A method for preparing tris-hydroxymethyl aminomethane by continuous flow

Abstract

The present application relates to a kind of method for preparing trimethylolamine in continuous flow method, comprising the following steps: mixing paraformaldehyde and alkali solution, to obtain first mixed solution;The first mixed solution and nitromethane solution are as reaction liquid, the reaction liquid is passed into first continuous flow reactor at 0.1mL / min~1.5mL / min flow rate, reaction is ended to obtain second mixed solution, the reaction temperature in first continuous flow reactor is 20~30 ℃;Second continuous flow reactor is pressurized to 2MPa~6MPa, and the second mixed solution is passed into the second continuous flow reactor at 0.1mL / min~0.6mL / min flow rate, reaction is ended, to obtain the trimethylolamine, the reaction temperature in second continuous flow reactor is 40~80 ℃, the present application is easy to operate, synthesis is efficient, and high safety.

Description

Technical Field

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

[0002] Tris(hydroxymethyl)aminomethane (Tris) is an important biochemical, chemical, and pharmaceutical intermediate widely used in acute metabolic and respiratory acidosis. It is an alkaline buffer that provides good buffering against metabolic enzyme poisoning and enzyme activity. It is also commonly used in biochemical diagnostic kits, DNA / RNA extraction kits, and PCR diagnostic kits.

[0003] Traditional synthesis routes for Tris series products generally employ large-scale autoclave hydrogenation catalytic synthesis and other production methods. Autoclaves require high-temperature and high-pressure systems and consume large quantities of raw materials such as nitromethane and hydrogen, posing significant safety risks. Furthermore, traditional hydrogenation catalytic reduction systems use precious metal catalysts, which are difficult to recover. Intermittent batch reactions require large amounts of hydrogen, resulting in low raw material utilization. The maintenance and operating costs of batch production equipment under high-pressure systems are also high, leading to low yields of tris(hydroxymethyl)aminomethane. Summary of the Invention

[0004] Therefore, it is necessary to provide a continuous flow method for preparing tris(hydroxymethyl)aminomethane to increase the yield of tris(hydroxymethyl)aminomethane.

[0005] To achieve the above objectives, the present invention provides a technical solution:

[0006] A method for preparing tris(hydroxymethyl)aminomethane using a continuous flow process includes the following steps:

[0007] Paraformaldehyde and an alkaline solution are mixed to obtain the first mixture;

[0008] The first mixture and nitromethane solution are used as reaction solutions. The reaction solutions are introduced into the first continuous flow reactor at a flow rate of 0.1 mL / min to 1.5 mL / min. After the reaction is completed, a second mixture is obtained. The reaction temperature in the first continuous flow reactor is 20℃ to 30℃.

[0009] The second continuous flow reactor is pressurized to 2 MPa to 6 MPa, and the second mixture is introduced into the second continuous flow reactor at a flow rate of 0.1 mL / min to 0.6 mL / min. After the reaction is completed, the trihydroxymethylaminomethane is obtained. The reaction temperature in the second continuous flow reactor is 40℃ to 80℃.

[0010] Preferably, the catalyst comprises a PdCo / C catalyst.

[0011] Preferably, the catalyst preparation steps include:

[0012] The activated carbon solution and the precursor metal salt solution were mixed to obtain a third mixture;

[0013] After freeze-drying the third mixture, a sample to be subjected to thermal shock is obtained;

[0014] The PdCo / C catalyst is obtained by subjecting the sample to thermal shock to thermal shock.

[0015] Preferably, the specific steps of freeze-drying the third mixture include:

[0016] The third mixed solution was placed in a freeze dryer and frozen for 3 to 20 hours, then vacuum dried for 10 to 30 hours to obtain the sample to be subjected to thermal shock.

[0017] The specific steps for subjecting the sample to thermal shock include:

[0018] The sample to be subjected to thermal shock is evenly spread on carbon cloth. The shock voltage is 30V, the shock current is 10+(2n-1)A, where n is the number of shocks. Each shock lasts for 6 seconds, and the interval between two adjacent shocks is 10 seconds. The shock is stopped when the surface temperature of the sample to be subjected to thermal shock reaches 850℃, thus obtaining the PdCo / C catalyst.

[0019] Preferably, the alkali equivalent in the alkaline solution is 0.01 to 0.1.

[0020] Preferably, the alkali in the alkaline solution includes at least one of potassium hydroxide, sodium hydroxide, sodium acetate, and potassium carbonate.

