A 1,3,4-tris(3-hydroxypropyl)-6-(3-methylbutyryloxypropyl)glycoluril compound, and a preparation method and application thereof

Abstract

The application discloses a 1,3,4-tri(3-hydroxypropyl)-6-(3-methylbutyryloxypropyl) glycoluril compound and a preparation method and application thereof, and belongs to the material field. The preparation method is characterized in that isovaleric acid is reacted with dichlorosulfide to prepare an isovaleryl chloride solution; 1,3,4,6-tetra(3-hydroxypropyl) glycoluril is mixed with triethylamine, and acylation reaction is carried out with the isovaleryl chloride solution at room temperature to obtain the 1,3,4-tri(3-hydroxypropyl)-6-(3-methylbutyryloxypropyl) glycoluril compound. The preparation method realizes acylation of one hydroxyl group in a 1,3,4,6-tetra(3-hydroxypropyl) glycoluril molecule, and the prepared compound can be used as a key intermediate and is used for preparing a mercapto glycoluril derivative.

Description

A 1,3,4-tris(3-hydroxypropyl)-6-(3-methylbutyryloxypropyl)glycourea compound, its preparation method and application Technical Field

[0001] This application belongs to the field of materials, specifically relating to a 1,3,4-tris(3-hydroxypropyl)-6-(3-methylbutyryloxypropyl)glycourea compound, its preparation method and application. Background Technology

[0002] Glycourea, a compound with a symmetrical rigid bicyclic structure, is an important platform molecule for constructing supramolecular hosts, such as cucurbituril, and functional materials. Its molecule has four nitrogen atoms, and different substituents can be introduced through reactions such as alkylation and acylation, thereby modulating its physicochemical properties.

[0003] Currently, research on glycourea derivatives mainly focuses on the synthesis of their symmetrical structures and their applications in supramolecular chemistry. For example, tetra(alkyl) or tetra(aryl) substituted glycoureas have been widely reported. However, there is less research on the precise construction of asymmetric structures, such as polyhydroxy or ester groups, on the glycourea skeleton, which are intermediates with both reactivity and specific functions.

[0004] This asymmetric structure disrupts the symmetry of the molecule, significantly altering its crystallization behavior, solubility, and subsequent reaction pathways as a synthetic intermediate. More importantly, such intermediates are key precursors for the preparation of structurally complex and functionally specific polymers, such as high-performance epoxy resin curing agents.

[0005] Therefore, developing a new, structure-specific asymmetric glycourea intermediate and its efficient preparation method is of great significance to the technological advancement in this field. Summary of the Invention

[0006] To address the aforementioned technical problems, this application provides a 1,3,4-tris(3-hydroxypropyl)-6-(3-methylbutyryloxypropyl)glycourea compound, its preparation method, and its application.

[0007] In a first aspect, this application provides a 1,3,4-tris(3-hydroxypropyl)-6-(3-methylbutyryloxypropyl)glycourea, the structural formula of which is shown in Formula I.

[0008] Formula I.

[0009] Secondly, this application provides a method for preparing the 1,3,4-tris(3-hydroxypropyl)-6-(3-methylbutyryloxypropyl)glycourea compound described in the first aspect, comprising the following steps:

[0010] S1: Preparation of isovaleryl chloride solution

[0011] Isovalerate was added to dichloromethane, and thionyl chloride was slowly added dropwise. After the addition was completed, the temperature was raised and refluxed. The solvent was evaporated and then an equal volume of dichloromethane was added again to dissolve it, so as to obtain isovaleryl chloride solution.

[0012] S2: Acylation reaction

[0013] 1,3,4,6-Tetra(3-hydroxypropyl)glycourea was added to dichloromethane, followed by triethylamine. Isovalerate chloride solution was then added dropwise at room temperature. Stirring continued until the reaction was complete.

[0014] Furthermore, in step S1, the molar ratio of isovaleric acid to thionyl chloride is 1:(1-2).

[0015] Furthermore, the heating and reflux time in step S1 is 1-3 hours.

[0016] Furthermore, in step S1, the mass concentration of isovaleric acid in dichloromethane is 0.04-0.06 g / mL.

