A continuous method for the synthesis of amine compounds

Abstract

The application discloses a continuous synthesis method of an amine compound, and preparation steps comprise the following steps: (1) a first catalyst is filled in a first reaction module, the first catalyst is activated under a nitrogen atmosphere and is heated; (2) reactants A are introduced into the first reaction module under the condition of having a solvent A1 or without a solvent, and reactants B are introduced into the first reaction module under the condition of having a solvent B1 or without a solvent, and a nitro compound intermediate C is obtained through condensation separation of a product; (3) a second catalyst is filled in a second reaction module, the second catalyst is activated under a nitrogen atmosphere and is heated; (4) the obtained nitro compound intermediate C is introduced into the second reaction module under the condition of having a solvent D or without a solvent, and a product is collected through condensation and gas-liquid separation, so that the amine compound is obtained. The reaction route is more green, the catalyst can be recycled, the defect that the amine compound cannot be continuously reacted at present is overcome, and sustainable production can be realized.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical intermediate synthesis. It relates to a method for the continuous synthesis of amine compounds from aldehydes and nitroalkanes. Background Technology

[0002] Amine compounds have wide applications in pharmaceutical synthesis. They are important pharmaceutical intermediates. For example, serine (2-amino-1,3-propanediol), a key intermediate used in the nonionic contrast agent iopamidol, is a typical amine compound. Iopamidol, as a nonionic contrast agent, can be used as a diagnostic reagent for the blood, lymphatic, urinary, and nervous systems, and is now widely used in many countries abroad.

[0003]

[0004] For example, Tris (tris(hydroxymethyl)aminomethane), a commonly used solvent for nucleic acids and proteins in molecular biology, has wide applications in the detection of sudden medical events.

[0005]

[0006] Currently, the existing technology for synthesizing the above-mentioned amine compounds mainly involves preparing nitro compounds from the corresponding nitroalkanes and aldehydes through a condensation reaction, and then reducing them to obtain amine compounds.

[0007] Taking serine as an example, current technologies often use formaldehyde and nitromethane in a reactor to generate 2-nitro-1,3-propanediol under alkaline catalysis, and then reduce it with hydrogen to generate 2-amino-1,3-propanediol.

[0008] Conventional batch reactors suffer from uneven mass transfer due to stirring, a tendency to over-react, and slow temperature control and feedback. Furthermore, batch reactors place higher demands on operator skills, product quality is more susceptible to human factors, and the operation is more dangerous.

[0009] Due to the drawbacks of the aforementioned processes, cleaner and newer processes are still being explored and developed. For example, US Patent 4448999 uses sodium 2-nitro-1,3-propanediol as a raw material and methanol as a solvent, employing a catalytic hydrogenation reaction, but the yield of serine is only 74%. CN101100439 reports the preparation of serine from diethyl malonate via nitrosation and reduction with sodium metal and ethanol. While these methods are relatively simple, the use of sodium metal poses a significant risk in actual production.

[0010] With increasing safety awareness and stricter product quality requirements, the demands for safety, operating environment, and operational stability are constantly rising. Everyone is looking forward to a green and safe continuous production facility for continuous production. Since the rise of microreaction technology in the mid-20th century, there have been thousands of reports on its application in organic synthesis. However, currently, there are very few reports, both domestically and internationally, on the condensation synthesis of serinel from nitromethane and formaldehyde / paraformaldehyde using heterogeneous catalysts, and even fewer reports on modifying the reaction process to adopt a continuous flow reaction design. The main reason is that traditional alkaline catalysts, such as sodium hydroxide, are easily lost in packed fixed beds, and it is difficult to separate the product and catalyst in fluidized beds. In microchannel reactions, the generated solids easily clog the pipelines. Currently, the mainstream approach reported is still to use batch reactors for condensation reactions to prepare serinel. However, batch reactors inevitably suffer from unstable selectivity in the condensation reaction, high labor costs, and operational safety issues.

[0011] For example, in a reaction vessel, nitromethane and formaldehyde / paraformaldehyde undergo a condensation reaction under the action of sodium hydroxide to produce sodium 2-nitro-1,3-propanediol. During the reaction, the temperature rises rapidly by 20-30°C, posing a safety hazard. In addition, the product yield is relatively low due to factors such as alkali concentration, stirring, and uneven heat exchange.

[0012] In summary, current synthesis processes for amine-based pharmaceutical intermediates all suffer from drawbacks such as uncontrollable exothermic reactions, poor selectivity, large equipment footprint, and uncontrollable risks. Furthermore, these processes are all batch reactions with low concentrations and generally low production efficiency. Summary of the Invention

[0013] To address the problems encountered in the aforementioned methods, this invention provides a continuous synthesis method for amine compounds. This method utilizes a specific catalyst, using aldehydes and nitroalkanes as raw materials, to directly prepare amine compounds through condensation followed by hydrogenation under the catalytic action. The method for synthesizing amine compounds in this invention is simple, safe, and can be operated continuously, with high yields, reduced emissions of waste, and is beneficial for industrial production.

