Supported TBD-IPTS / SBA-15 catalyst as well as preparation method and application thereof

Abstract

The invention relates to the technical field of catalyst preparation, in particular to a supported TBD-IPTS / SBA-15 catalyst and a preparation method and application thereof.The preparation method comprises the following steps that an SBA-15 carrier is treated with acid liquor, washed to be neutral and then dried, and an activated carrier SBA-15-OH is obtained; the preparation method comprises the following steps: dispersing SBA-15-OH in anhydrous toluene under the protection of nitrogen, adding IPTS (isopropyl-beta-d-thiosulfate) for reflux reaction, and washing and drying after the reaction is finished to obtain IPTS / SBA-15; iPTS / SBA-15 is dispersed in anhydrous dichloromethane, a TBD solution is added for a reaction, washing and drying are performed after the reaction is finished, and a supported TBD-IPTS / SBA-15 catalyst is obtained; the problems that in existing captopril intermediate synthesis, a by-product L-MAT is difficult to utilize, a traditional homogeneous TBD catalyst is difficult to recycle and reuse, and in an existing loading technology, active components are poor in stability and low in catalytic efficiency are solved.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of catalyst preparation, in particular to a supported TBD-IPTS / SBA-15 catalyst and a preparation method and application thereof. BACKGROUND

[0002] Captopril is an important antihypertensive drug of angiotensin converting enzyme inhibitor (ACEI). D-3-acetylthio-2-methylpropionic acid (D-AT) is a key chiral intermediate in the synthesis process. At present, DL-3-acetylthio-2-methylpropionic acid methyl ester (DL-MAT) is often used as raw material in industry to synthesize D-AT by enzyme catalytic resolution method. A large amount of L-3-acetylthio-2-methylpropionic acid methyl ester (L-MAT) is produced as a byproduct in the process. Since L-MAT cannot be directly used for the synthesis of D-AT, the utilization rate of raw materials is reduced, which not only causes resource waste, but also increases production cost and environmental pressure. Therefore, it is of great significance to realize the racemization of L-MAT and convert it into recyclable DL-MAT for improving the economy and environmental protection of captopril production.

[0003] The key to realizing the racemization of L-MAT lies in an efficient catalyst. 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) is a strong organic base (pKa = 25.98 in acetonitrile), which can effectively catalyze the ester epimerization / racemization reaction due to the highly conjugated resonance structure of the guanidino group. However, as a homogeneous catalyst, TBD is easily dissolved in common non-polar organic solvents such as ethyl acetate and dichloromethane, and is difficult to separate and recover after the reaction, resulting in high catalyst loss and high use cost, which seriously limits its application in industrial scale production.

[0004] Heterogenization is an effective way to solve the above problems. By loading TBD onto insoluble carriers, the advantages of high activity of homogeneous catalysts and easy separation of heterogeneous catalysts can be combined. Among them, mesoporous silica SBA-15 is an ideal catalyst carrier due to its high specific surface area, regular and size-controllable pore structure, and rich surface silanol groups for easy functionalization. In the prior art, physical adsorption or simple chemical bonding methods are often used to load strong organic bases, but there are problems such as easy detachment of active components, poor stability, and low catalytic efficiency. Therefore, developing a heterogeneous catalyst that can stably load TBD on the surface of the carrier while maintaining its strong alkalinity and high catalytic activity is the key to solving the above technical problems. SUMMARY

[0005] The present application is provided in order to overcome the problems of the existing captopril intermediate synthesis, such as the difficulty of using by-product L-MAT, the difficulty of recycling the traditional homogeneous TBD catalyst, and the problems of the existing loading technology, such as the easy falling off of the active component, the poor stability, and the low catalytic efficiency, and provides a supported TBD-IPTS / SBA-15 catalyst and a preparation method and application thereof.

[0006] The present application is realized by adopting the following technical scheme: A preparation method of a supported TBD-IPTS / SBA-15 catalyst comprises the following steps: S1: carrier pretreatment: after mesoporous silica SBA-15 carrier is treated by acid liquid and washed to neutral, drying is performed to obtain an activated carrier SBA-15-OH; S2: 3-isocyanate propyl triethoxysilane (IPTS) grafting: under the protection of an inert atmosphere, the SBA-15-OH is dispersed in anhydrous toluene, IPTS is added for reflux reaction, after the reaction is completed, washing and drying are performed to obtain the IPTS grafted carrier IPTS / SBA-15; S3: 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) loading: under the protection of an inert atmosphere, the TBD is dissolved in anhydrous dichloromethane to obtain a TBD solution; the IPTS / SBA-15 is dispersed in anhydrous dichloromethane, and then the TBD solution is added dropwise, stirring reaction is first performed at room temperature, then the temperature is increased to reflux for continuous reaction, after the reaction is completed, washing and drying are performed to obtain the supported TBD-IPTS / SBA-15 catalyst.