[0017] Furthermore, in step S2, the molar ratio of 1,3,4,6-tetra(3-hydroxypropyl)glycourea to triethylamine is 1:(1-3).

[0018] Furthermore, in step S2, the mass concentration of 1,3,4,6-tetra(3-hydroxypropyl)glycourea in dichloromethane is 0.1-0.2 g / mL.

[0019] Furthermore, the stirring time in step S2 is 16-20 hours.

[0020] It should be noted that triethylamine in step S2 is only one example; other organic bases can also be used, such as...

[0021] Pyridine or diisopropylamine.

[0022] Furthermore, the preparation method of the 1,3,4-tris(3-hydroxypropyl)-6-(3-methylbutyryloxypropyl)glycourea compound further includes a post-processing step, wherein the post-processing step is S3, and the details are as follows:

[0023] S3: Post-processing

[0024] After the acylation reaction in step S2 is completed, water is added dropwise to the reaction system to separate the layers; the aqueous layer is extracted with dichloromethane; the organic layer is washed sequentially with saturated sodium bicarbonate solution and water, and the solvent is concentrated and evaporated after washing with water to obtain the 1,3,4-tris(3-hydroxypropyl)-6-(3-methylbutyryloxypropyl)glycourea compound.

[0025] Furthermore, in step S3, the volume ratio of the water added to the total volume of the reaction system is 1:1;

[0026] The volume ratio of dichloromethane to water added is 2:1;

[0027] During the washing process, the volume ratio of saturated sodium bicarbonate solution to water is 1:1.

[0028] Thirdly, this application provides the use of the 1,3,4-tris(3-hydroxypropyl)-6-(3-methylbutyryloxypropyl)glycourea compound described in the first aspect in the preparation of mercaptoglycourea derivatives.

[0029] Furthermore, the mercaptoglycourea derivatives include compounds with the following structural formulas:

[0030] , , , .

[0031] Compared with the prior art, this application includes the following beneficial technical effects:

[0032] This application provides a novel asymmetric glycourea compound with three reactive hydroxyl groups and an inert flexible ester chain in its molecule. This unique trifunctional active and functionally inert structure makes it an ideal platform for synthesizing functional molecules with both rigid and flexible properties.

[0033] The preparation method provided in this application can efficiently introduce a single ester group into the tetraol glycourea molecule, achieving a precise conversion from a symmetrical molecule to an asymmetrical molecule. The reaction conditions are mild and the operation is simple. Step S1, by converting isovaleric acid into its acyl chloride derivative, creates a highly reactive electrophilic reagent, laying the foundation for subsequent efficient reactions under mild conditions. Step S2, in the presence of an organic base (triethylamine), allows the acyl chloride reagent to preferentially react with one of the four hydroxyl groups in the tetraol intermediate, efficiently generating the desired asymmetric monoester product. This reaction proceeds smoothly at room temperature, without the need for high temperatures or strong acid / base environments, avoiding potential decomposition of the glycoure nucleus, ester bond breakage, or side reactions that might occur under harsh conditions, thus ensuring the integrity of the product structure. By controlling the molar ratio of 1,3,4,6-tetra(3-hydroxypropyl)glycourea to triethylamine (1:1 to 1:3), sufficient base is ensured to capture the HCl generated during the reaction, maintaining the stability of the reaction system. Step S3, the post-processing step, establishes an efficient and reliable product purification process. This process progressively achieves multiple objectives: reaction quenching, efficient product extraction, neutralization of acidic impurities, and thorough removal of water-soluble impurities, ensuring that the target compound can be obtained with a high recovery rate and high purity. After the reaction is complete, adding water of the same volume as the reaction solution can quickly quench any remaining highly reactive isovaleryl chloride, hydrolyzing it into harmless isovaleric acid. Secondly, it can significantly reduce the viscosity of the entire mixture and dilute the byproducts dissolved in the organic phase (such as triethylamine hydrochloride), creating favorable conditions for subsequent liquid-liquid extraction. During the extraction process, the volume ratio of dichloromethane to the volume of water added is 2:1, which efficiently extracts the target product dissolved in the aqueous phase into the organic phase, ensuring the product recovery rate. The combined organic phase is washed sequentially with equal volumes of saturated sodium bicarbonate solution and water. The purpose of washing with saturated sodium bicarbonate solution is to neutralize and remove residual acidic impurities in the organic phase, mainly excess isovaleric acid and isovaleric acid produced during quenching of acyl chlorides. The weak alkalinity of sodium bicarbonate is sufficient to neutralize acidic impurities, but it will not cause saponification and hydrolysis of ester bonds in a short time, thus protecting the structural integrity of the target product. After alkaline washing, an equal volume of water is used for washing to remove residual water-soluble salts (such as sodium carbonate and sodium bicarbonate) and other water-soluble impurities in the organic phase, resulting in a clean organic phase.