[0014] To achieve the above-mentioned objectives of this invention, this invention provides a continuous synthesis method for amine compounds, the preparation steps of which are as follows:

[0015] (1) The first catalyst is loaded into the first reaction module and heated and activated in a nitrogen atmosphere;

[0016] (2) Reactant A is introduced into the first reaction module under the conditions of having solvent A1 or no solvent, and reactant B is introduced into the first reaction module under the conditions of having solvent B1 or no solvent. The product is separated by condensation to obtain nitro compound intermediate C.

[0017] (3) The second catalyst is loaded into the second reaction module, and the second catalyst is heated and activated in a nitrogen atmosphere;

[0018] (4) The obtained nitro compound intermediate C is introduced into the second reaction module for reaction under the condition of solvent D or without solvent; the product is collected by condensation and gas-liquid separation to obtain amine compounds.

[0019] The first catalyst and the second catalyst are different supported metal compound catalysts.

[0020] The first reaction module and the second reaction module are the same or different reactors, respectively selected from one of the following: microchannel reactor, tubular reactor, helical propulsion reactor, fixed bed reactor, and fluidized bed reactor;

[0021] As a preferred embodiment of the present invention, reactant A is selected from aldehyde compounds with the following structure:

[0022] ,

[0023] R1 and R2 are each individually selected from hydrogen or C1-C6 alkyl groups, that is, when R1 is hydrogen, R2 is a C1-C6 alkyl group; when R1 is a C1-C6 alkyl group, R2 is hydrogen; preferably hydrogen, methyl, or ethyl.

[0024] In a preferred embodiment of the present invention, reactant B has the general formula R3NO2.

[0025] R3 is selected from C1-C6 alkyl groups, preferably methyl or ethyl;

[0026] As a preferred embodiment of the present invention, intermediate C is a nitrate compound with the following structure:

[0027]

[0028] R4, R5, and R6 are selected from -H, -CH3, -CH2OH, and -CHOH(CH2). n CH3, where n is an integer from 0 to 3, such as 0, 1, 2 or 3.

[0029] In step (2),

[0030] As a preferred embodiment of the present invention, the mass percentage concentration of aldehyde compounds in the solution formed by reactant A dissolved in solvent A1 is 10-100%, preferably 20%-70%, more preferably 25%-40%, wherein 100% indicates that it may be solvent-free.

[0031] As a preferred embodiment of the present invention, the mass percentage concentration of nitroalkane in the solution formed by reactant B dissolving in solvent B1 is 10-100%, preferably 50%-100%, more preferably 70%-100%, wherein 100% indicates that it may be solvent-free.

[0032] As a preferred embodiment of the present invention, the molar ratio of reactant A to reactant B is 1:(0.1-1), preferably 1:(0.2-1), and more preferably 1:(0.3-1). By adjusting the molar ratio of reactant A to reactant B and selecting a specific catalyst, the number of hydroxymethyl groups on the nitro-containing compound can be controlled to obtain the target product.

[0033] In step (4),

[0034] As a preferred embodiment of the present invention, the mass percentage concentration of the nitro compound in the solution formed by dissolving the nitro compound intermediate C in solvent D is 10-100%, preferably 20%-70%, more preferably 25%-40%, wherein 100% indicates that it may be solvent-free.

[0035] In step (1),

[0036] The first catalyst includes a support and a first metal compound supported on the support.

[0037] As a preferred embodiment of the present invention, the active metal component corresponding to the first metal compound is selected from one or more of cesium, rubidium, barium, cerium, ytterbium, and scandium;

[0038] Preferably, it is one or more of barium, cerium, ytterbium, and scandium;

[0039] More preferably, it is one or more of cerium, ytterbium, and scandium.

[0040] In step (1),

[0041] As a preferred embodiment of the present invention, the first carrier is selected from one or more of activated carbon, SiO2, γ-Al2O3, ZrO2, MgO, CaCO3, ZnO, and zeolite molecular sieves;

[0042] Preferably, it is one or more of γ-Al2O3, ZrO2, MgO, CaCO3, ZnO, and zeolite molecular sieves;

[0043] More preferably, it is one or more of γ-Al2O3, ZrO2, MgO, and zeolite molecular sieves.

[0044] In step (1),

[0045] As a preferred embodiment of the present invention, the loading of the metal compound in the first catalyst is 0.1%-10wt%; preferably 0.1%-5wt%; more preferably 0.1%-3wt%.

[0046] In step (3),

[0047] The second catalyst comprises a second support and a second metal compound supported on the support;

[0048] As a preferred embodiment of the present invention, the active metal component corresponding to the second metal compound is selected from one or more of ruthenium, palladium, platinum, rhodium, nickel, copper, and zinc; preferably one or more of ruthenium, palladium, nickel, and zinc; more preferably one or more of ruthenium, palladium, and nickel.

[0049] As a preferred embodiment of the present invention, the second carrier is selected from one or more of activated carbon, SiO2, γ-Al2O3, ZrO2, MgO, ZnO, TiO2, and zeolite molecular sieves; preferably one or more of SiO2, γ-Al2O3, MgO, ZnO, TiO2, and zeolite molecular sieves; more preferably one or more of SiO2, γ-Al2O3, TiO2, and zeolite molecular sieves.

