A method for preparing methenamine hippurate

Abstract

The application discloses a preparation method of urotropine hippurate, wherein starting materials are urotropine and hippuric acid, the starting materials are heated in an alcohol good solvent until completely dissolved to obtain a stable clear solution, the solution is filtered through a filter membrane to remove bacteria and possible insoluble substances (mechanical impurities or inorganic salts), and the filtrate is transferred to a preheated crystallization kettle; in the process of temperature reduction and stirring, a suspension liquid containing product seed crystals and an ether poor solvent is added dropwise, so that urotropine hippurate (i.e. a hippurate urotropine salt type compound) can be stably generated, instead of urotropine, a physical mixture of hippuric acid and alkali or a urotropine hippurate eutectic crystal. The preparation method can ensure that high-purity urotropine hippurate is generated, the solubility of the product is improved, and the bioavailability of a pharmaceutical preparation and the medicine-making property are improved.

Description

Technical Field

[0001] This invention relates to a novel method for preparing urotropine hippurate, belonging to the field of pharmaceutical preparation technology. Background Technology

[0002] Methenamine Hippurate, also known as urotropine, has the molecular formula C9H9NO3.C6H 12 N4, CAS number [5714-73-8]; also reported as CAS number [13474-00-5], molecular formula C9H9NO3 . ·C6H 12 N4. Both forms have the chemical name 1,3,5,7-tetraaza-tricyclic[3,3,1,13,7]decane-mono-N-benzoylglycine, and their structural formulas are shown below:

[0003] Urotropine hippurate is stable in air, readily soluble in methanol, and soluble in water and ethanol. Urotropine is a weak base with a pKa of 5.2 (in water). Hippuric acid is a weak acid with a pKa of 3.61 (in water). According to the ΔpKa rule, 0 < ΔpKa (pKa...) 乌洛托品 - pKa 马尿酸 Since 3 < 3, they can combine in two different ways: eutectic and salt form. The core difference lies in the substantial proton transfer that occurs. If, during crystallization, the active hydrogen of hippuric acid completely dissociates and transfers to hexamethylenetetramine, hexamethylenetetramine hippurate is formed; if the active hydrogen of the carboxyl group of hippuric acid does not undergo proton transfer, hippuric acid and hexamethylenetetramine are bound together as neutral molecules through intermolecular forces (mainly hydrogen bonds), forming a eutectic. Hexamethylenetetramine and hippuric acid may also exist only as a physical mixture. The difference between the eutectic and salt forms of hexamethylenetetramine hippuric acid is shown in the following formula:

[0004] In its 2013 guidance, the FDA first clarified that cocrystals are crystalline substances composed of two or more different molecules within the same crystal lattice. The revised guidance in 2020 further clarified that cocrystals should be considered a new crystal form of the active pharmaceutical ingredient (API) under regulatory considerations. According to the FDA's definition, a salt form is "any of the many compounds resulting from the substitution of some or all of the acidic hydrogen atoms by a metal or metalloid group," and different salts are considered different active pharmaceutical ingredients.

[0005] Physical mixtures, eutectic crystals, and salt forms have completely different solubilities and bioavailability, and the corresponding formulation processes are also different. Therefore, the key to the synthesis of hexamethylenetetramine hippurate lies in the ability to prepare a high-purity, single, stable salt form.

[0006] Literature has reported that organic weak bases such as hexamethylenetetramine and other organic weak acids, due to their ΔpKa < 3, require specific conditions to stably and controllably form salts or eutectics, rather than simple physical mixtures, mixtures of eutectics and salts, or mixtures of the aforementioned forms. These methods include the following four processes: 1) Urotropin and succinic acid form a eutectic or salt using mechanochemistry (Bhattacharya, S.; Saraswatula, VG; Saha, BK). Thermal Expansion in Alkane Diacids - Another Property Showing Alternation in an Odd-Even Series. Cryst. Growth Des. 2013, 13 , 3651−3656).

[0007] 2) Urotropin and succinic acid are reacted by sublimation to form a eutectic or salt (Crystals of Organic Acid−Base Complexes Defy the ΔpKa Rule Under Compression, Shovan Das, Said MdPratik, and Ayan Datta*). Cryst. Growth Des. 2023, 23, 8212−8220).