[0021] Preferably, the molar concentration of the first mixture is 0.1 mol / L to 0.5 mol / L.

[0022] Preferably, the flow rate ratio of the first mixture to the nitromethane solution is 1:1.

[0023] Preferably, the flow rate of hydrogen gas introduced during the reaction process in the second continuous flow reactor is 10 sccm to 50 sccm.

[0024] The beneficial effects of this invention are:

[0025] This invention relates to the synthesis of tris(hydroxymethyl)aminomethane using a continuous flow reactor. This invention features a novel method, simple and practical operation, and high product quality and yield, thereby reducing production costs and minimizing environmental pollution.

[0026] The products obtained in this invention are easy to separate and process, and the process flow is simple, the reaction conditions are relatively mild, and the pollution is relatively small. The self-synthesized catalyst greatly reduces the difficulties in product separation and the problem of low catalyst utilization. The process flow of this invention effectively avoids the shortcomings of existing reactions that cannot be mass-produced, making it more conducive to meeting the requirements of large-scale industrial production, while improving the quality and yield of Tris.

[0027] This invention employs a continuous flow synthesis method, which enhances the mass and heat transfer performance of the reaction, maintains a constant reaction temperature, and avoids phenomena such as temperature runaway, material surge, and reaction runaway during the reaction, greatly improving operability and safety. Attached Figure Description

[0028] Figure 1 The image shows the hydrogen nuclear magnetic resonance spectrum of the product trihydroxymethylaminomethane in the examples. Detailed Implementation

[0029] To better illustrate the purpose, technical solution, and advantages of the present invention, the present invention will be further described below in conjunction with specific embodiments.

[0030] In the embodiments, unless otherwise specified, the experimental methods used are conventional methods, and the materials and reagents used are commercially available unless otherwise specified.

[0031] A method for preparing tris(hydroxymethyl)aminomethane using a continuous flow process includes the following steps:

[0032] S100. Mix paraformaldehyde and alkaline solution to obtain the first mixture;

[0033] S200. The first mixture and nitromethane solution are used as reaction solutions. The reaction solutions are introduced into the first continuous flow reactor at a flow rate of 0.1 mL / min to 1.5 mL / min. After the reaction is completed, a second mixture is obtained. The reaction temperature in the first continuous flow reactor is 20℃ to 30℃. Specifically, the molar ratio of paraformaldehyde and nitromethane is (1 to 4): 1.

[0034] S300. Pressurize the second continuous flow reactor to 2MPa~6MPa, and introduce the second mixture into the second continuous flow reactor at a flow rate of 0.1mL / min~0.6mL / min. After the reaction is completed, the tris(hydroxymethyl)aminomethane is obtained. The reaction temperature in the second continuous flow reactor is 40℃~80℃.

[0035] Specifically, the condensation reaction takes place in the first continuous flow reactor, and the catalytic hydrogenation reaction takes place in the second continuous flow reactor. The catalytic hydrogenation reaction requires higher temperatures and specific pressures (2 MPa to 6 MPa) to break the NO bonds of the aliphatic nitro compounds and thus proceed with the reaction.

[0036] This invention relates to the synthesis of tris(hydroxymethyl)aminomethane using a continuous flow reactor. This invention features a novel method, simple and practical operation, and high product quality and yield, thereby reducing production costs and minimizing environmental pollution.

[0037] The products obtained in this invention are easy to separate and process, and the process flow is simple, the reaction conditions are relatively mild, and the pollution is relatively small. The self-synthesized catalyst greatly reduces the difficulties in product separation and the problem of low catalyst utilization. The process flow of this invention effectively avoids the shortcomings of existing reactions that cannot be mass-produced, making it more conducive to meeting the requirements of large-scale industrial production, while improving the quality and yield of Tris.

[0038] This invention employs a continuous flow synthesis method, which enhances the mass and heat transfer performance of the reaction, maintains a constant reaction temperature, and avoids phenomena such as temperature runaway, material surge, and reaction runaway during the reaction, greatly improving operability and safety.

[0039] Compared to traditional batch reaction processes, continuous flow chemistry offers advantages such as higher heat and mass transfer efficiency, narrower residence time and 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, or high toxicity. The synthesis of an increasing number of pharmaceuticals and natural compounds using continuous flow technology has achieved higher yields and purity, enabling continuous production, reducing production costs and risks, and ultimately achieving reaction scale-up for industrial application.

