A method for preparing tris-hydroxymethyl aminomethane by continuous flow

Abstract

The application discloses a method for preparing trimethylolamine by a continuous flow method, and comprises the following steps: mixing polyformaldehyde and alkali to obtain a mixed solution 1; mixing a nitromethane solution and the mixed solution 1 to form a reaction solution, and then introducing the reaction solution into a micro-channel continuous flow reactor to obtain a mixed solution 2 after reaction; adjusting the flow rates of the mixed solution 2 and hydrogen, and then mixing the gas-liquid mixture into a gas-liquid mixer at the inlet of a micro-packed bed continuous flow reactor, passing through a catalyst bed layer of the micro-packed bed continuous flow reactor to react, and then adjusting the temperature through a reactor heat exchange cavity of the micro-packed bed continuous flow reactor to obtain a crude product after reaction, and then performing post-treatment and purification to obtain a trimethylolamine product; and the catalyst comprises a supported Pd catalyst, a supported Ni catalyst or a Raney nickel catalyst. The preparation method of the application enables the solid catalyst to fully contact with the mixed solution 2 and hydrogen, compared with a conventional intermittent hydrogenation preparation method, the reaction time is shortened, the product purity is high, the safety is high, and the method is beneficial to industrialized scale production.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis, specifically relating to a method for preparing tris(hydroxymethyl)aminomethane using a continuous flow process. Background Technology

[0002] Tris(hydroxymethyl)aminomethane (Tris) is an important pharmaceutical intermediate that can be used as a biological buffer for metabolic acidosis and respiratory acidosis. It has a good buffering effect on metabolic acidosis and enzyme activity. In addition, it can also be used in electronic materials.

[0003] Traditional industrial routes for synthesizing tris(hydroxymethyl)aminomethane (TCM) often employ a two-step process involving polymerization and hydrogenation in large high-pressure reactors. This process requires large quantities of nitromethane and hydrogen, posing significant safety risks. Traditional reactors are highly exothermic and high-pressure, requiring large batch sizes. The use of nitromethane or hydrogen for purging is extremely dangerous, and reaction safety is difficult to control. The hydrogenation process in traditional reactors uses rapid mechanical stirring, which can easily break the catalyst and leach heavy metals. After the reaction, the catalyst must be filtered out, resulting in long reaction times and cumbersome purification and processing. Localized overheating is prone to occur during the reaction in traditional reactors, leading to decreased conversion or selectivity and low yield. Furthermore, in catalytic hydrogenation in traditional reactors, the hydrogen produced can only be burned off or vented, and cannot be recovered. In addition, batch processes suffer from cumbersome operation, low raw material utilization, long reaction times, large equipment size, high maintenance and operating costs, difficult post-processing, low yield, high energy consumption, and significant waste generation.

[0004] Compared to traditional batch reaction processes, continuous flow chemistry offers advantages such as higher heat and mass transfer efficiency, narrower residence time, better distribution, better repeatability, rapid system response, convenient automation control, reduced scale-up effects, lower liquid holdup, and higher safety. It is particularly suitable for hazardous chemical reactions involving strong exothermic reactions, unstable reactants or products, and high toxicity. Patent CN 117142965A discloses a continuous flow method for preparing tris(hydroxymethyl)aminomethane, specifically disclosing the mixing of paraformaldehyde and an alkaline solution to obtain a first mixture; the first mixture and a nitromethane solution are then introduced into a first continuous flow reactor as reaction solutions, resulting in a second mixture; the second mixture is then introduced into a second continuous flow reactor, and a catalyst is added; the reaction is then completed to obtain the tris(hydroxymethyl)aminomethane. While this method uses a continuous flow reactor in the second step, it requires adding the catalyst along with the second mixture, and still involves catalyst filtration and discharge after the reaction. Furthermore, the catalytic effect is not as good as that of a micro-packed bed continuous flow reactor, and the purity does not reach product grade. Summary of the Invention

[0005] Purpose of the invention: The purpose of this invention is to overcome the shortcomings of the existing technology and provide a method for preparing tris(hydroxymethyl)aminomethane by continuous flow.

