A preparation method of urotropine quaternary ammonium salt

Abstract

The present invention provides a method for preparing a quaternary ammonium salt of methenamine, which can be quickly prepared and accurately detected under relatively mild preparation conditions. The method includes a preparation method and a detection method. Preparation steps: (1) adding methenamine and sodium chloroacetate (or other halogenated organic carboxylic acid metal salt) to a reaction solvent, stirring to mix them evenly, and maintaining a certain temperature for reaction; (2) after the reaction is completed, separating the solid and the liquid, and drying the solid to obtain the quaternary ammonium salt of methenamine. Detection steps: (3) grinding the prepared quaternary ammonium salt of methenamine into fine particles, dissolving it in water to prepare a solution; (4) using high performance liquid chromatography to detect the product solution and analyze the purity. According to the embodiment, the yield of the prepared quaternary ammonium salt of methenamine is not less than 90%, and the purity is as high as 97%.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis and relates to a preparation and detection method of hexamethylenetetramine quaternary ammonium salt. Background Art

[0002] Hexamethylenetetramine, also known as hexamethylenetetramine, is an organic base that usually appears as a white powder. It is soluble in organic solvents such as methanol, ethanol, and acetone, easily soluble in water, and hydrolyzes under acidic conditions. It has a wide range of uses. It is used as a bactericidal and antibacterial drug to treat urinary disturbances, axillary odor, and sweaty feet. It is also an important raw material for organic synthesis, such as a curing agent for resins and plastics, an accelerator for rubber vulcanization, and a nitrogen source for high-nitrogen energetic materials. The new quaternary ammonium salt compounds derived from hexamethylenetetramine have the characteristics of both the hexamethylenetetramine group and other carbon chains, and their application prospects cover industrial disinfectants, pest control pesticides, organic synthesis and pharmaceutical intermediates, metal corrosion inhibitors, and other fields.

[0003] In the traditional process for producing glycine using chloroacetic acid and ammonia as raw materials, hexamethylenetetramine acts as a catalyst to accelerate the rate of the ammonolysis reaction, thereby improving the efficiency of glycine synthesis. The English literature "A high-yielding synthesis and kinetics of glycine formation from monochloroacetic acid and NH3 in the presence of hexamethylenetetramine (ACH - Models in Chemistry, 2000, 137(40): 503-509)" and "Setup of glycine continuous synthesis by ammonolysis of monochloroacetic acid (Laboratory Robotics and Automation, 1999, 11(1):29-35)" further studies and speculates that hexamethylenetetramine and chloroacetic acid first undergo a condensation reaction to form a condensation intermediate, which then undergoes an ammonolysis reaction, with ammonia replacing the hexamethylenetetramine on the intermediate to produce glycine. However, this intermediate is unstable and difficult to detect in the final product. There are no reports on the synthesis and physical property studies of this compound.

[0004] Chinese patent CN104988510A discloses a method for preparing a quaternary ammonium salt corrosion inhibitor for hexamethylenetetramine and its application. Hexamethylenetetramine and a halogenated alkane are mixed and reacted in an organic solvent such as chloroform or methanol for 6-10 hours, filtered twice, and dried to produce a hexamethylenetetramine quaternary ammonium salt corrosion inhibitor. This quaternary ammonium salt corrosion inhibitor exhibits excellent corrosion inhibition efficiency and water solubility, making it particularly suitable for high-temperature working environments such as oil pipelines and boiler pipes. The molecular structure is formed by hexamethylenetetramine replacing halogen atoms on halogenated hydrocarbons. When dissolved in water, it forms a quaternary ammonium salt with a positive ionic charge, which spreads on metal surfaces, isolating water molecules and thereby slowing electrochemical corrosion.

[0005] Chinese patent CN116549361A reports a method for preparing a methenamine composition, which has the advantages of effectively reducing sweat secretion and excretion, as well as antifouling, antiperspirant, sterilizing, and deodorizing properties. The method involves extracting Chinese medicinal materials such as sage and ephedra with water, then uniformly mixing the extract with a methenamine quaternary ammonium salt and aluminum chloride, and then adding TiO2 / SiO2 porous microspheres coated with polydopamine to produce the methenamine composition. The methenamine quaternary ammonium salt is obtained by reacting methenamine, an alkali, and a halogenated hydrocarbon, but its preparation process and method are essentially the same as those described in CN104988510A. Therefore, the novel methenamine quaternary ammonium salt of the present invention may have external sterilizing and deodorizing effects due to the presence of the methenamine group. Furthermore, the carboxylic acid group enhances water solubility, promoting blood transport and cellular absorption of the drug when used in oral medications.