[0034] The 1,3,4-tris(3-hydroxypropyl)-6-(3-methylbutyryloxypropyl)glycourea compound provided in this application is a key precursor for the preparation of mercaptoglycourea derivatives. Attached Figure Description

[0035] The present application will be described in further detail below with reference to the accompanying drawings and preferred embodiments. However, those skilled in the art will understand that these drawings are drawn only for the purpose of explaining the preferred embodiments and therefore should not be construed as limiting the scope of this disclosure. Furthermore, unless specifically indicated, the drawings are only schematic representations of the composition or structure of the described objects and may contain exaggerated depictions, and the drawings are not necessarily drawn to scale.

[0036] Figure 1 shows the 1H NMR spectrum of the compound 1,3,4-tris(3-hydroxypropyl)-6-(3-methylbutyryloxypropyl)glycourea. Detailed Implementation

[0037] The present invention will be further illustrated below with examples, but the implementation of this application is not limited thereto. The following embodiments should not be construed as limiting the scope of protection of this application. If those skilled in the art make some non-essential improvements and adjustments to this application based on the above content, they shall still fall within the scope of protection of this application.

[0038] Chemicals and reagents

[0039] DCC: N,N'-dicyclohexylcarbodiimide, purchased from Aladdin Reagents.

[0040] DMAP: 4-Dimethylaminopyridine, purchased from Aladdin Reagents.

[0041] Unless otherwise specified, all other reagents used in the embodiments of this application are from conventional commercially available products.

[0042] Example 1

[0043] This embodiment provides a method for preparing 1,3,4-tris(3-hydroxypropyl)-6-(3-methylbutyryloxypropyl)glycourea (compound 2), and the preparation route is as follows:

[0044]

[0045] Compound 1 (1,3,4,6-tetra(3-hydroxypropyl)glycourea) was prepared according to the patent application published JP2017-43571A.

[0046] S1: Preparation of isovaleryl chloride solution (acyl chloride reaction)

[0047] Add 5.1 g (0.05 M) of isovaleric acid to 100 ml of dichloromethane, and slowly add 8.3 g (0.07 M) of thionyl chloride dropwise. After the addition is complete, heat and reflux for 2 hours. After the solvent is evaporated, add another 100 ml of dichloromethane to dissolve it, and obtain isovaleryl chloride solution.

[0048] S2: Acylation reaction

[0049] 18.7 g (0.05 M) of compound 1 was added to 100 ml of dichloromethane, followed by 10 g (0.1 M) of triethylamine. The isovaleryl chloride solution prepared in the previous step was slowly added dropwise at room temperature, and stirring was continued for 18 hours after the addition was complete.

[0050] S3: Post-processing

[0051] After the acylation reaction in step S2 was completed, 100 ml of water was slowly added dropwise to the reaction system, and the layers were separated. The aqueous layer was extracted with 200 ml of dichloromethane. The organic layers were combined and washed successively with 100 ml of saturated sodium bicarbonate solution and 100 ml of water. The solvent was concentrated and evaporated to obtain 18.1 g of compound 2, 1,3,4-tris(3-hydroxypropyl)-6-(3-methylbutyryloxypropyl)glycourea.

[0052] The structural characterization of the compound 1,3,4-tris(3-hydroxypropyl)-6-(3-methylbutyryloxypropyl)glycourea is as follows:

[0053] MS [M+1] + 458.27.

