A continuous flow process for the preparation of an amino alcohol compound

Abstract

The present application belongs to the technical field of pharmaceutical engineering, and particularly relates to a continuous flow preparation method of an amino alcohol compound. The present application adopts a micro-reaction system composed of a micro-mixer, a micro-channel reactor and a back pressure device in sequence; the preparation steps comprise the following steps: raw material aldehyde and amine are simultaneously delivered into the micro-mixer for mixing to obtain mixed reaction materials; the mixed reaction materials are directly flowed into the micro-channel reactor for addition reaction; the reaction mixed solution flowed out from the reactor is collected, concentrated and separated and purified to obtain the amino alcohol compound. The present application has the advantages of short reaction time, high energy utilization rate, small environmental pollution and easy industrial amplification application.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical engineering technology, specifically relating to a method for preparing amino alcohol compounds. Background Technology

[0002] Amino alcohols are a class of compounds with unique chemical structures, containing both amino (NH2) and hydroxyl (OH) groups. Due to their diverse molecular structures, amino alcohols have wide applications in various fields. They play important roles in drug synthesis, organic synthesis, chemical catalysis, and other chemical processes. Some typical amino alcohols include ethanolamine, propanolamine, and isopropanolamine, which are used to prepare chemical products such as pharmaceuticals, coatings, adhesives, surfactants, and pigments.

[0003] Its chemical structural formula is as follows:

[0004]

[0005] Among current methods for synthesizing amino alcohols, the most commonly used 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 has a short process and high atom economy (95%). However, it also faces some challenges, such as high technical difficulty and the separation, recovery, and recycling of the Raney nickel catalyst. In addition, Li Baoqiang et al. (Fine Chemical Intermediates, 2014, 6, 40-42) developed another method using 1,5-pentanediol as a raw material. First, it undergoes a monochlorochemical reaction with concentrated hydrochloric acid to produce 5-chloropentanol. Then, 5-chloropentanol further reacts with ammonia to amination, yielding the amino alcohol. A product with a purity higher than 99% can be obtained through distillation. However, this method is less efficient and generates a large amount of waste. Another method for synthesizing amino alcohols is through the oxidation reaction of amino compounds (CN112469692A). For example, aminomethane can be used as a raw material and hydrogen peroxide as an oxidant to synthesize the corresponding amino alcohols, releasing water (H2O) as a byproduct in the process. However, in addition to their respective limitations, these methods generally suffer from drawbacks such as long reaction times, cumbersome operation, safety hazards, low efficiency, and high energy consumption, which are unfavorable for the large-scale production of amino alcohols. Summary of the Invention

[0006] The purpose of this 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.

[0007] Compared with existing preparation methods, this method greatly improves safety, significantly reduces energy consumption, significantly shortens reaction time, and significantly improves the automation and efficiency of the process, making it easy to apply industrially.

[0008] The continuous flow preparation method for amino alcohols provided by this invention employs a microreaction system consisting of a feed pump, a micromixer, a microchannel reactor, and a back pressure device connected in sequence. The specific steps are as follows:

[0009] (1) An organic solution containing aldehyde (II) and an organic solution containing amine (III) are simultaneously fed into a micro mixer for mixing to obtain a mixed reaction material;

[0010] (2) The mixed reactants from step (1) are directly fed into the microchannel reactor to carry out the addition reaction;

[0011] (3) Collect the reaction mixture flowing out of the microchannel reactor, and then concentrate and separate it to obtain the product amino alcohol compound (I).

[0012] ;

[0013] Among them, R 1 R 2 and R 3 Each group is independently selected from hydrogen, halogen, C1-C12 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, unsaturated alkyl, aromatic, nitrogen-containing alkyl, sulfur-containing alkyl, carboxylic acid, amide, aldehyde, and ester.

[0014] In step (1), the organic solvent is selected independently from at least one 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; preferably, the organic solvent in step (1) is selected independently from at least one of acetone, butanone, methyl isobutyl ketone, tetrahydrofuran, 2-methyltetrahydrofuran, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol ethyl ether, and methyl tert-butyl ether.