[0006] Chinese patent CN106831377 A and international patent WO2016CN105940 disclose a method for preparing isophorone. This method utilizes an organic hexamethylenetetramine quaternary ammonium base as a catalyst. Specifically, under nitrogen, methylhexamethylenetetramine chloride and a 30% sodium methoxide methanol solution are mixed and reacted for 4 hours. The mixture is filtered to obtain a mother liquor containing the quaternary ammonium salt, which is then subjected to high-pressure synthesis of isophorone.

[0007] To this end, the present invention provides a method for preparing a quaternary ammonium salt of methenamine, specifically a method for preparing a novel quaternary ammonium salt of methenamine sodium chloride, and provides a reliable detection method, and the method has broad potential application prospects. Summary of the Invention

[0008] The invention provides a preparation and detection method of a methenamine quaternary ammonium salt, which can quickly prepare and accurately detect the novel methenamine quaternary ammonium salt under relatively mild preparation conditions.

[0009] In order to achieve the purpose of the invention, the present invention adopts the following technical solutions:

[0010] A method for preparing a quaternary ammonium salt of methenamine comprises the following steps:

[0011] (1) Hexamethylenetetramine and sodium chloroacetate (or other halogenated organic carboxylic acid metal salts) are added to the reaction solvent, stirred to mix evenly, and maintained at a certain temperature for reaction;

[0012] (2) After the reaction is completed, the solid and liquid are separated, and the solid is dried to obtain the quaternary ammonium salt of urotropine.

[0013] The halogenated organic carboxylic acid metal salt in step (1) can be sodium chloroacetate, sodium dichloroacetate, sodium chloropropionate, sodium bromoacetate, sodium iodoacetate and the like, or can be other metal carboxylates such as potassium chloroacetate, lithium chloroacetate, potassium bromoacetate, etc.; but it is not limited to the listed compounds, and other halogenated organic carboxylic acid metal salts not listed are also applicable.

[0014] In water or a water-organic solvent system, a new type of urotropine quaternary ammonium salt (urotropine sodium chloride quaternary ammonium salt, or urotropine metal chloride quaternary ammonium salt, hereinafter referred to as urotropine quaternary ammonium salt) can be obtained by condensation reaction with sodium chloroacetate (or other halogenated organic carboxylate) and urotropine as raw materials. The reaction process is shown below. Its chemical formula is C8H 14 ClN4NaO2, relative molecular weight is 256.67 g / mol.

[0015] .

[0016] The reaction solvent is preferably a methanol aqueous solution or an ethanol aqueous solution, and may be a mixture of an aqueous phase and other organic phases; the volume percentage of methanol in the methanol aqueous solution is 75-85%, and the volume percentage of ethanol in the ethanol aqueous solution is 75-85%; the other organic phase may be an organic solvent miscible with water, such as ethylene glycol, propanol, or acetone; but is not limited to the listed reaction solvents, and other reaction solvents not listed are also applicable.

[0017] The type of stirring applied is preferably magnetic stirring, but may also be mechanical stirring, turbine stirring, or manual stirring.

[0018] The reaction temperature is preferably 50-80°C, and can be 50°C, 60°C, 70°C and 80°C, but is not limited to the listed values, and other values ​​not listed within the numerical range are also applicable.

[0019] The reaction time is preferably 1-2.5 h, and can be 1.0 h, 1.5 h, 2.0 h, and 2.5 h, but is not limited to the listed values, and other values ​​not listed within the numerical range are also applicable.

[0020] The solid-liquid separation in step (2) is preferably performed by hot filtration, which can be hot filtration at normal pressure, hot filtration at reduced pressure, or centrifugation, but is not limited to the solid-liquid separation methods listed above. Other methods not listed within the numerical range are also applicable.

[0021] The solid drying method is preferably heating drying and vacuum drying, or natural air drying, freeze drying, etc.; the heating drying temperature is 40-80°C, which can be 40°C, 50°C, 60°C, 70°C and 80°C, but is not limited to the listed values, and other values ​​not listed within the numerical range are also applicable.

[0022] The drying time is preferably 5-12 hours, and can be 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours and 12 hours, but is not limited to the listed values, and other values ​​not listed within the numerical range are also applicable.

[0023] A method for detecting urotropine quaternary ammonium salt comprises the following steps:

[0024] (3) Grinding the prepared urotropine quaternary ammonium salt into fine powder and dissolving it in water to prepare a solution;

[0025] (4) Use high performance liquid chromatography to test the product solution and analyze its purity.