[0050] As a preferred embodiment of the present invention, the loading of the metal compound in the second catalyst is 0.1%-10wt%; preferably 0.1%-5wt%; more preferably 0.1%-3wt%.

[0051] In step (2),

[0052] The solvent A1 is selected from one or more of water, methanol, ethanol, propanol, isopropanol, n-hexane, n-heptane, DMF, dichloroethane, dichloromethane, and tetrahydrofuran;

[0053] Preferably, it is one or more of water, methanol, ethanol, propanol, isopropanol, n-hexane, n-heptane, and tetrahydrofuran;

[0054] More preferably, it is one or more of water, methanol, and ethanol.

[0055] In step (2),

[0056] The solvent B1 is selected from one or more of water, methanol, ethanol, propanol, isopropanol, n-hexane, n-heptane, DMF, dichloroethane, dichloromethane, and tetrahydrofuran; preferably one or more of water, methanol, ethanol, propanol, isopropanol, n-hexane, n-heptane, and tetrahydrofuran; more preferably one or more of water, methanol, and ethanol.

[0057] In step (4),

[0058] The solvent D is selected from one or more of water, methanol, ethanol, propanol, isopropanol, n-hexane, n-heptane, DMF, dichloroethane, dichloromethane, and tetrahydrofuran; preferably one or more of water, methanol, ethanol, propanol, isopropanol, n-hexane, n-heptane, and tetrahydrofuran; more preferably one or more of water, methanol, and ethanol.

[0059] As a preferred technical solution of the present invention, in step (2), the reaction temperature is 10-60℃, and in step (4), the reaction temperature is 100-400℃;

[0060] As a preferred embodiment of the present invention, when the reaction occurs in the first reactor and the second reactor, the reaction pressure is 0.1-3 MPa, preferably 0.1-2 MPa, and more preferably 0.1-0.5 MPa.

[0061] As a preferred embodiment of the present invention, in step (2), during the reaction in the first reactor, the mass hourly space velocity (MSV) of the reaction feed (based on aldehyde compounds) is 0.01-10 h⁻¹. -1 Preferably 0.01-5h -1 More preferably 0.01-1h -1 The calculation formula is as follows:

[0062]

[0063] The mass flow rate of aldehyde compounds is expressed in g / min, and the mass of catalyst is expressed in g.

[0064] As a preferred embodiment of the present invention, in step (2), when the reaction occurs in the first reactor, the reaction pressure is 0.1-3 MPa, preferably 0.1-2 MPa, and more preferably 0.1-0.5 MPa.

[0065] As a preferred embodiment of the present invention, in step (4), during the reaction in the second reactor, the mass hourly space velocity (based on nitro compounds) of the reaction feed is 0.01-10 h⁻¹. -1 Preferably 0.01-5h -1 More preferably 0.01-1h -1 The calculation formula is as follows:

[0066]

[0067] The mass flow rate of the nitro compound is expressed in g / min, and the mass of the catalyst is expressed in g.

[0068] As a preferred embodiment of the present invention, in step (4), when the reaction is carried out in the second reactor, the pressure is 0.1-5 MPa, preferably 0.1-3 MPa, and more preferably 0.1-2 MPa.

[0069] As a preferred technical solution of the present invention, in step (4), the reaction temperature with hydrogen is 100-400℃ and the pressure is 0.1-5Mpa.

[0070] As a preferred embodiment of the present invention, the first catalyst is prepared by a preparation method comprising the following steps:

[0071] 1) Dissolve the first metal compound in a solvent to prepare a 0.1-10 wt% aqueous solution of the first metal; the solvent is one of water, aqueous nitric acid solution, and aqueous hydrochloric acid solution;

[0072] 2) Impregnate the first carrier with an aqueous solution of one or more first metals;

[0073] 3) Dry the impregnated solid at 60-160℃ for 3-12 hours, preferably at 90℃ for 6 hours;

[0074] 4) The dried solid is calcined at 300-600℃ for 2-6 hours, preferably at 500℃ for 3 hours, to obtain the first catalyst;

[0075] Preferably, the heating rate during the drying process is 2-5℃ / min, and the heating rate during the calcination process is 2-5℃ / min.

[0076] As a preferred embodiment of the present invention, the second catalyst is prepared by a preparation method comprising the following steps:

[0077] 1) Dissolve the second metal compound in a solvent to prepare a 0.01-20 wt% aqueous solution of the second metal; the solvent is one of water, aqueous nitric acid solution, or aqueous hydrochloric acid solution;

[0078] 2) Add the second carrier to the second metal aqueous solution, stir for 3-8 hours, preferably 5 hours, and then evaporate to dryness;

[0079] 3) Dry the impregnated solid at 80-160℃ for 3-12 hours, preferably at 100℃ for 6 hours;

[0080] 4) The dried solid is calcined at 300-600℃ for 2-6 hours, preferably at 500℃ for 3 hours, to obtain the second catalyst;

[0081] Preferably, the heating rate during the drying process is 2-5℃ / min, and the heating rate during the calcination process is 2-5℃ / min.

