Continuous-flow preparation method for amino alcohol compounds

Abstract

To provide a continuous-flow preparation method for an amino alcohol compound, the method belonging to the technical field of pharmaceutical engineering.SOLUTION: A micro-reaction system comprising a micro-mixer, a micro-channel reactor, and a back pressure device that are sequentially connected is used. The preparation step includes introducing a raw material aldehyde and an amine simultaneously into the micro-mixer to mix and obtain a mixed reaction material, introducing the mixed reaction material into the micro-channel reactor to undergo an addition reaction, and collecting the reaction mixture flowing out of the reactor and subjecting it to concentration and separation purification treatment to obtain an amino alcohol compound. The method has short reaction time, high energy utilization efficiency, low environmental pollution, and is applicable to industrial scale-up.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention belongs to the technical field of pharmaceutical engineering, and specifically relates to a method for preparing amino alcohol compounds. [Background technology]

[0002] Amino alcohols are compounds with unique chemical structures, containing both an amino group (NH2) and a hydroxyl group (OH). Due to their diverse molecular structures, amino alcohols have a wide range of applications in various fields. They play an important role in pharmaceutical synthesis, organic synthesis, chemical catalysis, and other chemical processes. Some typical amino alcohols include ethanolamine, propanolamine, and isopropanolamine. They are used in the production of pharmaceuticals, coatings, adhesives, surfactants, pigments, and other chemical products.

[0003] Its chemical structure is as follows: [ka] A commonly used method for synthesizing amino alcohols is the hydrogenation of hydroxypropionitrile using a modified Raney nickel catalyst in the presence of ammonia (Fine Chemical Intermediates, 2004, 4, 4-6). This method requires few process steps and has a relatively high atom economy (95%). However, this method is technically challenging, and there are problems with the separation, recovery, and recycling of the Raney nickel catalyst. Li Baoqiang et al. (Fine Chemical Intermediates, 2014, 6, 40-42) also developed a different method. Specifically, 1,5-pentylene glycol is used as a raw material, and the monochlorination reaction with concentrated hydrochloric acid produces 5-chloropentanol. This 5-chloropentanol is then further reacted with ammonia gas and aminated to obtain amino alcohols. Purity levels exceeding 99% can be obtained by rectification. However, this method is inefficient and generates a large amount of waste. Another method for synthesizing amino alcohols involves the oxidation of amino compounds (CN112469692A). For example, aminomethane can be used as a raw material to synthesize the corresponding amino alcohol using hydrogen peroxide as an oxidant, with HO being released as a by-product during the reaction. However, these methods, in addition to their limitations, have drawbacks such as the long reaction time of the traditional kettle-type batch reaction, complicated operation, safety risks, low efficiency, and high energy consumption. These drawbacks make the large-scale production of amino alcohols unfavorable. Summary of the Invention

[0004] The object of the present invention is to provide a continuous flow method for preparing amino alcohol compounds, which has good safety, short reaction time, low energy consumption and high efficiency.

[0005] Compared with the conventional preparation methods, the method of the present invention has greatly improved safety, greatly reduced energy consumption, significantly shortened reaction time, significantly improved automation level and efficiency of the process, and is applicable to industrial use.

[0006] The continuous flow method for preparing an amino alcohol compound provided by the present invention uses a micro reaction system consisting of a feed pump, a micro mixer connected in series, a microchannel reactor and a back pressure device, and includes the following steps (1) to (3): (1) simultaneously introducing an organic solution containing an aldehyde (II) and an organic solution containing an amine (III) into a micromixer and mixing them to obtain a mixed reaction material; (2) The mixed reactants from step (1) are directly introduced into a microchannel reactor and subjected to an addition reaction; (3) collecting the reaction mixture flowing out of the microchannel reactor, concentrating, separating and purifying it to obtain the product amino alcohol compound (I); [ka] where R 1 , R 2 and R 3 are each independently selected from hydrogen, halogen, C1 to C12 alkyl, C3 to C6 cycloalkyl, C1 to C6 alkoxy, unsaturated alkyl, aryl, nitrogen-containing alkyl, sulfur-containing alkyl, carboxylic acid group, amide group, aldehyde group, and ester group.

[0007] In step (1), the organic solvents are each independently at least one selected from toluene, ethylbenzene, acetonitrile, n-butyronitrile, acetone, butanone, methyl isobutyl ketone, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, DMSO, DMF, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutyl alcohol ethyl ether, and methyl tert-butyl ether. Preferably, in step (1), the organic solvents are each independently at least one selected from acetone, butanone, methyl isobutyl ketone, tetrahydrofuran, 2-methyltetrahydrofuran, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutyl alcohol ethyl ether, and methyl tert-butyl ether.

