Method for preparing continuous flow of 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 Art

[0002] Amino alcohol is a compound having a unique chemical structure and has both an amino group (NH2) and a hydroxy group (OH). Due to the diverse molecular structures of amino alcohols, they are widely applied in various fields. They play an important role in the synthesis of pharmaceuticals, organic synthesis, chemical catalysts, and other chemical processes. Some typical amino alcohols include ethanolamine, propanolamine, and isopropanolamine. These are used in the manufacture of chemical products such as pharmaceuticals, coating agents, adhesives, surfactants, and pigments.

[0003] Its chemical structural formula is as follows.

Chemical Formula

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

[0005] Compared to conventional preparation methods, the method of the present invention offers significantly improved safety, greatly reduced energy consumption, remarkably shorter reaction times, and significantly improved automation and efficiency of the process, making it suitable for industrial use.

[0006] The present invention provides a continuous flow preparation method for amino alcohol compounds, which uses a microreaction system comprising a feed pump, sequentially connected micromixers, a microchannel reactor, and a back pressure device, and includes the following steps (1) to (3). (1) An organic solution containing aldehyde(II) and an organic solution containing amine(III) are simultaneously introduced into a micromixer and mixed to obtain a mixed reaction material. (2) The mixed reaction materials from step (1) are introduced directly into a microchannel reactor and subjected to an addition reaction. (3) The reaction mixture discharged from the microchannel reactor is collected, concentrated, separated, and purified to obtain the product amino alcohol compound (I). [ka] Here, R 1 , R 2 and R 3 Each of these groups is 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.

[0007] In step (1), the organic solvent is 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, orthopropanol, isopropanol, n-butanol, isobutyl alcohol ethyl ether, and methyl tert-butyl ether. Preferably, in step (1), the organic solvent is 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 inside the micromixer is controlled to 25-60°C, preferably to 40-60°C.

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

[0010] In step (2), the mixed reaction material resides in the microchannel reactor for 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, preferably 0.3 to 1.5 MPa.

[0011] In the present invention, the micromixer is one of the following: 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 dispersed confluence mixer. Preferably, the micromixer is one of the following: a static mixer, a T-type, Y-type, Z-type, X-type, or gourd-shaped dispersed confluence mixer.

[0012] In the present invention, the micromixer is preferably a circular embedded rectangular dispersive-converging mixer, the structure of which is shown in Figure 2. Specifically, it consists of a plurality of (for example, 4 to 10) mixing units connected in series. The mixing unit is composed of an outer rectangular part and an inner circular part, with an annular mixing passage between the outer rectangular part and the inner circular part, and the mixing units are connected by pipes at the two relative apex angles of the rectangular part, and the mixed liquid separates within the annular passage and merges at the apex angles. For this reason, it is called a dispersive-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 arranged sequentially from top to bottom. The reaction layer is provided with a reaction channel, the hydraulic diameter of which is 100 μm to 8 mm, and preferably 100 μm to 50 mm.

[0015] In the present invention, the microchannel reactor is preferably a gourd-shaped dispersed confluence type microchannel reactor. Its structure is shown in Figure 3. Specifically, it consists of a plurality (for example, 10-20) rings or elliptical rings connected in sequence, with two adjacent rings or elliptical rings connected by a conduit, or connected by a through-hole at a point where they touch, and two adjacent rings or elliptical rings being gourd-shaped, with the reaction liquid dispersed within the rings and confluenced at the intersection of the two rings. For this reason, it is called a gourd-shaped dispersed confluence type microchannel reactor.

[0016] Beneficial Effects of the Present Invention This invention provides a microreaction system comprising sequentially connected micromixers, microchannel reactors, and back pressure devices to carry out the addition reaction of aldehydes and amines to prepare amino alcohol compounds. Compared to conventional synthesis methods, it has the following advantages. (1) Multiphase mixing, mass transfer, and reaction processes in the reaction are completed within a micromixer and microchannel reactor, making it easy to operate, requiring less equipment, having a high level of automation, significantly reducing energy consumption and production costs in the process, and shortening 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 carcinogenic reagents is avoided.

