1-{2-[3-(4-hydroxyphenyl) propionyl] diazo alkyl} docosan-1-ketone, and application and preparation method thereof

Abstract

The invention relates to the technical field of organic synthetic chemistry, in particular to 1-{2-[3-(4-hydroxyphenyl) propionyl] diazo alkyl} docosan-1-ketone as well as application and a preparation method of 1-{2-[3-(4-hydroxyphenyl) propionyl] diazo alkyl} docosan-1-ketone. According to the method, docosanoic acid and 3-(4-hydroxyphenyl) propanohydrazide are used as raw materials, and in a polar aprotic solvent, a benzotriazole coupling reagent and organic base are adopted for catalysis and a coupling reaction is carried out. According to the method, one-step coupling without protecting groups can be realized, the synthesis efficiency is remarkably improved, and the production cost is reduced; the method also has the advantages of mild conditions, high yield, excellent product purity, safety, environmental protection, suitability for large-scale popularization and the like.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis chemistry, and more specifically, to 1-{2-[3-(4-hydroxyphenyl)propionyl]diazyl}docosahexaeno-1-one, its applications, and preparation methods. Background Technology

[0002] The reversible color developer structure of thermal paper generally requires the simultaneous presence of a flexible long carbon chain, a rigid conjugated structure, and a proton-depleting group. 1-{2-[3-(4-hydroxyphenyl)propionyl]diazyl}docodecane-1-one belongs to the N,N'-diachydrazide class of compounds. Its structure simultaneously includes a long hydrophobic chain (docodecaneyl group), a hydrophilic reactive group (phenolic hydroxyl group), and a special acylhydrazide skeleton (R1-CO-NH-NH-CO-R2). This structural requirement makes it a promising candidate for reversible color developers in thermal recording materials.

[0003] In modern organic synthesis, the precise construction strategy that integrates hydrophilic segments, hydrophobic long chains, and bioactive heterocycles into a single molecule is a core driving force behind drug discovery and materials science advancements. These complex molecules have attracted significant attention due to their potential multifunctionality. Current trends in synthetic chemistry strongly favor green, efficient, and atom-economical strategies, aiming to overcome the problems common in traditional multi-step synthesis, such as lengthy routes, poor functional group compatibility, and the use of hazardous reagents. Therefore, developing a universal method that can directly and mildly achieve efficient coupling of different structural units has become an urgent technological need in this field.

[0004] 1-{2-[3-(4-hydroxyphenyl)propionyl]diazyl}docodecane-1-one is a typical complex system with multiple functional groups, and its synthesis is particularly challenging in the following ways: Dodecanoic acid long chain: low reactivity, and its derivatives are prone to steric hindrance in the reaction.

[0005] Phenolic hydroxyl groups are sensitive to acid, alkali and oxidative conditions, and often require protection during the reaction process, which increases the complexity of the steps.

[0006] Diazyl alkyl and hydrazide bonds: N-N bonds and amide bonds are unstable under strong acids, strong bases or high temperatures, and are prone to breakage or rearrangement.

[0007] These inherent structural sensitivities make it impractical to use traditional, harsh reaction conditions, placing extremely high demands on the mildness and chemoselectivity of the synthetic route, for which no definitive existing technology has yet been found.

[0008] Based on its chemical structure, it can be inferred that the synthesis of this compound likely involves the preparation and linkage of two key intermediates: 3-(4-hydroxyphenyl)propionylhydrazine and a docosanoic acid derivative. The core step lies in how to efficiently link these two fragments to form the final amide bond, while ensuring the stability of other functional groups in the molecule (such as phenolic hydroxyl groups).

[0009] Therefore, based on conventional methods, the main synthetic routes are speculated to be stepwise synthesis, activation of carboxylic acids and linkage with acyl hydrazides, coupling reaction mediated by acyl chlorides, and condensation reaction using carbodiimide condensing agents.

[0010] However, to avoid interference from functional groups, these synthetic techniques require the introduction of protection and deprotection steps for phenolic hydroxyl groups. This adds at least two reaction steps, making the entire synthetic route lengthy and reducing the overall yield due to the accumulation of multiple steps, which does not conform to the principle of "step economy" pursued by modern synthetic chemistry.

[0011] Meanwhile, existing technologies rely on reagents such as thionyl chloride (SOCl2) or oxalyl chloride to activate carboxyl groups. These reagents are highly toxic and corrosive, and the reaction produces a large amount of corrosive acidic gases, posing a serious threat to production equipment, operator safety, and environmental protection.

[0012] Furthermore, the high reactivity of acyl chlorides and the potentially strong alkaline environment involved in the reaction pose a significant risk to the sensitive diazoxide alkyl groups (NN bonds are unstable) and phenolic hydroxyl groups coexisting in the molecule. This can easily lead to heterocycle decomposition, isomerization, or other side reactions, resulting in poor reaction selectivity, low purity of the final product, and a complex impurity spectrum.

