釜相比，安全性能得到大幅提升，尤其是在较高的温度和压力条件下更为安全。This application uses hydrogen to hydrogenate and reduce amide to obtain a better yield. Compared with the use of reducing agents such as lithium aluminum tetrahydrogen for reduction, post-processing operations such as quenching, filtration, and water washing are avoided. The post-processing process is simple, the amount of waste is small, and more Suitable for industrial production. The use of homogeneous catalysts for continuous hydrogenation reduction reactions avoids the problems of poor tolerance and selectivity of heterogeneous catalysts to functional groups. The homogeneous hydrogenation system only has two phases of gas/liquid, and the impact of mass transfer on the reaction is also greatly reduced; this method All catalysts in the application are soluble in solvents and are active sites. Compared with heterogeneous hydrogenation, their catalytic efficiency is significantly improved; and the catalysts used in this application can be purchased directly in the market and come from a wide range of sources, which reduces material costs; the use of continuous In the hydrogenation method, the reactor is relatively simple, the equipment cost is low, and it occupies a small area. The reaction can be carried out uninterrupted, the efficiency is improved, and the production capacity is increased. It is especially suitable for large-scale industrial production; in addition, the reaction of the continuous hydrogenation reactor of this application The space is dispersed in the pipeline, and the safety performance is greatly improved compared with the autoclave, especially under higher temperature and pressure conditions.
上述结构式I中的n的数量和R 1、R 2、R 3、R 4所表示的取代基团理论上可以是任意的化学可接受的基团，为了提高上述结构式II的转化率，优选的，n为1～5中的任意一个整数，R 1、R 2、R 3、R 4各自独立的为氢、C 1～C 6的直链烷基、C 3～C 6的支链烷基、C 3～C 6的环烷基、C 6～C 10的芳基、C 6～C 12的芳烷基、C 2～C 5的烷氧基、硅氧基；R 1和R 3、R 2和R 4可以分别成环，环是三元环、四元环、五元环、六元环或七元环；环上的氢可以被以下取代基任意的取代，取代基包括C 1～C 6的直链烷基、C 3～C 6的支链烷基、C 3～C 6的环烷基、C 6～C 10的芳基、C 6～C 12的芳烷基、C 2～C 5的烷氧基、硅氧基；进一步优选的，n为1或2，R 1、R 2、R 3、R 4各自独立的为氢、C 1～C 3的直链烷基、C 3或C 4的支链烷基、C 6～C 10的芳基、C 2～C 5的烷氧基、硅氧基；R 1和R 3，或者R 2和R 4可以成环，环是三元环、四元环；环上的氢可以被以下取代基任意的取代，取代基包括C 1～C 6的直链烷基、C 3～C 6的支链烷基、C 3～C 6的环烷基、C 6～C 10的芳基、C 6～C 12的芳烷基、C 2～C 5的烷氧基、硅氧基；最为优选的，n为1或2，R 1、R 2、R 3、R 4各自独立的为氢，或者R 1和R 3、或者R 2和R 4可以成环，环是三元环或者六元环，环上的氢可以被甲基或乙基中的一种或者多种任意的取代。 The number of n in the above structural formula I and the substituent groups represented by R 1 , R 2 , R 3 and R 4 can theoretically be any chemically acceptable group. In order to improve the conversion rate of the above structural formula II, it is preferred to , n is any integer from 1 to 5, R 1 , R 2 , R 3 , and R 4 are each independently hydrogen, a linear alkyl group of C 1 to C 6 , or a branched alkyl group of C 3 to C 6 , C 3 to C 6 cycloalkyl group, C 6 to C 10 aryl group, C 6 to C 12 aralkyl group, C 2 to C 5 alkoxy group, siloxy group; R 1 and R 3 , R 2 and R 4 can form a ring respectively, and the ring can be a three-membered ring, a four-membered ring, a five-membered ring, a six-membered ring or a seven-membered ring; the hydrogen on the ring can be optionally substituted by the following substituents, and the substituents include C 1 ~C 6 linear alkyl group, C 3 to C 6 branched alkyl group, C 3 to C 6 cycloalkyl group, C 6 to C 10 aryl group, C 6 to C 12 aralkyl group, C 2 to C 5 alkoxy group and siloxy group; further preferably, n is 1 or 2, and R 1 , R 2 , R 3 and R 4 are each independently hydrogen or C 1 to C 3 linear alkyl group. , C 3 or C 4 branched alkyl group, C 6 to C 10 aryl group, C 2 to C 5 alkoxy group, siloxy group; R 1 and R 3 , or R 2 and R 4 can form a ring , the ring is a three-membered ring or a four-membered ring; the hydrogen on the ring can be optionally substituted by the following substituents. The substituents include C 1 to C 6 straight chain alkyl groups, C 3 to C 6 branched chain alkyl groups, C 3 to C 6 cycloalkyl group, C 6 to C 10 aryl group, C 6 to C 12 aralkyl group, C 2 to C 5 alkoxy group, siloxy group; most preferably, n is 1 or 2. R 1 , R 2 , R 3 and R 4 are each independently hydrogen, or R 1 and R 3 , or R 2 and R 4 can form a ring. The ring is a three-membered ring or a six-membered ring, and the hydrogen on the ring Can be optionally substituted by one or more of methyl or ethyl.
由于利用氢气进行氢化还原一般都需要在大于常压的条件下进行，上述酰胺的氢化还原反应压力可以参考现有技术，为了提高反应速度和氢化还原产物的转化率，优选氢化还原反应的压力为3～10MPa。在本申请的一些实施例中，为了进一步提高氢化还原产物的收率和转化速度，并综合考虑对反应设备的要求，进一步优选的氢化还原反应的压力为5～8MPa，比如氢化还原反应的压力为5MPa、6MPa、7MPa或8MPa，可以在较短的时间内获得较高的收率。Since hydrogenation reduction using hydrogen generally needs to be carried out under conditions greater than normal pressure, the hydrogenation reduction reaction pressure of the above-mentioned amide can refer to the existing technology. In order to increase the reaction speed and the conversion rate of the hydrogenation reduction product, the preferred pressure of the hydrogenation reduction reaction is: 3～10MPa. In some embodiments of the present application, in order to further improve the yield and conversion speed of the hydrogenation reduction product, and comprehensively consider the requirements for the reaction equipment, the further preferred pressure of the hydrogenation reduction reaction is 5 to 8 MPa, such as the pressure of the hydrogenation reduction reaction When it is 5MPa, 6MPa, 7MPa or 8MPa, a higher yield can be obtained in a shorter time.
本申请所用的氢气可以由氢气钢瓶直接提供，也可以在氢气钢瓶后设置氢气储气罐，并在氢气钢瓶或者储气罐后设置减压阀以提供反应体系的压力，还可以在连续反应器后设置背压阀以维持反应压力，本申请对氢气的供给方式和压力保持方法不做限定。The hydrogen used in this application can be directly provided by a hydrogen cylinder, or a hydrogen gas storage tank can be installed behind the hydrogen cylinder, and a pressure reducing valve can be installed behind the hydrogen cylinder or gas storage tank to provide the pressure of the reaction system. It can also be installed in a continuous reactor A back pressure valve is set up to maintain the reaction pressure. This application does not limit the hydrogen supply method and pressure maintenance method.
为了提高酰胺氢化还原反应速度和上述氢化还原产物的选择性，优选的反应温度为150～250℃，进一步优选为200～250℃。加热可以采用油浴，也可以是电加热，还可以是任意其他加热方式，本申请不做限定。In order to improve the reaction rate of amide hydrogenation reduction and the selectivity of the above-mentioned hydrogenation reduction product, the preferred reaction temperature is 150 to 250°C, and more preferably 200 to 250°C. Heating can use an oil bath, electric heating, or any other heating method, which is not limited in this application.