Brief Description of the Drawings

[0017] [Figure 1] It is a structural schematic diagram of the micro reaction system used in the present invention. [Figure 2] It is a structural schematic diagram of the gourd-shaped dispersion confluence type micro mixer used in the embodiment of the present invention. [Figure 3] It is a structural schematic diagram of the gourd-shaped dispersion confluence type microchannel reactor used in the present invention.

[0018] Description of the Reference Numerals 1 Feed pump, 2 Oil bath, 3 Micro mixer, 4 Microchannel reactor, 5 Back pressure valve, 6 Storage tank, 7 Material inlet of the micro mixer, 8 Material inlet of the micro mixer, 9 Material inlet of the microchannel reactor, 10 Material outlet of the microchannel reactor.

Modes for Carrying Out the Invention

[0019] Hereinafter, the present invention will be further described with specific examples.

[0020] Example 1 A method for continuously preparing amino alcohol compounds using a microreaction system. The microreaction system includes a sequentially connected micromixer 3 and a microchannel reactor 4, as shown in Figure 1. The microreaction system further includes a feed pump 1, an oil bath 2, the micromixer 3, the microchannel reactor 4, a back pressure 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 microreaction system. The oil bath 2 is used to adjust and control the reaction temperature of the microchannel reactor 4. The back pressure valve 5 is used to adjust and control the reaction pressure in the microreaction system. The storage tank 6 is used to collect the reaction mixture. The micromixer 3 is a circular, embedded, rectangular split-flow-convergence mixer, the structure of which is shown in Figure 2. The inner diameter of the inlet and outlet passages is 500 μm, the side length of the outer rectangular section is 5 mm, the diameter of the inner circular section is 4.5 mm, and the rectangular and circular sections share the same center. The distance between two adjacent rectangular 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 this was designated as material 1. Alanine (40.6 g, 1.0 eq) was added to 200 mL of methanol, stirred and dissolved, and this was designated as material 2. (2) The flow rate of material 1 was controlled to 1.0 mL / min, the flow rate of material 2 was controlled to 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 discharged from the microreaction system was collected, concentrated, separated, and purified to obtain the product hydroxymethylalanine (yield 82%).

[0021] Example 2 This embodiment was the same as in Embodiment 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, dissolved by stirring, and this was designated as material 1. Alanine (40.6 g, 1.0 eq) was added to 200 mL of methanol, dissolved by stirring, and this was designated as material 2. (2) The flow rate of material 1 was controlled to 1.0 mL / min, the flow rate of material 2 was controlled to 1.2 mL / min, the micromixer temperature was 45°C, the microchannel reactor temperature was 45°C, and the residence time of the reactants was 2.3 minutes. (3) The reaction mixture discharged from the microreaction system was collected, concentrated, separated, and purified to obtain the product hydroxymethylalanine (yield 70%).

[0022] Example 3 This embodiment was the same as in Embodiment 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 this was designated as material 1. Alanine (40.6 g, 1.0 eq) was added to 200 mL of methanol, stirred and dissolved, and this was designated as material 2. (2) The flow rate of material 1 was controlled to 1.0 mL / min, the flow rate of material 2 was controlled to 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 discharged from the microreaction system was collected, concentrated, separated, and purified to obtain the product hydroxymethylalanine (yield 89%).

[0023] Example 4 This embodiment was the same as in Embodiment 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 this was designated as material 1. Methylamine (42.45 g, 1.0 eq) was added to 200 mL of methanol, stirred and dissolved, and this was designated as material 2. (2) The flow rate of material 1 is controlled to 1.0 mL / min, the flow rate of material 2 is controlled to 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 discharged from the microreaction system was collected, concentrated, separated, and purified to obtain the product isopropanolamine (yield 82%).

[0024] Example 5 This embodiment was the same as in Embodiment 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 this was designated as material 1. Phenylalanine (225.75 g, 1.0 eq) was added to 200 mL of methanol, stirred and dissolved, and this was designated as material 2. (2) The flow rate of material 1 was controlled to 1.0 mL / min, the flow rate of material 2 was controlled to 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 discharged from the microreaction system was collected, concentrated, separated, and purified to obtain the product hydroxymethylphenylcarbamic acid (yield 73%).