[0026] The grinding method in step (3) is manual mortar grinding or grinding with a grinder;

[0027] The water used to prepare the solution is preferably ultrapure water or deionized water;

[0028] The concentration of the prepared solution is preferably 500-4500 mg / L, and can be 500 mg / L, 1500 mg / L, 2500 mg / L, 3500 mg / L and 4500 mg / L, but is not limited to the listed values, and other values ​​not listed within the numerical range are also applicable;

[0029] In the step (4), the high performance liquid chromatography method preferably uses an anion chromatography column, a potassium dihydrogen phosphate buffer mobile phase, a flow rate of 0.9±0.1 mL / min, and a detection wavelength of 200±10 nm; the pH of the potassium dihydrogen phosphate buffer is preferably 2-4, and can be 2.0, 2.5, 3.0, 3.5, or 4.0; the flow rate of 0.9±0.1 mL / min is preferably 0.8 mL / min, and can also be 0.85 mL / min, 0.90 mL / min, 0.95 mL / min, or 1.00 mL / min; the detection wavelength of 200±10 nm is preferably 195 nm, and can also be 190 nm, 200 nm, 205 nm, or 210 nm; but the values ​​listed are not limited thereto, and other values ​​not listed within the numerical range are also applicable.

[0030] Compared with the prior art, the present invention has the following beneficial effects:

[0031] The present invention provides a method for preparing and detecting a quaternary ammonium salt of urotropine. Water and an organic solvent are introduced into a reaction solvent. The reaction rate of the reactants in the aqueous phase can be accelerated, and the remaining reactants are removed with the liquid during solid-liquid separation, thereby rapidly preparing a high-purity solid quaternary ammonium salt product. Relatively mild preparation conditions, such as low reaction temperature and drying temperature, can ensure the thermal stability of the quaternary ammonium salt of urotropine. The raw material urotropine is essentially not retained in an anion column, while sodium chloroacetate (or other halogenated organic carboxylic acid metal salts) has a longer retention time. The product quaternary ammonium salt of urotropine has a retention time between that of urotropine and carboxylates. Sodium chloride (metal chloride salt) is in the form of a free ion Na in a potassium dihydrogen phosphate buffer mobile phase. + 、Cl - , and Cl - The retention time in the chromatographic column is the longest, thus accurately detecting the new urotropine quaternary ammonium salt and its purity. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 It is a schematic diagram of the preparation and detection method provided in Example 1 of the present invention.

[0033] Figure 2 This is the HPLC test result of the product prepared in Example 1 of the present invention.

[0034] Figure 3 This is the HPLC test result of the product prepared in Example 2 of the present invention. DETAILED DESCRIPTION

[0035] The technical solution of the present invention is further illustrated below with reference to examples and comparative examples, but the scope of protection claimed in the present invention is not limited to the scope described in the examples.

[0036] Example 1

[0037] The process of this method is as follows Figure 1 The specific implementation steps are as follows.

[0038] (1) Add 15.421 g of hexamethylenetetramine (0.11 mol), 116.479 g of sodium chloroacetate (0.1 mol), 10 mL of water, and 35 mL of ethanol to a 250 mL flask. Place the flask in a constant temperature water bath and apply magnetic stirring to dissolve the reactants. Set the temperature to 65°C and allow to react for 2 h.

[0039] (2) After the reaction is completed, the reaction solution is filtered while hot and vacuum pumped for 20 min. The solid is sent to a vacuum drying oven and dried at 55°C to obtain a block of hexamethylenetetramine quaternary ammonium salt, weighing 23.127 g;

[0040] (3) Grind the prepared urotropine quaternary ammonium salt into fine powder, weigh 2 g and dissolve it in ultrapure water to prepare a 2000 mg / L aqueous solution, then take a small amount of the solution and filter it through a membrane before filling it into a sample bottle;

[0041] (4) The samples were analyzed using a Shimadzu LC Solution-15C series high performance liquid chromatography workstation. The test conditions were as follows:

[0042] Chromatographic column: ShimNex HE SAX anion chromatography column; mobile phase: potassium dihydrogen phosphate buffer, pH = 2.50; mobile phase flow rate: 0.80 mL / min; injection volume: 10 μL; UV detection wavelength: 195 nm.

[0043] Product test results such as Figure 2 As shown in the figure, the mass fraction of hexamethylenetetramine (retention time 3.55 min, peak area 35670 mV·ms) is 1.01 wt%, the mass fraction of hexamethylenetetramine quaternary ammonium salt ion (retention time 4.60 min, peak area 3280606 mV·ms) is 98.84 wt%, and it is free chloride ion (retention time 12.78 min, peak area 736093 mV·ms) in the mobile phase. The reaction is complete as no peak of sodium chloroacetate (retention time 9.00 min) is observed.