[0006] To achieve the above objectives, the technical solution provided by the present invention is as follows:

[0007] This application improves a method for preparing tris(hydroxymethyl)aminomethane using a continuous flow process, comprising:

[0008] Paraformaldehyde and alkali are dissolved in a solvent and mixed to obtain mixture 1;

[0009] Nitromethane is dissolved in a solvent to obtain a nitromethane solution. The nitromethane solution is mixed with mixture 1 to form a reaction solution. The reaction solution is passed into a microchannel continuous flow reactor for reaction. After the reaction is completed, mixture 2 containing tris(hydroxymethyl)nitromethane is obtained.

[0010] The flow rates of mixed liquid 2 and hydrogen gas are adjusted and introduced into the gas-liquid mixer at the inlet of the micro-packed bed continuous flow reactor to obtain a gas-liquid mixed fluid. The gas-liquid mixed fluid is then flowed through the catalyst bed of the micro-packed bed continuous flow reactor and reacted. The reaction temperature is controlled by the reactor heat exchange chamber of the micro-packed bed continuous flow reactor. After the reaction is completed, crude tris(hydroxymethyl)aminomethane is obtained, which is then purified by post-treatment to obtain pure tris(hydroxymethyl)aminomethane. The catalyst includes a supported Pd catalyst, a supported Ni catalyst, or a Raney nickel catalyst.

[0011] In some embodiments, the support for the supported Pd catalyst includes an activated carbon support, a silica support, or an alumina support, and the support for the supported Ni catalyst includes an activated carbon support, a silica support, or an alumina support.

[0012] In some embodiments, the metal loading of the supported Pd-based catalyst or the supported Ni-based catalyst is 1.0 wt% to 30.0 wt%.

[0013] In some embodiments, the flow rate ratio of the mixture 2 to hydrogen is in the range of 1:15 to 200.

[0014] In some embodiments, the reaction temperature in the micro-filled bed continuous flow reactor is 40°C to 120°C, the reaction pressure is 0.5 MPa to 6.0 MPa, and the reaction time is 2 min to 30 min.

[0015] In some embodiments, the micro-packed bed continuous flow reactor includes a gas-liquid mixer, a catalyst bed, and a reactor heat exchange chamber.

[0016] In some embodiments, the molar ratio of nitromethane to paraformaldehyde in the reaction solution ranges from 1:3 to 4.

[0017] In some embodiments, the molar ratio of nitromethane to alkali in the reaction solution is in the range of 1:0.001 to 0.1, and the alkali is potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate, or sodium carbonate.

[0018] In some embodiments, the solvent is methanol, ethanol, isopropanol or water, and the volume hourly space velocity ratio of the nitromethane solution to mixture 1 is 1:1.

[0019] In some embodiments, the reaction temperature in the microchannel continuous flow reactor is 40℃~70℃, the reaction pressure is 0.2Mpa~2.0Mpa, and the reaction time is 3~10min.

[0020] In some embodiments, the post-processing purification method is as follows: concentrating the crude product, slurrying it with methyl tert-butyl ether or ethyl acetate, and filtering to obtain white tris(hydroxymethyl)aminomethane.

[0021] Beneficial Effects: This invention discloses a continuous flow method for preparing tris(hydroxymethyl)aminomethane, comprising: dissolving paraformaldehyde and alkali in a solvent and mixing to obtain a mixture 1; dissolving nitromethane in a solvent to obtain a nitromethane solution, mixing the nitromethane solution with the mixture 1 to form a reaction solution, passing the reaction solution into a microchannel continuous flow reactor, reacting, and obtaining a mixture 2 containing tris(hydroxymethyl)nitromethane; adjusting the flow rates of the mixture 2 and hydrogen gas, and mixing them in a gas-liquid mixer at the inlet of a micro-packed bed continuous flow reactor to obtain a gas-liquid mixed fluid; passing the gas-liquid mixed fluid through the catalyst bed of the micro-packed bed continuous flow reactor and reacting; controlling the reaction temperature through the reactor heat exchange chamber of the micro-packed bed continuous flow reactor; obtaining crude tris(hydroxymethyl)aminomethane after the reaction, and obtaining pure tris(hydroxymethyl)aminomethane after post-treatment purification; wherein the catalyst includes a supported Pd catalyst, a supported Ni catalyst, or a Raney nickel catalyst. The preparation method of this invention enables the solid catalyst to fully contact the mixture 2 and hydrogen. Compared with conventional batch hydrogenation, the reaction time is shortened, the solvent consumption is reduced, the reaction selectivity is improved, and the yield and product purity are increased. Furthermore, the continuous catalytic hydrogenation method used in this invention ensures stable hydrogen flow, has recycling value, is environmentally friendly, and reduces costs. The catalyst can be reused without loss, further reducing production costs. The continuous flow reactor used reduces the generation of waste gas, wastewater, and solid waste, and the catalyst is easy to separate and recover, reducing environmental pollution. The equipment is small, with low maintenance and operating costs and low energy consumption. It has a high degree of automation, is simple to operate, and has controllable safety risks, eliminating safety hazards and reducing the occurrence of safety and quality accidents. It is suitable for large-scale production and application. Attached Figure Description