[0054] 1 ¹H-NMR (CDCl₃) δ: 5.15 (s, 2H), 4.12–4.15 (t, 2H), 3.60–3.66 (m, 6H), 3.41–3.44 (m, 5H), 3.36–3.40 (m, 6H), 2.19–2.23 (q, 2H), 1.94–2.09 (m, 3H), 1.72–1.78 (d, 6H), 0.98–1.00 (d, 3H), 0.93–0.95 (d, 3H), as shown in Figure 1.

[0055] Application Example 1

[0056] In this application example, the 1,3,4-tris(3-hydroxypropyl)-6-(3-methylbutyryloxypropyl)glyurea prepared in Example 1 is used to prepare the mercaptoglyurea derivative 1,3,4-tris(3-mercaptobutyryloxypropyl)-6-(3-methylbutyryloxypropyl)glyurea compound (compound 3). The preparation route is as follows:

[0057]

[0058] 4.6 g (0.01 M) of compound 2, 8.2 g (0.04 M) of DCC, and 0.4 g of DMAP were added to 200 mL of acetonitrile. After cooling to 0 °C, 4.8 g (0.04 M) of 3-mercaptobutyric acid was added. The mixture was stirred for 16 hours after the addition was complete. 100 mL of water was slowly added dropwise, followed by extraction with 200 mL of ethyl acetate. The aqueous layer was extracted again with 200 mL of ethyl acetate. The organic layers were combined and washed successively with 100 mL of 5% citric acid solution, 100 mL of saturated sodium bicarbonate aqueous solution, and 100 mL of water. The mixture was then dried over anhydrous sodium sulfate and filtered. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (on silica gel, ethyl acetate:petroleum ether = 1:3) to give 4.2 g of 1,3,4-tris(3-mercaptobutyryloxypropyl)-6-(3-methylbutyryloxypropyl)glycourea compound (compound 3).

[0059] The structure of the compound 1,3,4-tris(3-mercaptobutyryloxypropyl)-6-(3-methylbutyryloxypropyl)glycourea is characterized as follows:

[0060] MS [M+1] + 764.32.

[0061] 1 H-NMR (CDCl3) δ: 5.15 (s, 2H), 4.12-4.15 (t, 8H), 3.57-3.63 (m, 4H), 3.40-3.44 (m, 4H), 3.09-3.14 (m, 3H), 2.59-2.63 (m, 3H), 2.50-2.55(m,3H), 2.17-2.24(q,2H), 1.95-2.05(m,9H), 1.84-1.85(d,3H), 1.35-1.36(d,9H), 0.98-1.00(d,3H), 0.93-0.95(d,3H).

[0062] Application Example 2

[0063] In this application example, the 1,3,4-tris(3-hydroxypropyl)-6-(3-methylbutyryloxypropyl)glycourea prepared in Example 1 is used to prepare mercaptoglycourea derivatives that simultaneously have two thiol functional groups, one hydroxypropyl group, and one 3-methylbutyryloxypropyl group on the glycourea core.

[0064] 4.6 g (0.01 M) of 1,3,4-tris(3-hydroxypropyl)-6-(3-methylbutyryloxypropyl)glycourea, 4.1 g (0.02 M) of DCC, and 0.4 g of DMAP were added to 200 mL of acetonitrile. After cooling to 0 °C, 2.4 g (0.02 M) of 3-mercaptobutyric acid was added. The mixture was stirred for 16 hours after the addition was complete. 100 mL of water was slowly added dropwise, followed by extraction with 200 mL of ethyl acetate. The aqueous layer was extracted again with 200 mL of ethyl acetate. The organic layers were combined and washed successively with 100 mL of 5% citric acid solution, 100 mL of saturated sodium bicarbonate aqueous solution, and 100 mL of water. The mixture was then dried over anhydrous sodium sulfate and filtered. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (silica gel column, ethyl acetate:petroleum ether = 1:3) to give a mixture of compounds 4, 5, and 6, weighing 3.7 g.

[0065] The preparation route for this application example is as follows:

[0066]

[0067] The mass spectrum of the mixture of compounds 4, 5, and 6 is as follows: MS [M+1]+ 662.30.