[0008] In step (1), the temperature in the micromixer is controlled to 25-60°C, preferably the temperature is controlled to 40-60°C.

[0009] In step (1), the molar ratio of the aldehyde (II) to the amine (III) is 1:(0.5-6), preferably 1:(0.5-3). Specifically, the molar ratio of the aldehyde (II) to the amine (III) is controlled by adjusting the flow rate of the solutions introduced into the micromixer. In step (2), the temperature in the microchannel reactor is controlled to 30-60°C, preferably 40-60°C.

[0010] In step (2), the residence time of the mixed reaction materials in the microchannel reactor is 2 to 10 minutes, preferably 5 to 10 minutes. In step (2), the back pressure of the back pressure valve is 0.1 to 2 MPa, and preferably the back pressure is 0.3 to 1.5 MPa.

[0011] In the present invention, the micromixer is one of static mixers, coaxial flow micromixers, flow focusing micromixers, and T-type, Y-type, Z-type, X-type, SK-type, SX-type, SV-type, and gourd-shaped dispersive and converging mixers. Preferably, the micromixer is one of static mixers, T-type, Y-type, Z-type, X-type, and gourd-shaped dispersive and converging mixers.

[0012] In the present invention, the micromixer is preferably a circular embedded square dispersing and converging mixer, the structure of which is shown in Figure 2. Specifically, it is composed of multiple (e.g., 4-10) mixing units connected in series. The mixing unit is composed of an outer square section and an inner circular section, and an annular mixing passage is between the outer square section and the inner circular section. The mixing units are connected by pipes at the two relative apex angles of the square sections, and the mixed liquid is divided within the annular passage and converges at the apex angle. For this reason, it is called a dividing and converging mixer.

[0013] In the present invention, the microchannel reactor is selected from a tubular microchannel reactor or a plate-type microchannel reactor. The inner diameter of the tubular microchannel reactor is 100 μm to 8 mm, preferably 100 μm to 50 mm.

[0014] The plate-type microchannel reactor includes a first heat exchange layer, a reaction layer, and a second heat exchange layer, which are arranged in this order from top to bottom. The reaction layer is provided with a reaction flow path, and the hydraulic diameter of the reaction flow path is 100 μm to 8 mm, preferably 100 μm to 50 mm.

[0015] In the present invention, the microchannel reactor is preferably a gourd-shaped dispersed-converging microchannel reactor. Its structure is shown in Figure 3. Specifically, it is composed of a plurality of (e.g., 10-20) circular or elliptical rings connected in sequence, and two adjacent circular or elliptical rings are connected by a pipe, or two adjacent circular or elliptical rings are connected by penetrating through at their contact points. The two adjacent circular or elliptical rings are gourd-shaped, and the reaction solution is dispersed within the rings and converges at the intersection of the two rings. Therefore, it is called a gourd-shaped dispersed-converging microchannel reactor.

[0016] Beneficial Effects of the Invention The present invention uses a micro-reaction system including a micro-mixer, a micro-channel reactor, and a back-pressure device in series to carry out the addition reaction of aldehydes and amines to prepare amino alcohol compounds, which has the following advantages over conventional synthesis methods: (1) The multiphase mixing, mass transfer and reaction process during the reaction process are completed in the micromixer and microchannel reactor, which is simple to operate, has low equipment requirements, and a high level of automation. This significantly reduces the energy consumption and production costs of the process, and shortens the reaction time. (2) The addition process is carried out in a microchannel reactor, which has high atom utilization, good reaction reproducibility, and is easy to scale up. (3) The use of highly toxic and carcinogenic reagents is avoided. [Brief explanation of the drawings]

[0017] [Figure 1] 1 is a structural schematic diagram of a micro reaction system used in the present invention. [Figure 2] FIG. 2 is a structural schematic diagram of a gourd-shaped dispersing and converging micromixer used in an embodiment of the present invention. [Figure 3] FIG. 1 is a structural schematic diagram of a gourd-shaped dispersed and confluent microchannel reactor used in the present invention.

[0018] Explanation of symbols 1 Feed pump, 2 Oil bath, 3 Micro mixer, 4 Micro channel reactor, 5 Back pressure valve, 6 Storage tank, 7 Material inlet of micro mixer, 8 Material inlet of micro mixer, 9 Material inlet of micro channel reactor, 10 Material outlet of micro channel reactor. DETAILED DESCRIPTION OF THE INVENTION

[0019] The present invention will be further described below with reference to specific examples.