[0082] Beneficial effects

[0083] The reaction process provided by this invention is safer than traditional processes, effectively preventing drastic temperature fluctuations caused by excessively rapid reactions. The reaction route is more environmentally friendly, allowing for catalyst recycling and overcoming the limitation of continuous reactions of amine compounds. It enables long-term continuous reactions and sustainable production. Furthermore, continuous reactions are easier to automate and simpler to operate. Continuous feeding reduces backmixing and improves product selectivity. It also significantly improves heat and mass transfer efficiency, keeping the reaction away from explosion hazards and achieving a safe, stable, and efficient process. Attached Figure Description

[0084] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0085] Figure 1 This is a process flow diagram of the synthesis method of the present invention. Detailed Implementation

[0086] The present invention will now be described in detail. Before proceeding with the description, it should be understood that the terminology used in this specification and the appended claims should not be construed as limited to its general or dictionary meaning, but rather should be interpreted according to the meaning and concept corresponding to the technical aspects of the invention, based on the principle that the inventors are allowed to appropriately define the terms for the best interpretation. Therefore, the description presented herein is merely a preferred example for illustrative purposes and is not intended to limit the scope of the invention. It should be understood that other equivalents or modifications can be obtained from it without departing from the spirit and scope of the invention.

[0087] The following embodiments are merely examples illustrating implementations of the present invention and do not constitute any limitation on the present invention. Those skilled in the art will understand that modifications made without departing from the spirit and concept of the present invention fall within the protection scope of the present invention. Unless otherwise specified, the reagents and instruments used in the following embodiments are commercially available products.

[0088] Preferred embodiments of the present disclosure will be described in detail below with reference to the accompanying drawings. Before description, it should be understood that the terminology used in the specification and appended claims should not be construed as limited to its general and dictionary meaning, but rather should be interpreted based on the principle of allowing the inventors to appropriately define the terminology for the best interpretation, and based on its meaning and concept corresponding to the technical level of the invention. Therefore, the description herein is merely a preferred example for illustrative purposes and is not intended to limit the scope of the invention; thus, it should be understood that other equivalent implementations and modifications can be made without departing from the spirit and scope of the invention.

[0089] In this document, the terms “comprising,” “including,” “having,” “containing,” or any other similar terms are open-ended conjunctions intended to cover non-exclusive inclusions. For example, a composition or article containing a plurality of elements is not limited to those listed herein, but may also include other elements not explicitly listed but typically inherent to the composition or article. Furthermore, unless explicitly stated to the contrary, the term “or” is inclusive, not exclusive. For example, the condition “A or B” is satisfied in any of the following cases: A is true (or exists) and B is false (or does not exist); A is false (or does not exist) and B is true (or exists); A and B are both true (or exist). Moreover, in this document, the terms “comprising,” “including,” “having,” and “containing” should be interpreted as specifically disclosed and simultaneously cover closed or semi-closed conjunctions such as “composed of” and “substantially composed of.”

[0090] In this document, all features or conditions defined in the form of numerical ranges or percentage ranges are for the sake of brevity and convenience only. Accordingly, descriptions of numerical ranges or percentage ranges should be considered as covering and specifically disclosing all possible secondary ranges and individual values ​​within those ranges, particularly integer values. For example, a range description of "1 to 8" should be considered as specifically disclosing all secondary ranges such as 1 to 7, 2 to 8, 2 to 6, 3 to 6, 4 to 8, 3 to 8, etc., particularly secondary ranges defined by all integer values, and should be considered as specifically disclosing individual values ​​within those ranges such as 1, 2, 3, 4, 5, 6, 7, 8, etc. Unless otherwise specified, the foregoing interpretation applies to all content throughout this invention, regardless of its scope.

[0091] If a quantity or other numerical value or parameter is expressed as a range, a preferred range, or a series of upper and lower limits, it should be understood that this document has specifically disclosed all ranges consisting of any upper or preferred value of that range and the lower or preferred value of that range, regardless of whether such ranges are separately disclosed. Furthermore, when a range of numerical values ​​is mentioned herein, unless otherwise stated, the range shall include its endpoints and all integers and fractions within the range.

[0092] In this document, numerical values ​​are to be understood as having a precision with significant digits, provided that the purpose of the invention can be achieved. For example, the number 40.0 should be understood to cover a range from 39.50 to 40.49.

[0093] To clarify the invention, parts irrelevant to the description have been omitted from the drawings, and throughout the specification, the same or similar parts are indicated by the same reference numerals.

[0094] The terms “first,” “second,” etc., used in this article are used to explain various constituent elements, and they are only used for the purpose of distinguishing one constituent element from another.

[0095] Unless otherwise specified, the raw materials, reagents and methods used in the examples are all commonly used in the art.

[0096] In the following examples, unless otherwise stated, the reagents and solvents disclosed were purchased from Sinopharm Chemical Reagent Co., Ltd. Formaldehyde and paraformaldehyde were purchased from Tieta Reagent. Water was selected from Wahaha. SiO2 and γ-Al2O3 were selected from Qingdao Hailang Silica Gel Desiccant Co., Ltd., and zeolite molecules were screened from Tianjin Nanhua Catalyst Co., Ltd. High-purity nitrogen and high-purity hydrogen were selected from Qingdao Dehai Weiye Gas Technology Co., Ltd.