[0007] Further, in the step S1, the particle size of the mesoporous silica SBA-15 carrier is 100-200 mesh, the specific surface area is 650 m² / g, and the pore size is 7.2 nm; the acid liquid is 1 mol / L hydrochloric acid, and the treatment time is 2 h; the drying condition is vacuum drying at 120 DEG C for 6 h.

[0008] Further, in the step S1, before the mesoporous silica SBA-15 carrier is treated by acid liquid, a step of vacuum drying at 120 DEG C for 4 h is further included.

[0009] Further, in the step S2, the mass molar ratio of the SBA-15-OH to IPTS is 5.0 g:10 mmol; and the reflux reaction time is 24 h.

[0010] Further, in the step S3, the mass molar ratio of the IPTS / SBA-15 to TBD is 4.0 g:8 mmol; the stirring reaction time at room temperature is 12 h, and the temperature is increased to reflux for continuous reaction for 8 h.

[0011] Further, in steps S2 and S3, the inert atmosphere is a nitrogen atmosphere; the anhydrous toluene and the anhydrous dichloromethane each have a purity of ≥ 99.5%.

[0012] The supported TBD-IPTS / SBA-15 catalyst is prepared by the preparation method of the supported TBD-IPTS / SBA-15 catalyst described in the application, the catalyst is a light yellow powder, the strong alkaline active site is covalently loaded on the surface of the SBA-15 carrier, the catalyst is insoluble in a non-polar organic solvent, and the loaded active component does not fall off, and the catalyst can be separated and recovered by filtration.

[0013] The application of the supported TBD-IPTS / SBA-15 catalyst in catalyzing the racemization of L-3-acetylmercapto-2-methylpropionic acid methyl ester includes the following steps: mixing L-3-acetylmercapto-2-methylpropionic acid methyl ester, the supported TBD-IPTS / SBA-15 catalyst and a non-polar organic solvent, heating to reflux to perform the racemization, after the reaction is completed, the catalyst is recovered by hot filtration, and after the solvent is recovered by distillation from the filtrate, DL-3-acetylmercapto-2-methylpropionic acid methyl ester is obtained.

[0014] Further, the recovered supported TBD-IPTS / SBA-15 catalyst can be directly reused for the racemization of L-3-acetylmercapto-2-methylpropionic acid methyl ester without activation.

[0015] Further, the non-polar organic solvent is ethyl acetate or toluene; the mass ratio of L-3-acetylmercapto-2-methylpropionic acid methyl ester to the supported TBD-IPTS / SBA-15 catalyst is 2.5:1 to 3:1; the mass-volume ratio of L-3-acetylmercapto-2-methylpropionic acid methyl ester to the non-polar organic solvent is 0.2 g / mL to 0.3 g / mL; the time of the racemization is 8-12 h; and the progress of the racemization is monitored by gas chromatography.

[0016] The application provides a supported TBD-IPTS / SBA-15 catalyst, a preparation method and application thereof. 1. The application realizes the stable covalent loading of TBD and the SBA-15 carrier through the IPTS functionalization bridge, solves the technical problems of difficult recovery and high use cost of the traditional homogeneous TBD catalyst, the catalyst can be reused, and the industrial application cost is reduced.

[0017] 2. The prepared supported catalyst has strong alkalinity, high stability and high mass transfer performance, the catalytic L-MAT racemization has high efficiency, is completely racemized and no byproduct is generated.

[0018] 3. The application realizes resource utilization of the by-product L-MAT of captopril synthesis, improves raw material utilization, reduces resource waste and environmental pressure, and meets the development trend of green chemical industry.

[0019] 4. The preparation method of the application has simple process and mild conditions, and the solvent and catalyst can be recycled and used, so that industrial scale production is easy to realize. BRIEF DESCRIPTION OF DRAWINGS

[0020] Figure 1 is the reaction equation of the racemization reaction of L-MAT catalyzed by the supported TBD-IPTS / SBA-15 catalyst in the application.

