Preparation method of 9-fluorenyl methyl-N-succinimido carbonic ester

Abstract

The invention belongs to the field of organic matter preparation, and particularly relates to a preparation method of 9-fluorenyl methyl-N-succinimido carbonic ester, which comprises the following steps: dissolving N-hydroxysuccinimide, mixing with dried chloroformic acid-9-fluorenyl methyl ester and silicon-based solid alkali to react, quenching and washing after the reaction is completed, drying and purifying to obtain the 9-fluorenyl methyl-N-succinimido carbonic ester. The 9-fluorenyl methyl-N-succinimido carbonic ester is subjected to a reaction to obtain 9- The solid alkali is doped with ester groups. According to the method, the high-quality and high-purity product can be obtained, the requirement of a high-precision experiment for the product purity can be met, and the method is easy to operate and suitable for industrial popularization.

Description

Technical Field

[0001] This invention belongs to the field of organic compound preparation, specifically relating to a method for preparing 9-fluorenylmethyl-N-succinimide carbonate. Background Technology

[0002] 9-fluorenylmethyl-N-succinimidyl carbonate is used to prepare Fmoc-amino acid derivatives. It can selectively protect hydroxyl-containing amino acids, is stable and efficient, has few impurities, and reacts quickly. The preparation of 9-fluorenylmethyl-N-succinimidyl carbonate involves adding a step to the reaction of 9-fluorenylmethyl chloroformate, resulting in a yield of only 65-70% in a single step, and impurities are difficult to separate. Because the reaction is based on 9-fluorenylmethyl chloroformate, the problems encountered in the 9-fluorenylmethyl chloroformate preparation process—adding the raw materials, solvent, and alkali to the reactor first, then cooling and adding solid phosgene in batches—are also present here. Furthermore, the original production process of 9-fluorenylmethyl-N-succinimidyl carbonate uses an aqueous solution and an inorganic alkali system, which is prone to hydrolysis during the reaction, generating impurities that are difficult to separate. Summary of the Invention

[0003] To address the problems of high technical difficulty and high cost in the production process of 9-fluorenmethyl-N-succinimidyl carbonate, which easily generates impurities that are difficult to separate and requires precise control of alkali content, this invention mainly provides a method for preparing 9-fluorenmethyl-N-succinimidyl carbonate with high yield and high purity. The technical solution is as follows: A method for preparing 9-fluorenmethyl-N-succinimide carbonate includes the following steps: dissolving N-hydroxysuccinimide, mixing and reacting it with dried chloroformate-9-fluorenylmethyl ester and a silicon-based solid base, quenching and washing with water after the reaction is completed, drying and purifying to obtain 9-fluorenmethyl-N-succinimide carbonate; wherein the solid base is doped with ester groups.

[0004] .

[0005] Furthermore, the solvent in the reaction system is an organic solvent; the molar ratio of N-hydroxysuccinimide to 9-fluorenyl chloroformate is 1.1~1.5:1; and the mass ratio of 9-fluorenyl chloroformate to solid base is 1:0.7~1.2.

[0006] Furthermore, the preparation of the solid base includes the following steps: preparing a silicon-based matrix filled with silanol groups; partially grafting the silicon-based matrix with methyl chloroacetate to obtain a partially modified matrix; and then further modifying it with a coupling agent containing imidazole groups to obtain a solid base.

[0007] Furthermore, the preparation of the solid alkali includes the following steps: Methyl chloroacetate was dissolved in toluene to obtain a methyl chloroacetate solution; a silicon-based matrix and sodium bicarbonate were mixed in water, and then added to the methyl chloroacetate solution. After mixing evenly, the mixture was reacted at 30-50°C for 2-4 hours; the product was separated, thoroughly washed, and dried to obtain a partially modified matrix; A portion of the modified matrix was mixed thoroughly with triethoxy-3-(2-imidazolin-1-yl)propylsilane in ethanol, dilute sulfuric acid was added, and the mixture was reacted at 70-80°C for 18-30 h. The product was collected, washed thoroughly, and dried to obtain the precursor. The precursor was fully dispersed in dichloromethane, triethylamine was added, and the reaction was carried out at 5-15°C for 3-5 hours. The solvent was evaporated, and the product was thoroughly washed and dried to obtain a solid base.