[0068] Based on Example 1, this application investigated the process parameters for preparing the compound 1,3,4-tris(3-hydroxypropyl)-6-(3-methylbutyryloxypropyl)glycourea. The investigated parameters are shown in Table 1.

[0069] Table 1. Preparation method process parameters

[0070]

[0071] This application describes the yield and purity of 1,3,4-tris(3-hydroxypropyl)-6-(3-methylbutyryloxypropyl)glycourea prepared in Examples 1-3 and Comparative Examples 1-2. The purity was determined using high-performance liquid chromatography (HPLC), and the product purity was calculated using the area normalization method. The results are shown in Table 2.

[0072] Table 2 Results of the preparation method and process study

[0073]

[0074] As shown in Table 2, Examples 1 and 3 exhibited the best overall results, with the highest yield (≥79%) and purity (>96%), followed by Example 2. Comparative Examples 1 and 2 showed significant decreases in both yield and purity, indicating that the molar ratio of reactants is a key factor affecting reaction efficiency and product quality.

[0075] The molar ratio of isovaleric acid to thionyl chloride directly affects the degree of conversion of isovaleric acid to isovaleryl chloride. Examples 1, 2, 3, and Comparative Example 2 used excess or sufficient thionyl chloride to ensure that isovaleric acid was fully converted to the acyl chloride. In Comparative Example 1, the amount of thionyl chloride was insufficient, resulting in some isovaleric acid failing to convert to the more reactive acyl chloride. Consequently, it could not react with the glycourea derivative in the subsequent acylation reaction, ultimately leading to a decrease in yield and purity. Unreacted isovaleric acid would be mixed into the product, making complete separation difficult and resulting in a decrease in purity.

[0076] Triethylamine, acting as a base, neutralizes the HCl generated in the reaction and activates the hydroxyl groups on 1,3,4,6-tetra(3-hydroxypropyl)glycourea. Examples 1 and 3 used excess triethylamine to ensure sufficient consumption of the acyl chloride and a sufficiently alkaline environment to maintain reaction efficiency and prevent side reactions (such as hydrolysis of the acyl chloride), resulting in the highest yield and purity. Example 2 used equimolar ratios of reactants; any minor material loss or incomplete reaction would lead to a decrease in yield. The results showed that its yield (72.1%) and purity (90.7%) were lower than those of Examples 1 and 3, indicating that using excess reactants is beneficial for improving reaction efficiency. In Comparative Example 2, insufficient triethylamine prevented the timely neutralization of all HCl, leading to increased acidity in the reaction system. This could cause protonation of the hydroxyl group on 1,3,4,6-tetra(3-hydroxypropyl)glyurea, reducing nucleophilicity and slowing the reaction rate. Isovaleryl chloride is more prone to hydrolysis and other side reactions under acidic conditions. 1,3,4,6-tetra(3-hydroxypropyl)glyurea itself may be unstable under acidic conditions. These side reactions produce various impurities such as isovaleric acid and decomposition products. The impurities (such as isovaleric acid) have similar polarity to the products and are difficult to completely remove by conventional water washing and alkali washing (saturated sodium bicarbonate), resulting in a significant decrease in the purity of the final product.

[0077] In summary, the complete formation of the acyl chloride is a prerequisite in the preparation method of the compound 1,3,4-tris(3-hydroxypropyl)-6-(3-methylbutyryloxypropyl)glycourea of ​​this application. Comparative Example 1 illustrates that if the first step of the acyl chloride reaction is incomplete, the yield and purity will be limited regardless of the optimization of subsequent steps. An alkaline environment and excess reactants are essential in the preparation method. Comparative Example 2 demonstrates that sufficient base (triethylamine) is crucial in the main acylation reaction, serving not only as a neutralizing agent but also as the key to maintaining the required alkaline environment and ensuring the reaction rate.

[0078] The optimal conditions for this process are a molar ratio of isovaleric acid to thionyl chloride of 1:(1.4-2) in the isovaleryl chloride solution preparation step and a molar ratio of glycourea derivative to triethylamine of 1:(2-3) in the acylation reaction step. Under these conditions, the reaction conversion rate is the highest, thus yielding products with high yield and high purity.