[0022] Figure 1 The process flow diagram for preparing tris(hydroxymethyl)aminomethane is shown in the example. Detailed Implementation

[0023] The present invention will be further illustrated below with reference to specific embodiments. These embodiments are implemented based on the technical solution of the present invention and should be understood as being for illustrative purposes only and not for limiting the scope of the invention. To better illustrate the purpose, technical solution, and advantages of the present invention, the present invention will be further described below with reference to specific embodiments. Unless otherwise specified, the experimental methods used in the embodiments are conventional methods, and the materials and reagents used are commercially available unless otherwise specified. Unless otherwise specified, all units used in the present invention are international standard units, and the numerical values ​​and ranges appearing in the present invention should be understood to include unavoidable systematic errors in industrial production. The process flow of the embodiments is as follows: Figure 1 As shown, the synthetic route of the embodiment is as follows:

[0024]

[0025] Example 1

[0026] Take 90g of paraformaldehyde (3mol) and 2.8g of KOH and mix them evenly in 215.0g of methanol to obtain mixture 1;

[0027] Dissolve 61.0 g of nitromethane (1 mol) in 244.0 g of methanol to obtain a nitromethane solution;

[0028] Mixture 1 and nitromethane methanol solution were introduced into the corresponding feed inlet of the microchannel continuous flow reactor at a flow rate of 0.3 mL / min. The temperature of the microchannel continuous flow reactor was set to 40℃ and the pressure to 1.0 MPa. After the reaction stabilized, mixture 2 containing tris(hydroxymethyl)nitromethane was obtained.

[0029] The micro-packed bed continuous flow reactor was set at a pressure of 3.0 MPa and a reaction temperature of 70 °C. Mixture 2 was introduced into the reactor, which contained 5 mL of Raney nickel catalyst, at a flow rate of 0.5 mL / min and hydrogen at a flow rate of 100 sccm (i.e., 100 mL / min). Once the reaction reached stability, the crude product was collected. The crude product was concentrated, pulped with methyl tert-butyl ether or ethyl acetate, and filtered to obtain 117 g of white tris(hydroxymethyl)aminomethane (Tris), with a final yield of 96.5% and a final purity of 99.9%. The alcohol solvent used in the reaction could be recovered by distillation.

[0030] Example 2-13

[0031] The difference between Examples 2-13 and Example 1 lies in the catalyst and process parameters used in the micro-packed bed continuous flow reactors. The catalysts and process parameters for the micro-packed bed continuous flow reactors in Examples 1-13 are shown in Table 1.

[0032] Table 1. Conditional parameters of the micro-packed bed continuous flow reactors in Examples 1-13

[0033]

[0034] As shown in Table 1, using a continuous flow reactor, both Pd-based and Ni-based catalysts can successfully synthesize tris(hydroxymethyl)aminomethane, with controlled yields exceeding 94.0%. The continuous flow process offers a wider range of reaction temperature and pressure, facilitating process parameter control. No catalyst replacement is required after each batch of feedstock is reacted, resulting in no catalyst loss. Furthermore, the catalyst shows no significant activity degradation even after continuous operation for over 360 days, reducing catalyst costs and effectively adapting to industrial production. In addition, continuous flow reactors are smaller, have lower equipment costs, and offer significant improvements in reaction conversion, selectivity, and yield.

[0035] Examples 14-17

[0036] The difference between Examples 14-17 and Example 1 lies in the different process parameters of the microchannel continuous flow reactor. The process parameters of the microchannel continuous flow reactor in Examples 1 and 14-17 are shown in Table 2.