[0097] The continuous flow reactor used was selected from Shandong Weijing Chemical Technology Co., Ltd. and Haomai Group. The electronic scale was selected from Changzhou Lucky Electronic Equipment Co., Ltd. The top-mounted stirring and mixing equipment was selected from Shanghai Huxi Industrial Co., Ltd. The drying oven was selected from Gongyi Yuhua Instrument Co., Ltd. The muffle furnace was selected from Longkou Electric Furnace Factory.

[0098] Example 1 of catalyst preparation

[0099] 1) Dissolve 10g of cerium nitrate in 1L of water by stirring thoroughly.

[0100] 2) Immerse 500g of γ-Al2O3 (carrier) in the above solution for 8h.

[0101] 3) Dry the impregnated γ-Al2O3 at 90℃ for 6 hours.

[0102] 4) The dried γ-Al2O3 was calcined at 500℃ for 3 hours to obtain catalyst 1-1.

[0103] Example 2 of catalyst preparation

[0104] 1) Dissolve 10g of ytterbium nitrate in 1L of water by stirring thoroughly.

[0105] 2) Immerse 500g of γ-Al2O3 (carrier) in the above solution for 8h.

[0106] 3) Dry the impregnated γ-Al2O3 at 90℃ for 6 hours.

[0107] 4) The dried γ-Al2O3 was calcined at 500℃ for 3 hours to obtain catalyst 1-2.

[0108] Example 3 of catalyst preparation

[0109] 1) Dissolve 10g of ytterbium nitrate in 1L of water by stirring thoroughly.

[0110] 2) Soak 500g of ZrO2 in the above solution for 8 hours.

[0111] 3) Dry the impregnated ZrO2 at 90℃ for 6 hours.

[0112] 4) The dried ZrO2 was calcined at 500℃ for 3 hours to obtain catalyst 1-3.

[0113] Example 4 of catalyst preparation

[0114] 1) Dissolve 10g of ytterbium nitrate in 1L of water by stirring thoroughly.

[0115] 2) Soak 500g of MgO in the above solution for 8 hours.

[0116] 3) Dry the impregnated MgO at 90℃ for 6 hours.

[0117] 4) The dried MgO was calcined at 500℃ for 3 hours to obtain catalyst 1-4.

[0118] Example 1 of Second Catalyst Preparation

[0119] 1) Dissolve 50g of ruthenium nitrate in 3L of water by stirring thoroughly.

[0120] 2) Immerse 1500g of SiO2 (support) in the above solution for 8 hours.

[0121] 3) Dry the impregnated SiO2 (support) at 100℃ for 6 hours.

[0122] 4) The dried SiO2 (support) is calcined at 500℃ for 3 hours to obtain catalyst 2-1.

[0123] Example 2 of second catalyst preparation

[0124] 1) Dissolve 50g of palladium nitrate in 3L of water by stirring thoroughly.

[0125] 2) Immerse 1500g of SiO2 (support) in the above solution for 8 hours.

[0126] 3) Dry the impregnated SiO2 (support) at 100℃ for 6 hours.

[0127] 4) The dried SiO2 (support) is calcined at 500℃ for 3 hours to obtain catalyst 2-2.

[0128] Example 3 of Second Catalyst Preparation

[0129] 1) Dissolve 50g of nickel nitrate in 3L of water by stirring thoroughly.

[0130] 2) Immerse 1500g of SiO2 (support) in the above solution for 8 hours.

[0131] 3) Dry the impregnated SiO2 (support) at 100℃ for 6 hours.

[0132] 4) The dried SiO2 (support) is calcined at 500℃ for 3 hours to obtain catalyst 2-3.

[0133] Example 4 of second catalyst preparation

[0134] 1) Dissolve 50g of nickel nitrate in 3L of water by stirring thoroughly.

[0135] 2) Immerse 1500g of TiO2 (support) in the above solution for 8 hours.

[0136] 3) Dry the impregnated TiO2 (support) at 100℃ for 6 hours.

[0137] 4) The dried TiO2 (support) is calcined at 500℃ for 3 hours to obtain catalyst 2-4.

[0138] Examples 1-10

[0139] 1) Load the first catalyst (200g) into reaction module 1, heat to the reaction temperature in a nitrogen atmosphere of 100ml / min, and maintain for 3h to activate the catalyst.

[0140] 2) Reactants A and B are fed into the first reaction module separately using a plunger pump for reaction. The product is then separated by condensation to obtain intermediate C1-C10 nitro compounds;

[0141]

[0142] Example 11

[0143] 1) Reactant A, reactant B and the first catalyst solution are fed into the first reaction module by a plunger pump to carry out the reaction. The product is separated by condensation to obtain nitro compound C11.

[0144] 2) The ratio of the catalyst molar amount to reactant B is 0.2, and the concentration of the sodium hydroxide solution is 30%.

[0145]

[0146] Note: The reaction pressure is atmospheric pressure.