上述酰胺氢化还原反应中应用的均相催化剂可以在现有的用于催化氢化还原的均相催化剂中进行选择，在本申请的一些实施例中，均相催化剂包括金属配合物和配体。比如金属配合物选自钌配合物、钴配合物中的任意一种或者多种，优选为乙酰丙酮钌(Ru(acac) 3)，其催化时选择性好，且来源较为经济。金属配合物用量为酰胺的0.1mol％～50mol％，优选为0.1mol％～10mol％，进一步优选为1mol％～5mol％，例如1mol％、2mol％、3mol％、4mol％、5mol％；配体选自膦配体、氮配体、膦-氮配体中的任意一种或者多种，优选为1,1,1-三(二苯基膦甲基)乙烷(Triphos)；配体用量为酰胺的0.1mol％～50mol％；优选为0.1mol％～10mol％；进一步优选为1mol％～5mol％，例如1mol％、2mol％、3mol％、4mol％、5mol％。 The homogeneous catalyst used in the above amide hydrogenation reduction reaction can be selected from the existing homogeneous catalysts used for catalytic hydrogenation reduction. In some embodiments of the present application, the homogeneous catalyst includes metal complexes and ligands. For example, the metal complex is selected from any one or more of ruthenium complexes and cobalt complexes, preferably ruthenium acetylacetonate (Ru(acac) 3 ), which has good catalytic selectivity and is relatively economical in source. The amount of metal complex used is 0.1 mol% to 50 mol% of the amide, preferably 0.1 mol% to 10 mol%, more preferably 1 mol% to 5 mol%, such as 1 mol%, 2 mol%, 3 mol%, 4 mol%, 5 mol%; ligand Any one or more selected from phosphine ligands, nitrogen ligands, and phosphine-nitrogen ligands, preferably 1,1,1-tris(diphenylphosphinemethyl)ethane (Triphos); ligand dosage It is 0.1 mol% to 50 mol% of the amide; preferably 0.1 mol% to 10 mol%; more preferably 1 mol% to 5 mol%, such as 1 mol%, 2 mol%, 3 mol%, 4 mol%, and 5 mol%.
上述酰胺氢化还原反应中的溶剂的种类和用量可以从现有技术中进行选择，能够溶解上述酰胺和均相催化剂即可，比如四氢呋喃(THF)、乙二醇二甲醚、2-甲基四氢呋喃、甲基叔丁基醚、二氧六环、甲苯、二甲苯、庚烷中的任意一种或者多种，其中优选四氢呋喃和/或乙二醇二甲醚，二者对上述还原底物和催化剂的溶解性好，更有利于提高反应的收率和便于产物分析和分离纯化。The type and amount of solvent in the above-mentioned amide hydrogenation reduction reaction can be selected from the existing technology, as long as it can dissolve the above-mentioned amide and the homogeneous catalyst, such as tetrahydrofuran (THF), ethylene glycol dimethyl ether, 2-methyltetrahydrofuran , any one or more of methyl tert-butyl ether, dioxane, toluene, xylene, and heptane, among which tetrahydrofuran and/or ethylene glycol dimethyl ether are preferred, both of which are effective for the above reduction substrate and The catalyst has good solubility, which is more conducive to improving the yield of the reaction and facilitating product analysis, separation and purification.
在本申请的一些实施例中，综合考虑既能完全溶解原料和催化剂，又可以保证底物的浓度，减少浪费，溶剂的体积为酰胺体积的5～50倍，优选为15～30倍。上述溶剂在应用于本反应前，优选进行除氧干燥，避免影响还原反应进行。In some embodiments of the present application, the volume of the solvent is 5 to 50 times the volume of the amide, preferably 15 to 30 times, taking into account the ability to completely dissolve the raw materials and catalyst, and to ensure the concentration of the substrate and reduce waste. Before the above solvent is used in this reaction, it is preferred to carry out oxygen removal and drying to avoid affecting the reduction reaction.
为了进一步提高产物的收率，在本申请的一些实施例中，上述反应体系中还包括路易斯酸类添加剂，其可以与酰胺羰基的氧进行络合，起到活化羰基的作用。比如路易斯酸类添加剂选自三氟化硼乙醚(BF 3.Et 2O)、三氟甲磺酸镓、三氟甲磺酸锌、三氟甲磺酸银、三氟甲磺酸铈、三氟甲磺酸镱、三氟甲磺酸、甲基磺酸中的任意一种或者多种；路易斯酸类添加剂的用量为酰胺的0.1～200mol％；优选为1mol％～50mol％；进一步优选为2mol％～10mol％。 In order to further improve the yield of the product, in some embodiments of the present application, the above reaction system also includes Lewis acid additives, which can complex with the oxygen of the amide carbonyl group and activate the carbonyl group. For example, Lewis acid additives are selected from boron trifluoride ether (BF 3 .Et 2 O), gallium triflate, zinc triflate, silver triflate, cerium triflate, and trifluoromethanesulfonate. Any one or more of ytterbium fluomethanesulfonate, trifluoromethanesulfonic acid, and methylsulfonic acid; the amount of Lewis acid additives is 0.1 to 200 mol% of the amide; preferably 1 mol% to 50 mol%; further preferably 2mol%～10mol%.
上述的均相催化剂和路易斯酸添加剂的用量大小会影响酰胺氢化还原的产物组成，较小的均相催化剂和路易斯酸添加剂的用量仅还原其中一个碳氧双键，加大用量可以将两个碳氧双键全部加氢还原，因此可以通过调节上述的均相催化剂和路易斯酸添加剂用量来制备不同的还原产物。The dosage of the above-mentioned homogeneous catalyst and Lewis acid additive will affect the product composition of the amide hydrogenation reduction. The smaller dosage of the homogeneous catalyst and Lewis acid additive will only reduce one of the carbon-oxygen double bonds. Increasing the dosage can reduce the two carbon-oxygen double bonds. All oxygen double bonds are hydrogenated and reduced, so different reduction products can be prepared by adjusting the dosage of the above-mentioned homogeneous catalyst and Lewis acid additive.
在本申请的一些实施例中，酰胺连续氢化还原方法包括：将氢气和液相成分连续输送至连续反应器中进行连续氢化还原反应，其中液相成分包括酰胺、催化剂、路易斯酸类添加剂和溶剂。通过控制氢气和液相成分的流速使氢气和液相成分在常温常压下的体积比为10～500:1，维持该体积比可以使反应体系在连续反应器中的流体流型得以保持：一方面，避免因氢气在反应过程中被消耗而影响流体流型；另一方面，体积比保持在一定范围内可以使流体保持一定的流型，避免液体并聚，影响传质效果。优选氢气和液相成分在常温常压下的体积比为10～100:1，进一步优选为25～100:1，使反应体系的流型更好，从而使酰胺连续氢化还原取得更佳的效率。In some embodiments of the present application, the continuous hydrogenation reduction method of amide includes: continuously transporting hydrogen gas and liquid phase components into a continuous reactor to perform a continuous hydrogenation reduction reaction, wherein the liquid phase components include amide, catalyst, Lewis acid additives and solvents . By controlling the flow rates of hydrogen and liquid components, the volume ratio of hydrogen and liquid components at normal temperature and pressure is 10 to 500:1. Maintaining this volume ratio can maintain the fluid flow pattern of the reaction system in the continuous reactor: On the one hand, it avoids the influence of the fluid flow pattern due to hydrogen being consumed during the reaction; on the other hand, keeping the volume ratio within a certain range can keep the fluid in a certain flow pattern and avoid liquid aggregation, which affects the mass transfer effect. The volume ratio of hydrogen gas and liquid phase components at normal temperature and pressure is preferably 10 to 100:1, and further preferably 25 to 100:1, so as to make the flow pattern of the reaction system better and achieve better efficiency in the continuous hydrogenation and reduction of amide. .
可以通过在输入管路中设置流量测量装置检测氢气或者液相成分的流量，例如在氢气钢瓶和/或储气罐后设置氢气质量流量计，来控制氢气流量；也可以通过打料泵实现对液相成分流量的控制。The flow of hydrogen or liquid phase components can be detected by setting up a flow measuring device in the input pipeline, for example, setting up a hydrogen mass flow meter after the hydrogen cylinder and/or gas storage tank to control the hydrogen flow; it can also be achieved through a dosing pump. Control of liquid component flow.