[0008] Furthermore, the average particle size of the silicon-based matrix is ​​50-100 nm, and the pore size is 2-10 nm; the mass ratio of ethyl chloroformate to the silicon-based matrix is ​​1:3-5; and the mass ratio of ethyl chloroformate to sodium bicarbonate is 1:2-3.

[0009] Furthermore, the mass ratio of the partially modified matrix to triethoxy-3-(2-imidazolin-1-yl)propylsilane is 1:1.2~1.8; the volume ratio of ethanol to dilute sulfuric acid is 1~3:1; and the mass concentration of sulfuric acid in the dilute sulfuric acid is not greater than 20%.

[0010] Furthermore, the mass ratio of triethylamine to the precursor is 1.5 to 2:1.

[0011] Furthermore, this includes the following steps: Take dried chloroformate-9-fluorenyl methyl ester and dissolve it thoroughly in an organic solvent; mix N-hydroxysuccinimide and solid base in an organic solvent to obtain a reaction solution; cool the system to below 5°C and add the reaction solution dropwise; after the addition is complete, react at room temperature and control the reaction to complete; quench, wash with saturated brine, filter, dry and purify to obtain 9-fluorenylmethyl-N-succinimide carbonate.

[0012] Furthermore, the time required for the dropwise addition of the reaction solution is 6 to 10 hours.

[0013] Further, the solid base is fully dispersed in dichloromethane, triethylamine is added, and the reaction is carried out at 5-15°C for 3-5 hours. The solvent and unreacted triethylamine are evaporated, and the mixture is thoroughly washed and dried to complete the regeneration.

[0014] By adopting the above scheme, the method of the present invention has the following advantages: 1. The preparation method of the present invention is carried out in an anhydrous and solid alkali system, which solves the problem of easy hydrolysis of chloroformate-9-fluorenyl methyl ester in aqueous solution and inorganic alkali system, and prevents the generation of impurities; and the solid alkali is easy to separate, which solves the problem of difficult separation of organic alkali, resulting in a significant increase in yield and purity.

[0015] 2. The solid alkali of the present invention is solid and has significant differences in physical properties from the liquid reactants and products. After the reaction is completed, it can be separated from the reaction system by simple physical methods such as filtration and centrifugation. The operation is simple, reducing separation costs and the impact on product purity.

[0016] 3. The solid base of the present invention, as an acid-binding agent, has high selectivity for the preparation of 9-fluorenyl-N-succinimide carbonate from chloroformate-9-fluorenylmethyl ester. It has suitable alkalinity and good acid-binding effect, keeping the reaction system under near-neutral conditions. Moreover, the high specific surface area and suitable pore size of the solid base are conducive to the diffusion of reactants and products, promoting the reaction.

[0017] 4. The high specific surface area of ​​the solid base of the present invention allows for the loading of more imidazole groups on the surface, and the hydroxyl chains of the imidazole groups are relatively long. The reaction between the imidazole groups, 9-fluorenyl chloroformate and N-hydroxysuccinimide is less sterically hindered, and the reaction proceeds easily.

[0018] 5. The solid base of the present invention first utilizes chlorine in ethyl chloroformate to graft silanol groups onto the surface of the solid base, thereby loading a small amount of ester groups onto the surface of the solid base, and then continues to introduce imidazole groups; the ester groups are uniformly distributed between the imidazole groups, which can regulate the spacing between the imidazole groups, reduce steric hindrance, and synergistically form a catalytic promoting effect with imidazole; moreover, the ester groups compete with 9-fluorenyl chloroformate for the reaction of trace water molecules generated during the reaction or the extremely small amount of water that cannot be avoided from entering, thus forming a defensive barrier against the hydrolysis of 9-fluorenyl chloroformate.

[0019] 6. After the preparation of 9-fluorenylmethyl-N-succinimide carbonate, the solid base catalyst of the present invention can be regenerated by deprotonating the reacted imidazole through a simple method, which can be reused multiple times, reducing the amount of catalyst used, lowering costs, and reducing waste generation; while the ester group on the solid base is consumed in very small amounts, so for cost considerations, the ester group is not regenerated.