[0015] In step (1), the temperature inside the micro mixer is controlled at 25-60 ℃; preferably, the temperature is controlled at 40-60 ℃.

[0016] In step (1), the molar ratio of aldehyde (II) to amine (III) is 1:(0.5-6); preferably, the molar ratio of aldehyde (II) to amine (III) is 1:(0.5-3); specifically, the molar ratio of aldehyde (II) to amine (III) is controlled by controlling the flow rate of the solution delivered to the micro mixer.

[0017] In step (2), the temperature inside the microchannel reactor is controlled at 30–60 ºC; preferably, the temperature is controlled at 40–60 ºC.

[0018] In step (2), the residence time of the mixed reactants in the microchannel reactor is 2 to 10 minutes; preferably, the residence time is 5 to 10 minutes.

[0019] In step (2), the back pressure of the back pressure valve is 0.1 to 2 MPa; preferably, the back pressure is 0.3 to 1.5 MPa.

[0020] In this invention, the micro mixer is one of a static mixer, a coaxial flow micro mixer, a flow focusing micro mixer, and a T-type, Y-type, Z-type, X-type, SK-type, SX-type, SV-type, or gourd-type dispersion-converging mixer; preferably, the micro mixer is one of a static mixer, a T-type, Y-type, Z-type, X-type, or gourd-type dispersion-converging mixer.

[0021] In this invention, the micro-mixer is preferably a square-shaped, internally-built, circular dispersion-converging mixer, the structure of which is described below. Figure 2 As shown. Specifically, it consists of several (e.g., 4-10) mixing units connected in series. Each mixing unit is composed of an outer square and an inner circle, with a mixing channel (ring-shaped) between the outer square and the inner circle. The mixing units are connected by pipes at the two opposite corners of the square. The mixture is diverted within the ring channel and converges at the corners, hence it is called a diversion-converging type mixer.

[0022] In this invention, the microchannel reactor is selected from tubular microchannel reactors or plate microchannel reactors; wherein:

[0023] The inner diameter of the tubular microchannel reactor is 100 micrometers to 8 millimeters; preferably, the inner diameter is 100 micrometers to 50 millimeters.

[0024] 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 fluid channel; the hydraulic diameter of the reaction fluid channel is 100 micrometers to 8 millimeters; preferably, the hydraulic diameter is 100 micrometers to 50 millimeters.

[0025] In this invention, the microchannel reactor is preferably a gourd-shaped dispersed-converging microchannel reactor, the structure of which is described below. Figure 3 As shown. Specifically, it consists of several (e.g., 10-20) circular or elliptical rings connected in sequence, with adjacent rings connected by pipes, or adjacent rings connected at their tangent points, resembling a gourd shape. The reaction liquid is dispersed within the rings and converges at the intersection of the two rings; hence, it is called a gourd-shaped dispersion-convergence microchannel reactor.

[0026] Beneficial effects of the present invention

[0027] This invention employs a microreactor system comprising a micromixer, a microchannel reactor, and a back pressure device connected in sequence to perform an addition reaction between aldehydes and amines to prepare amino alcohols. Compared with traditional synthesis methods, this invention offers the following advantages:

[0028] (1) The multiphase mixing, mass transfer and reaction processes are completed in micro mixers and microchannel reactors, which are easy to operate, have low equipment requirements, and are highly automated, which greatly reduces the energy consumption and production cost of the process and shortens the reaction time.

[0029] (2) The addition process is carried out in a microchannel reactor, which has good atom utilization, good reaction reproducibility, and is easy to scale up;

[0030] (3) Avoid the use of highly toxic and carcinogenic reagents. Attached Figure Description

[0031] Figure 1 This is a schematic diagram of the microreaction system used in this invention.

[0032] Figure 2 This is a schematic diagram of the square-shaped built-in circular dispersion-converging mixer structure used in an embodiment of the present invention.

[0033] Figure 3 This is a schematic diagram of the gourd-shaped dispersed-converging microchannel reactor used in this invention.