[0040] The degree of polymerization of polymethylol is 1–4. Specifically, when the degree of polymerization of polymethylol is 3, the process for preparing tris(hydroxymethyl)aminomethane is as follows:

[0041]

[0042] In one embodiment, the catalyst comprises a PdCo / C catalyst. The preparation steps of the catalyst include:

[0043] The activated carbon solution and the precursor metal salt solution were mixed to obtain a third mixture;

[0044] After freeze-drying the third mixture, a sample to be subjected to thermal shock is obtained;

[0045] The PdCo / C catalyst is obtained by subjecting the sample to thermal shock to thermal shock.

[0046] Specifically, the freeze-drying steps of the third mixture include:

[0047] The third mixed solution was placed in a freeze dryer and frozen for 3 to 20 hours, then vacuum dried for 10 to 30 hours to obtain the sample to be subjected to thermal shock.

[0048] More specifically, the specific steps for subjecting the sample to thermal shock include:

[0049] The sample to be subjected to thermal shock is evenly spread on carbon cloth. The shock voltage is 30V, the shock current is 10+(2n-1)A, where n is the number of shocks. Each shock lasts for 6 seconds, and the interval between two adjacent shocks is 10 seconds. The shock is stopped when the surface temperature of the sample to be subjected to thermal shock reaches 850℃, thus obtaining the PdCo / C catalyst.

[0050] The precursor metal salt solution comprises an aqueous solution of palladium chloride and an aqueous solution of cobalt salt; wherein the concentrations of the aqueous solutions of palladium chloride and cobalt salt are 0.007-0.150 mol / L, and the concentration of the activated carbon solution is 1-20 mg / mL. The atomic ratio of Pd atoms in the aqueous solution of palladium chloride to Co atoms in the aqueous solution of cobalt salt is (1-3):1; the mass ratio of the total mass of palladium chloride and cobalt salt to the mass of activated carbon is 1:(5-15).

[0051] Specifically, the required catalyst mass is 0.5g to 0.8g.

[0052] In one embodiment, the alkali equivalent in the alkaline solution is 0.01 to 0.1, specifically, the alkali equivalent (eq) is relative to nitromethane, where eq = nalkali / nnitromethane. Aldehyde groups exhibit strong reducing properties in alkaline solutions, which can provide alkaline conditions, acting as a catalyst to accelerate the condensation reaction.

[0053] Preferably, the alkali in the alkaline solution includes at least one of potassium hydroxide, sodium hydroxide, sodium acetate, and potassium carbonate.

[0054] In one embodiment, the solvent in the alkaline solution includes methanol.

[0055] In one embodiment, the molar concentration of the first mixture is 0.1-0.5 mol / L.

[0056] In one embodiment, the flow rate ratio of the first mixture to the nitromethane solution is 1:1.

[0057] In one embodiment, hydrogen gas is introduced during the reaction process in the second continuous flow reactor.

[0058] In one embodiment, the hydrogen flow rate is 10 sccm to 50 sccm.

[0059] Specifically, before pressurizing the second continuous flow reactor to 2MPa to 6MPa, it is necessary to completely purge the air and other impurities inside the second continuous flow reactor. The specific steps are as follows: under the condition of nitrogen flow rate of 20sccm to 30sccm, the second continuous flow reactor is flushed with methanol at 4-6mL / min for 20min to 30min.

[0060] More specifically, the first continuous flow reactor and the second continuous flow reactor are installed in the same continuous flow equipment, and are named the first continuous flow reactor and the second continuous flow reactor to distinguish the reaction stages. The present invention is further illustrated below by way of examples, but the examples do not limit the present invention in any way.

[0061] Unless otherwise specified, the experimental methods used in the following examples are conventional methods. All quantitative experiments in the following examples were performed in triplicate, and the data are the average of the three replicates or the average ± standard deviation.

[0062] Example 1:

[0063] Take 36g of paraformaldehyde and 0.45g of KOH and mix them evenly in 790g of methanol to obtain the first mixture;

[0064] The first mixture and 24.4 g of nitromethane were used as the reaction solution. The reaction solution was fed into the corresponding feed inlet of the first continuous flow reactor at a flow rate of 0.2 mL / min. The temperature of the first continuous flow reactor was set to 25 °C. After the reaction stabilized, the second mixture was obtained.