[0020] 7. Compared to the existing processes that achieve a yield of 65-70% and a purity of 99%, the preparation method of this invention can achieve a yield of over 80% and a purity of over 99.5%, even reaching 99.9%. This results in high-quality, high-purity products that meet the purity requirements of high-precision experiments, solving the bottleneck problem of purity improvement in existing technologies. Furthermore, the preparation process is simple and suitable for industrial application. Attached Figure Description

[0021] Figure 1 The liquid chromatogram of the product of Example 1 of the present invention; Figure 2 The liquid chromatogram of the product of Example 2 of the present invention; Figure 3 This is a liquid chromatogram of the product of Example 3 of the present invention. Detailed Implementation

[0022] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0023] Example 1: (1) Dissolve 0.5g of methyl chloroacetate in 25mL of toluene to obtain a methyl chloroacetate solution; mix 2g of mesoporous silicon matrix with an average particle size of 80nm and a pore size of 3nm and 1.2g of sodium bicarbonate in water, then add it to the methyl chloroacetate solution, mix evenly and react at 40℃ for 3h; separate the product, wash thoroughly, and dry at 60℃ to obtain a partially modified matrix; (2) 1.5g of the modified matrix and 2.3g of triethoxy-3-(2-imidazolin-1-yl)propylsilane were placed in 100mL of anhydrous ethanol and mixed thoroughly. 70mL of 10% dilute sulfuric acid was added and the mixture was reacted at 75℃ for 24h. The product was collected, washed thoroughly and dried at 60℃ to obtain the precursor. (3) Take 2g of precursor and disperse it fully in dichloromethane, add 3.5g of triethylamine, react at 10℃ for 4h, remove the solvent and unreacted triethylamine in stages, wash thoroughly and dry to obtain solid base; (4) Fluorene-methanol and solid phosgene are reacted in dichloromethane to prepare 9-fluorenyl methyl chloroformate; the prepared 9-fluorenyl methyl chloroformate is thoroughly dried; (5) Disperse 0.6g of N-hydroxysuccinimide and 1g of solid base evenly in dichloromethane to obtain a reaction solution; dissolve 1g of dried chloroformate-9-fluorenyl methyl ester in dichloromethane; cool the system to 0℃, add the reaction solution dropwise, and complete the addition in 8h, then react at room temperature; after the reaction is completed, quench the reaction, wash with saturated brine, filter and dry, and enter the crystallization kettle, distill part of the solution, add raw material petroleum ether to crystallize, centrifuge and dry to obtain the finished product; yield 88.3%, purity 99.95%.

[0024] Example 2: The difference from Example 1 is as follows: (1) Dissolve 0.5g of methyl chloroacetate in 25mL of toluene to obtain a methyl chloroacetate solution; mix 2.5g of silicon-based matrix with an average particle size of 80nm and a pore size of 3nm with 1.2g of sodium bicarbonate in water, then add the mixture to the methyl chloroacetate solution, mix thoroughly, and react at 40℃ for 3h; separate the product, wash thoroughly, and dry at 60℃ to obtain a partially modified matrix; yield 85.8% and purity 99.85%.

[0025] Example 3: The difference from Example 1 is as follows: (1) Dissolve 0.5g of methyl chloroacetate in 25mL of toluene to obtain a methyl chloroacetate solution; mix 1.5g of silicon-based matrix with an average particle size of 80nm and a pore size of 3nm with 1.2g of sodium bicarbonate in water, then add it to the methyl chloroacetate solution, mix evenly, and react at 40℃ for 3h; separate the product, wash thoroughly, and dry at 60℃ to obtain a partially modified matrix; yield 86.4%, purity 99.77%.

[0026] Example 4: The difference from Example 1 is as follows: (2) 1.5g of the modified matrix and 2.3g of triethoxy-3-(2-imidazolin-1-yl)propylsilane were placed in 100mL of anhydrous ethanol and mixed thoroughly. 100mL of 10% dilute sulfuric acid was added and the mixture was reacted at 75℃ for 24h. The product was collected, washed thoroughly and dried at 60℃ to obtain the precursor. The yield was 82.9% and the purity was 99.64%.