[0021] Figure 2 is the GC spectrum of L-MAT before the racemization reaction in Example 2 of the application.

[0022] Figure 3 is the GC spectrum of DL-MAT after the racemization reaction in Example 2 of the application. DETAILED DESCRIPTION

[0023] The technical solutions in the embodiments of the application will be described below in conjunction with the embodiments of the application. Obviously, the described embodiments are only part of the embodiments of the application, not all. Based on the embodiments in the application, all other embodiments obtained by those skilled in the art without creative labor are within the scope of protection of the application. Example 1

[0024] A preparation method of a supported TBD-IPTS / SBA-15 catalyst, comprising the following steps: S1: carrier pretreatment: taking 5.0 g of mesoporous silica SBA-15 carrier with a particle size of 100-200 mesh, a specific surface area of 650 m² / g and a pore size of 7.2 nm, vacuum drying at 120℃ for 4 h, adding the dried mesoporous silica SBA-15 carrier into a 250 mL round-bottom flask, then adding 100 mL of 1 mol / L hydrochloric acid into the round-bottom flask, stirring at room temperature for 2 h, then filtering, washing with deionized water until pH=7, and vacuum drying at 120℃ for 6 h to obtain the activated carrier SBA-15-OH.

[0025] S2: IPTS grafting: Under the protection of nitrogen atmosphere, 5.0 g of SBA-15-OH prepared in step S1 and 150 mL of anhydrous toluene were added into a 250 mL three-necked flask, and ultrasonic dispersion was performed for 30 min, then the temperature was raised to 60 ℃, and 10 mmol (2.61 g in mass) of IPTS was slowly added dropwise under stirring, and after the addition was completed, the temperature was raised to reflux and reacted for 24 h. After the reaction was completed, the temperature was cooled to room temperature, and the solid was collected by suction filtration, washed with anhydrous toluene for 3 times (20 mL each time), and then dried at 80 ℃ under vacuum for 8 h to obtain IPTS / SBA-15.

[0026] S3: TBD loading: Under the protection of nitrogen atmosphere, 8 mmol (1.12 g in mass) of TBD was dissolved in 20 mL of anhydrous dichloromethane to obtain a TBD solution; another 250 mL three-necked flask was taken, 4.0 g of IPTS / SBA-15 prepared in step S2 and 100 mL of anhydrous dichloromethane were added into the flask, and ultrasonic dispersion was performed for 20 min, then the TBD solution was slowly added dropwise, and after the addition was completed, the temperature was raised to room temperature and stirred for 12 h, and then the temperature was raised to reflux and reacted for 8 h. After the reaction was completed, the solid was collected by suction filtration, washed with anhydrous dichloromethane for 3 times (15 mL each time), washed with anhydrous ethanol for 3 times (15 mL each time), and then dried at 80 ℃ under vacuum for 12 h to obtain 4.8 g of light yellow powder of TBD-IPTS / SBA-15 catalyst.

[0027] The present application takes mesoporous silica SBA-15 as a carrier and IPTS as a functional reagent, and realizes the covalent stable loading of TBD by the active groups at both ends of the IPTS molecule reacting with the carrier and TBD in turn. The core loading mechanism includes: First, the triethoxysilyl group at one end of the IPTS molecule reacts with the silicon hydroxyl group on the surface of the SBA-15 carrier to form a firm siloxane bond, thereby grafting the IPTS on the surface of the carrier; Then, the isocyanate group at the other end of the IPTS molecule reacts with the amino group in the TBD molecule to form a stable urea bond, thereby covalently anchoring the TBD on the carrier, and finally obtaining the supported TBD-IPTS / SBA-15 catalyst.

[0028] In the preparation process, the nitrogen protection is aimed at excluding the moisture in the air to avoid the side reaction of the isocyanate group at the end of the IPTS molecule, thereby ensuring the smooth progress of the grafting and loading reaction; the washing process of the catalyst needs to use anhydrous solvent to prevent the water from destroying the siloxane bond and urea bond that have been formed, thereby causing the destruction of the catalyst structure or the shedding of the active component. Through the control of the above conditions, the side reaction of the key reaction group and the hydrolysis of the material are effectively avoided, thereby ensuring the integrity and stability of the final structure of the catalyst.