[0025] Example 6 In this embodiment, the micromixer 3 was a Y-type micromixer, and the yield of the resulting product isopropanolamine was 71%, otherwise it was the same as in Example 4.

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

[0027] Example 8 In this embodiment, the microchannel reactor 4 is a gourd-shaped dispersed confluence reactor, and as shown in Figure 3, the inner diameter of the inlet and outlet passages is 800 μm, the major axis of the outer ellipse is 15 mm, the minor axis of the outer ellipse is 9 mm, the major axis of the inner ellipse is 13 mm, the minor axis of the inner ellipse is 7 mm, and a black circle with a diameter of 0.5 mm is provided at the center point of the intersection of adjacent ellipses to cut the fluid, and the yield of the obtained product isopropanolamine was 85%, except that it was the same as in Example 4.

Claims

1. A method for continuous-flow preparation of amino alcohol compounds using a microreaction system comprising a feed pump, sequentially connected micromixers, a microchannel reactor, and a back pressure device, This includes steps (1) to (3) below, (1) An organic solution containing aldehyde(II) and an organic solution containing amine(III) are simultaneously introduced into a micromixer and mixed to obtain a mixed reaction material. (2) The mixed reaction materials from step (1) are introduced directly into a microchannel reactor and subjected to an addition reaction. (3) The reaction mixture discharged from the microchannel reactor is collected, concentrated, separated, and purified to obtain the product amino alcohol compound (I). 【Chemistry 1】 Here, R １ , R ２ and R ３ A continuous flow preparation method characterized in that each of the elements is independently selected from hydrogen, halogen, C1-C12 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, unsaturated alkyl, aryl, carboxylic acid group, and aldehyde group.

2. The continuous flow preparation method according to claim 1, characterized in that in step (1), the organic solvent is at least one independently 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, isobutanol ethyl ether, and methyl tert-butyl ether.

3. The continuous flow preparation method according to claim 1, characterized in that, in step (1), the temperature inside the micromixer is controlled to 25-60°C, the molar ratio of aldehyde(II) to amine(III) is 1:(0.5-6), and specifically, the molar ratio of aldehyde(II) to amine(III) is controlled by the flow rate ratio of the solution introduced into the micromixer.

4. The continuous flow preparation method according to claim 1, characterized in that, in step (2), the temperature inside the microchannel reactor is controlled to 30 to 60°C, and the residence time of the mixed reaction material in the microchannel reactor is 2 to 10 minutes.

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

6. The continuous flow preparation method according to claim 1, characterized in that the micromixer is one of the following: 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 dispersed confluence 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. The continuous flow preparation method according to claim 1, characterized in that the plate-type microchannel reactor includes a first heat exchange layer, a reaction layer, and a second heat exchange layer arranged in order from top to bottom, the reaction layer is provided with a reaction channel, and the hydraulic diameter of the reaction channel is 100 μm to 8 mm.

8. The continuous flow preparation method according to claim 6, characterized in that the micromixer is a circular embedded rectangular dispersive confluence mixer, specifically comprising a plurality of mixing units connected in series, each mixing unit consisting of an outer rectangular section and an inner circular section, with an annular mixing passage between the outer rectangular section and the inner circular section, the mixing units being connected by a pipeline at two relative apex angles of the rectangular section, and the mixed liquid being divided within the annular passage and merged at the apex angles.

9. The present invention is characterized in that the microchannel reactor is a gourd-shaped dispersed confluence type microchannel reactor, comprising a plurality of rings or elliptical rings connected in sequence, two adjacent rings or elliptical rings communicating by a conduit, or two adjacent rings or elliptical rings communicating by penetrating at a point where they are in contact, two adjacent rings or elliptical rings being gourd-shaped, the reaction liquid being dispersed within the rings and converging at the intersection of the two rings, as described in claim 7.

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