[0147] The structure of C1, C2, C3, C4, C5, and C11 is as follows: The C6, C7, C8, and C9 structures are The structure of C10 is .

[0148] As can be seen from Examples 1-5 and Example 11, using conventional sodium hydroxide as a catalyst, the conversion rate of nitromethane is 97.8%. The selectivity was only 86.1%, and the product contained some sodium salt, which significantly affected subsequent hydrogenation. Often, the pH needed to be adjusted to 5-6 before proceeding to the next hydrogenation step, increasing the number of reaction steps and generating more waste. However, using catalysts 1, 2, 3, and 4 described in this invention achieved a conversion rate of over 98.5%, with superior product selectivity. This demonstrates that metal-supported catalysts can significantly improve catalytic activity.

[0149] As can be seen from Examples 6-9, when the molar ratio of reactant A to reactant B is ≥3, the conversion rate of nitromethane is greater than 99% using the catalyst of the present invention. The selectivity is greater than 98.5%. The catalytic effect is significant.

[0150] As can be seen from Example 10, when the molar ratio of reactant A to reactant B is close to 1, the conversion rate of nitroalkanes is greater than 99% using the catalyst of the present invention. The selectivity is greater than 97%.

[0151] Examples 12-22

[0152] 1) The second catalyst (800g) is loaded into the second reaction module, and the temperature is raised to the reaction temperature in a nitrogen atmosphere at 200ml / min and maintained for 3h to activate the catalyst. Then the nitrogen is replaced with hydrogen.

[0153] 2) The obtained nitro compound intermediate C was introduced into the second reaction module via a plunger pump to react with hydrogen gas at a flow rate of 100 ml / min and a final hydrogen back pressure of 1.5 MPa. The product was collected by condensation and gas-liquid separation to obtain amine compounds.

[0154]

[0155] Note: The reaction pressure above is 1.5 MPa.

[0156] As can be seen from Examples 12-17, under the catalysis of Raney nickel, intermediate C1 ( At a temperature not exceeding 150°C, the mass hourly space velocity (MHV) is 0.1 h⁻¹. -1 At that time, the conversion rate was 94.3%. The selectivity is 87%. When using catalysts 2-1 to 2-4 described in this invention, the conversion rate is higher under the same conditions, and the selectivity is greater than 95% in all cases. This demonstrates that the catalyst of this invention has higher activity and catalytic selectivity.

[0157] As can be seen from Examples 18-21, when using the catalyst described in this invention, intermediate C7 ( At a temperature not exceeding 250℃, the mass hourly space velocity (MHV) is 0.1-0.2 h⁻¹. -1 At that time, the conversion rate was greater than 95%. Selectivity is greater than 96%.

[0158] As can be seen from Example 22, when using the catalyst described in this invention, the intermediate... Conversion rate greater than 98%, selectivity greater than 97%.

[0159] The above embodiments are merely illustrative of the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features, without departing from the spirit and substance defined by the claims of the present invention; and such modifications and substitutions are still within the scope defined by the claims of the present invention.

Claims

1. A continuous synthesis method for amine compounds, characterized in that, The preparation steps are as follows: (1) The first catalyst is loaded into the first reaction module and heated and activated in a nitrogen atmosphere; (2) Reactant A is introduced into the first reaction module under the conditions of having solvent A1 or no solvent, and reactant B is introduced into the first reaction module under the conditions of having solvent B1 or no solvent. The product is separated by condensation to obtain nitro compound intermediate C. (3) The second catalyst is loaded into the second reaction module, and the second catalyst is heated and activated in a nitrogen atmosphere; (4) The obtained nitro compound intermediate C is introduced into the second reaction module to react with hydrogen under the condition of solvent D or without solvent; the product is collected by condensation and gas-liquid separation to obtain amine compounds; The first catalyst and the second catalyst are different supported metal compound catalysts; Reactant A is formaldehyde, paraformaldehyde, and triformaldehyde; reactant B is nitromethane; intermediate C is... or ; Alternatively, reactant A is acetaldehyde, reactant B is nitrobenzene, and intermediate C is... ; The first catalyst includes a first support and a first metal compound supported on the first support; the active metal component corresponding to the metal compound on the first support is selected from one or more of cerium and ytterbium, and the first support is selected from one or more of γ-Al2O3, ZrO2, and MgO; The second catalyst includes a second support and a second metal compound supported on the second support; the metal active component corresponding to the second metal compound is selected from one or more of ruthenium, palladium, and nickel.

2. The continuous synthesis method of an amine compound according to claim 1, characterized in that, The first reaction module and the second reaction module are the same or different reactors, respectively selected from one of the following: microchannel reactor, tubular reactor, helical propulsion reactor, fixed bed reactor, and fluidized bed reactor.

3. The continuous synthesis method of an amine compound according to claim 1, characterized in that, In step (2), The mass percentage concentration of aldehydes in the solution formed by reactant A dissolving in solvent A1 is 10-100%, where 100% indicates that the solution contains no solvent. The mass percentage concentration of nitroalkanes in the solution formed by reactant B dissolved in solvent B1 is 10-100%, where 100% indicates that the solvent is not present. In step (4), The mass percentage concentration of the nitro compound in the solution formed by dissolving the nitro compound intermediate C in solvent D is 10-100%, where 100% indicates that the solvent is not present.