[0034] In the diagram, the labels are as follows: 1 is the feed pump, 2 is the oil bath, 3 is the micro mixer, 4 is the microchannel reactor, 5 is the back pressure valve, 6 is the storage tank, 7 is the material inlet of the micro mixer, 8 is the material inlet of the micro mixer, 9 is the material inlet of the microchannel reactor, and 10 is the material outlet of the microchannel reactor. Detailed Implementation

[0035] The present invention will be further described below with reference to specific embodiments.

[0036] Example 1: A method for the continuous preparation of amino alcohol compounds using a microreaction system, wherein the microreaction system is, for example... Figure 1 As shown, the microreactor system includes a micromixer 3 and a microchannel reactor 4 connected in sequence. The system also includes a feed pump 1, an oil bath 2, a back pressure valve 5, and a storage tank 6. The feed pump 1 is used to regulate and control the flow rate of the reaction mixture in the microreactor system. The oil bath 2 is used to regulate and control the reaction temperature of the microchannel reactor 4. The back pressure valve 5 is used to regulate and control the reaction pressure in the microreactor system. The storage tank 6 is used to collect the reaction liquid. The micromixer 3 is a square-shaped, internally-built, circular diverting and converging mixer, with the structure shown below. Figure 2As shown. The inlet and outlet channels have an inner diameter of 500 μm, an outer square with a side length of 5 mm, and an inner circular diameter of 4.5 mm. The square and circular structures are concentric. The interval between two adjacent squares 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:

[0037] (1) Add paraformaldehyde (82.08 g, 2.0 eq) to 130 mL of methanol, stir and dissolve to obtain material 1; add alanine (40.6 g, 1.0 eq) to 200 mL of methanol, stir and dissolve to obtain material 2;

[0038] (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 ºC; the temperature of the microchannel reactor was 45 ºC; and the residence time of the reaction was 2.3 minutes.

[0039] (3) The reaction mixture flowing out of the micro-reaction system was collected, concentrated and purified to obtain the product hydroxymethylalanine with a yield of 82%.

[0040] Example 2 is the same as Example 1, except that in this example, the method includes the following steps:

[0041] (1) Add paraformaldehyde (82.08 g, 2.0 eq) to 130 mL of methyl tert-butyl ether, stir and dissolve to obtain material 1; add alanine (40.6 g, 1.0 eq) to 200 mL of methanol, stir and dissolve to obtain material 2;

[0042] (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 ºC; the temperature of the microchannel reactor was 45 ºC; and the residence time of the reaction was 2.3 minutes.

[0043] (3) Collect the reaction mixture flowing out of the microreaction system, concentrate and separate it to obtain the product hydroxymethylalanine with a yield of 70%.

[0044] Example 3 is the same as Example 1, except that in this example, the method includes the following steps:

[0045] (1) Add paraformaldehyde (82.08 g, 2.0 eq) to 130 mL of methanol, stir and dissolve to obtain material 1; add alanine (40.6 g, 1.0 eq) to 200 mL of methanol, stir and dissolve to obtain material 2;

[0046] (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 ºC; the temperature of the microchannel reactor was 60 ºC; and the residence time of the reaction was 2.3 minutes.

[0047] (3) The reaction mixture flowing out of the microreaction system was collected, concentrated and purified to obtain the product hydroxymethylalanine with a yield of 89%.

[0048] Example 4 is the same as Example 1, except that in this example, the method includes the following steps:

[0049] (1) Add acetaldehyde (82.08 g, 2.0 eq) to 130 mL of methanol, stir and dissolve to obtain material 1; add methylamine (42.45 g, 1.0 eq) to 200 mL of methanol, stir and dissolve to obtain material 2;

[0050] (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 ºC; the temperature of the microchannel reactor was 60 ºC; and the residence time of the reaction was 2.3 minutes.

[0051] (3) The reaction mixture flowing out of the micro-reaction system was collected, concentrated and purified to obtain the product isopropanolamine with a yield of 82%.

[0052] Example 5 is the same as Example 1, except that in this example, the method includes the following steps:

[0053] (1) Add acetaldehyde (82.08 g, 2.0 eq) to 130 mL of methanol, stir and dissolve to obtain material 1; add phenylalanine (225.75 g, 1.0 eq) to 200 mL of methanol, stir and dissolve to obtain material 2;

[0054] (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 ºC; the temperature of the microchannel reactor was 60 ºC; and the residence time of the reaction was 2.3 minutes.