[0008] 3) Urotropin reacts with succinic acid at high temperature and normal pressure to form a salt (same as above in the literature).

[0009] 4) Urotropin and hippuric acid are pre-prepared into a suitable acid-base pair using strong bases (NaOH) and strong bases (HCl), respectively, and then the hippuric acid-urotropin salt is generated in a tubular reactor (CN 118812547A).

[0010] The mechanochemical, sublimation, and high-temperature methods mentioned above all require specialized reaction equipment and operate under harsh conditions, making them unsuitable for industrial-scale preparation and only suitable for small-scale laboratory preparation (e.g., USP reference standards). Pre-prepared acids and bases using tubular reactors require specialized equipment, and the generated sodium chloride cannot be effectively separated from the product or filtered, making stable and controllable production difficult in industrial settings. Therefore, how to stably and controllably obtain hexamethylenetetramine hippurate in industrial settings has become a pressing problem to be solved.

[0011] Other existing patent applications that cannot yield a single product include the following: 5) The earliest method for synthesizing urotropine hippuric acid was reported by Alexander Galat in 1959 by US Patent 3004026A. The method involved dissolving equimolar amounts of hippuric acid and urotropine in methanol, heating to boiling, adding water until the solution became clear, and then evaporating the mixture to dryness to crystallize the product. However, this patent did not specify the yield and quality of the product. Patent CS252431B, in replicating this patent, confirmed that the yield of urotropine hippuric acid prepared by this method was 87%, and the purity was 94%. In replicating the experiments of this patent, this patent found that urotropine readily forms solvates with methanol, which is likely the reason for the low purity of the product prepared by this patent.

[0012] 6) Rexall Drug and Chemical Company filed Dutch patent NL6414633A (1964) and Canadian patent CA717094A (1965) in the Netherlands and Canada, respectively. The core preparation method involved dissolving 1 mole of hippuric acid and 0.8 to 1.0 moles of hexamethylenetetramine in n-propanol or isopropanol under reflux, followed by decolorization with activated charcoal, and then cooling the hot filtrate after hot filtration to allow product crystallization. This patent did not specify the quality of the product. Patent CS252431B, when replicating the above patent, confirmed that the purity of the product prepared by this method was 97%–98%, with a low yield of only about 75%. Replicating this patent revealed that the method could not generate a single hexamethylenetetramine hippurate-type compound; the formation of hexamethylenetetramine-hippuric acid eutectic was observed.

[0013] 7) In 1985, Zikan VTKTor of the Czech Republic published patent CS252432B1, disclosing a method for synthesizing high-purity hexamethylenetetramine hippuric acid. The specific preparation method involves mixing hippuric acid, hexamethylenetetramine, isopropanol, and water at a temperature of 10 to 30 °C. o The mixture is prepared at a temperature of C, with a molar ratio of 1 to 1.1 moles of hippuric acid and 7 to 13 moles of isopropanol per 1 mole of hexamethylenetetramine, and water comprising 0.3 to 5% of the total weight of the reaction mixture. This produces high-purity hexamethylenetetramine-hippuric acid in yields of 79.8% to 92.4%. This preparation process is claimed to be effective at temperatures between 20 and 25°C. oUnder stirring, the suspension of the two components first dissolves to form hexamethylenetetramine-hippuric acid, which then crystallizes out. This patent, in replicating the patented process, found that this process of dissolving and then precipitating is extremely short and unstable, easily affected by factors such as raw material particle size and stirring. Sometimes, a completely dissolved state may not even occur, making it impossible to guarantee a stable dissolved state for filtration to remove insoluble particles, and further impossible to guarantee that the precipitated compound is a single salt or a mixture.

[0014] 8) Patent CN108358937A discloses a method for producing hexamethylenetetramine-hippuric acid through a solid-solid reaction in the presence of a small amount of water in ethyl acetate. However, hexamethylenetetramine and hippuric acid have poor solubility in ethyl acetate, and this method cannot yield a clear solution. Furthermore, the product obtained by this process is also a physical mixture of hexamethylenetetramine and hippuric acid.