[0013] Finally, multi-step reactions mean that multiple separations, purifications, and intermediate transfers are required. The entire process is cumbersome and complex, with high operational requirements, and it is difficult to scale up production efficiently, which limits its potential for industrial application. Summary of the Invention

[0014] The technical problem to be solved by the present invention is to provide 1-{2-[3-(4-hydroxyphenyl)propionyl]diazyl}docosahexaeno-1-one, its application and preparation method.

[0015] The technical solution of the present invention to solve the above-mentioned technical problems is as follows: This invention provides a method for preparing 1-{2-[3-(4-hydroxyphenyl)propionyl]diazyl}docosahexaeno-1-one, using docosanoic acid and 3-(4-hydroxyphenyl)propionylhydrazine as raw materials, and in a polar aprotic solvent, using a benzotriazole coupling reagent and an organic base as catalysts for a coupling reaction to obtain 1-{2-[3-(4-hydroxyphenyl)propionyl]diazyl}docosahexaeno-1-one.

[0016] Based on the above technical solution, the present invention can be further improved as follows.

[0017] Furthermore, the coupling reaction is carried out at a temperature of 40°C-60°C.

[0018] Furthermore, the benzotriazole coupling agent is PyBOP, the organic base is N,N-diisopropylethylamine, and the polar aprotic solvent is N,N-dimethylformamide.

[0019] Furthermore, the molar ratio of docosanoic acid to 3-(4-hydroxyphenyl)propionylhydrazine is 1:1-1.3, the molar ratio of docosanoic acid to polar aprotic solvent is 1:40-70, the molar ratio of docosanoic acid to benzotriazole coupling reagent is 1:1-1.1, and the mass ratio of organic base is 1:1.5-1.9.

[0020] Furthermore, the following steps are included: S1. Activation reaction: Under the protection of an inert gas, docosanoic acid is dissolved in a polar aprotic solvent; under continuous stirring, a benzotriazole coupling reagent and an organic base are added sequentially to carry out the activation reaction; S2. Coupling reaction: Add 3-(4-hydroxyphenyl)propionylhydrazine to the activated reaction system, stir continuously and react for 15-18 hours to obtain the reactant; S3. Post-processing: The reactants are filtered to obtain a crude product, which is then purified by recrystallization from ethanol to obtain the final product.

[0021] Furthermore, in step S1, the organic base is added dropwise for 30 minutes; the activation reaction takes 20-40 minutes, and the activation reaction is carried out at a temperature of 40°C-60°C.

[0022] Further, in step S3, the ethanol recrystallization process is as follows: the crude product is dissolved in hot ethanol at 60-80℃ to form a saturated solution, and after slow cooling, crystals are precipitated. After separating the crystals, they are washed and dried to obtain the product.

[0023] The present invention also provides 1-{2-[3-(4-hydroxyphenyl)propionyl]diazyl}docosahexadecane-1-one prepared by the method described above.

[0024] Application of 1-{2-[3-(4-hydroxyphenyl)propionyl]diazyl}docosahexadecane-1-one in the preparation of colorimetric agents for thermal recording materials The present invention also provides a colorimetric agent for thermal recording materials, the composition of which includes 1-{2-[3-(4-hydroxyphenyl)propionyl]diazyl}docosahexaeno-1-one as described above.

[0025] The beneficial effects of this invention are as follows: (1) The preparation method of 1-{2-[3-(4-hydroxyphenyl)propionyl]diazyl}docosahexadecane-1-one of the present invention uses benzotriazole coupling reagents to achieve "one-step coupling without protecting group", which shortens the traditional reaction that requires 3-4 steps to a key 1 step, significantly improving the synthesis efficiency and reducing the production cost; (2) The preparation method of 1-{2-[3-(4-hydroxyphenyl)propionyl]diazyl}docosahexadecane-1-one of the present invention is carried out in a moderate temperature and neutral reaction system. The conditions are mild and effectively avoid the destruction of phenolic hydroxyl groups and N-N bonds that are sensitive to acids, bases and high temperatures, and exhibit extremely high chemical selectivity. (3) The method for preparing 1-{2-[3-(4-hydroxyphenyl)propionyl]diazyl}docosahexadecane-1-one of the present invention has a high yield and excellent product purity, which far exceeds the traditional method, and a high-quality white crystalline product can be obtained by simple recrystallization; (4) The preparation method of 1-{2-[3-(4-hydroxyphenyl)propionyl]diazyl}docosahexadecane-1-one of the present invention has a low toxicity of coupling agent system, which greatly improves the safety of operation, reduces waste emissions, and is in line with the development trend of green chemistry; (5) The method for preparing 1-{2-[3-(4-hydroxyphenyl)propionyl]diazyl}docosahexadecane-1-one of the present invention can maintain extremely high yield and purity even after doubling the concentration of reactants, demonstrating the good concentration tolerance and robustness of the process, and laying a solid foundation for industrial-scale production. Attached Figure Description