[0055] (3) The reaction mixture flowing out of the micro-reaction system was collected, concentrated and purified to obtain the product hydroxymethylphenylcarbamic acid with a yield of 73%.

[0056] Example 6 is the same as Example 4, except that the micro mixer 3 described in this example is a Y-type micro mixer, and the yield of the obtained product isopropanolamine is 71%.

[0057] Example 7 is the same as Example 4, except that the micro mixer 3 described in this example is an SX type micro mixer, and the yield of the obtained product isopropanolamine is 62%.

[0058] Example 8 is the same as Example 4, except that the microchannel reactor 4 described in this example is a gourd-shaped dispersed-converging reactor. See [link to example 8]. Figure 3 As shown, the inner diameter of the inlet and outlet channels is 800 μm, the major semi-axis of the outer ellipse is 15 mm, the minor semi-axis of the outer ellipse is 9 mm, the major semi-axis of the inner ellipse is 13 mm, the minor semi-axis of the outer ellipse is 7 mm, and a solid circle with a diameter of 0.5 mm is set at the center point of the intersection of adjacent ellipses to cut the fluid. The yield of the obtained product isopropanolamine is 85%.

Claims

1. A continuous flow preparation method for an amino alcohol compound, characterized in that, The microreactor system, consisting of a feed pump, a micromixer, a microchannel reactor, and a back pressure valve connected in sequence, employs the following steps: (1) An organic solution containing aldehydes and an organic solution containing amines are simultaneously fed into a micro mixer for mixing to obtain a mixed reaction material; (2) The mixed reactants from step (1) are directly fed into the microchannel reactor to carry out the addition reaction; (3) Collect the reaction mixture flowing out of the microchannel reactor, and then concentrate and separate it to obtain the product amino alcohol compound; Wherein, the aldehyde is formaldehyde or acetaldehyde; and the amine is alanine, phenylalanine, or methylamine.

2. The continuous flow preparation method according to claim 1, characterized in that, The solvent of the organic solution in step (1) is independently selected from at least one 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. The continuous flow preparation method according to claim 1, characterized in that, In step (1), the temperature inside the micro mixer is controlled at 25-60 ℃; the molar ratio of aldehyde to amine is 1:(0.5-6), specifically controlled by controlling the flow rate of the solution delivered to the micro mixer.

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

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

6. The continuous flow preparation method according to claim 1, characterized in that, The micro mixer is one of the following: static mixer, coaxial flow micro mixer, flow focusing micro mixer, and T-type, Y-type, Z-type, X-type, SK-type, SX-type, SV-type, and gourd-type dispersed-converging mixer.

7. The continuous flow preparation method according to claim 1, characterized in that, The microchannel reactor is selected from tubular microchannel reactors or plate microchannel reactors; wherein: The inner diameter of the tubular microchannel reactor is 100 micrometers to 8 millimeters; 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 fluid channel; the hydraulic diameter of the reaction fluid channel is 100 micrometers to 8 millimeters.

8. The continuous flow preparation method according to claim 1, characterized in that, The micro-mixer is a square-shaped, internally circular, dispersion-converging mixer; specifically, it consists of several mixing units connected in series. Each mixing unit is composed of an outer square and an inner circle, with a mixing channel between the outer square and the inner circle, forming a ring shape. The mixing units are connected by pipes at the two opposite corners of the square. The mixture is diverted within the ring channel and converges at the corners.

9. The continuous flow preparation method according to claim 1, characterized in that, The microchannel reactor is a gourd-shaped dispersion-convergence microchannel reactor, specifically composed of several circular or elliptical rings connected in sequence. Adjacent circular or elliptical rings are connected by pipes, or adjacent circular or elliptical rings are connected through each other at the tangent point. Adjacent circular or elliptical rings form a gourd shape, and the reaction liquid is dispersed in the rings and converges at the intersection of the two rings.

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