[0044] The calculated yield is 23.127÷25.667×100%=90%, and the purity is 99 wt%.

[0045] The hexamethylenetetramine quaternary ammonium salt obtained by the present invention has good stability, with a decomposition temperature of above 170°C in a thermal stability test. After being slightly dampened for one month under a normal temperature and humidity of 60%, it gained 4.1% in weight, still having a purity of 95wt% and high reactivity. Furthermore, the hexamethylenetetramine quaternary ammonium salt formed by hexamethylenetetramine and ethyl bromide gained 10.8% in weight after being kept for one month under a normal temperature and humidity of 60%. Furthermore, compared to other hexamethylenetetramine quaternary ammonium salts, the hexamethylenetetramine quaternary ammonium salt obtained by the present invention is easier to dry.

[0046] Example 2

[0047] This embodiment provides a method for preparing and detecting a quaternary ammonium salt of methenamine. The difference from Example 1 is that the halogenated organic carboxylic acid metal salt in step (1) is sodium 2-chloropropionate (13.051 g, 0.1 mol), and the rest is the same as Example 1.

[0048] Product test results such as Figure 3As shown in the figure, the mass fraction of methenamine (retention time 3.55 min, peak area 53647 mV·ms) is 1.84 wt%, the mass fraction of methenamine quaternary ammonium salt ion (retention time 4.14 min, peak area 3690601 mV·ms) is 97.36 wt%, and it is free chloride ion (retention time 12.78 min, peak area 804399 mV·ms) in the mobile phase. No peak of sodium 2-chloropropionate (retention time 8.02 min) is observed, indicating that the reaction is complete.

[0049] Dried urotropine quaternary ammonium salt (chemical formula C9H 16 ClN4NaO2, relative molecular weight 270.69g / mol) weighed 25.642g, the calculated yield was 95%, and the purity was 97 wt%.

[0050] The hexamethylenetetramine quaternary ammonium salt obtained by the invention has good stability, a decomposition temperature of above 180° C. in a thermal stability test, and after being kept in an environment of normal temperature and 60% humidity for one month, it is slightly damp and gains weight by 3.2%, while still having a purity of 95wt% and high reaction activity.

[0051] Comparative Example 1

[0052] This comparative example provides a method for preparing and detecting a quaternary ammonium salt of urotropine. The difference from Example 1 is that the amount of water used in step (1) is 5 mL, and the remaining methods and conditions are the same as those in Example 1.

[0053] The dried urotropine quaternary ammonium salt weighed 12.123 g, with a calculated yield of 47% and a purity of 67 wt %. Compared with Example 1, Comparative Example 1 showed significantly reduced product yield and purity. Because the amount of water used in the reaction solvent was too little, the sodium chloride quaternary ammonium salt was saturated in the water-ethanol solution, and sodium chloride precipitated first during the reaction, while the urotropine quaternary ammonium salt precipitated slowly, resulting in a solid product composed mainly of sodium chloride salt.

[0054] Comparative Example 2

[0055] This comparative example provides a method for preparing and detecting a quaternary ammonium salt of urotropine. The difference from Example 1 is that the amount of water used in step (1) is 15 mL, and the remaining methods and conditions are the same as those in Example 1.

[0056] The dried urotropine quaternary ammonium salt weighed 14.245 g, with a calculated yield of 56% and a purity of 96 wt %. Compared with Example 1, Comparative Example 1 shows a significantly reduced product yield. This is because the quaternary ammonium salt is water-soluble and carries away some of the product during filtration of the reaction solvent. Therefore, appropriately reducing the amount of water in the reaction solvent is beneficial to improving the product yield. However, when there is no water or too little water, the urotropine quaternary ammonium salt is difficult to synthesize because salts are insoluble in organic solvents.

[0057] Comparative Example 3

[0058] This comparative example provides a preparation and detection method of urotropine quaternary ammonium salt, which differs from Example 1 in that the reaction temperature in step (1) is 40°C, and the other methods and conditions are the same as those in Example 1.

[0059] The dried urotropine quaternary ammonium salt weighed 15.134 g, with a calculated yield of 59% and a purity of 82 wt %. Compared with Example 1, the yield of the product prepared in Comparative Example 2 was lower. This was because the reaction temperature was lower, the rate of synthesizing the urotropine quaternary ammonium salt was slower, and the solubility also decreased with temperature. Unreacted sodium chloroacetate was not completely dissolved in the reaction solvent and remained in the solid, resulting in a decrease in purity.