在本申请的一些实施例中，反应体系中的上述液相成分共同进入连续反应器中，或者液相成分中的一种或者多种分别进入连续反应器中，且催化剂以催化剂溶液、路易斯酸类添加剂以路易斯酸类添加剂的溶液形式进入连续反应器中，后者反应体系中的液相成分分成多路进入连续反应器，便于对其中的物质进行控制和监测。在一些实施例中，酰胺和路易斯酸类添加剂的溶液分为一路，金属配合物和配体的溶液为一路，同时向连续反应器内输送，有利于提高产物的收率。当液相成分分为多路进入连续反应器时，优选连续反应器前设置混合装 置，以将进入连续反应器的催化剂溶液和路易斯酸类添加剂溶液与酰胺溶液混合，提高反应效率。In some embodiments of the present application, the above-mentioned liquid phase components in the reaction system enter the continuous reactor together, or one or more of the liquid phase components enter the continuous reactor separately, and the catalyst is used as a catalyst solution, Lewis acid The additives enter the continuous reactor in the form of a solution of Lewis acid additives. The liquid phase components in the latter reaction system are divided into multiple channels and enter the continuous reactor to facilitate the control and monitoring of the substances therein. In some embodiments, the solutions of the amide and Lewis acid additives are divided into one channel, and the solutions of the metal complex and the ligand are divided into one channel, and are simultaneously transported to the continuous reactor, which is beneficial to improving the yield of the product. When the liquid phase components are divided into multiple channels and enter the continuous reactor, it is preferable to install a mixing device in front of the continuous reactor to mix the catalyst solution and Lewis acid additive solution entering the continuous reactor with the amide solution to improve the reaction efficiency.
上述的连续反应器，可以从现有技术中能满足上述反应条件的反应器中进行选择，比如连续反应器采用盘管反应器、柱式反应器、连续反应釜等，尤其是盘管反应器，其结构较为简单，热能利用更充分，能够大幅提高产能，尤其适用于大规模工业化生产。优选盘管反应器的内径为1～20mm，进一步优选为2～8mm，更进一步优选为2～4mm，所述液体和气体在盘管中的停留时间为10min～5h，优选为30min～2h。The above-mentioned continuous reactor can be selected from reactors in the existing technology that can meet the above reaction conditions. For example, the continuous reactor adopts a coil reactor, a column reactor, a continuous reactor, etc., especially a coil reactor. , its structure is relatively simple, heat energy can be fully utilized, and production capacity can be greatly increased, especially suitable for large-scale industrial production. The inner diameter of the coil reactor is preferably 1 to 20 mm, more preferably 2 to 8 mm, and even more preferably 2 to 4 mm. The residence time of the liquid and gas in the coil is 10 min to 5 h, preferably 30 min to 2 h.
下面将结合实施例进一步说明本申请提供的酰胺连续氢化还原方法的有益效果。The beneficial effects of the continuous hydrogenation reduction method of amide provided by the present application will be further explained below in conjunction with the examples.
实施例1Example 1
本实施例采用如图1所示的装置进行酰胺的氢化还原反应，所用的酰胺为6,6-二甲基-3-氮杂二环[3.1.0]己烷-2,4-二酮，还原产物为6,6-二甲基-3-氮杂二环[3.1.0]己烷-2-酮。制备方法如下步骤：In this embodiment, the device shown in Figure 1 is used to perform the hydrogenation reduction reaction of the amide. The amide used is 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione. , the reduction product is 6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-one. The preparation method is as follows:
(1)配溶液(1) Prepare solution
溶液A：氮气保护下，向A容器1中加入上述酰胺，然后加入预先除氧的溶剂THF，THF的添加量为酰胺体积的15倍，再加入酰胺2.2mol％的BF 3.Et 2O，混合均匀后，氮气保护好，待用； Solution A: Under nitrogen protection, add the above amide to container 1 of A, then add the pre-deoxygenated solvent THF, the amount of THF added is 15 times the volume of the amide, then add 2.2 mol% of amide BF 3 .Et 2 O, After mixing evenly, protect with nitrogen and set aside;
溶液B：氮气保护下，向B容器5中加入酰胺1mol％的Ru(acac) 3、再加入酰胺1.1mol％的Triphos，15倍酰胺体积的THF，混合均匀后，氮气保护好，待用。 Solution B: Under nitrogen protection, add 1 mol% of amide Ru(acac) 3 to B container 5, then add 1.1 mol% of amide in Triphos, and 15 times the volume of amide in THF. After mixing evenly, protect with nitrogen and set aside.
(2)将盘管反应器6外浴温度控温在245～255℃，同时通过调节减压阀和背压阀将盘管反应器6内氢气压力调节至8MPa，调节进气端氢气质量流量计至流量为15mL/min。其中，盘管反应器6的内部直径为2mm，盘管长度为12m；氢气由氢气钢瓶4供应，并经氢气储罐3输出。(2) Control the temperature of the outer bath of coil reactor 6 at 245-255°C. At the same time, adjust the hydrogen pressure in coil reactor 6 to 8MPa by adjusting the pressure reducing valve and back pressure valve, and adjust the hydrogen mass flow rate at the inlet end. Measure until the flow rate is 15mL/min. Among them, the internal diameter of the coil reactor 6 is 2mm, and the coil length is 12m; hydrogen is supplied from the hydrogen cylinder 4 and output through the hydrogen storage tank 3.
(3)同时启动A容器和B容器后的打料泵2，向盘管反应器中泵入溶液A和溶液B，溶液A的流量为0.16mL/min，溶液B的流量为0.15mL/min，持续打料。期间通过调节背压阀，使盘管反应体系压力维持在8MPa左右。反应过程中，可以通过取样装置9获取反应体系样品，对样品进行检测获取反应进程情况或者对体系内各组分进行分析。随着打料泵不断的泵入溶液，盘管反应器6内的反应完毕的组分进入气液分离器7，气体经氢气出口8排出，液体由气液分离器7进入接收容器10。(3) Start the feeding pump 2 behind container A and B at the same time, and pump solution A and solution B into the coil reactor. The flow rate of solution A is 0.16mL/min, and the flow rate of solution B is 0.15mL/min. , continue to make materials. During this period, the pressure of the coil reaction system was maintained at about 8MPa by adjusting the back pressure valve. During the reaction process, a sample of the reaction system can be obtained through the sampling device 9, and the sample can be detected to obtain the reaction progress or each component in the system can be analyzed. As the dosing pump continuously pumps the solution, the reacted components in the coil reactor 6 enter the gas-liquid separator 7 , the gas is discharged through the hydrogen outlet 8 , and the liquid enters the receiving container 10 from the gas-liquid separator 7 .
(4)打料完毕后，继续保持体系氢气压力8MPa，将溶液A和溶液B都替换成THF，继续打料2h。(4) After the mixing is completed, continue to maintain the system hydrogen pressure at 8MPa, replace both solution A and solution B with THF, and continue mixing for 2 hours.
(5)将盘管反应器冷却至室温。(5) Cool the coil reactor to room temperature.
(6)调节背压阀，逐步降低体系压力，通过氢气出口8将反应体系压力排放至0，然后，用氮气置换，加压至0.4～0.5MPa，然后释压至0～0.05MPa，重复3次。(6) Adjust the back pressure valve, gradually reduce the system pressure, discharge the reaction system pressure to 0 through hydrogen outlet 8, then replace it with nitrogen, increase the pressure to 0.4~0.5MPa, then release the pressure to 0~0.05MPa, repeat 3 Second-rate.
实施例2Example 2
与实施例1的不同之处在于：Ru(acac) 3的用量为酰胺的4mol％，Triphos的用量为酰胺的8mol％，BF 3.Et 2O的用量为酰胺的8mol％；盘管反应器外浴温度控温在(150±5)℃；氢气的流量为10mL/min；溶液A的流量为0.1mL/min，溶液B的流量为0.1mL/min。 The difference from Example 1 is that: the amount of Ru(acac) 3 is 4 mol% of the amide, the amount of Triphos is 8 mol% of the amide, and the amount of BF 3.Et 2 O is 8 mol% of the amide; coil reactor The temperature of the external bath is controlled at (150±5)°C; the flow rate of hydrogen is 10mL/min; the flow rate of solution A is 0.1mL/min, and the flow rate of solution B is 0.1mL/min.