[0026] Figure 1 The ultraviolet absorption spectrum of the product in Example 1 of the present invention; Figure 2 In Embodiment 1 of the present invention, the product 1 H-NMR spectrum; Figure 3 The infrared spectrum of the product in Example 1 of the present invention; Figure 4 The high-performance liquid chromatogram of the product in Example 1 of the present invention; Figure 5 The DSC spectrum of the product in Example 1 of the present invention; Figure 6 This is a TGA curve of the product in Embodiment 1 of the present invention. Detailed Implementation

[0027] The principles and features of the present invention are described below. The examples given are only for explaining the present invention and are not intended to limit the scope of the present invention.

[0028] The method for preparing 1-{2-[3-(4-hydroxyphenyl)propionyl]diazyl}docosahexaeno-1-one of the present invention uses docosanoic acid and 3-(4-hydroxyphenyl)propionylhydrazine as raw materials, and carries out a coupling reaction in a polar aprotic solvent using a benzotriazole coupling reagent and an organic base as catalysts to obtain 1-{2-[3-(4-hydroxyphenyl)propionyl]diazyl}docosahexaeno-1-one.

[0029] The present invention provides a method for preparing 1-{2-[3-(4-hydroxyphenyl)propionyl]diazyl}docosahexaeno-1-one, using icosanoic acid and p-hydroxyphenylpropionylhydrazine as starting materials. The reaction proceeds directly in a polar aprotic solvent under the catalysis of a benzotriazole coupling reagent and an organic base, achieving a "one-step direct condensation" preparation process. This method is the first to efficiently and selectively generate the target product 1-{2-[3-(4-hydroxyphenyl)propionyl]diazyl}docosahexaeno-1-one. This reaction route eliminates the traditional functional group protection and acyl chloride activation steps, providing a simple, safe, and efficient synthetic route.

[0030] Preferably, the benzotriazole coupling agent is PyBOP, the organic base is N,N-diisopropylethylamine (DIEA), and the polar aprotic solvent is N,N-dimethylformamide (DMF).

[0031] Specifically, the reaction formula of this invention is as follows: The core of this synthetic route is the use of the peptide coupling reagent PyBOP to directly link docosanoic acid and p-hydroxyphenylpropionyl hydrazine in the presence of the organic base DIEA. The mechanism is a classic condensation reaction of a carboxylic acid with an amine (hydrazide), but the participation of PyBOP makes it more efficient and milder.

[0032] In the preparation method of this invention, the specific reaction steps (stages) and corresponding mechanisms can be divided into two core stages: "activation" and "nucleophilic substitution," and the complete process is shown in the following reaction formula: The specific process is as follows: S1. Activation reaction: Under the protection of an inert gas (nitrogen), docosanoic acid is dissolved in anhydrous DMF; PyBOP and organic base DIEA are added sequentially under continuous stirring to carry out the activation reaction.

[0033] This step is the activation of carboxylic acid. PyBOP reacts with carboxylic acid in situ to generate a highly reactive benzotriazole ester intermediate. DIEA serves both as an acid-binding agent to neutralize the acidic byproducts produced in the reaction and to accelerate the activation process by promoting deprotonation.

[0034] Specifically, in the initial state, in the presence of the organic base DIEA, the carboxyl group (-COOH) of docosanoic acid may be deprotonated to form a more nucleophilic carboxylate group (-COO—).

[0035] Then a nucleophilic attack occurs, where the oxygen atom in the carboxylate group (or neutral carboxylic acid) nucleophilically attacks the phosphorus atom at the center of the PyBOP molecule. This is a crucial step.

[0036] Finally, an activated ester is formed. The attack leads to the substitution of the benzotriazole oxygen (OBt) in the PyBOP structure, generating a mixed anhydride intermediate, which then rearranges or directly generates a highly reactive benzotriazole ester. This is the rate-determining step of the entire reaction and the core of PyBOP's high-efficiency coupling agent.

[0037] During this activation process, byproducts 1-hydroxybenzotriazole (HOBt) and hexafluorophosphate are generated. The role of DIEA is to neutralize the acidic protons produced in the reaction (such as protons that may be released by HOBt), push the reaction equilibrium to the right, and maintain a suitable reaction environment.