[0060] Application Example 1

[0061] This example provides an application of a quaternary ammonium salt of hexamethylenetetramine. The hexamethylenetetramine quaternary ammonium salt prepared in Example 1 (0.1010 mol) was added with water to obtain a 0.3333 mol / L solution of hexamethylenetetramine. Approximately ten times the molar amount of 25-28 wt% industrial ammonia (3.333 mol) was then added to efficiently synthesize glycine. This process involves the following aminolysis reaction:

[0062]

[0063] The reaction temperature was maintained at 65°C for 20 minutes. After the reaction was complete, the reaction solution was immediately analyzed by liquid chromatography (under the same conditions as in Example 1). If the chromatographic peak of the urotropine quaternary ammonium salt in the reaction solution fell below the detection limit, it indicated complete consumption. Simultaneously, the concentrations of glycine and chloride ions were nearly equal (molar ratio of 0.99:1), indicating a complete reaction.

[0064] Since glycine has an isoelectric point of 5.97, an appropriate amount of acid was added to the reaction solution to adjust the pH to 6, converting the glycine radical into glycine. Finally, methanol was added to precipitate glycine crystals, which were filtered and dried to yield glycine (0.0896 mol). The filtrate was concentrated by evaporation and cooled for crystallization, yielding sodium chloride and ammonium chloride as byproducts, weighing 3.0045 g.

[0065] The yield of glycine synthesized in this application example can reach up to 99% based on the quaternary ammonium salt of urotropine sodium chloride. Due to the thermodynamic equilibrium constraints of alcohol precipitation crystallization, the actual yield of glycine is 0.0896 / 0.1010 = 88.7%, which is not limited by the present invention. However, in this application example, the system always maintains an alkaline environment, which limits the decomposition loss of urotropine and quaternary ammonium salt due to the acidic environment. The above is only a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Those skilled in the art should understand that any changes or substitutions that can be easily imagined by those skilled in the art within the technical scope disclosed by the present invention fall within the protection scope and disclosure range of the present invention.

Claims

1. A method for preparing a quaternary ammonium salt of methenamine, characterized in that: The following steps are involved: (1) Hexamethylenetetramine and a halogenated organic carboxylic acid metal salt are added to a reaction solvent and reacted under stirring at a reaction temperature of 50-80° C. and a reaction time of 1-2.5 h; the halogenated organic carboxylic acid metal salt comprises any one of sodium chloroacetate, sodium dichloroacetate, sodium chloropropionate, sodium bromoacetate, sodium iodoacetate, potassium chloroacetate, lithium chloroacetate, and potassium bromoacetate; the reaction solvent comprises any one of methanol aqueous solution, ethanol aqueous solution, ethylene glycol aqueous solution, propanol aqueous solution, and acetone aqueous solution, wherein the volume percentage of methanol in the methanol aqueous solution is 75-85%; the volume percentage of ethanol in the ethanol aqueous solution is 75-85%; the volume percentage of ethylene glycol in the ethylene glycol aqueous solution is 75-85%; the volume percentage of propanol in the propanol aqueous solution is 75-85%; and the volume percentage of acetone in the acetone aqueous solution is 75-85%; (2) After the reaction is completed, the solid and liquid are separated, and the solid is dried to obtain the quaternary ammonium salt of urotropine.

2. The method for preparing a quaternary ammonium salt of methenamine according to claim 1, wherein The reaction temperature in step (1) is 50°C, 60°C, 70°C or 80°C.

3. The method for preparing a quaternary ammonium salt of methenamine according to claim 2, wherein The reaction time in step (1) is 1.0 h, 1.5 h, 2.0 h or 2.5 h.

4. The method for preparing a quaternary ammonium salt of methenamine according to claim 1, wherein The solid drying method in step (2) is heating drying, vacuum drying, natural air drying, or freeze drying.

5. The method for preparing a quaternary ammonium salt of urotropine according to claim 4, wherein The heating and drying temperature is 40-80° C., and the drying time is 5-12 hours.

6. The method for preparing a quaternary ammonium salt of methenamine according to claim 1, wherein The temperature for heating and drying is 40°C, 50°C, 60°C, 70°C or 80°C.

7. The method for preparing a quaternary ammonium salt of methenamine according to claim 6, wherein The drying time is 5h, 6h, 7h, 8h, 9h, 10h, 11h or 12h.

8. Use of hexamethylenetetramine quaternary ammonium salt prepared by the method according to any one of claims 1 to 7 in the preparation of glycine.

9. A method for preparing glycine, characterized in that: The method for preparing the urotropine quaternary ammonium salt according to any one of claims 1 to 7, and the step of preparing glycine; The reaction formula for preparing glycine is as follows: 。

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