[0015] In summary, the synthesis process of urotropine hippuric acid is very sensitive. Whether it "becomes a physical mixture", "forms a salt" or "forms a eutectic" is easily affected by a variety of factors, which may result in the inability to obtain a stable single compound. Summary of the Invention

[0016] To address the aforementioned technical problems, this invention provides a novel method for preparing high-purity, stable, single-component hexamethylenetetramine mapurate, which is highly reproducible and cost-effective.

[0017] To achieve the above objectives, the technical solution adopted by the present invention is as follows: A method for preparing urotropine hippurate involves heating and dissolving urotropine, hippuric acid, and a good solvent to obtain a clear solution. The clear solution is then filtered, and the filtrate is introduced into a preheated crystallization vessel. After the crystallization vessel is cooled to the pre-crystallization temperature, it is continuously and slowly cooled to the aging temperature while a suspension of a poor solvent containing high-purity urotropine hippuric acid seed crystals is added dropwise to induce crystallization. After complete crystallization, the mixture is stirred at the aging temperature and finally filtered to obtain pure urotropine hippurate.

[0018] The urotropine to hippuric acid equivalent ratio is 1:(1~1.05), preferably 1:1.

[0019] The preferred solvent is an alcohol (including cyclic alcohols) such as ethanol, isopropanol, butanol, 2-butanol, pentanol, and cyclopentanol; ethanol is preferred.

[0020] The volume of a good solvent is 5-10 mL / g or L / Kg (relative to hexamethylenetetramine).

[0021] The undesirable solvent is an ether (including cyclic ether) solvent such as methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, diisopropyl ether, and dibutyl ether; preferably methyl tert-butyl ether.

[0022] The volume of the poor solvent is 1.5 to 2.5 times that of the good solvent (relative to the good solvent), preferably 2 times.

[0023] Preferably, the good solvent is ethanol, and the bad solvent is methyl tert-butyl ether or tetrahydrofuran, with the volume of the bad solvent being twice the volume of the good solvent.

[0024] Pre-crystallization temperature is 30-60°C o C; preferably 50~60 o C.

[0025] The seed crystal is high-purity hexamethylenetetramine hippurate, with a seed crystal equivalent of 0.001-0.1 (relative to hexamethylenetetramine).

[0026] Aging temperature is 0-30°C o C, preferably 5~15 o C.

[0027] This invention uses one or more filtration stages, wherein the first stage is a conventional filter to remove possible insoluble matter (mechanical impurities and salts invisible to the naked eye, with a filter specification of 0.50~5 microns), and the second stage is a sterilization filter (with a filter specification of 0.20~0.50 microns).

[0028] Crystallization yields using a single alcohol solvent are low, and the solubility of the two raw materials in a single alcohol solvent is inconsistent, leading to a decrease in the purity of the final product. This invention has found that complete dissolution of the raw materials hexamethylenetetramine and hippuric acid, as well as the addition of high-purity hexamethylenetetramine-hippuric acid seed crystals, are crucial for the preparation of hexamethylenetetramine-hippuric acid compounds.

[0029] This invention employs a composite solvent. The introduction of poor solvent ether compounds can form a large number of hydrogen bonds with good solvents such as alcohols, providing a stable environment for the crystallization of hexamethylenetetramine hippurate-type compounds.

[0030] Alcohols are excellent solvents for hexamethylenetetramine and hippuric acid, ensuring complete dissolution of both components under heating. However, the presence of insoluble or sparingly soluble particles during crystallization can interfere with the crystallization process, leading to a deviation between salt formation and eutectic formation. Dissolution and filtration to ensure a clear and homogeneous state are essential for crystallization. Furthermore, the highly polar hydroxyl groups in alcohols make hexamethylenetetramine and hippuric acid, with a ΔpKa of only 1.59, very sensitive during crystallization. Therefore, continuously adding an ether suspension containing high-purity hexamethylenetetramine and hippuric acid seed crystals during cooling crystallization ensures that a single salt-type compound is induced to precipitate.