[0027] Example 5: The difference from Example 1 is as follows: (2) 1.5g of the modified matrix and 2.3g of triethoxy-3-(2-imidazoline-1-yl)propylsilane were placed in 100mL of anhydrous ethanol and mixed thoroughly. 35mL of 10% dilute sulfuric acid was added and the mixture was reacted at 75℃ for 24h. The product was collected, washed thoroughly and dried at 60℃ to obtain the precursor. The yield was 85.4% and the purity was 99.79%.

[0028] Example 6: The difference from Example 1 is as follows: (3) Take 2g of precursor and disperse it in dichloromethane. Add 3g of triethylamine and react at 10℃ for 4h. Remove the solvent and unreacted triethylamine in stages. Wash thoroughly and dry to obtain solid base; yield 81.8% and purity 99.58%.

[0029] Comparative Example: The difference from Example 1 is that: Fluorene-methanol and solid phosgene were reacted in dichloromethane to prepare 9-fluorenyl methyl chloroformate. 0.5 g to 0.7 g of N-hydroxysuccinimide was dissolved in water and then mixed with 1 g of the prepared 9-fluorenyl methyl chloroformate. 0.7 to 1.2 g of sodium carbonate was added and the mixture was reacted for 3-4 h. The crude product was filtered and purified to obtain the final product. The yield was 68.3% and the purity was 99.24%.

[0030] Example Sample Testing: The appearance of the samples in each embodiment was visually inspected; white or pale yellow powder was considered acceptable. The melting point of the samples in each embodiment was tested using a melting point apparatus; a melting point of 147-151℃ was considered acceptable. The loss on drying of the samples in each embodiment was tested using a moisture analyzer; the maximum loss was not more than 0.5%. 1g of each embodiment's sample was dissolved in 10mL of acetonitrile, and the clarity was observed; clarity and transparency were considered acceptable. The sample content was tested using high-performance liquid chromatography (HPLC). The results are as follows:

[0031] Combining the above table with Figures 1-3 The liquid chromatograms show that the signals on the spectrum correspond to 9-fluorenylmethyl-N-succinimidyl carbonate, with no obvious unknown signals. The purity of the obtained product is at least 99.77%, and can even reach 99.95%, with very few impurities. This indicates that the method of the present invention can produce high-purity 9-fluorenylmethyl-N-succinimidyl carbonate. The appearance and melting point of the sample prepared by the method of Comparative Example 1 are different from those of the sample prepared by the present invention. The sample contains significantly more impurities, and its yield is less than 70%, with a purity much lower than that of the examples. This shows that the method of the present invention can significantly improve the yield and purity of 9-fluorenylmethyl-N-succinimidyl carbonate.

[0032] In step (1), the modification with methyl chloroacetate directly affects the distribution of silanol groups in the silicon matrix. A higher methyl chloroacetate content results in fewer silanol groups available for imidazole grafting. Examples 2 and 3 altered the ratio of the silicon matrix to ethyl chloroformate, thus changing the grafting ratio of methyl chloroacetate to triethoxy-3-(2-imidazolin-1-yl)propylsilane. As shown in the table above, the yield and content of samples in Examples 2 and 3 decreased compared to Example 1. At the order of 0.1%, this decrease in content is not only due to error factors but also influenced by the formula change, indicating that the grafting ratio of ester groups and imidazole affects the purity of the product. Example 4 added more dilute sulfuric acid, resulting in a decrease in both the yield and content compared to Example 1. This may be because the imidazole groups have a higher degree of protonation, making deprotonation after grafting more difficult, and the alkalinity of the solid base is more easily affected. The low sulfuric acid content in Example 5 resulted in lower yield and content compared to Example 1. This is likely due to the reduced sulfuric acid content, which decreases the inhibitory effect on ester hydrolysis, reduces the number of ester groups retained on the solid base, and diminishes the ability to capture free water molecules. In Example 6, the addition of even less triethylamine during the deprotonation of imidazole affected the deprotonation effect, leading to a decrease in both yield and content.

[0033] For those skilled in the art, various other corresponding changes and modifications can be made based on the technical solutions and concepts described above, and all such changes and modifications should fall within the protection scope of the claims of this invention.