[0038] Preferably, the docosanoic acid, anhydrous DMF, PyBOP, and DIEA are all commercially available products. Among them, the purity of docosanoic acid is 97%, the moisture content of anhydrous DMF is less than 0.01% and the purity is 99.5%, and the purity of PyBOP and DIEA is 99.8%.

[0039] Preferably, the DIEA dripping time is 30 minutes; Preferably, the reaction temperature is 40℃~60℃, and optimally 50℃.

[0040] Preferably, the activation reaction time is 20-40 min, and optimally 30 min.

[0041] S2. Coupling reaction: Add 3-(4-hydroxyphenyl)propionylhydrazine to the activated reaction system, stir continuously and react for 15-18 hours to obtain the reactants; the reaction temperature for this step is 40℃~60℃, with 50℃ being optimal.

[0042] In this stage, nucleophilic substitution of the acylhydrazine occurs, forming an amide bond. After activation in the S1 stage, the acylhydrazine acts as a nucleophile to attack the activated ester, completing the construction of the target molecule. The specific process is as follows: (1) Nucleophilic attack: The nucleophilic amino group (-NH2) at the end of p-hydroxyphenylpropionylhydrazine attacks the carbonyl carbon atom of the activated ester.

[0043] (2) Tetrahedral transition state: carbonyl carbon transitions from sp 2 Hybridization transforms into sp 3 Hybridization forms a tetrahedral transition state.

[0044] (3) Removal of leaving group: The transition state is unstable and then cleaves, removing a good leaving group - benzotriazole anion (OBt-).

[0045] (4) Formation of the target product: Finally, a new amide bond is formed between the carbonyl group of docosanoic acid and the amino group of p-hydroxyphenylpropionylhydrazine, thereby generating the target molecule 1-{2-[3-(4-hydroxyphenyl)propionyl]diazyl}docosahexaeno-1-one. The "diazyl" here is composed of the newly formed amide bond (-NH-CO-) and the original NN bond of the hydrazine.

[0046] S3. Post-processing: The reactants are filtered to obtain a crude product, which is then purified by recrystallization from ethanol to obtain the final product.

[0047] Preferably, the specific process of ethanol recrystallization purification is as follows: the crude product is dissolved in hot ethanol at 70°C to form a saturated solution. After slow cooling, the target product selectively precipitates due to decreased solubility. Finally, high-purity crystals are collected by double filtration and thoroughly dried at 100°C to remove solvent residue, yielding a structurally complete 1-{2-[3-(4-hydroxyphenyl)propionyl]diazyl}docosahexaeno-1-one white crystalline solid. This purification process effectively separates the byproducts phosphate and HOBt by utilizing differences in solubility, ensuring the chemical purity and crystal stability of the final product.

[0048] Preferably, the p-hydroxyphenylpropionyl hydrazine used in the preparation method of the present invention is prepared in the laboratory. The specific preparation method is as follows: 50g of methyl p-hydroxyphenylpropionate is dissolved in 200mL of methanol, 35mL of hydrazine hydrate is added, and the mixture is refluxed at 60°C for 16h and reacted overnight. After the reaction is completed and cooled to room temperature, a certain amount of molecular water is added, and the mixture is filtered and dried at 45°C to obtain a white solid for subsequent reactions.

[0049] The 1-{2-[3-(4-hydroxyphenyl)propionyl]diazyl}docosahexadecane-1-one prepared by this invention can be used to prepare colorimetric agents for thermal recording materials.

[0050] The thermal recording material developer of the present invention comprises 1-{2-[3-(4-hydroxyphenyl)propionyl]diazyl}docosahexaeno-1-one as described above.

[0051] The present invention will be illustrated by specific embodiments below.

[0052] Example 1 Under nitrogen protection, 24g of docosanoic acid was added to 300mL of anhydrous N,N-dimethylformamide (DMF) solution, and stirred and heated at 50℃ until completely dissolved. The mixture was kept at this temperature for 15min, and then 36g of benzotriazol-1-yl-oxytripyrrolidinephosphide (PyBOP) was added. After stirring and dispersing evenly, 22mL of N,N-diisopropylethylamine (DIEA) was slowly added dropwise over about 30min. After the addition was complete, the mixture was kept at this temperature for 30min.

[0053] 14g of p-hydroxyphenylpropionylhydrazine was slowly added, and the mixture was stirred at 50℃ for 16h. After the reaction was completed, the temperature was slowly lowered to 0℃-10℃, and crystals were allowed to precipitate for 24h. The mixture was then filtered, and the filter cake was dissolved in a large amount of ethanol at 70℃. The solid precipitated after cooling was filtered and dried to obtain a white solid.

[0054] The white solid was dried in a 100°C forced-air drying oven for 12 hours to obtain a white powdery product.