[0031] A mixed solvent of alcohols (good solvent) and ethers (poor solvent) in a volume ratio of 1:2 maximizes the yield while ensuring the precipitation of pure hexamethylenetetramine hippurate-type compounds and avoiding the yield loss caused by using only alcohols (good solvent).

[0032] Beneficial effects

[0033] The method described in this invention is suitable for industrial production, with extremely high process stability. The generated solid is hexamethylenetetramine hippurate rather than hexamethylenetetramine hippurate eutectic or an acid-base physical mixture, or a mixture of the above. The product purity is above 98%, the yield is as high as 99%, and the product XRPD and infrared spectrum are consistent with the United States Pharmacopeia standard.

[0034] Furthermore, this preparation method produces a completely dissolved and clear state, which can be filtered through a biofiltration membrane and placed in a clean room for GMP-compliant, sterile, high-quality industrial production. Attached Figure Description

[0035] Figure 1 Compare the infrared spectrum of the hexamethylenetetramine-hippuric acid cocrystal of product Example 1; Figure 2 Compare with the infrared spectrum of the acid-base mixture in Example 2; Figure 3 Infrared spectrum of urotropine hippurate, a reference standard in the United States Pharmacopeia; Figure 4 Compare the infrared spectrum of the product in Example 3; Figure 5 Compare the infrared spectrum of the product in Example 4; Figure 6 Compare the infrared spectrum of the product in Example 5; Figure 7 Compare the infrared spectrum of the product in Example 6; Figure 8 Compare with the infrared spectrum of the product in Example 7; Figure 9 Example 1: Infrared spectrum of the product; Figure 10 Example 1: Infrared superposition spectra of the product and the United States Pharmacopeia reference standard; Figure 11 Example 1: XPRD overlay spectrum of physical mixture of product and United States Pharmacopeia reference standard; Figure 12 Example 2: Infrared spectrum of the product; Figure 13 Example 3: Infrared spectrum of the product; Figure 14 Example 4: Infrared spectrum of the product; Figure 15 Example 5: Infrared spectrum of the product; Figure 16 Example 6: Infrared spectrum of the product; Figure 17 Example 7: Infrared spectrum of the product; Figure 18 Example 8: Infrared spectrum of the product; Figure 19 Example 9: Infrared spectrum of the product. Detailed Implementation

[0036] This invention provides a rapid method for determining the salt formation of a product. The acid-base physical mixture of urotropine and hippuric acid, including eutectic and salt-type compounds, can be well distinguished using infrared spectroscopy (IR) methods from the United States Pharmacopeia. Example 1, a repeat of US Patent 3004026A, yielded the following IR spectrum: Figure 1 As shown, research revealed that it is a urotropine-hippuric acid cocrystal. The infrared spectrum of the product obtained by repeating Czech patent CS252432B1 in Comparative Example 2 is shown below. Figure 2 As shown, the infrared spectrum of the mixture after physical mixing with the two component raw materials in the same proportion is... Figure 1 The substance was identified as a physical mixture of urotropine and hippuric acid. Figure 3 The image shows the infrared spectrum of urotropine hippurate, a reference standard in the United States Pharmacopeia, which is a salt-type compound.

[0037] The following examples further illustrate the present invention, but should not be construed as limiting the protection of the present invention. Comparative Examples 3-7 are non-standard processes, and the infrared spectra of the resulting products are as follows: Figure 4-8 As shown, none of them are hexamethylenetetramine hippurate type compounds, and their infrared spectra are inconsistent with those of the United States Pharmacopeia reference standards. Examples 1-8 of this case describe the process of this patented invention, and the spectra of the resulting products are as follows. Figure 9-19 As shown, this is a hexamethylenetetramine-hippurate type compound.

[0038] Compare with Example 1 (Methanol Process) 14.0 g (0.1 mol) of hexamethylenetetramine and 17.9 g (0.1 mol) of hippuric acid were added to a 250 mL single-necked flask, followed by 50 mL of methanol. The mixture was heated to 65 °C with rapid stirring, and a small amount of water was added until dissolved. The solution was then concentrated to dryness by vacuum distillation to obtain a translucent oily substance. This substance was dried overnight in a vacuum oven at 45 °C. The dried solid was then pulverized as follows: Figure 1 As shown in the infrared spectrum, the product of this comparative example 1 is a hexamethylenetetramine-hippuric acid cocrystal.