实施例3Example 3
与实施例1的不同之处在于：Ru(acac) 3的用量为酰胺的2mol％，Triphos的用量为酰胺的4mol％，BF 3.Et 2O的用量为酰胺的4mol％；盘管反应器外浴温度控温在(200±5)℃；氢气的流量为10mL/min；溶液A的流量为0.1mL/min，溶液B的流量为0.1mL/min。 The difference from Example 1 is that: the amount of Ru(acac) 3 is 2 mol% of the amide, the amount of Triphos is 4 mol% of the amide, and the amount of BF 3.Et 2 O is 4 mol% of the amide; coil reactor The temperature of the external bath is controlled at (200±5)°C; the flow rate of hydrogen is 10mL/min; the flow rate of solution A is 0.1mL/min, and the flow rate of solution B is 0.1mL/min.
实施例4Example 4
与实施例1的不同之处在于：Ru(acac) 3的用量为酰胺的2mol％，Triphos的用量为酰胺的4mol％，BF 3.Et 2O的用量为酰胺的4mol％；盘管反应器外浴温度控温在(200±5)℃。 The difference from Example 1 is that: the amount of Ru(acac) 3 is 2 mol% of the amide, the amount of Triphos is 4 mol% of the amide, and the amount of BF 3.Et 2 O is 4 mol% of the amide; coil reactor The temperature of the external bath is controlled at (200±5)℃.
实施例5Example 5
与实施例1的不同之处在于：Ru(acac) 3的用量为酰胺的2mol％，Triphos的用量为酰胺的4mol％，BF 3.Et 2O的用量为酰胺的4mol％；盘管反应器外浴温度控温在(200±5)℃；氢气的流量为30mL/min。 The difference from Example 1 is that: the amount of Ru(acac) 3 is 2 mol% of the amide, the amount of Triphos is 4 mol% of the amide, and the amount of BF 3.Et 2 O is 4 mol% of the amide; coil reactor The temperature of the external bath is controlled at (200±5)℃; the flow rate of hydrogen is 30mL/min.
实施例6Example 6
与实施例1的不同之处在于：Ru(acac) 3的用量为酰胺的1mol％，Triphos的用量为酰胺的2mol％，BF 3.Et 2O的用量为酰胺的2mol％。 The difference from Example 1 is that: the amount of Ru(acac) 3 is 1 mol% of the amide, the amount of Triphos is 2 mol% of the amide, and the amount of BF 3 .Et 2 O is 2 mol% of the amide.
实施例7Example 7
与实施例1的不同之处在于：Ru(acac) 3的用量为酰胺的1mol％，Triphos的用量为酰胺的2mol％，BF 3.Et 2O的用量为酰胺的2mol％；氢气的流量为30mL/min，溶液A和溶液B中溶剂THF的体积之和为酰胺体积的20倍。 The difference from Example 1 is that: the amount of Ru(acac) 3 is 1 mol% of the amide, the amount of Triphos is 2 mol% of the amide, the amount of BF 3.Et 2 O is 2 mol% of the amide; the flow rate of hydrogen is 30mL/min, the sum of the volumes of solvent THF in solution A and solution B is 20 times the volume of the amide.
实施例8Example 8
与实施例1的不同之处在于：Ru(acac) 3的用量为酰胺的1mol％，Triphos的用量为酰胺的2mol％，BF 3.Et 2O的用量为酰胺的2mol％；氢气的流量为45mL/min，溶液A和溶液B中溶剂THF的体积之和为酰胺体积的10倍。 The difference from Example 1 is that: the amount of Ru(acac) 3 is 1 mol% of the amide, the amount of Triphos is 2 mol% of the amide, the amount of BF 3.Et 2 O is 2 mol% of the amide; the flow rate of hydrogen is 45mL/min, the sum of the volumes of solvent THF in solution A and solution B is 10 times the volume of the amide.
实施例9Example 9
与实施例1的不同之处在于：Ru(acac) 3的用量为酰胺的1mol％，Triphos的用量为酰胺的2mol％，BF 3.Et 2O的用量为酰胺的2mol％；氢气的流量为20mL/min；溶液A的流量为0.21mL/min，溶液B的流量为0.2mL/min。 The difference from Example 1 is that: the amount of Ru(acac) 3 is 1 mol% of the amide, the amount of Triphos is 2 mol% of the amide, the amount of BF 3.Et 2 O is 2 mol% of the amide; the flow rate of hydrogen is 20mL/min; the flow rate of solution A is 0.21mL/min, and the flow rate of solution B is 0.2mL/min.
实施例10Example 10
与实施例1的不同之处在于：Ru(acac) 3的用量为酰胺的1mol％，Triphos的用量为酰胺的2mol％，BF 3.Et 2O的用量为酰胺的2mol％；氢气的流量为25mL/min；溶液A的流量为0.27mL/min，溶液B的流量为0.25mL/min。 The difference from Example 1 is that: the amount of Ru(acac) 3 is 1 mol% of the amide, the amount of Triphos is 2 mol% of the amide, the amount of BF 3.Et 2 O is 2 mol% of the amide; the flow rate of hydrogen is 25mL/min; the flow rate of solution A is 0.27mL/min, and the flow rate of solution B is 0.25mL/min.
实施例11Example 11
与实施例1的不同之处在于：Ru(acac) 3的用量为酰胺的1mol％，Triphos的用量为酰胺的1.1mol％，BF 3.Et 2O的用量为酰胺的1.1mol％。 The difference from Example 1 is that: the amount of Ru(acac) 3 is 1 mol% of the amide, the amount of Triphos is 1.1 mol% of the amide, and the amount of BF 3 .Et 2 O is 1.1 mol% of the amide.
实施例12Example 12
与实施例1的不同之处在于：Ru(acac) 3的用量为酰胺的1mol％，Triphos的用量为酰胺的1.1mol％，BF 3.Et 2O的用量为酰胺的5mol％。 The difference from Example 1 is that: the amount of Ru(acac) 3 is 1 mol% of the amide, the amount of Triphos is 1.1 mol% of the amide, and the amount of BF 3 .Et 2 O is 5 mol% of the amide.
实施例13Example 13
(1)配溶液(1) Prepare solution
溶液A：氮气保护下，向A容器中加入与实施例1相同种类的酰胺，然后加入预先除氧的溶剂THF，THF的添加量为酰胺体积的15倍，再加入酰胺2.2mol％的BF 3.Et 2O，混合均匀后，氮气保护好，待用； Solution A: Under nitrogen protection, add the same type of amide as in Example 1 to container A, and then add the pre-deoxygenated solvent THF. The amount of THF added is 15 times the volume of the amide, and then add 2.2 mol% of BF 3 of the amide. .Et 2 O, after mixing evenly, protect it with nitrogen and set aside;
溶液B：氮气保护下，向B容器中加入酰胺1mol％的Ru(acac) 3、再加入酰胺1.1mol％Triphos，酰胺体积15倍的THF，混合均匀后，氮气保护好，待用； Solution B: Under nitrogen protection, add 1 mol% of amide Ru(acac) 3 to container B, then add 1.1 mol% of amide Triphos, and 15 times the volume of amide in THF. After mixing evenly, protect with nitrogen and set aside;
(2)将盘管反应器外浴温度控温在245～255℃，同时通过调节减压阀和背压阀将盘管反应器内氢气压力调节至8MPa，调节进气端氢气质量流量计至流量为60mL/min。其中，盘管反应器的内部直径为4mm，盘管长度为12m。(2) Control the temperature of the outer bath of the coil reactor at 245~255°C. At the same time, adjust the hydrogen pressure in the coil reactor to 8MPa by adjusting the pressure reducing valve and back pressure valve, and adjust the hydrogen mass flow meter at the inlet end to The flow rate is 60mL/min. Among them, the internal diameter of the coil reactor is 4mm, and the coil length is 12m.
(3)同时启动A容器和B容器后的打料泵，向盘管反应器中泵入溶液A和溶液B，溶液A的流量为0.64mL/min，溶液B的流量为0.6mL/min，持续打料。期间通过调节背压阀，使盘管反应体系压力维持在8MPa左右。气体经氢气出口排出，液体由气液分离器进入接收容器。(3) Start the feeding pumps behind containers A and B at the same time, and pump solution A and solution B into the coil reactor. The flow rate of solution A is 0.64mL/min, and the flow rate of solution B is 0.6mL/min. Keep feeding. During this period, the pressure of the coil reaction system was maintained at about 8MPa by adjusting the back pressure valve. The gas is discharged through the hydrogen outlet, and the liquid enters the receiving container through the gas-liquid separator.