[0055] This embodiment employs multiple mutually corroborating analytical methods to confirm the structure, purity, and physicochemical properties of the obtained product, forming a complete chain of evidence to comprehensively and clearly support the structure and purity of the product, fully meeting the requirements of the Patent Law for sufficiency of invention disclosure.

[0056] (1) Structural verification: UV-Vis absorption spectra, such as Figure 1 As shown, the maximum absorption wavelength of the product is 275 nm, which is consistent with the expected characteristics of the target product.

[0057] 1H NMR spectrum 1 H-NMR: as a core method for structural confirmation. 1 H-NMR spectra can clearly show the proton signals in all different chemical environments of the target molecule.

[0058] This embodiment 1 H-NMR spectrum as shown Figure 2 As shown in the figure, the specific parameters are shown in Table 1.

[0059] Table 1 1 H-NMR spectrum information It can be seen that the chemical shift, integral area, and split peak shape of each signal are completely consistent with the theoretical structure of 1-{2-[3-(4-hydroxyphenyl)propionyl]diazyl}docodecane-1-one, providing the most direct structural evidence at the atomic level.

[0060] FT-IR Spectroscopy: The infrared spectrum of the product in this embodiment is shown below. Figure 3 As shown in the figure, the peak positions and chemical structure information are shown in Table 2.

[0061] Table 2 Infrared Spectral Information It can be seen that the spectrum is at 3221 cm⁻¹ -1 The absorption peaks at 2916 and 2848 cm⁻¹ show the superimposed stretching vibrations of OH and NH. -1 The peaks at 1591 and 1515 cm⁻¹ show the CH stretching vibration of the long-chain methylene group. -1 The area shows characteristic absorption peaks for amide I and II bands and the benzene ring skeleton. The presence of these functional group characteristic peaks is related to... 1 The H-NMR results corroborated each other, jointly confirming the functional group composition and skeletal structure of the target molecule.

[0062] (2) Proof of purity and physicochemical properties: High-performance liquid chromatography (HPLC) detection: The product prepared in this example was analyzed by HPLC. The detection parameters are shown in Table 3, and the chromatogram is shown in the figure. Figure 4 As shown in Table 4, the retention times and peak parameters of each chromatographic peak are as follows.

[0063] Table 3 HPLC detection parameters Table 4 HPLC Chromatogram Information As can be seen, when detected at a wavelength of 275 nm, the chromatogram shows a single, symmetrical main peak with a retention time of 4.242 min. According to the area normalization method, its peak area ratio (purity) is as high as 98.90%. The baseline is stable and there are no obvious impurity peaks, which directly proves that the product has extremely high chemical purity.

[0064] Differential Scanning Calorimetry (DSC): The DSC detection procedure in this embodiment is set as follows: first, hold at 25°C for 2 minutes, then raise the temperature to 90°C at 20°C / min and hold for 2 minutes, then lower the temperature to 0°C at -20°C / min and hold for 2 minutes, and finally raise the temperature to 220°C at 10°C / min and hold for 2 minutes. The result is based on 0°C to 220°C.

[0065] The DSC spectrum of the product in this embodiment is as follows: Figure 5 As shown, the product exhibits only one set of endothermic peaks at 171.89℃, and these peaks are sharp and symmetrical. A single, sharp melting point is a classic physical indicator for judging the purity of crystalline compounds. This DSC result indicates that the product of this embodiment is a crystalline substance with a melting point of 171.89℃, possessing high purity and a well-defined, narrow melting range, thus meeting the high purity requirements.

[0066] Thermogravimetric analysis (TGA): Approximately 5 mg of sample was weighed and heated at a rate of 10 °C / min under a nitrogen atmosphere. The resulting TGA curve is shown below. Figure 6 As shown.

[0067] The TGA curve shows that the mass loss of the sample in this embodiment was less than 0.1% during the heating process to 200°C, which strongly proves that the final product does not contain residual solvents (such as DMF, ethanol) or volatile impurities such as water. This data provides independent evidence of the thermal stability of the product's purity. (3) (6) Thermogravimetric analysis: Weigh about 5 mg of the product and heat it to 600°C at a rate of 10°C / min under a nitrogen atmosphere.

[0068] In summary, through spectroscopic methods ( 1 The precise identification of the molecular structure by ¹H-NMR and FT-IR, combined with the quantification of chemical purity by HPLC and the confirmation of phase purity, crystal form and thermal stability by DSC and TGA, proves that the product synthesized in this embodiment is high-purity 1-{2-[3-(4-hydroxyphenyl)propionyl]diazyl}docosahexaeno-1-one.