[0039] Comparative Example 2 (Isopropanol-water room temperature process) Add 14.0 g (0.1 mol) hexamethylenetetramine and 18.0 g (0.1 mol) hippuric acid to a 250 mL three-necked flask, then add 80 mL of isopropanol with a water content of 0.3% (w / w). Stir at 20-25°C for 3 hours, then continue stirring at 15°C for 1 hour. Filter and wash with 5 mL of isopropanol. Dry the wet product overnight in a vacuum oven at 45°C. The dried product is as follows: Figure 2 As shown in the infrared spectrum, the product of this comparative example 2 is a physical mixture of hexamethylenetetramine and hippuric acid.

[0040] Compare with Example 3 (Tetrahydrofuran process) Add 2.8 g (0.02 mol) of hexamethylenetetramine and 3.6 g (0.02 mol) of hippuric acid to a 100 mL jacketed flask, then add 25 mL of tetrahydrofuran. Heat to 65 °C, add a small amount of water until the solid is completely dissolved, and stir at 65 °C for 1 hour. Then gradually cool to 10 °C and continue stirring for 4 hours. Filter, and dry the wet product overnight in a vacuum oven at 45 °C. After drying, as shown... Figure 4 As shown in the infrared spectrum, the product of this comparative example 3 is a physical mixture of hexamethylenetetramine and hippuric acid.

[0041] Comparative Example 4 (Isopropyl Ethanol Acetate Process) Add 2.8 g (0.02 mol) of hexamethylenetetramine and 3.6 g (0.02 mol) of hippuric acid to a 100 mL jacketed flask. First, add 20 mL of ethanol, heat to 80 °C and reflux until the solid is completely dissolved. Slowly add 30 mL of isopropyl acetate and stir at 60 °C for 1 hour. Then gradually cool to 10 °C and continue stirring for 3 hours. Filter, and dry the wet product in a vacuum oven at 45 °C overnight. After drying, as shown... Figure 5 As shown in the infrared spectrum, the product of this comparative example 4 is a physical mixture of hexamethylenetetramine and hippuric acid.

[0042] Comparative Example 5 (Ethanol-Heptane Process) Add 5.6 g (0.04 mol) hexamethylenetetramine and 7.2 g (0.04 mol) hippuric acid to a 100 mL jacketed flask, then add 40 mL of ethanol, a small amount of water, and heat to 80 °C under reflux until the solid is completely dissolved. Cool to 70 °C and slowly add 90 mL of n-heptane. During the addition, the solid gradually precipitates. Then gradually cool to 10 °C and continue stirring overnight. Filter, and dry the wet product overnight in a vacuum oven at 45 °C. The dried product is as follows: Figure 6 As shown in the infrared spectrum, the product of this comparative example 5 is a physical mixture of urotropine and hippuric acid.

[0043] Comparative Example 6 (ethanol methyl tert-butyl ether process without filtration) 10.0 g (0.071 mol) of hexamethylenetetramine and 13.0 g (0.073 mol) of hippuric acid were added to a 250 mL jacketed flask, followed by 60 mL of ethanol. The mixture was heated to 78 °C and stirred rapidly until dissolved. The temperature was then lowered to 56 °C and continued to slowly decrease to the aging temperature of 10 °C. During the cooling process, 120 mL of a methyl tert-butyl ether suspension containing 0.05 g of seed crystals (hexamethylenetetramine hippurate) was added dropwise. A solid gradually precipitated during the addition. After complete precipitation, the mixture was stirred overnight at 10 °C, filtered, and the wet product was dried in a vacuum oven at 45 °C for 6 hours to obtain 22 g of a white crystalline solid. Figure 7 As shown in the infrared spectrum, the product of this comparative example 6 is a mixture of hexamethylenetetramine-hippuric acid cocrystal and salt-type compound.