(4)打料完毕后，继续保持体系氢气压力8MPa，将溶液A和溶液B都替换成THF，继续打料2h。(4) After the mixing is completed, continue to maintain the system hydrogen pressure at 8MPa, replace both solution A and solution B with THF, and continue mixing for 2 hours.
(5)将盘管反应器冷却至室温。(5) Cool the coil reactor to room temperature.
(6)调节背压阀，逐步降低体系压力，通过氢气出口将反应体系压力排放至0，然后，用氮气置换，加压至0.4～0.5MPa，然后释压至0～0.05MPa，重复3次。(6) Adjust the back pressure valve, gradually reduce the system pressure, discharge the reaction system pressure to 0 through the hydrogen outlet, then replace it with nitrogen, increase the pressure to 0.4~0.5MPa, and then release the pressure to 0~0.05MPa, repeat 3 times .
实施例14：Example 14:
(1)配溶液(1) Prepare solution
溶液A：氮气保护下，向A容器中加入与实施例1相同种类的酰胺，然后加入预先除氧的溶剂THF，THF添加量为酰胺体积的15倍，再加入酰胺2.2mol％的BF 3.Et 2O，混合均匀后，氮气保护好，待用； Solution A: Under nitrogen protection, add the same type of amide as in Example 1 to container A, then add pre-deoxygenated solvent THF, the amount of THF added is 15 times the volume of the amide, and then add 2.2 mol% of amide BF 3 . Et 2 O, mix evenly, protect with nitrogen, and set aside;
溶液B：氮气保护下，向B容器中加入酰胺1mol％的Ru(acac) 3、再加入酰胺1.1mol％的Triphos，15倍酰胺体积的THF，混合均匀后，氮气保护好，待用； Solution B: Under nitrogen protection, add 1 mol% of amide Ru(acac) 3 to container B, then add 1.1 mol% of amide in Triphos, and 15 times the volume of amide in THF. After mixing evenly, protect with nitrogen and set aside;
(2)将盘管反应器外浴温度控温在245-255℃，同时通过调节减压阀和背压阀将盘管反应器内氢气压力调节至8MPa，调节进气端氢气质量流量计至流量为240mL/min。其中，盘管反应器的内部直径为8mm，盘管长度为12m。(2) Control the temperature of the outer bath of the coil reactor at 245-255°C. At the same time, adjust the hydrogen pressure in the coil reactor to 8MPa by adjusting the pressure reducing valve and back pressure valve, and adjust the hydrogen mass flow meter at the inlet end to The flow rate is 240mL/min. Among them, the internal diameter of the coil reactor is 8mm, and the coil length is 12m.
(3)同时启动A容器和B容器后的打料泵，向盘管反应器中泵入溶液A和溶液B，溶液A的流量为2.56mL/min，溶液B的流量为2.4mL/min，持续打料。期间通过调节背压阀，使盘管反应体系压力维持在8MPa左右。气体经氢气出口排出，液体由气液分离器进入接收容器。(3) Start the feeding pumps behind containers A and B at the same time, and pump solution A and solution B into the coil reactor. The flow rate of solution A is 2.56mL/min, and the flow rate of solution B is 2.4mL/min. Keep feeding. During this period, the pressure of the coil reaction system was maintained at about 8MPa by adjusting the back pressure valve. The gas is discharged through the hydrogen outlet, and the liquid enters the receiving container through the gas-liquid separator.
(4)打料完毕后，继续保持体系氢气压力8MPa，将溶液A和溶液B都替换成THF，继续打料2h。(4) After the mixing is completed, continue to maintain the system hydrogen pressure at 8MPa, replace both solution A and solution B with THF, and continue mixing for 2 hours.
(5)将盘管反应器冷却至室温。(5) Cool the coil reactor to room temperature.
(6)调节背压阀，逐步降低体系压力，通过氢气出口将反应体系压力排放至0，然后，用氮气置换，加压至0.4～0.5MPa，然后释压至0～0.05MPa，重复3次。(6) Adjust the back pressure valve, gradually reduce the system pressure, discharge the reaction system pressure to 0 through the hydrogen outlet, then replace it with nitrogen, increase the pressure to 0.4~0.5MPa, and then release the pressure to 0~0.05MPa, repeat 3 times .
实施例15Example 15
(1)配溶液：氮气保护下，向圆底瓶中加入与实施例相同种类的酰胺、酰胺1mol％的Ru(acac) 3、酰胺1.1mol％的Triphos，然后加入预先除氧的15倍酰胺体积的溶剂THF，再加入2.2mol％的BF 3.Et 2O，最后再加入15倍酰胺体积的THF，混合均匀后，氮气保护好，待用。 (1) Preparation of solution: Under nitrogen protection, add the same type of amide as in the example, 1 mol% of amide Ru(acac) 3 , and 1.1 mol% of amide Triphos into a round-bottomed bottle, and then add 15 times the pre-deoxygenated amide volume of the solvent THF, then add 2.2 mol% of BF 3 .Et 2 O, and finally add 15 times the volume of the amide in THF. After mixing evenly, protect with nitrogen and set aside.
(2)将盘管反应器外浴温度控温在245-255℃，同时通过调节减压阀和背压阀将盘管反应器内氢气压力调节至8MPa，调节进气端氢气质量流量计至流量为15mL/min。其中，盘管反应器的内部直径为2mm，盘管长度为12m。(2) Control the temperature of the outer bath of the coil reactor at 245-255°C. At the same time, adjust the hydrogen pressure in the coil reactor to 8MPa by adjusting the pressure reducing valve and back pressure valve, and adjust the hydrogen mass flow meter at the inlet end to The flow rate is 15mL/min. Among them, the internal diameter of the coil reactor is 2mm, and the coil length is 12m.
(3)同时启动打料泵向盘管反应器中泵入配置好的溶液，控制其流量为0.31mL/min，持续打料。期间通过调节出气端氢气质量流量计，使盘管反应体系压力维持在8MPa左右。气体经氢气出口排出，液体由气液分离器进入接收容器。(3) At the same time, start the dosing pump to pump the configured solution into the coil reactor, control the flow rate to 0.31mL/min, and continue to dope. During this period, the pressure of the coil reaction system was maintained at about 8MPa by adjusting the hydrogen mass flow meter at the gas outlet. The gas is discharged through the hydrogen outlet, and the liquid enters the receiving container through the gas-liquid separator.
(4)打料完毕后，继续保持体系氢气压力8MPa，将溶液都替换成THF，继续打料2h。(4) After the mixing is completed, continue to maintain the hydrogen pressure of the system at 8MPa, replace all the solutions with THF, and continue mixing for 2 hours.
(5)将盘管反应器冷却至室温。(5) Cool the coil reactor to room temperature.
(6)调节背压阀，逐步降低体系压力，通过氢气出口将反应体系压力排放至0，然后，用氮气置换，加压至0.4～0.5MPa，然后释压至0～0.05MPa，重复3次。(6) Adjust the back pressure valve, gradually reduce the system pressure, discharge the reaction system pressure to 0 through the hydrogen outlet, then replace it with nitrogen, increase the pressure to 0.4~0.5MPa, and then release the pressure to 0~0.05MPa, repeat 3 times .
实施例16Example 16
与实施例1的不同之处在于：还原产物为6,6-二甲基-3-氮杂二环[3.1.0]己烷；Ru(acac) 3的用量为酰胺的4mol％，Triphos的用量为酰胺的5mol％，BF 3.Et 2O的用量为酰胺的200mol％。 The difference from Example 1 is that: the reduction product is 6,6-dimethyl-3-azabicyclo[3.1.0]hexane; the amount of Ru(acac) 3 is 4 mol% of the amide, and the amount of Triphos The dosage of BF 3.Et 2 O is 5 mol% of the amide, and the dosage of BF 3.Et 2 O is 200 mol% of the amide.
实施例17Example 17
与实施例1的不同之处在于：被还原的酰胺为2,6-哌啶二酮，还原产物为哌啶-2-酮。The difference from Example 1 is that the reduced amide is 2,6-piperidinedione, and the reduction product is piperidin-2-one.