[0069] Example 2 This embodiment increases the amount of p-hydroxyphenylpropionyl hydrazide compared to Example 1. The specific preparation process is as follows: Under nitrogen protection, 24 g of docosanoic acid was added to a solution containing 300 mL of anhydrous DMF, and the mixture was stirred and heated at 50 °C until completely dissolved, and kept at this temperature for 15 min. 36 g of benzotriazol-1-yl-oxytripyrrolidinephosphide hexafluorophosphate (PyBOP) was added, and after stirring and dispersing evenly, 22 mL of N,N-diisopropylethylamine (DIEA) was slowly added dropwise over 30 minutes. After the addition was complete, the reaction was kept at this temperature for 30 min.

[0070] Subsequently, 18g of laboratory-prepared p-hydroxyphenylpropionylhydrazine (1.3 equivalents relative to docosanoic acid) was added, and the reaction was carried out at 50℃ with stirring for 16h. After the reaction was completed, the temperature was slowly lowered to 0-10℃, and crystallization was allowed to occur for 24h. The product was filtered, and the filter cake was dissolved in a large amount of ethanol at 70℃. After cooling, the solid precipitated, filtered, dried, and then dried in a 100℃ forced-air drying oven for 12h. 35.9g of white powdery product was obtained, with a yield of 94.5% and a purity of 98.0%.

[0071] Example 3 This embodiment increases the reaction temperature based on Example 1. The specific preparation process is as follows: Under nitrogen protection, 24 g of docosanoic acid was added to a solution containing 300 mL of anhydrous DMF, and the mixture was stirred and heated at 60 °C until completely dissolved, and kept at this temperature for 15 min. 36 g of PyBOP was then added, and after stirring to disperse evenly, 22 mL of DIEA was slowly added dropwise over 30 minutes. After the addition was complete, the reaction was kept at this temperature for 30 min.

[0072] Subsequently, 14 g of p-hydroxyphenylpropionylhydrazine was added, and the reaction was carried out at 60 °C with stirring for 16 h. Subsequent crystallization, filtration, recrystallization, and drying conditions were the same as in Example 1. 32.1 g of a white powder product was obtained, with a yield of 84.5% and a purity of 98.2%.

[0073] Example 4 This embodiment reduces the reaction temperature compared to Example 1. The specific preparation process is as follows: Under nitrogen protection, 24 g of docosanoic acid was added to a solution containing 300 mL of anhydrous DMF. The mixture was heated at 40 °C with stirring until completely dissolved, and maintained at this temperature for 15 min. Then, 36 g of PyBOP was added and stirred until evenly dispersed. Finally, 22 mL of DIEA was slowly added dropwise over 30 minutes. After the addition was complete, the reaction mixture was kept at this temperature for 30 min. Subsequently, 14 g of p-hydroxyphenylpropionylhydrazine was added, and the mixture was stirred at 40 °C for 16 h. Subsequent crystallization, filtration, recrystallization, and drying conditions were the same as in Example 1. 32.5 g of a white powdery product was obtained, with a yield of 85.5% and a purity of 97.9%.

[0074] Example 5 This embodiment reduces the activation time compared to Example 1. The specific preparation process is as follows: Under nitrogen protection, 24g of docosanoic acid was added to 300mL of anhydrous N,N-dimethylformamide (DMF) solution, and stirred and heated at 50℃ until completely dissolved. The mixture was kept at this temperature for 15min, and then 36g of benzotriazol-1-yl-oxytripyrrolidinephosphide (PyBOP) was added. After stirring and dispersing evenly, 22mL of N,N-diisopropylethylamine (DIEA) was slowly added dropwise over about 30min. After the addition was complete, the mixture was kept at this temperature for 20min.

[0075] 14g of p-hydroxyphenylpropionylhydrazine was slowly added, and the mixture was stirred at 50℃ for 16h. After the reaction was completed, the temperature was slowly lowered to 0℃~10℃, and crystals were allowed to precipitate for 24h. The mixture was filtered, and the filter cake was dissolved in a large amount of ethanol at 70℃. The solid precipitated after cooling was filtered and dried to obtain a white solid. The solid was then dried in a 100℃ oven for 12h to obtain 31.5g of white powder 1-{2-[3-(4-hydroxyphenyl)propionyl]diazyl}docosahexadecane-1-one, with a yield of 82.9% and a purity of 97.9%.

[0076] Example 6 This embodiment adds an activation time to the process described in Example 1. The specific preparation process is as follows: Under nitrogen protection, 24g of docosanoic acid was added to 300mL of anhydrous N,N-dimethylformamide (DMF) solution, stirred and heated at 50℃ until completely dissolved, and kept at this temperature for 15min. Then, 36g of benzotriazol-1-yl-oxytripyrrolidinephosphide (PyBOP) was added, stirred and dispersed evenly, and then 22mL of N,N-diisopropylethylamine (DIEA) was slowly added dropwise over about 30min. After the addition was completed, the reaction was kept at this temperature for 40min.