[0044] Comparative Example 7 (Ethanol Methyl Tert-Butyl Ether Process without Seed Crystals) 10.0 g (0.071 mol) of hexamethylenetetramine and 13.0 g (0.073 mol) of hippuric acid were added to a 250 mL jacketed flask A, followed by 60 mL of ethanol. The mixture was heated to 78 °C and stirred rapidly until dissolved. The solution was filtered through a membrane filter and transferred to a preheated 250 mL jacketed flask B. The solution was then cooled to the pre-crystallization temperature of 56 °C and slowly further cooled to the aging temperature of 10 °C. During the cooling process, 120 mL of methyl tert-butyl ether suspension was added dropwise. After complete precipitation, the mixture was stirred overnight at 10 °C, filtered, and the wet product was dried in a vacuum oven at 45 °C for 6 hours to obtain 22 g of a white crystalline solid. Figure 8 As shown in the infrared spectrum, the product of this comparative example 7 is a hexamethylenetetramine-hippuric acid cocrystal.

[0045] Example 1

[0046] 10.0 g (0.071 mol) of hexamethylenetetramine and 13.0 g (0.073 mol) of hippuric acid were added to a 250 mL jacketed flask A, followed by 50 mL of ethanol. The mixture was heated to 80 °C and stirred rapidly until dissolved. The solution was filtered through a membrane filter and transferred to a preheated 250 mL jacketed flask B. The solution was then cooled to the pre-crystallization temperature of 56 °C and continued to cool slowly to the aging temperature of 10 °C. During the cooling process, 100 mL of a methyl tert-butyl ether suspension containing 0.1 g of seed crystals (high-purity hexamethylenetetramine hippurate) was added dropwise. The solid gradually precipitated during the addition (completed over 1-4 hours). After complete precipitation, the mixture was stirred overnight at 10 °C, filtered, and the wet product was dried in a vacuum oven at 45 °C for 6 hours to obtain 22.6 g of a white crystalline solid, with a yield of 99.2% and a purity of 99.3%. Melting point: 105-110 °C.

[0047] like Figure 10 As shown, the infrared spectrum of the product of Example 1 prepared by this method ( Figure 9Infrared spectra of urotropine hippurate reference standard (USP) Figure 3 The product in Example 1 of this case is completely identical to that of urotropine hippurate.

[0048] like Figure 11 As shown, the XPRD spectrum of the product in Example 1 of this case is completely consistent with that of the U.S. Pharmacopeia reference standard of urotropine hippurate, and completely different from that of the physical mixture of raw materials urotropine and hippuric acid in equimolar proportions.

[0049] Example 2

[0050] 10.0 g (0.071 mol) of hexamethylenetetramine and 13.1 g (0.073 mol) of hippuric acid were added to a 250 mL jacketed flask A, followed by 60 mL of ethanol. The mixture was heated to 78 °C and stirred rapidly until dissolved. The solution was filtered through a membrane filter, and the clear solution was transferred to a preheated 250 mL jacketed flask B. The solution was then cooled to the pre-crystallization temperature of 55 °C, and then slowly cooled to 10 °C. During the cooling process, 150 mL of a suspension of methyl tert-butyl ether containing 0.2 g of seed crystals was added dropwise. The solid gradually precipitated during the addition. After complete precipitation, the mixture was stirred overnight at 10 °C, filtered, and the wet product was dried in a vacuum oven at 50 °C for 6 hours to obtain 22.3 g of a white crystalline solid, with a yield of 98.0% and a purity of 99.5%. Melting point: 105-110 °C. Figure 12 As shown, the product is urotropine hippurate.

[0051] Example 3

[0052] 10.0 g (0.071 mol) of hexamethylenetetramine and 13.1 g (0.073 mol) of hippuric acid were added to a 250 mL jacketed flask A, followed by 60 mL of ethanol. The mixture was heated to 78 °C and stirred rapidly until dissolved. The solution was filtered through a membrane filter, and the clear solution was transferred to a preheated 250 mL jacketed flask B. The solution was then cooled to the pre-crystallization temperature of 55 °C, and then slowly cooled to 10 °C. During the cooling process, 90 mL of a suspension of methyl tert-butyl ether containing 0.1 g of seed crystals was added dropwise. The solid gradually precipitated during the addition. After complete precipitation, the mixture was stirred overnight at 10 °C, filtered, and the wet product was dried in a vacuum oven at 50 °C for 6 hours to obtain 21.5 g of a white crystalline solid, with a yield of 94.4% and a purity of 99.1%. Melting point: 105-110 °C. Figure 13 As shown, the product is urotropine hippurate.