[0065] The pressure of the second continuous flow reactor was set to 4 MPa, and the reaction temperature was set to 50 °C. The second mixture was introduced into the second continuous flow reactor at a rate of 0.2 mL / min and a hydrogen flow rate of 30 sccm. 0.6 g of PdCo / C catalyst was added. After the reaction reached steady state, the crude product was collected. The crude product was purified to obtain tris(hydroxymethyl)aminomethane (tris), which was then dried to obtain 42.49 g of tris(hydroxymethyl)aminomethane, with a yield of 87.8% and a purity of 99.9%.

[0066] The preparation steps of the PdCo / C catalyst in Example 1 are as follows:

[0067] The activated carbon solution and the precursor metal salt solution were mixed to obtain a third mixture; wherein the precursor metal salt solution comprised a 0.150 mol / L aqueous solution of palladium chloride and a 0.150 mol / L aqueous solution of cobalt salt.

[0068] After freeze-drying the third mixture, the sample to be subjected to thermal shock was obtained; the concentration of activated carbon solution was 20 mg / mL.

[0069] The PdCo / C catalyst is obtained by subjecting the sample to thermal shock.

[0070] Specifically, the freeze-drying steps for the third mixture include:

[0071] The third mixed solution was placed in a freeze dryer and frozen for 15 hours, then vacuum dried for 20 hours to obtain the sample to be subjected to thermal shock.

[0072] More specifically, the specific steps for subjecting the sample to thermal shock include:

[0073] The sample to be subjected to thermal shock is evenly spread on carbon cloth. The shock voltage is 30V, the shock current is 10+(2n-1)A, where n is the number of shocks. Each shock lasts for 6 seconds, and the interval between two adjacent shocks is 10 seconds. The shock is stopped when the surface temperature of the sample reaches 850℃, thus obtaining the PdCo / C catalyst.

[0074] The difference between Examples 2-21 and Example 1 lies in the different condition parameters of the second continuous flow reactor. The condition parameters of the second continuous flow reactor in Examples 1-21 are shown in Table 1.

[0075] Table 1. Conditional parameters of the second continuous flow reactor in Examples 1-21

[0076]

[0077]

[0078]

[0079]

[0080]

[0081]

[0082] The difference between Comparative Example 1 and Example 4 is that the catalyst is PtMn / C.

[0083] The difference between Comparative Example 2 and Example 4 is that the catalyst is Raney nickel.

[0084] The difference between Comparative Example 3 and Example 4 is that the catalyst is Pd / C.

[0085] The yields of the product tris(hydroxymethyl)aminomethane generated in Examples 4, 1, 2, and 3 are shown in Table 2.

[0086] Table 2. Yield of Tris(hydroxymethyl)aminomethane (%)

[0087] Example 4 95.3％ Comparative Example 1 74.38％ Comparative Example 2 77.9％ Comparative Example 3 76.4％

[0088] As shown in Table 2, the PdCo / C catalyst can successfully produce tris(hydroxymethyl)aminomethane with a yield as high as 95.3%, which is higher than that of Raney nickel catalyst in Comparative Example 2. However, Raney nickel has dangerous properties such as being highly flammable when exposed to air and producing harmful gases during combustion; long-term exposure may lead to pneumonia and other marker-induced nickel-like rashes.

[0089] The yield of the PdCo / C catalyst was higher than that of the Pd / C catalyst in Comparative Example 3, indicating that the doping of non-precious metals can significantly improve the catalyst activity and thus improve the catalytic efficiency; it was also higher than that of the PtMn / C catalyst in Comparative Example 1, indicating that the doping of metals has different effects on the modification of catalytic activity, and the doping effect of Co is better.

[0090] The PdCo / C catalyst of this invention has the advantages of being stable, safe and easy to store, making it more suitable for industrial production. At the same time, its catalytic effect is superior to other catalysts.

[0091] The difference between Examples 22-26 and Example 1 lies in the different conditions of the first continuous flow reactor, and the catalyst used in Examples 22-26 is the catalyst recovered after the reaction in Examples 1-21 through washing. The continuous flow reaction parameters in Examples 22-26 are shown in Table 3.

[0092] Table 3 Continuous flow reaction parameters in Examples 6-10

[0093]

[0094]

[0095] It can be found that reducing the alkali equivalent, reducing the reaction flow rate, increasing the reaction temperature, and reducing the reactant concentration can all ensure that the reaction proceeds fully and increase the final yield.

[0096] The difference between Comparative Example 4 and Example 6 is that the equivalent of alkali is 0.04.

[0097] The difference between Comparative Example 5 and Example 6 is that the equivalent of alkali is 0.06.

[0098] The difference between Comparative Example 6 and Example 6 is that the equivalent of alkali is 0.1.