[0037] Table 2. Process condition parameters for the microchannel continuous flow reactors in Examples 1 and 14-17

[0038]

[0039]

[0040] As shown in Table 2, excessive alkali does not increase the yield of the final trihydroxymethylaminomethane. The reason may be that if the alkali equivalence is too large, formaldehyde will condense into byproducts such as hydroxyacetaldehyde, which will reduce the purity of the reactants in the second step and thus reduce the yield of the final product. If the alkali equivalence is too small, it cannot provide a strong alkaline environment, which will slow down the condensation rate. The same residence time cannot be used to complete the reaction, which will reduce the purity of the reactants in the second step and thus reduce the yield of the final product.

[0041] Comparative Example 1

[0042] Take 90g of paraformaldehyde, 2.8g of KOH and 215.0g of methanol and stir them evenly in a reaction vessel to obtain mixture 1;

[0043] Dissolve 61.0 g of nitromethane in 244.0 g of methanol to obtain a nitromethane solution;

[0044] The nitromethane solution was slowly added dropwise to the reaction vessel. The temperature in the reaction vessel was maintained at 40°C and the pressure at 1.0 MPa. After the addition was completed, the mixture was stirred for 1 hour. After the reaction was completed, a mixture containing tris(hydroxymethyl)nitromethane was obtained.

[0045] Mixture 2 and 5 mL of Raney nickel catalyst were placed in an autoclave, purged three times with hydrogen gas, and the hydrogen pressure was controlled at 3.0 MPa. The mixture was stirred at 70°C for 2 hours. After the reaction was completed, heating was stopped, the temperature was lowered, and the product was cooled to crystallize. The mixture was filtered, and the crude product was collected. After recrystallization and purification, and decolorization with activated carbon, 81 g of pale yellow tris(hydroxymethyl)aminomethane (Tris) was obtained, with a final yield of 67.1% and a final purity of 99.4%. The alcohol solvent used in the reaction can be recovered by distillation.

[0046] Comparative Example 2

[0047] Take 90g of paraformaldehyde, 2.8g of KOH and 215.0g of methanol and stir them evenly in a reaction vessel to obtain mixture 1;

[0048] Dissolve 61.0 g of nitromethane in 244.0 g of methanol to obtain a nitromethane solution;

[0049] The nitromethane solution was slowly added dropwise to the reaction vessel. The temperature in the reaction vessel was maintained at 40°C and the pressure at 1.0 MPa. After the addition was completed, the mixture was stirred for 1 hour. After the reaction was completed, a mixture containing tris(hydroxymethyl)nitromethane was obtained.

[0050] The micro-packed bed continuous flow reactor was set at a pressure of 3.0 MPa and a reaction temperature of 70 °C. Mixture 2 was introduced into the reactor, which contained 5 mL of Raney nickel catalyst, at a flow rate of 0.5 mL / min and a hydrogen flow rate of 100 sccm. Once the reaction reached stability, the crude product was collected. After purification, 102 g of tris(hydroxymethyl)aminomethane (Tris) was obtained, with a final yield of 84.3% and a final purity of 99.8%. The alcohol solvent used in the reaction could be recovered through distillation.

[0051] Comparative Example 3

[0052] Take 90g of paraformaldehyde and 2.8g of KOH and mix them evenly in 215.0g of methanol to obtain mixture 1;

[0053] Dissolve 61.0 g of nitromethane in 244.0 g of methanol to obtain a nitromethane solution;

[0054] Mixture 1 and nitromethane methanol solution were introduced into the corresponding feed inlet of the microchannel continuous flow reactor at a flow rate of 0.3 mL / min. The temperature of the microchannel continuous flow reactor was set to 40℃ and the pressure to 1.0 MPa. After the reaction stabilized, mixture 2 containing tris(hydroxymethyl)nitromethane was obtained.

[0055] Mixture 2 and 5 mL of Raney nickel catalyst were placed in an autoclave, purged three times with hydrogen gas, and the hydrogen pressure was controlled at 3.0 MPa. The mixture was stirred at 70°C for 2 hours. After the reaction was completed, heating was stopped, the temperature was lowered, and the product was cooled to crystallize. The mixture was filtered, and the crude product was collected. After recrystallization and purification, and decolorization with activated carbon, 91 g of pale yellow tris(hydroxymethyl)aminomethane (Tris) was obtained, with a final yield of 75.5% and a final purity of 99.5%. The alcohol solvent used in the reaction can be recovered by distillation.