Claims

1. A method for preparing 9-fluorenylmethyl-N-succinimide carbonate, characterized in that, The process includes the following steps: dissolving N-hydroxysuccinimide, reacting it with dried chloroformate-9-fluorenyl methyl ester and a silicon-based solid base, quenching and washing with water after the reaction is complete, drying and purifying to obtain 9-fluorenylmethyl-N-succinimide carbonate; the solid base is doped with ester groups.

2. The method for preparing 9-fluorenylmethyl-N-succinimide carbonate according to claim 1, characterized in that, The solvent in the reaction system is an organic solvent; the molar ratio of N-hydroxysuccinimide to 9-fluorenyl chloroformate is 1.1~1.5:1; the mass ratio of 9-fluorenyl chloroformate to solid base is 1:0.7~1.

2.

3. The method for preparing 9-fluorenylmethyl-N-succinimide carbonate according to claim 1, characterized in that, The preparation of the solid base includes the following steps: preparing a silicon-based matrix filled with silanol groups; partially grafting the silicon-based matrix with methyl chloroacetate to obtain a partially modified matrix; and then further modifying it with a coupling agent containing imidazole groups to obtain a solid base.

4. The method for preparing 9-fluorenylmethyl-N-succinimide carbonate according to claim 1, characterized in that, The preparation of the solid alkali includes the following steps: Methyl chloroacetate was dissolved in toluene to obtain a methyl chloroacetate solution; a silicon-based matrix and sodium bicarbonate were mixed in water, and then added to the methyl chloroacetate solution. After mixing evenly, the mixture was reacted at 30-50°C for 2-4 hours; the product was separated, thoroughly washed, and dried to obtain a partially modified matrix; A portion of the modified matrix was mixed thoroughly with triethoxy-3-(2-imidazolin-1-yl)propylsilane in ethanol, dilute sulfuric acid was added, and the mixture was reacted at 70-80°C for 18-30 h. The product was collected, washed thoroughly, and dried to obtain the precursor. The precursor was fully dispersed in dichloromethane, triethylamine was added, and the reaction was carried out at 5-15°C for 3-5 hours. The solvent was evaporated, and the product was thoroughly washed and dried to obtain a solid base.

5. The method for preparing 9-fluorenylmethyl-N-succinimide carbonate according to claim 4, characterized in that, The silicon-based matrix has an average particle size of 50-100 nm and a pore size of 2-10 nm; the mass ratio of ethyl chloroformate to silicon-based matrix is ​​1:3-5; and the mass ratio of ethyl chloroformate to sodium bicarbonate is 1:2-3.

6. The method for preparing 9-fluorenylmethyl-N-succinimide carbonate according to claim 4, characterized in that, The mass ratio of the partially modified matrix to triethoxy-3-(2-imidazolin-1-yl)propylsilane is 1:1.2~1.8; the volume ratio of ethanol to dilute sulfuric acid is 1~3:1; and the mass concentration of sulfuric acid in the dilute sulfuric acid is not greater than 20%.

7. The method for preparing 9-fluorenylmethyl-N-succinimide carbonate according to claim 4, characterized in that, The mass ratio of triethylamine to the precursor is 1.5 to 2:

1.

8. The method for preparing 9-fluorenylmethyl-N-succinimide carbonate according to claim 1, characterized in that, Includes the following steps: Take dried chloroformate-9-fluorenyl methyl ester and dissolve it thoroughly in an organic solvent; mix N-hydroxysuccinimide and solid base in an organic solvent to obtain a reaction solution; cool the system to below 5°C and add the reaction solution dropwise; after the addition is complete, react at room temperature and control the reaction to complete; quench, wash with saturated brine, filter, dry and purify to obtain 9-fluorenylmethyl-N-succinimide carbonate.

9. The method for preparing 9-fluorenylmethyl-N-succinimide carbonate according to claim 8, characterized in that, The time required for the dropwise addition of the reaction solution is 6 to 10 hours.

10. The method for preparing 9-fluorenylmethyl-N-succinimide carbonate according to any one of claims 1 to 9, characterized in that, The solid base is fully dispersed in dichloromethane, triethylamine is added, and the reaction is carried out at 5-15°C for 3-5 hours. The solvent and unreacted triethylamine are removed by evaporation, and the mixture is thoroughly washed and dried to complete the regeneration.

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