[0020] Example 1 A method for continuously preparing amino alcohol compounds using a microreactor system is described. As shown in Figure 1, the microreactor system includes a micromixer 3 and a microchannel reactor 4, which are connected in series. The microreactor system further includes a feed pump 1, an oil bath 2, the micromixer 3, the microchannel reactor 4, a backpressure valve 5, and a storage tank 6. The feed pump 1 is used to adjust and control the flow rate of the reaction mixture in the microreactor system. The oil bath 2 is used to adjust and control the reaction temperature in the microchannel reactor 4. The backpressure valve 5 is used to adjust and control the reaction pressure within the microreactor system. The storage tank 6 is used to collect the reaction mixture. The micromixer 3 is a circular, embedded, square, branching and merging mixer, the structure of which is shown in Figure 2. The inner diameter of the inlet / outlet passage is 500 μm, the side length of the outer square section is 5 mm, the diameter of the inner circular section is 4.5 mm, and the square and circular sections are concentric. The distance between two adjacent square sections is 12 mm. The microchannel reactor 4 is a polytetrafluoroethylene tubular microchannel reactor with an inner diameter of 0.8 mm and a reaction volume of 5 mL. The back pressure valve 5 provides a pressure of 0.5 MPa. The method includes the following steps: (1) Paraformaldehyde (82.08 g, 2.0 eq) was added to 130 mL of methanol, stirred and dissolved, and then used as material 1. Alanine (40.6 g, 1.0 eq) was added to 200 mL of methanol, stirred and dissolved, and then used as material 2. (2) The flow rate of material 1 was controlled at 1.0 mL / min, the flow rate of material 2 was controlled at 1.2 mL / min, the temperature of the micromixer was 45°C, the temperature of the microchannel reactor was 45°C, and the residence time of the reactants was 2.3 minutes. (3) The reaction mixture flowing out of the micro-reaction system was collected, concentrated, separated and purified to obtain the product hydroxymethylalanine (yield 82%).

[0021] Example 2 This example was similar to Example 1, except that it included the following steps: (1) Paraformaldehyde (82.08 g, 2.0 eq) was added to 130 mL of methyl tert-butyl ether, stirred and dissolved, and then used as material 1. Alanine (40.6 g, 1.0 eq) was added to 200 mL of methanol, stirred and dissolved, and then used as material 2. (2) The flow rate of material 1 was controlled at 1.0 mL / min, the flow rate of material 2 was controlled at 1.2 mL / min, the micromixer temperature was 45°C, the temperature of the microchannel reactor was 45°C, and the residence time of the reactants was 2.3 minutes. (3) The reaction mixture flowing out of the micro-reaction system was collected, concentrated, separated and purified to obtain the product hydroxymethylalanine (yield 70%).

[0022] Example 3 This example was similar to Example 1, except that it included the following steps: (1) Paraformaldehyde (82.08 g, 2.0 eq) was added to 130 mL of methanol, stirred and dissolved, and then used as material 1. Alanine (40.6 g, 1.0 eq) was added to 200 mL of methanol, stirred and dissolved, and then used as material 2. (2) The flow rate of material 1 was controlled at 1.0 mL / min, the flow rate of material 2 was controlled at 1.2 mL / min, the temperature of the micromixer was 60°C, the temperature of the microchannel reactor was 60°C, and the residence time of the reactants was 2.3 minutes. (3) The reaction mixture flowing out of the micro-reaction system was collected, concentrated, separated and purified to obtain the product hydroxymethylalanine (yield 89%).

[0023] Example 4 This example was similar to Example 1, except that it included the following steps: (1) Acetaldehyde (82.08 g, 2.0 eq) was added to 130 mL of methanol, stirred and dissolved, and then used as material 1. Methylamine (42.45 g, 1.0 eq) was added to 200 mL of methanol, stirred and dissolved, and then used as material 2. (2) The flow rate of material 1 is controlled at 1.0 mL / min, the flow rate of material 2 is controlled at 1.2 mL / min, the temperature of the micromixer is 60°C, the temperature of the microchannel reactor is 60°C, and the residence time of the reactants is 2.3 minutes. (3) The reaction mixture flowing out of the micro-reaction system was collected, concentrated, separated and purified to obtain the product isopropanolamine (yield 82%).

[0024] Example 5 This example was similar to Example 1, except that it included the following steps: (1) Acetaldehyde (82.08 g, 2.0 eq) was added to 130 mL of methanol, stirred and dissolved, and then used as material 1. Phenylalanine (225.75 g, 1.0 eq) was added to 200 mL of methanol, stirred and dissolved, and then used as material 2. (2) The flow rate of material 1 was controlled at 1.0 mL / min, the flow rate of material 2 was controlled at 1.2 mL / min, the temperature of the micromixer was 60°C, the temperature of the microchannel reactor was 60°C, and the residence time of the reactants was 2.3 minutes. (3) The reaction mixture flowing out of the micro-reaction system was collected, concentrated, separated and purified to obtain the product hydroxymethylphenylcarbamic acid (yield 73%).