[0056] Compared with Example 1 and Comparative Examples 1-3, the final yield of Example 1 was as high as 96.5%, and the final content was 99.9%. Comparative Example 1 used a batch reactor for both steps, and the final yield was only 67.1%. Comparative Example 2 used a batch reactor for the first step and a continuous flow process for the second step. Comparative Example 3 used a continuous flow process for the first step and a batch reactor for the second step. It can be seen that using a continuous flow process for polymerization and hydrogenation synthesis can effectively improve the selectivity of the reaction, reduce the difficulty of post-processing, greatly increase the content and yield of tris(hydroxymethyl)aminomethane (Tris) product, and reduce production costs.

[0057] The above specific embodiments further illustrate the purpose, technical solution and beneficial effects of this application. It should be understood that the above are only specific embodiments of this application and are not intended to limit the scope of protection of this application. Any modifications, equivalent substitutions, improvements, etc., made on the basis of the technical solution of this application should be included within the scope of protection of this application.

Claims

1. A method for preparing tris(hydroxymethyl)aminomethane using a continuous flow process, characterized in that, include: Paraformaldehyde and alkali are dissolved in a solvent and mixed to obtain mixture 1; Nitromethane is dissolved in a solvent to obtain a nitromethane solution. The nitromethane solution is mixed with mixture 1 to form a reaction solution. The reaction solution is passed into a microchannel continuous flow reactor for reaction. After the reaction is completed, mixture 2 containing tris(hydroxymethyl)nitromethane is obtained. The flow rates of mixed liquid 2 and hydrogen gas are adjusted and introduced into the gas-liquid mixer at the inlet of the micro-packed bed continuous flow reactor to obtain a gas-liquid mixed fluid. The gas-liquid mixed fluid is then flowed through the catalyst bed of the micro-packed bed continuous flow reactor and reacted. The reaction temperature is controlled by the reactor heat exchange chamber of the micro-packed bed continuous flow reactor. After the reaction is completed, crude tris(hydroxymethyl)aminomethane is obtained, which is then purified by post-treatment to obtain pure tris(hydroxymethyl)aminomethane. The catalyst includes a supported Pd catalyst, a supported Ni catalyst, or a Raney nickel catalyst.

2. The method for preparing tris(hydroxymethyl)aminomethane by continuous flow according to claim 1, characterized in that, The supports for the supported Pd catalysts include activated carbon supports, silica supports, and alumina supports, while the supports for the supported Ni catalysts include activated carbon supports, silica supports, and alumina supports.

3. A method for preparing tris(hydroxymethyl)aminomethane by continuous flow according to claim 1 or 2, characterized in that, The metal loading of the supported Pd-based catalyst or the supported Ni-based catalyst is 1.0 wt% to 30.0 wt%.

4. The method for preparing tris(hydroxymethyl)aminomethane by continuous flow according to claim 1, characterized in that, The flow rate ratio of the mixture 2 to hydrogen is in the range of 1:15 to 200.

5. The method for preparing tris(hydroxymethyl)aminomethane by continuous flow according to claim 1, characterized in that, The reaction temperature in the micro-filled bed continuous flow reactor is 40℃~120℃, the reaction pressure is 0.5Mpa~6.0Mpa, and the reaction time is 2min~30min.

6. The method for preparing tris(hydroxymethyl)aminomethane by continuous flow according to claim 5, characterized in that, The micro-filled bed continuous flow reactor includes a gas-liquid mixer, a catalyst bed, and a reactor heat exchange chamber.

7. The method for preparing tris(hydroxymethyl)aminomethane by continuous flow according to claim 1, characterized in that, The molar ratio of nitromethane to paraformaldehyde in the reaction solution is in the range of 1:3 to 4.

8. The method for preparing tris(hydroxymethyl)aminomethane by continuous flow according to claim 7, characterized in that, The molar ratio of nitromethane to alkali in the reaction solution is in the range of 1:0.001 to 0.1, and the alkali is potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate, or sodium carbonate.

9. The method for preparing tris(hydroxymethyl)aminomethane by continuous flow according to claim 1, characterized in that, The solvent is methanol, ethanol, isopropanol or water, and the volume hourly space velocity ratio of the nitromethane solution to the mixture 1 is 1:

1.

10. The method for preparing tris(hydroxymethyl)aminomethane by continuous flow according to claim 1, characterized in that, The reaction temperature in the microchannel continuous flow reactor is 40℃~70℃, the reaction pressure is 0.2Mpa~2.0Mpa, and the reaction time is 3~10min.

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