[0079] The present application has been described in detail above. Specific examples have been used to illustrate the principles and implementation methods of the present application. The descriptions of the embodiments above are only for the purpose of helping to understand the present disclosure. It should be noted that those skilled in the art can make several improvements and modifications to the present application without departing from the principles of the present application, and these improvements and modifications also fall within the protection scope of the claims of the present application.

Claims

1. A 1,3,4-tris(3-hydroxypropyl)-6-(3-methylbutyryloxypropyl)glycourea compound, characterized in that, The structural formula of the 1,3,4-tris(3-hydroxypropyl)-6-(3-methylbutyryloxypropyl)glycourea compound is shown in Formula I. Equation I.

2. The method for preparing the 1,3,4-tris(3-hydroxypropyl)-6-(3-methylbutyryloxypropyl)glycourea compound as described in claim 1, characterized in that, The process includes the following steps: S1: Preparation of isovaleryl chloride solution: Isovalerate is added to dichloromethane, thionyl chloride is added dropwise, and after the addition is complete, the mixture is heated to reflux, the solvent is evaporated, and an equal volume of dichloromethane is added again to dissolve it, thus obtaining isovaleryl chloride solution; S2: Acylation reaction: 1,3,4,6-tetra(3-hydroxypropyl)glycourea is added to dichloromethane, triethylamine is added, and the isovaleryl chloride solution prepared in step S1 is added dropwise at room temperature. After the addition is complete, stirring is continued until the reaction is complete.

3. The method for preparing the 1,3,4-tris(3-hydroxypropyl)-6-(3-methylbutyryloxypropyl)glycourea compound as described in claim 2, characterized in that, In step S1, the molar ratio of isovaleric acid to thionyl chloride is 1:(1-2).

4. The method for preparing the 1,3,4-tris(3-hydroxypropyl)-6-(3-methylbutyryloxypropyl)glycourea compound as described in claim 2, characterized in that, In step S1, the mass concentration of isovaleric acid in dichloromethane is 0.04-0.06 g / mL.

5. The method for preparing the 1,3,4-tris(3-hydroxypropyl)-6-(3-methylbutyryloxypropyl)glycourea compound as described in claim 2, characterized in that, The heating and reflux time in step S1 is 1-3 hours.

6. The method for preparing the 1,3,4-tris(3-hydroxypropyl)-6-(3-methylbutyryloxypropyl)glycourea compound as described in claim 2, characterized in that, In step S2, the molar ratio of 1,3,4,6-tetra(3-hydroxypropyl)glycourea to triethylamine is 1:(1-3).

7. The method for preparing the 1,3,4-tris(3-hydroxypropyl)-6-(3-methylbutyryloxypropyl)glycourea compound as described in claim 2, characterized in that, In step S2, the mass concentration of 1,3,4,6-tetra(3-hydroxypropyl)glycourea in dichloromethane is 0.1-0.2 g / mL.

8. The method for preparing the 1,3,4-tris(3-hydroxypropyl)-6-(3-methylbutyryloxypropyl)glycourea compound as described in claim 2, characterized in that, The stirring time in step S2 is 16-20 hours.

9. The method for preparing the 1,3,4-tris(3-hydroxypropyl)-6-(3-methylbutyryloxypropyl)glycourea compound as described in claim 2, characterized in that, The preparation method further includes a post-treatment step, which is S3, as follows: S3: After the acylation reaction in post-treatment step S2 is completed, water is added dropwise to the reaction system to separate the layers; the aqueous layer is extracted with dichloromethane; the organic layer is washed sequentially with saturated sodium bicarbonate solution and water; after washing with water, the solvent is concentrated and evaporated to obtain the 1,3,4-tris(3-hydroxypropyl)-6-(3-methylbutyryloxypropyl)glycourea compound.

10. The use of the 1,3,4-tris(3-hydroxypropyl)-6-(3-methylbutyryloxypropyl)glycourea compound as described in claim 1 in the preparation of mercaptoglycourea derivatives with the following structure, 。

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