[0025] Example 6 In this example, the micro-mixer 3 was a Y-type micro-mixer, and the yield of the resulting product isopropanolamine was 71%, which was the same as in Example 4.

[0026] Example 7 In this example, the micromixer 3 was an SX-type micromixer, and the yield of the resulting product isopropanolamine was 62%, which was the same as in Example 4.

[0027] Example 8 In this example, the microchannel reactor 4 was a gourd-shaped dispersed confluence reactor, and as shown in FIG. 3, the inner diameter of the inlet / outlet passage was 800 μm, the major axis of the outer ellipse was 15 mm, the minor axis of the outer ellipse was 9 mm, the major axis of the inner ellipse was 13 mm, and the minor axis of the inner ellipse was 7 mm. A black circle with a diameter of 0.5 mm was provided at the center of the intersection of adjacent ellipses to cut the fluid. The yield of the resulting product, isopropanolamine, was 85%, which was the same as in Example 4.

Claims

1. A continuous flow method for preparing an amino alcohol compound using a micro reaction system consisting of a feed pump, a micro mixer connected in series, a micro channel reactor and a back pressure device, comprising: The method includes the following steps (1) to (3): (1) simultaneously introducing an organic solution containing aldehyde (II) and an organic solution containing amine (III) into a micromixer and mixing them to obtain a mixed reaction material; (2) introducing the mixed reactants from step (1) directly into a microchannel reactor for addition reaction; (3) collecting the reaction mixture flowing out of the microchannel reactor, concentrating, separating and purifying it to obtain the product amino alcohol compound (I); 【Chemistry 1】 Here, R １ , R ２ and R ３ are each independently selected from hydrogen, halogen, C1-C12 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, unsaturated alkyl, aryl, nitrogen-containing alkyl, sulfur-containing alkyl, carboxylic acid group, amide group, aldehyde group, and ester group.

2. 2. The method of claim 1, wherein in step (1), the organic solvents are each independently at least one selected from the group consisting of toluene, ethylbenzene, acetonitrile, n-butyronitrile, acetone, butanone, methyl isobutyl ketone, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, DMSO, DMF, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol ethyl ether, and methyl tert-butyl ether.

3. 2. The continuous flow method according to claim 1, wherein in step (1), the temperature in the micro-mixer is controlled at 25-60°C, the molar ratio of the aldehyde (II) to the amine (III) is 1:(0.5-6), and the molar ratio of the aldehyde (II) to the amine (III) is specifically controlled by the flow rate ratio of the solutions introduced into the micro-mixer.

4. 2. The method of claim 1, wherein in step (2), the temperature in the microchannel reactor is controlled at 30-60°C, and the residence time of the mixed reactants in the microchannel reactor is 2-10 minutes.

5. 2. The continuous flow preparation method according to claim 1, wherein in step (2), the back pressure of the back pressure valve is 0.1 to 2 MPa.

6. 2. The method for preparing a continuous flow according to claim 1, wherein the micromixer is one of a static mixer, a coaxial flow micromixer, a flow focusing micromixer, and a T-type, Y-type, Z-type, X-type, SK-type, SX-type, SV-type, or gourd-shaped dispersive and converging mixer.

7. The microchannel reactor is selected from a tubular microchannel reactor or a plate-type microchannel reactor; the inner diameter of the tubular microchannel reactor is 100 μm to 8 mm; 2. The method of claim 1, wherein the plate-type microchannel reactor comprises a first heat exchange layer, a reaction layer, and a second heat exchange layer, which are arranged in this order from top to bottom, and the reaction layer is provided with a reaction channel, and the hydraulic diameter of the reaction channel is 100 μm to 8 mm.

8. 7. The method for preparing a continuous flow according to claim 6, wherein the micromixer is a circular embedded square dispersive-converging mixer, specifically, a plurality of mixing units connected in series, the mixing unit being composed of an outer square section and an inner circular section, the outer square section and the inner circular section being connected by an annular mixing passage, the mixing units being connected by pipes at two relative apex angles of the square sections, and the mixed liquid being diverged in the annular passage and merging at the apex angle.

9. 8. The method for preparing a continuous flow according to claim 7, wherein the microchannel reactor is a gourd-shaped dispersion-confluence type microchannel reactor, which is composed of a plurality of circular or elliptical rings connected in sequence, and two adjacent circular or elliptical rings are connected by a pipe, or two adjacent circular or elliptical rings are connected by penetrating each other at a contact point, and the two adjacent circular or elliptical rings are gourd-shaped, and the reaction solution is dispersed within the rings and converges at the intersection of both rings.

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