[0077] 14g of p-hydroxyphenylpropionylhydrazine was slowly added, and the mixture was stirred at 50℃ for 16h. After the reaction was completed, the temperature was slowly lowered to 0℃~10℃, and crystallization was allowed to occur for 24h. The mixture was filtered, and the filter cake was dissolved in a large amount of ethanol at 70℃. The solid precipitated after cooling was filtered and dried to obtain a white solid. The solid was then dried in a 100℃ oven for 12h to obtain 35.7g of white powder 1-{2-[3-(4-hydroxyphenyl)propionyl]diazyl}docosahexaeno-1-one, with a yield of 93.9% and a purity of 98.5%.

[0078] Example 7 This embodiment increases the reaction concentration by two times based on Example 1. The specific preparation process is as follows: Under nitrogen protection, 48g of docosanoic acid was added to a solution containing 300mL of anhydrous DMF (concentration doubled), and the mixture was stirred and heated at 50°C until completely dissolved, and kept at this temperature for 15min. 72g of PyBOP was added, and after stirring and dispersing evenly, 44mL of DIEA was slowly added dropwise over 30 minutes. After the addition was complete, the reaction was kept at this temperature for 30min.

[0079] Then, 28g of p-hydroxyphenylpropionylhydrazine was added, and the mixture was stirred at 50°C for 16 hours. After the reaction was completed, the temperature was slowly lowered to 0-10°C, and crystals were allowed to precipitate for 24 hours. The crystals were then filtered, and subsequent purification steps were the same as in Example 1. 70.4g of a white powdery product was obtained, with a yield of 92.6% and a purity of 98.0%.

[0080] Comparative Example 1 Compared with Example 1, this comparative example removes the nitrogen protection process. The specific preparation process is as follows: In an air environment, 24 g of docosanoic acid was added to a solution containing 300 mL of anhydrous DMF, and the mixture was stirred and heated at 50 °C until completely dissolved. The subsequent order of reagent addition, dosage, reaction temperature, and time were exactly the same as in Example 1.

[0081] Testing yielded 25.3 g of a light yellow powder, with a yield of 66.6% and a purity of 78.5%. The darkening of the product's color and the significant decrease in yield and purity demonstrate that oxygen can cause side reactions, highlighting the necessity of nitrogen protection.

[0082] Comparative Example 2 This comparative example was prepared using the traditional acyl chloride method, and the specific process is as follows: Under nitrogen protection, 24 g of docosanoic acid was added to 300 mL of anhydrous dichloromethane and stirred at 50 °C. 20 mL of thionyl chloride was slowly added dropwise, and the mixture was refluxed for 3 hours. Excess reagents and solvent were then removed by vacuum distillation to obtain crude docosanoyl chloride. This crude product was redissolved in 300 mL of anhydrous DMF, cooled to 0 °C, and 22 mL of DIEA was added dropwise, followed by the slow addition of 14 g of p-hydroxyphenylpropionyl hydrazine. The mixture was then heated to 50 °C and reacted for 16 hours. Subsequent processing steps were the same as in Example 1. 24.1 g of a pale yellow solid product was obtained, with a yield of 63.4% and a purity of 80.1%.

[0083] Traditional methods are cumbersome, use highly toxic reagents, and produce products with poor phase, yield, and purity.

[0084] Comparative Example 3 This comparative example uses the traditional condensing agent DCC, and the specific process is as follows: Under nitrogen protection, 24 g of docosanoic acid and 14 g of p-hydroxyphenylpropionylhydrazine were dissolved in 300 mL of anhydrous DMF and cooled to 0 °C in an ice bath. After adding 22 mL of DIEA, 22 g of DCC (dicyclohexylcarbodiimide) was added in portions, and the mixture was allowed to rise naturally to room temperature for 12 h. The large amount of white precipitate (DCU) was removed by filtration, and the filtrate was concentrated and recrystallized from ethanol.

[0085] 26.3 g of a pale yellow solid product was obtained, with a yield of 69.2% and a purity of 77.5%. The method of this comparative example is cumbersome to operate, the byproduct DCU is difficult to remove, and the product color and purity are not as good as those of the PyBOP method, demonstrating the significant advantages of PyBOP in this reaction.

[0086] The experimental results of the above embodiments and comparative examples are shown in Tables 5 and 6: Table 5. Parameters, results, and analysis of each embodiment and comparative example.

[0087] Table 6. Main parameters and differences between Example 1, Comparative Example 2 and Comparative Example 3 A comprehensive analysis of the experimental data from the above embodiments and comparative examples shows that the preparation method of the present invention achieved optimal results under the baseline conditions of Example 1 (reaction temperature of 50°C, activation time of 30 minutes, and material ratio of 1:1, with nitrogen protection), achieving a yield of 93.4% and a purity of 98.9%, thus establishing an efficient and reliable process window.