[0053] Example 4

[0054] 10.0 g (0.071 mol) of hexamethylenetetramine and 13.0 g (0.073 mol) of hippuric acid were added to a 250 mL jacketed flask A, followed by 65 mL of isopropanol. The mixture was heated to 80 °C and stirred rapidly until dissolved. The solution was filtered through a membrane filter, and the clear solution was transferred to a preheated 250 mL jacketed flask B. The solution was then cooled to the pre-crystallization temperature of 58 °C, and then slowly cooled to the aging temperature of 15 °C. During the cooling process, 140 mL of a tetrahydrofuran suspension containing 0.2 g of seed crystals (hexamethylenetetramine hippurate) was added dropwise. The solid gradually precipitated during the addition. After complete precipitation, the mixture was stirred overnight at 15 °C, filtered, and the wet product was dried in a vacuum oven at 45 °C for 6 hours to obtain 22.5 g of a white crystalline solid, with a yield of 98.8% and a purity of 98.6%. Melting point: 105-110 °C. Figure 14 The infrared spectrum shows that the product is a hexamethylenetetramine hippurate type compound.

[0055] Example 5

[0056] 10.0 g (0.071 mol) of hexamethylenetetramine and 13.1 g (0.073 mol) of hippuric acid were added to a 250 mL jacketed flask A, followed by 65 mL of ethanol. The mixture was heated to 80 °C and stirred rapidly until dissolved. The solution was filtered through a membrane filter, and the clear solution was transferred to a preheated 250 mL jacketed flask B. The solution was then cooled to the pre-crystallization temperature of 58 °C, and then slowly cooled to the aging temperature of 5 °C. During the cooling process, 150 mL of a tetrahydrofuran suspension containing 0.2 g of seed crystals (hexamethylenetetramine hippurate) was added dropwise. The solid gradually precipitated during the addition. After complete precipitation, the mixture was stirred overnight at 5 °C, filtered, and the wet product was dried in a vacuum oven at 45 °C for 5 hours to obtain 22.3 g of a white crystalline solid, with a yield of 97.9% and a purity of 98.9%. Melting point: 105-110 °C. Figure 15 The infrared spectrum shows that the product is a hexamethylenetetramine hippurate type compound.

[0057] Example 6

[0058] 10.0 g (0.071 mol) of hexamethylenetetramine and 13.1 g (0.073 mol) of 250 mL jacketed flask A were added, followed by 80 mL of 2-butanol. The mixture was heated to 76 °C and stirred rapidly until dissolved. The solution was filtered through a membrane filter, and the clear solution was transferred to a preheated 250 mL jacketed flask B. The solution was then cooled to the pre-crystallization temperature of 52 °C, and then slowly cooled to the aging temperature of 8 °C. During the cooling process, 160 mL of a suspension containing 0.25 g of seed crystals of methyl tert-butyl ether was added dropwise. The solid gradually precipitated. After complete precipitation, the solution was stirred overnight at 8 °C, filtered, and the wet product was dried in a vacuum oven at 55 °C for 8 hours to obtain 21.4 g of a white crystalline solid, with a yield of 93.9% and a purity of 99.2%. Melting point: 105-110 °C. Figure 16As shown, the product is urotropine hippurate.

[0059] Example 7

[0060] 10.0 g (0.071 mol) of hexamethylenetetrahydrofuran and 13.0 g (0.073 mol) of cyclopentanol were added to a 250 mL jacketed flask A, followed by 90 mL of cyclopentanol. The mixture was heated to 90 °C and stirred rapidly until dissolved. The solution was filtered through a membrane filter, and the clear solution was transferred to a preheated 250 mL jacketed flask B. The solution was then cooled to 60 °C, and then slowly cooled to 5 °C. During the cooling process, 180 mL of a 2-methyltetrahydrofuran suspension containing 0.18 g of seed crystals was added dropwise. The solid gradually precipitated during the addition. After complete precipitation, the mixture was stirred overnight at 5 °C, filtered, and the wet product was dried in a vacuum oven at 55 °C for 5 hours to obtain 20.8 g of a white crystalline solid, with a yield of 91.3% and a purity of 98.5%. Melting point: 105-110 °C. Figure 17 As shown, the product is urotropine hippurate.