[0029] The performance of the prepared supported TBD-IPTS / SBA-15 catalyst was tested, and the test process and results are as follows: Basicity test A small amount of TBD pure product and the supported TBD-IPTS / SBA-15 catalyst prepared in this example were taken as indicators and tested, respectively. The test results can change the indicator from yellow to blue, indicating that the strong basicity of the supported catalyst is not affected.

[0030] Stability test 0.1 g of the supported TBD-IPTS / SBA-15 catalyst prepared in this example was added to 10 mL of ethyl acetate, stirred at room temperature for 24 h, and then left to stand. The catalyst was in a suspended state and no dissolution was observed. After centrifugal separation, the supernatant was taken and detected by UV-Vis. No characteristic absorption peak of TBD was detected at 270 nm, proving that TBD did not fall off and the catalyst had good stability in non-polar solvents. Example 2

[0031] The supported TBD-IPTS / SBA-15 catalyst prepared in Example 1 was applied in the catalysis of L-MAT racemization reaction. The application process included the following steps: 30 g (corresponding to 0.17 mol of substance) of L-MAT, 12.0 g of supported TBD-IPTS / SBA-15 catalyst, and 150 mL of ethyl acetate were added to a 500 mL round-bottom flask, and then uniformly mixed and heated to reflux for 10 h. The strong basicity of TBD catalyzed the racemization of L-MAT to convert it into DL-MAT, and the reaction equation is shown in FIG. 2. The reaction process was monitored by gas chromatography (GC). The GC detection conditions included: Agilent CP Chirasil-Dex CB chiral column (25 m x 0.32 mm x 0.25 μm), vaporization temperature 270 °C, FID detector temperature 275 °C, carrier gas nitrogen, pre-column pressure 0.4 MPa, air pre-column pressure 0.2 MPa, hydrogen pre-column pressure 0.2 MPa, split ratio 30:1, and temperature programming column temperature 80 °C for 40 min, then increased to 150 °C at a rate of 5 °C / min and maintained for 30 min. The reaction was terminated after the complete racemization of L-MAT was confirmed by GC detection. Figure 1

[0032] After the reaction was completed, the reaction liquid was heated and filtered to recover the catalyst (11.6 g was recovered). The filtrate was first distilled at normal pressure to recover ethyl acetate, and the residue was further purified by distillation under reduced pressure to obtain 25 g of product. The product was detected by GC (the spectrum is shown in FIG. 3). Compared with the spectrum of L-MAT before the reaction (FIG. 1), it can be seen that the peak of L-MAT disappeared and the peak of DL-MAT appeared, indicating that the racemization of L-MAT was completed. Figure 3 ​​Figure 2 ) compared with the characteristic peak of the original L-MAT, indicating that the L-MAT has been completely converted into the DL-MAT. The purity of the product meets the application requirements as detected by GC.

[0033] The recovered supported TBD-IPTS / SBA-15 catalyst after the reaction can be directly reused for the racemization reaction of the L-MAT without activation, and the test and results are as follows: The recovered supported TBD-IPTS / SBA-15 catalyst in this example is reused for the racemization reaction of the L-MAT according to the reaction conditions described above in this example, and is used for 5 times in succession, and the recovered mass of the catalyst after each reaction and the reaction results are recorded as shown in Table 1.

[0034] Table 1. Results of repeated use of the catalyst

[0035] The experimental results show that after the supported TBD-IPTS / SBA-15 catalyst prepared in the application is used for 5 times in succession, the racemization conversion rate of the L-MAT still remains at 95% as detected by GC, the activity of the catalyst does not decrease obviously, and the catalyst has good mechanical integrity, stable recovery rate, and proves that the catalyst has excellent reusability and operating stability.

[0036] In addition, in the racemization reaction in this example, a non-polar organic solvent is selected as the solvent, aiming to ensure that the substrate L-MAT is fully dissolved, while maintaining the heterogeneous nature of the supported catalyst, so as to facilitate separation after the reaction. The reaction temperature is achieved by controlling the reflux of the solvent, so as to balance the reaction efficiency and avoid high-temperature side reactions. The recovered catalyst can be reused after simple drying, without additional activation, thereby simplifying the process and reducing the cost.