4. The continuous synthesis method of an amine compound according to claim 3, characterized in that, The mass percentage concentration of aldehydes in the solution formed by reactant A dissolved in solvent A1 is 20%-70%. The mass percentage concentration of nitroalkanes in the solution formed by reactant B dissolving in solvent B1 is 50%-100%, where 100% indicates that the solution contains no solvent. In step (4), The mass percentage concentration of the nitro compound in the solution formed by dissolving nitro compound intermediate C in solvent D is 20%-70%.

5. The continuous synthesis method of an amine compound according to claim 4, characterized in that, The mass percentage concentration of aldehydes in the solution formed by reactant A dissolved in solvent A1 is 25%-40%. The mass percentage concentration of nitroalkanes in the solution formed by reactant B dissolving in solvent B1 is 70%-100%, where 100% indicates that the solvent is not present. In step (4), The mass percentage concentration of the nitro compound in the solution formed by dissolving nitro compound intermediate C in solvent D is 25%-40%.

6. The continuous synthesis method of an amine compound according to claim 1, characterized in that, Step (1) includes the following features: (c) The loading of the metal compound in the first catalyst is 0.1%-10wt%.

7. The continuous synthesis method of an amine compound according to claim 6, characterized in that, Step (1) includes the following features: (c) The loading of the metal compound in the first catalyst is 0.1%-5wt%.

8. The continuous synthesis method of an amine compound according to claim 7, characterized in that, Step (1) includes the following features: (c) The loading of the metal compound in the first catalyst is 0.1%-3wt%.

9. The continuous synthesis method of an amine compound according to claim 1, characterized in that, Includes at least one of the following features (e) to (i): (e) In step (3), the second carrier is selected from one or more of activated carbon, SiO2, γ-Al2O3, ZrO2, MgO, ZnO, TiO2, and zeolite molecular sieve; (f) In step (3), the loading of the metal compound in the second catalyst is 0.1%-10 wt%; (g) In step (2), The solvent A1 is selected from one or more of water, methanol, ethanol, propanol, isopropanol, n-hexane, n-heptane, DMF, dichloroethane, dichloromethane, and tetrahydrofuran; (h) In step (2), The solvent B1 is selected from one or more of water, methanol, ethanol, propanol, isopropanol, n-hexane, n-heptane, DMF, dichloroethane, dichloromethane, and tetrahydrofuran; (i) in step (4), The solvent D is selected from one or more of water, methanol, ethanol, propanol, isopropanol, n-hexane, n-heptane, DMF, dichloroethane, dichloromethane, and tetrahydrofuran.

10. The continuous synthesis method of an amine compound according to claim 9, characterized in that, Includes at least one of the following features (e) to (i): (e) In step (3), the second support is selected from one or more of SiO2, γ-Al2O3, MgO, ZnO, TiO2, and zeolite molecular sieves; (f) In step (3), the loading of the metal compound in the second catalyst is 0.1%-5 wt%; (g) In step (2), The solvent A1 is selected from one or more of water, methanol, ethanol, propanol, isopropanol, n-hexane, n-heptane, and tetrahydrofuran; (h) In step (2), The solvent B1 is selected from one or more of water, methanol, ethanol, propanol, isopropanol, n-hexane, n-heptane, and tetrahydrofuran; (i) In step (4), The solvent D is selected from one or more of water, methanol, ethanol, propanol, isopropanol, n-hexane, n-heptane, and tetrahydrofuran.

11. The continuous synthesis method of an amine compound according to claim 10, characterized in that, Includes at least one of the following features (e) to (i): (e) In step (3), the second support is selected from one or more of SiO2, γ-Al2O3, TiO2, and zeolite molecular sieves; (f) In step (3), the loading of the metal compound in the second catalyst is 0.1%-3wt%; (g) In step (2), The solvent A1 is selected from one or more of water, methanol, and ethanol; (h) In step (2), The solvent B1 is selected from one or more of water, methanol, and ethanol; (i) In step (4), The solvent D is selected from one or more of water, methanol, and ethanol.

12. The continuous synthesis method of an amine compound according to claim 1, characterized in that, In step (2), the reaction temperature is 10-60℃, and in step (4), the reaction temperature is 100-400℃. The reaction pressure is 0.1-3 MPa when the reaction occurs in the first and second reactors.

13. The continuous synthesis method of an amine compound according to claim 12, characterized in that, The reaction pressure is 0.1-2 MPa when the reaction occurs in the first and second reactors.

14. The continuous synthesis method of an amine compound according to claim 13, characterized in that, The reaction pressure is 0.1-0.5 MPa when the reaction occurs in the first and second reactors.