[0061] Example 8

[0062] 10.0 g (0.071 mol) of hexamethylenetetramine and 13.1 g (0.073 mol) of isopropanol were added to a 250 mL jacketed flask A, followed by 75 mL of isopropanol. The mixture was heated to 80 °C and stirred rapidly until dissolved. The solution was filtered through a membrane filter, and the clear solution was transferred to a preheated 250 mL jacketed flask B. The solution was then cooled to the crystallization temperature of 50 °C, and then slowly and gradually cooled to 10 °C. During the cooling process, 150 mL of a diisopropyl ether suspension containing 0.18 g of seed crystals was added dropwise. The solid gradually precipitated during the dropwise addition. After complete precipitation, the solution was stirred overnight at 10 °C, filtered, and the wet product was dried in a vacuum oven at 45 °C for 5 hours to obtain 22 g of a white crystalline solid, with a yield of 96.6% and a purity of 98.8%. Melting point: 105-110 °C. Figure 18 As shown, the product is urotropine hippurate.

[0063] Example 9

[0064] 10.0 g (0.071 mol) of hexamethylenetetramine and 13.0 g (0.073 mol) of hippuric acid were added to a 250 mL jacketed flask A, followed by 65 mL of ethanol. The mixture was heated to 80 °C and stirred rapidly until dissolved. The solution was filtered through a membrane filter, and the clear solution was transferred to a preheated 250 mL jacketed flask B. The solution was then cooled to the pre-crystallization temperature of 58 °C, and then slowly cooled to the aging temperature of 10 °C. During the cooling process, 100 mL of a diisopropyl ether suspension containing 0.2 g of seed crystals (hexamethylenetetramine hippurate) was added dropwise. The solid gradually precipitated during the addition. After complete precipitation, the mixture was stirred overnight at 10 °C, filtered, and the wet product was dried in a vacuum oven at 45 °C for 7 hours to obtain 21.4 g of a white crystalline solid, with a yield of 93.9% and a purity of 99.4%. Melting point: 105-110 °C. Figure 19 The infrared spectrum shows that the product is a hexamethylenetetramine hippurate type compound.

Claims

1. A method for preparing urotropine hippurate, characterized in that, Hexamethylenetetramine and hippuric acid were dissolved in a good solvent by heating to obtain a clear solution. The clear solution was filtered, and the filtrate was fed into a preheated crystallization vessel. After the crystallization vessel was cooled to the pre-crystallization temperature, it was slowly cooled to the aging temperature while a suspension of a poor solvent containing seed crystals was continuously added dropwise. After complete precipitation, the mixture was stirred at the aging temperature and finally filtered to obtain hexamethylenetetramine hippurate.

2. The preparation method according to claim 1, characterized in that, The urotropine to hippuric acid equivalent ratio is 1:(1~1.05).

3. The preparation method according to claim 1, characterized in that, The good solvent is an alcohol solvent such as ethanol, isopropanol, butanol, 2-butanol, pentanol, and cyclopentanol.

4. The preparation method according to claim 1, characterized in that, The volume of a good solvent is 5-10 mL / g of hexamethylenetetramine.

5. The preparation method according to claim 1, characterized in that, The undesirable solvents mentioned are ether solvents such as methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, diisopropyl ether, and dibutyl ether.

6. The preparation method according to claim 1, characterized in that, The volume of a poor solvent is 1.5 to 2.5 times that of a good solvent.

7. The preparation method according to claim 1, characterized in that, The pre-crystallization temperature is 30-60℃.

8. The preparation method according to claim 1, characterized in that, The seed crystal is hexamethylenetetramine hippurate.

9. The preparation method according to claim 1, characterized in that, The seed crystal equivalent is 0.001-0.1, relative to hexamethylenetetramine.

10. The preparation method according to claim 1, characterized in that, The aging temperature is 0-30℃.

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