实施例18Example 18
与实施例1的不同之处在于：被还原的酰胺为丁二酰亚胺，还原产物为2-吡咯烷酮。The difference from Example 1 is that the reduced amide is succinimide and the reduction product is 2-pyrrolidone.
实施例19Example 19
与实施例1的不同之处在于：被还原的酰胺为邻苯二甲酰亚胺，还原产物为1-异吲哚啉酮。The difference from Example 1 is that the reduced amide is phthalimide and the reduction product is 1-isoindolinone.
实施例20Example 20
与实施例4的不同之处在于：体系中氢气的压力为3MPa。The difference from Example 4 is that the pressure of hydrogen in the system is 3MPa.
实施例21Example 21
与实施例4的不同之处在于：体系中氢气的压力为5MPa。The difference from Example 4 is that the pressure of hydrogen in the system is 5MPa.
实施例22Example 22
与实施例4的不同之处在于：体系中氢气的压力为10MPa。The difference from Example 4 is that the pressure of hydrogen in the system is 10 MPa.
实施例23Example 23
与实施例4的不同之处在于：盘管反应器外浴温度控温在(100±5)℃。The difference from Example 4 is that the temperature of the outer bath of the coil reactor is controlled at (100±5)°C.
实施例24Example 24
与实施例4的不同之处在于：盘管反应器外浴温度控温在(350±5)℃。The difference from Example 4 is that the temperature of the outer bath of the coil reactor is controlled at (350±5)°C.
实施例25Example 25
与实施例1的不同之处在于：Ru(acac) 3的用量为酰胺的0.1mol％、Triphos的用量为酰胺的0.1mol％。 The difference from Example 1 is that the amount of Ru(acac) 3 is 0.1 mol% of the amide, and the amount of Triphos is 0.1 mol% of the amide.
实施例26Example 26
与实施例16的不同之处在于：Ru(acac) 3的用量为酰胺的10mol％、Triphos的用量为酰胺的10mol％。 The difference from Example 16 is that the amount of Ru(acac) 3 is 10 mol% of the amide, and the amount of Triphos is 10 mol% of the amide.
实施例27Example 27
与实施例16的不同之处在于：Ru(acac) 3的用量为酰胺的50mol％、Triphos的用量为酰胺的50mol％。 The difference from Example 16 is that the amount of Ru(acac) 3 is 50 mol% of the amide, and the amount of Triphos is 50 mol% of the amide.
实施例28Example 28
与实施例1的不同之处在于：BF 3.Et 2O的用量为酰胺的0.1mol％。 The difference from Example 1 is that the amount of BF 3 .Et 2 O is 0.1 mol% of the amide.
实施例29Example 29
与实施例1的不同之处在于：BF 3.Et 2O的用量为酰胺的50mol％。 The difference from Example 1 is that the amount of BF 3 .Et 2 O is 50 mol% of the amide.
实施例30Example 30
与实施例1的不同之处在于：盘管反应器的内部直径为1mm，溶液A的流量为0.04mL/min，溶液B的流量为0.04mL/min，调节进气端氢气质量流量计至流量为4mL/min。The difference from Example 1 is that: the internal diameter of the coil reactor is 1mm, the flow rate of solution A is 0.04mL/min, the flow rate of solution B is 0.04mL/min, adjust the hydrogen mass flow meter at the inlet end to the flow rate is 4mL/min.
实施例31Example 31
与实施例1的不同之处在于：盘管反应器的内部直径为20mm，溶液A的流量为16mL/min，溶液B的流量为15mL/min，调节进气端氢气质量流量计至流量为1500mL/min。The difference from Example 1 is that: the internal diameter of the coil reactor is 20mm, the flow rate of solution A is 16mL/min, the flow rate of solution B is 15mL/min, and the hydrogen mass flow meter at the inlet end is adjusted to a flow rate of 1500mL. /min.
实施例32Example 32
与实施例1的不同之处在于：氢气的流量为8mL/min。The difference from Example 1 is that the flow rate of hydrogen is 8 mL/min.
实施例33Example 33
与实施例1的不同之处在于：氢气的流量为3mL/min。The difference from Example 1 is that the flow rate of hydrogen is 3 mL/min.
实施例34Example 34
与实施例1的不同之处在于：氢气的流量为150mL/min。The difference from Example 1 is that the flow rate of hydrogen is 150 mL/min.
对比例1Comparative example 1
在50mL高压釜中加入1g的6,6-二甲基-3-氮杂二环[3.1.0]己烷-2,4-二酮、250mg的Rh-Mo/SiO 2催化剂，30mL THF，搅拌下，进行氮气置换，氮气加压至0.4～0.5MPa，然后释压至0～0.05MPa，重复3次；然后进行氢气置换，氢气加压至0.4～0.5MPa，然后释压至0～0.05MPa，重复6次。然后再氢气加压至8MPa，设置温度为250℃，开始加热。反应18h后，降至室温。排压至0，然后充入氮气加压至0.4～0.5MPa，然后释压至0～0.05MPa，如此氮气置换3次。取少量反应体系溶液进行液相色谱(HPLC)分析。经HPLC分析显示还原产物6,6-二甲基-3-氮杂二环[3.1.0]己烷-2-酮的收率为8.2％，原料剩余90.1％。 Add 1g of 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione, 250mg of Rh-Mo/ SiO2 catalyst, and 30mL of THF into a 50mL autoclave. While stirring, perform nitrogen replacement, pressurize the nitrogen to 0.4~0.5MPa, and then release the pressure to 0~0.05MPa, repeat 3 times; then perform hydrogen replacement, pressurize the hydrogen to 0.4~0.5MPa, and then release the pressure to 0~0.05 MPa, repeat 6 times. Then pressurize the hydrogen gas to 8MPa, set the temperature to 250°C, and start heating. After reacting for 18 hours, the mixture was cooled to room temperature. Release the pressure to 0, then fill it with nitrogen and pressurize it to 0.4~0.5MPa, then release the pressure to 0~0.05MPa, and replace it with nitrogen three times. Take a small amount of the reaction system solution for liquid chromatography (HPLC) analysis. HPLC analysis showed that the yield of the reduction product 6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-one was 8.2%, and the remaining raw material was 90.1%.
将上述实施例中接收容器中得到的产物进行气相色谱(GC)或者液相色谱(HPLC)分析，计算相应的还原产物收率，如下表1所示。将接收容器内的反应物料进行重结晶或精馏，可以得到纯化的还原产物。The product obtained in the receiving container in the above embodiment was analyzed by gas chromatography (GC) or liquid chromatography (HPLC), and the corresponding reduction product yield was calculated, as shown in Table 1 below. The reaction material in the receiving container is recrystallized or distilled to obtain a purified reduction product.