15. The continuous synthesis method of an amine compound according to claim 1, characterized in that, Includes at least one of the following features (j) to (n): (j) In step (2), during the reaction in the first reactor, the mass hourly space velocity of the reaction feed, calculated for aldehyde compounds, is 0.01-10 h⁻¹. -1 The calculation formula is as follows: The mass flow rate of aldehyde compounds is expressed in g / min, and the mass of catalyst is expressed in g. (k) In step (2), the reaction pressure is 0.1-3 MPa when the reaction is carried out in the first reactor; (l) In step (4), during the reaction in the second reactor, the mass hourly space velocity of the reaction feed, calculated as nitro compounds, is 0.01-10 h⁻¹. -1 The calculation formula is as follows: The mass flow rate of the nitro compound is expressed in g / min, and the mass of the catalyst is expressed in g. (m) In step (4), the pressure is 0.1-5 MPa when the reaction is carried out in the second reactor; (n) In step (4), the reaction temperature with hydrogen is 100-400℃ and the pressure is 0.1-5Mpa.

16. The continuous synthesis method of an amine compound according to claim 15, characterized in that, Includes at least one of the following features (j) to (n): (j) In step (2), during the reaction in the first reactor, the mass hourly space velocity of the reaction feed, calculated for aldehyde compounds, is 0.01-5 h⁻¹. -1 ; (k) In step (2), the reaction pressure is 0.1-2 MPa when the reaction is carried out in the first reactor; (l) In step (4), during the reaction in the second reactor, the mass hourly space velocity of the reaction feed, calculated as nitro compounds, is 0.01-5 h⁻¹. -1 ; (m) In step (4), the pressure is 0.1-3 MPa when the reaction is carried out in the second reactor; (n) In step (4), the reaction temperature with hydrogen is 100-400℃ and the pressure is 0.1-5Mpa.

17. The continuous synthesis method of an amine compound according to claim 16, characterized in that, Includes at least one of the following features (j) to (n): (j) In step (2), during the reaction in the first reactor, the mass hourly space velocity of the reaction feed, calculated for aldehyde compounds, is 0.01-1 h⁻¹. -1 ; (k) In step (2), the reaction pressure is 0.1-0.5 MPa when the reaction is carried out in the first reactor; (l) In step (4), during the reaction in the second reactor, the mass hourly space velocity of the reaction feed, calculated as nitro compounds, is 0.01-1 h⁻¹. -1 , (m) In step (4), the pressure is 0.1-2 MPa when the reaction is carried out in the second reactor; (n) In step (4), the reaction temperature with hydrogen is 100-400℃ and the pressure is 0.1-5Mpa.

18. A continuous synthesis method for an amine compound according to any one of claims 1-17, characterized in that, The first catalyst is prepared by a preparation method comprising the following steps: 1) Dissolve the first metal compound in a solvent to prepare a 0.1-10 wt% aqueous solution of the first metal; the solvent is one of water, aqueous nitric acid solution, and aqueous hydrochloric acid solution; 2) Impregnate the first carrier with an aqueous solution of one or more first metals; 3) Dry the impregnated solid at 60-160℃ for 3-12 hours; 4) The dried solid is calcined at 300-600℃ for 2-6 hours to obtain the first catalyst; The heating rate during the drying process is 2-5℃ / min, and the heating rate during the calcination process is 2-5℃ / min.

19. The continuous synthesis method of an amine compound according to claim 18, characterized in that, The first catalyst is prepared by a preparation method comprising the following steps: 1) Dissolve the first metal compound in a solvent to prepare a 0.1-10 wt% aqueous solution of the first metal; the solvent is one of water, aqueous nitric acid solution, and aqueous hydrochloric acid solution; 2) Impregnate the first carrier with an aqueous solution of one or more first metals; 3) Dry the impregnated solid at 90℃ for 6 hours; 4) The dried solid was calcined at 500℃ for 3 hours to obtain the first catalyst; The heating rate during the drying process is 2-5℃ / min, and the heating rate during the calcination process is 2-5℃ / min.

20. The continuous synthesis method of an amine compound according to claim 18, characterized in that, The second catalyst is prepared by a method comprising the following steps: 1) Dissolve the second metal compound in a solvent to prepare a 0.01-20 wt% aqueous solution of the second metal; the solvent is one of water, aqueous nitric acid solution, or aqueous hydrochloric acid solution; 2) Add the second carrier to the second metal aqueous solution, stir for 3-8 hours, and evaporate to dryness; 3) Dry the impregnated solid at 80-160℃ for 3-12 hours; 4) The dried solid is calcined at 300-600℃ for 2-6 hours to obtain the second catalyst; The heating rate during the drying process is 2-5℃ / min, and the heating rate during the calcination process is 2-5℃ / min.

21. The continuous synthesis method of an amine compound according to claim 20, characterized in that, The second catalyst is prepared by a method comprising the following steps: 1) Dissolve the second metal compound in a solvent to prepare a 0.01-20 wt% aqueous solution of the second metal; the solvent is one of water, aqueous nitric acid solution, or aqueous hydrochloric acid solution; 2) Add the second carrier to the second metal aqueous solution, stir for 5 hours, and then evaporate to dryness; 3) Dry the impregnated solid at 100℃ for 6 hours; 4) The dried solid was calcined at 500℃ for 3 hours to obtain the second catalyst; The heating rate during the drying process is 2-5℃ / min, and the heating rate during the calcination process is 2-5℃ / min.

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