[0099] The difference between Comparative Example 7 and Example 6 is that the equivalent of alkali is 0.007.

[0100] The difference between Comparative Example 8 and Example 6 is that the equivalent of alkali is 0.005.

[0101] The yields of the product tris(hydroxymethyl)aminomethane generated in Examples 6, 4, 5, 6, 7 and 8 are shown in Table 4.

[0102] Table 4. Yield of Tris(hydroxymethyl)aminomethane (%)

[0103] Example 6 92.8％ Comparative Example 4 88.4％％ Comparative Example 5 86.2％ Comparative Example 6 80.9％ Comparative Example 7 74.4％ Comparative Example 8 65.3％

[0104] Excessive alkali does not increase the final yield of Tris. The reason may be that if the alkali stoichiometry is too high, formaldehyde undergoes self-condensation to form byproducts such as hydroxyacetaldehyde, reducing the purity of the second-step reactants and thus lowering the final product yield. Conversely, if the alkali stoichiometry is too low, it fails to provide a strongly alkaline environment, slowing the condensation rate. The same reaction time is insufficient for complete reaction, further reducing the purity of the second-step reactants and consequently lowering the final product yield.

[0105] If there is too much alkali, formaldehyde will condense to form byproducts such as hydroxyacetaldehyde; if there is too little alkali, no reaction will occur.

[0106] It should be noted that the specific parameters or reagents in the above embodiments are specific or preferred embodiments under the concept of the present invention, and not limitations thereof; those skilled in the art can make adaptive adjustments within the concept and protection scope of the present invention.

Claims

1. A method for the preparation of tris-hydroxymethyl-aminomethane in a continuous flow process, characterized in that, The method comprises the steps of: mixing paraformaldehyde and an alkali solution to obtain a first mixed solution; passing the first mixed solution and a nitromethane solution as a reaction liquid into a first continuous flow reactor at a flow rate of 0.1 mL / min to 1.5 mL / min, and obtaining a second mixed solution, wherein the reaction temperature in the first continuous flow reactor is 20°C to 30°C; pressurizing a second continuous flow reactor to 2 MPa to 6 MPa, passing the second mixed solution into the second continuous flow reactor at a flow rate of 0.1 mL / min to 0.6 mL / min, and adding a catalyst, and obtaining the trimethylol aminomethane, wherein the reaction temperature in the second continuous flow reactor is 40°C to 80°C; the equivalent of the alkali in the alkali solution is 0.01 to 0.1; hydrogen is passed into the second continuous flow reactor during the reaction process, and the flow rate of the hydrogen is 10 sccm to 50 sccm; the catalyst comprises a PdCo / C catalyst.

2. The process for the preparation of tris-hydroxymethyl-aminomethane in continuous flow according to claim 1, characterized in that, The preparation steps of the PdCo / C catalyst comprise: mixing an activated carbon solution and a precursor metal salt solution to obtain a third mixed solution; freezing and drying the third mixed solution to obtain a heat shock sample; heat shocking the heat shock sample to obtain the PdCo / C catalyst.

3. The method of claim 2, wherein the method is continuous flow. The specific steps of freezing and drying the third mixed solution comprise: placing the third mixed solution in a freeze dryer, freezing for 3h to 20h, and vacuum drying for 10h to 30h to obtain the heat shock sample.

4. The process for the continuous flow preparation of tris-hydroxymethyl aminomethane according to claim 2, characterized in that, The specific steps of heat shocking the heat shock sample comprise: uniformly laying the heat shock sample on a carbon cloth, the shock voltage is 30V, the shock current is 10+(2n-1)A, n is the number of shocks, the shock current is 6s for each shock, and the intermittent time between adjacent two shocks is 10s, until the surface temperature of the heat shock sample reaches 850°C to stop the shock, and the PdCo / C catalyst is obtained.

5. The process for the preparation of trimethylol aminomethane in continuous flow according to claim 1, characterized in that, In the alkali solution, the alkali comprises at least one of potassium hydroxide, sodium hydroxide, sodium acetate, and potassium carbonate.

6. The process for the preparation of trimethylol aminomethane in continuous flow according to claim 1, characterized in that, The amount-of-substance concentration of the first mixed solution is 0.1mol / L to 0.5mol / L.

7. The process for the preparation of trimethylol aminomethane in continuous flow according to claim 1, characterized in that, The flow rate ratio of the first mixed solution to the nitromethane solution is 1:1.

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