[0088] Parameter optimization experiments (Examples 2-7) confirmed that the route has good tolerance and operational flexibility to reaction temperature, activation time and material concentration. In particular, it can still maintain a high yield of 92.6% at double the concentration, showing significant potential for industrial scale-up.

[0089] The key comparative examples (Comparative Examples 1-3) powerfully demonstrate the superiority of the present invention from the opposite perspective: without nitrogen protection (Comparative Example 1) and using the traditional acyl chloride method (Comparative Example 2) or DCC condensing agent (Comparative Example 3), the yield (both below 70%) and purity (both below 81%) deteriorate sharply, fully highlighting the comprehensive advantages of the PyBOP coupling combined with nitrogen protection strategy in improving efficiency, ensuring safety and simplifying purification.

[0090] In summary, the method for preparing 1-{2-[3-(4-hydroxyphenyl)propionyl]diazyl}docosahexadecane-1-one of the present invention has the advantages of high yield and purity, simple steps and easy industrial scale-up, and has significant necessity and commercial value.

[0091] Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of the present invention.

Claims

1. A method for preparing 1-{2-[3-(4-hydroxyphenyl)propionyl]diazyl}docosahexadecane-1-one, characterized in that, Using docosanoic acid and 3-(4-hydroxyphenyl)propionylhydrazine as raw materials, a coupling reaction was carried out in a polar aprotic solvent using benzotriazole coupling reagents and organic bases as catalysts to obtain 1-{2-[3-(4-hydroxyphenyl)propionyl]diazyl}docosahexaeno-1-one.

2. The method for preparing 1-{2-[3-(4-hydroxyphenyl)propionyl]diazyl}docosahexadecane-1-one according to claim 1, characterized in that, The coupling reaction is carried out at a temperature of 40℃-60℃.

3. The method for preparing 1-{2-[3-(4-hydroxyphenyl)propionyl]diazyl}docosahexadecane-1-one according to claim 1, characterized in that, The benzotriazole coupling reagent is PyBOP, the organic base is N,N-diisopropylethylamine, and the polar aprotic solvent is N,N-dimethylformamide.

4. The method for preparing 1-{2-[3-(4-hydroxyphenyl)propionyl]diazyl}docosahexadecane-1-one according to claim 1, characterized in that, The molar ratio of docosanoic acid to 3-(4-hydroxyphenyl)propionylhydrazine is 1:1-1.3, the molar ratio of docosanoic acid to polar aprotic solvent is 1:40-70, the molar ratio of docosanoic acid to benzotriazole coupling reagent is 1:1-1.1, and the mass ratio of organic base is 1:1.5-1.

9.

5. A method for preparing 1-{2-[3-(4-hydroxyphenyl)propionyl]diazyl}docosahexadecane-1-one according to any one of claims 1-4, characterized in that, Includes the following steps: S1. Activation reaction: Under the protection of an inert gas, docosanoic acid is dissolved in a polar aprotic solvent; under continuous stirring, a benzotriazole coupling reagent and an organic base are added sequentially to carry out the activation reaction; S2. Coupling reaction: Add 3-(4-hydroxyphenyl)propionylhydrazine to the activated reaction system, stir continuously and react for 15-18 hours to obtain the reactant; S3. Post-processing: The reactants are filtered to obtain a crude product, which is then purified by recrystallization from ethanol to obtain the final product.

6. The method for preparing 1-{2-[3-(4-hydroxyphenyl)propionyl]diazyl}docosahexadecane-1-one according to claim 5, characterized in that, In step S1, the organic base is added over a period of 30 minutes; the activation reaction takes 20-40 minutes and is carried out at a temperature of 40°C-60°C.

7. The method for preparing 1-{2-[3-(4-hydroxyphenyl)propionyl]diazyl}docosahexadecane-1-one according to claim 5, characterized in that, In step S3, the ethanol recrystallization process is as follows: the crude product is dissolved in hot ethanol at 60℃-80℃ to form a saturated solution, and after slow cooling, crystals are precipitated. After separating the crystals, they are washed and dried to obtain the product. 8.1-{2-[3-(4-hydroxyphenyl)propionyl]diazyl}docosahexadecane-1-one, characterized in that, It is prepared by the method described in any one of claims 1-7. 9.1 Application of 2-[3-(4-hydroxyphenyl)propionyl]diazyl}docosahexaeno-1-one in the preparation of colorimetric agents for thermal recording materials.

10. A colorimetric agent for thermal recording materials, characterized in that, Its components include 1-{2-[3-(4-hydroxyphenyl)propionyl]diazyl}docosahexadecane-1-one as described in claim 8.

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