表1Table 1
组别Group 收率(％)Yield (%)
实施例1Example 1 85.485.4
实施例2Example 2 50.250.2
实施例3Example 3 92.792.7
实施例4Example 4 93.593.5
实施例5Example 5 93.593.5
实施例6Example 6 91.591.5
实施例7Example 7 76.676.6
实施例8Example 8 69.169.1
实施例9Example 9 84.084.0
实施例10Example 10 83.383.3
实施例11Example 11 81.481.4
实施例12Example 12 81.581.5
实施例13Example 13 86.286.2
实施例14Example 14 79.179.1
实施例15Example 15 83.683.6
实施例16Example 16 62.562.5
实施例17Example 17 83.183.1
实施例18Example 18 78.078.0
实施例19Example 19 86.986.9
实施例20Example 20 51.251.2
实施例21Example 21 68.368.3
实施例22Example 22 93.593.5
实施例23Example 23 34.334.3
实施例24Example 24 60.260.2
实施例25Example 25 36.836.8
实施例26Example 26 95.195.1
实施例27Example 27 95.495.4
实施例28Example 28 60.360.3
实施例29Example 29 84.584.5
实施例30Example 30 86.486.4
实施例31Example 31 30.530.5
实施例32Example 32 42.342.3
实施例33Example 33 25.625.6
实施例34Example 34 66.866.8
对比例1Comparative example 1 8.28.2
从以上的描述中，可以看出，本申请利用氢气氢化还原酰胺能够获得较好的收率，相对于使用四氢铝锂等还原剂还原，避免了淬灭、过滤、水洗等后处理操作，后处理过程简单，三废量小，更适合工业化生产。采用均相催化剂进行连续的氢化还原反应，避免了非均相催化剂对官能团耐受性和选择性差的问题，均相氢化体系只有气/液两相，传质对反应的影响也大大降低；本申请所有催化剂都溶于溶剂中，都是活性位点，相对于非均相氢化，其催化效率显著提高；而且本申请采用的催化剂可在市场直接购买，来源广泛，降低了物料成本；使用连续氢化方式，反应器较为简单，设备成本低，占地面积小，可以不间断的进行反应，效率得到提升，产能提高，尤其适用于大规模工业生产；另外，本申请的连续氢化反应器的反应空间分散在管道中，与高压釜相比，安全性能得到大幅提升，尤其是在较高的温度和压力条件下更为安全。From the above description, it can be seen that the present application uses hydrogen to hydrogenate and reduce amide to obtain a better yield. Compared with reduction using reducing agents such as lithium aluminum tetrahydride, post-processing operations such as quenching, filtration, and water washing are avoided. The post-processing process is simple and the amount of waste is small, making it more suitable for industrial production. The use of homogeneous catalysts for continuous hydrogenation reduction reactions avoids the problems of poor tolerance and selectivity of heterogeneous catalysts to functional groups. The homogeneous hydrogenation system only has two phases of gas/liquid, and the impact of mass transfer on the reaction is also greatly reduced; this method All catalysts in the application are soluble in solvents and are active sites. Compared with heterogeneous hydrogenation, their catalytic efficiency is significantly improved; and the catalysts used in this application can be purchased directly in the market and come from a wide range of sources, which reduces material costs; the use of continuous In the hydrogenation method, the reactor is relatively simple, the equipment cost is low, and it occupies a small area. The reaction can be carried out uninterrupted, the efficiency is improved, and the production capacity is increased. It is especially suitable for large-scale industrial production; in addition, the reaction of the continuous hydrogenation reactor of this application The space is dispersed in the pipeline, and the safety performance is greatly improved compared with the autoclave, especially under higher temperature and pressure conditions.
以上仅为本发明的优选实施例而已，并不用于限制本发明，对于本领域的技术人员来说，本发明可以有各种更改和变化。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。The above are only preferred embodiments of the present invention and are not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and changes. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention shall be included in the protection scope of the present invention.

Claims (18)

  1. 一种酰胺连续氢化还原方法，其特征在于，包括以下步骤：在均相催化剂作用下使酰胺和氢气在溶剂中进行连续氢化还原反应，得到酰胺的氢化还原产物，A continuous hydrogenation reduction method of amide, which is characterized in that it includes the following steps: performing a continuous hydrogenation reduction reaction of amide and hydrogen in a solvent under the action of a homogeneous catalyst to obtain a hydrogenation reduction product of amide,
    其中，所述连续氢化还原反应的温度为100～350℃，所述酰胺具有以下结构式I所示结构：Wherein, the temperature of the continuous hydrogenation reduction reaction is 100-350°C, and the amide has the structure shown in the following structural formula I:
    Figure PCTCN2022096391-appb-100001
    Figure PCTCN2022096391-appb-100001
    所述酰胺的氢化还原产物具有以下结构式II所示结构：The hydrogenation reduction product of the amide has the structure shown in the following structural formula II:
    Figure PCTCN2022096391-appb-100002
    Figure PCTCN2022096391-appb-100002
    其中，n为1～5中的任意一个整数，m为0或1，R 1、R 2、R 3、R 4各自独立的为氢、C 1～C 18的直链烷基、C 3～C 18的支链烷基、C 3～C 18的环烷基、C 6～C 20的芳基、C 6～C 20的芳烷基、C 1～C 18的烷氧基、硅氧基；所述R 1和所述R 3、所述R 2和所述R 4可以分别成环，所述环是三元环、四元环、五元环、六元环或七元环；所述环上的氢可以被以下取代基任意的取代，所述取代基包括C 1～C 18的直链烷基、C 3～C 18的支链烷基、C 3～C 18的环烷基、C 6～C 20的芳基、C 6～C 20的芳烷基、C 1～C 18的烷氧基、硅氧基。 Among them, n is any integer from 1 to 5, m is 0 or 1, R 1 , R 2 , R 3 , and R 4 are each independently hydrogen, a linear alkyl group of C 1 to C 18 , and C 3 to C 18 branched alkyl group, C 3 to C 18 cycloalkyl group, C 6 to C 20 aryl group, C 6 to C 20 aralkyl group, C 1 to C 18 alkoxy group, siloxy group ; The R 1 and the R 3 , the R 2 and the R 4 may respectively form a ring, and the ring is a three-membered ring, a four-membered ring, a five-membered ring, a six-membered ring or a seven-membered ring; The hydrogen on the ring can be optionally substituted by the following substituents, which include linear alkyl groups of C 1 to C 18 , branched alkyl groups of C 3 to C 18 , and cycloalkyl groups of C 3 to C 18 . , C 6 to C 20 aryl group, C 6 to C 20 aralkyl group, C 1 to C 18 alkoxy group, and siloxy group.
  2. 根据权利要求1所述的酰胺连续氢化还原方法，其特征在于，所述n为1～5中的任意一个整数，R 1、R 2、R 3、R 4各自独立的为氢、C 1～C 6的直链烷基、C 3～C 6的支链烷基、C 3～C 6的环烷基、C 6～C 10的芳基、C 6～C 12的芳烷基、C 2～C 5的烷氧基、硅氧基；所述R 1和所述R 3、所述R 2和所述R 4可以分别成环，所述环是三元环、四元环、五元环、六元环或七元环；所述环上的氢可以被以下取代基任意的取代，所述取代基包括C 1～C 6的直链烷基、C 3～C 6的支链烷基、C 3～C 6的环烷基、C 6～C 10的芳基、C 6～C 12的芳烷基、C 2～C 5的烷氧基、硅氧基。 The continuous hydrogenation reduction method of amide according to claim 1, characterized in that, n is any integer from 1 to 5, and R 1 , R 2 , R 3 and R 4 are each independently hydrogen, C 1 to C 6 linear alkyl group, C 3 to C 6 branched alkyl group, C 3 to C 6 cycloalkyl group, C 6 to C 10 aryl group, C 6 to C 12 aralkyl group, C 2 ~C 5 alkoxy group, siloxy group; the R 1 and the R 3 , the R 2 and the R 4 can respectively form a ring, and the ring is a three-membered ring, a four-membered ring, a five-membered ring Ring, six-membered ring or seven-membered ring; the hydrogen on the ring can be optionally substituted by the following substituents, which include linear alkyl groups of C 1 to C 6 and branched alkyl groups of C 3 to C 6 group, C 3 to C 6 cycloalkyl group, C 6 to C 10 aryl group, C 6 to C 12 aralkyl group, C 2 to C 5 alkoxy group, and siloxy group.
  3. 根据权利要求1所述的酰胺连续氢化还原方法，其特征在于，其中，n为1或2，R 1、R 2、R 3、R 4各自独立的为氢、C 1～C 3的直链烷基、C 3或C 4的支链烷基、C 6～C 10的芳基、C 2～C 5的烷氧基、硅氧基；所述R 1和所述R 3、或者所述R 2和所述R 4可以成环，所述环是三元环、四元环或六元环；所述环上的氢可以被以下取代基任意的取代，所述取代基包括C 1～C 6的直链烷基、C 3～C 6的支链烷基、C 3～C 6的环烷基、C 6～C 10的芳基、C 6～C 12的芳烷基、C 2～C 5的烷氧基、硅氧基。 The amide continuous hydrogenation reduction method according to claim 1, wherein n is 1 or 2, and R 1 , R 2 , R 3 , and R 4 are each independently hydrogen and a linear chain of C 1 to C 3 Alkyl group, C 3 or C 4 branched alkyl group, C 6 to C 10 aryl group, C 2 to C 5 alkoxy group, siloxy group; the R 1 and the R 3 , or the R 2 and the R 4 can form a ring, and the ring is a three-membered ring, a four-membered ring or a six-membered ring; the hydrogen on the ring can be optionally substituted by the following substituents, the substituents include C 1 ~ C 6 linear alkyl group, C 3 to C 6 branched alkyl group, C 3 to C 6 cycloalkyl group, C 6 to C 10 aryl group, C 6 to C 12 aralkyl group, C 2 ~C 5 alkoxy group, siloxy group.
  4. 根据权利要求1所述的酰胺连续氢化还原方法，其特征在于，所述n为1或2，所述R 1、所述R 2、所述R 3、所述R 4各自独立的为氢，或者所述R 1和所述R 3、或者所述R 2和所述 R 4可以成环，所述环是三元环或者六元环，所述环上的氢可以被甲基或乙基中的一种或者多种任意的取代。 The amide continuous hydrogenation reduction method according to claim 1, characterized in that, the n is 1 or 2, and the R 1 , the R 2 , the R 3 and the R 4 are each independently hydrogen, Or the R 1 and the R 3 , or the R 2 and the R 4 may form a ring, the ring is a three-membered ring or a six-membered ring, and the hydrogen on the ring may be replaced by a methyl group or an ethyl group. One or more of them may be substituted.
  5. 根据权利要求1所述的酰胺连续氢化还原方法，其特征在于，所述氢化还原反应的压力为3～10MPa；所述氢化还原反应的温度为200～250℃。The continuous hydrogenation reduction method of amide according to claim 1, characterized in that the pressure of the hydrogenation reduction reaction is 3 to 10 MPa; the temperature of the hydrogenation reduction reaction is 200 to 250°C.
  6. 根据权利要求5所述的酰胺连续氢化还原方法，其特征在于，所述氢化还原反应的压力为5～8MPa。The continuous hydrogenation reduction method of amide according to claim 5, characterized in that the pressure of the hydrogenation reduction reaction is 5 to 8 MPa.
  7. 根据权利要求1至6中任一项所述的酰胺连续氢化还原方法，其特征在于，所述均相催化剂包括金属配合物和配体，所述金属配合物选自钌配合物、钴配合物中的任意一种或者多种；所述金属配合物用量为所述酰胺的0.1mol％～50mol％；所述配体选自膦配体、氮配体、膦-氮配体中的任意一种或者多种；所述配体的用量为所述酰胺的0.1mol％～50mol％。The amide continuous hydrogenation reduction method according to any one of claims 1 to 6, characterized in that the homogeneous catalyst includes a metal complex and a ligand, and the metal complex is selected from a ruthenium complex and a cobalt complex. Any one or more of them; the amount of the metal complex is 0.1 mol% to 50 mol% of the amide; the ligand is selected from any one of phosphine ligands, nitrogen ligands, and phosphine-nitrogen ligands One or more kinds; the amount of the ligand is 0.1 mol% to 50 mol% of the amide.
  8. 根据权利要求7所述的酰胺连续氢化还原方法，其特征在于，所述金属配合物用量为所述酰胺的1mol％～5mol％。The continuous hydrogenation reduction method of amide according to claim 7, characterized in that the amount of the metal complex is 1 mol% to 5 mol% of the amide.
  9. 根据权利要求7所述的酰胺连续氢化还原方法，其特征在于，所述配体的用量为所述酰胺的1mol％～5mol％。The continuous hydrogenation reduction method of amide according to claim 7, characterized in that the amount of the ligand is 1 mol% to 5 mol% of the amide.
  10. 根据权利要求7所述的酰胺连续氢化还原方法，其特征在于，所述溶剂为四氢呋喃、乙二醇二甲醚、2-甲基四氢呋喃、甲基叔丁基醚、二氧六环、甲苯、二甲苯、庚烷中的任意一种或者多种；所述溶剂的体积为酰胺体积的5～50倍。The amide continuous hydrogenation reduction method according to claim 7, wherein the solvent is tetrahydrofuran, ethylene glycol dimethyl ether, 2-methyltetrahydrofuran, methyl tert-butyl ether, dioxane, toluene, Any one or more of xylene and heptane; the volume of the solvent is 5 to 50 times the volume of the amide.
  11. 根据权利要求10所述的酰胺连续氢化还原方法，其特征在于，所述连续氢化还原反应的反应体系中还包括路易斯酸类添加剂，所述路易斯酸类添加剂选自三氟化硼乙醚、三氟甲磺酸镓、三氟甲磺酸锌、三氟甲磺酸银、三氟甲磺酸铈、三氟甲磺酸镱、三氟甲磺酸、甲基磺酸中的任意一种或者多种；所述路易斯酸类添加剂的用量为所述酰胺的0.1mol％～200mol％。The continuous hydrogenation reduction method of amide according to claim 10, characterized in that the reaction system of the continuous hydrogenation reduction reaction also includes a Lewis acid additive, and the Lewis acid additive is selected from boron trifluoride ether, trifluoride Any one or more of gallium methanesulfonate, zinc triflate, silver triflate, cerium triflate, ytterbium triflate, triflate, and methanesulfonic acid. species; the dosage of the Lewis acid additive is 0.1 mol% to 200 mol% of the amide.
  12. 根据权利要求11所述的酰胺连续氢化还原方法，其特征在于，所述路易斯酸类添加剂的用量为所述酰胺的2mol％～10mol％。The continuous hydrogenation reduction method of amide according to claim 11, characterized in that the amount of the Lewis acid additive is 2 mol% to 10 mol% of the amide.
  13. 根据权利要求11所述的酰胺连续氢化还原方法，其特征在于，所述酰胺连续氢化还原方法包括：The amide continuous hydrogenation reduction method according to claim 11, characterized in that the amide continuous hydrogenation reduction method includes:
    将所述氢气和液相成分连续输送至连续反应器中进行所述连续氢化还原反应，The hydrogen gas and liquid phase components are continuously transported to a continuous reactor to perform the continuous hydrogenation reduction reaction,
    通过控制所述氢气和所述液相成分的流速使所述氢气和所述液相成分在常温常压下的体积比为10～500:1，所述的液相成分包括所述酰胺、所述催化剂、所述路易斯酸类添加剂和所述溶剂。By controlling the flow rates of the hydrogen gas and the liquid phase component, the volume ratio of the hydrogen gas and the liquid phase component at normal temperature and pressure is 10 to 500:1. The liquid phase component includes the amide, the The catalyst, the Lewis acid additive and the solvent.
  14. 根据权利要求13所述的酰胺连续氢化还原方法，其特征在于，所述氢气和所述液相成分在常温常压下的体积比为25～100:1。The continuous hydrogenation reduction method of amide according to claim 13, characterized in that the volume ratio of the hydrogen gas and the liquid phase component at normal temperature and pressure is 25 to 100:1.
  15. 根据权利要求13所述的酰胺连续氢化还原方法，其特征在于，所述液相成分共同进入所述连续反应器中，The continuous hydrogenation reduction method of amide according to claim 13, characterized in that the liquid phase components enter the continuous reactor together,
    或者，所述液相成分中的一种或者多种分别进入所述连续反应器中，且所述催化剂以催化剂溶液、所述路易斯酸类添加剂以路易斯酸类添加剂的溶液形式进入所述连续反应器中。Alternatively, one or more of the liquid phase components enter the continuous reactor respectively, and the catalyst enters the continuous reaction in the form of a catalyst solution, and the Lewis acid additives enter the continuous reaction in the form of a solution of Lewis acid additives. in the vessel.
  16. 根据权利要求13或15所述的酰胺连续氢化还原方法，其特征在于，所述连续反应器为盘管反应器，所述盘管反应器的内径为1～20mm。The continuous hydrogenation reduction method of amide according to claim 13 or 15, characterized in that the continuous reactor is a coil reactor, and the inner diameter of the coil reactor is 1 to 20 mm.
  17. 根据权利要求16所述的酰胺连续氢化还原方法，其特征在于，所述盘管反应器的内径为2～8mm。The continuous hydrogenation reduction method of amide according to claim 16, characterized in that the inner diameter of the coil reactor is 2 to 8 mm.
  18. 根据权利要求15所述的酰胺连续氢化还原方法，其特征在于，所述连续反应器前设置混合装置，以将进入所述连续反应器的所述催化剂溶液、所述路易斯酸类添加剂溶液与所述酰胺及所述溶剂混合。The continuous hydrogenation reduction method of amide according to claim 15, characterized in that a mixing device is provided in front of the continuous reactor to mix the catalyst solution, the Lewis acid additive solution entering the continuous reactor and the The amide and the solvent are mixed.
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