[0037] In summary, the supported TBD-IPTS / SBA-15 catalyst prepared in the application has excellent comprehensive performance, which is specifically manifested as follows: 1. Strong alkalinity retention: the guanidine active center structure of the TBD is not destroyed by the stable urea bond connection, and the 4-nitroaniline indicator is detected to be blue, the supported catalyst still maintains the strong alkalinity comparable to the homogeneous TBD, proving that the strong alkalinity remains unchanged.

[0038] 2. Heterogeneous nature: the SBA-15 inorganic framework is insoluble in any organic solvent, and the catalyst is in the form of a solid powder, and complete separation can be achieved by simple filtration or centrifugation after the reaction.

[0039] 3. High stability: the TBD does not fall off in the non-polar solvent through the double stabilization of the siloxane bond and the urea bond, and no characteristic absorption peak of the TBD is found by UV-Vis detection.

[0040] 4. High mass transfer efficiency: SBA-15 has a specific surface area as high as about 650 m² / g and regular mesoporous channels, which is conducive to the diffusion of substrate molecules and contact with the internal TBD active sites, and has high catalytic efficiency.

[0041] 5. Reusability: The recovered catalyst can be directly used for subsequent batch reactions, and the activity does not decrease significantly after multiple cycles, and has good mechanical integrity, which significantly reduces the production cost.

[0042] 6. Significant application effect: In the racemization reaction of L-MAT, the catalyst of the present application shows high activity and can quickly convert L-MAT into DL-MAT, which provides key technical support for the green and economic synthesis of captopril intermediates.

[0043] Although embodiments of the present application have been shown and described, it will be understood by those having ordinary skill in the art that various changes, modifications, substitutions and alterations can be made therein without departing from the principles and spirit of the present application, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A method for preparing a supported TBD-IPTS / SBA-15 catalyst, characterized by comprising the following steps: The method comprises the following steps: ​ S1: carrier pretreatment: the mesoporous silica SBA-15 carrier is treated with acid solution, washed to neutral, and then dried to obtain an activated carrier SBA-15-OH; S2: 3-isocyanate propyl triethoxysilane (IPTS) grafting: under the protection of an inert atmosphere, the SBA-15-OH is dispersed in anhydrous toluene, and IPTS is added for reflux reaction; after the reaction is completed, washing and drying are performed to obtain an IPTS grafted carrier IPTS / SBA-15; S3: 1,5,7-triazabicyclodec-5-ene (TBD) loading: under the protection of an inert atmosphere, the TBD is dissolved in anhydrous dichloromethane to obtain a TBD solution; the IPTS / SBA-15 is dispersed in anhydrous dichloromethane, and then the TBD solution is added dropwise; first, stirring reaction is performed at room temperature, and then the temperature is increased to continue the reaction; after the reaction is completed, washing and drying are performed to obtain the supported TBD-IPTS / SBA-15 catalyst.

2. The preparation method of the supported TBD-IPTS / SBA-15 catalyst according to claim 1, characterized in that: In step S1, the particle size of the mesoporous silica SBA-15 carrier is 100-200 mesh, the specific surface area is 650 m² / g, and the pore size is 7.2 nm; the acid solution is 1 mol / L hydrochloric acid, and the treatment time is 2 h; the drying condition is vacuum drying at 120°C for 6 h.

3. The preparation method of the supported TBD-IPTS / SBA-15 catalyst according to claim 1, characterized in that: In step S1, before the mesoporous silica SBA-15 carrier is treated with acid solution, a step of vacuum drying at 120°C for 4 h is further included.

4. The preparation method of the supported TBD-IPTS / SBA-15 catalyst according to claim 1, characterized in that: In step S2, the mass molar ratio of the SBA-15-OH to IPTS is 5.0 g:10 mmol; and the reflux reaction time is 24 h.

5. The method for preparing a supported TBD-IPTS / SBA-15 catalyst according to claim 1, characterized in that: In step S3, the mass molar ratio of the IPTS / SBA-15 to TBD is 4.0 g:8 mmol; the stirring reaction time at room temperature is 12 h, and the temperature is increased to continue the reaction for 8 h.

6. The method for preparing a supported TBD-IPTS / SBA-15 catalyst according to claim 1, characterized in that: In steps S2 and S3, the inert atmosphere is a nitrogen atmosphere; and the purity of the anhydrous toluene and anhydrous dichloromethane is ≥99.5%.

7. A supported TBD-IPTS / SBA-15 catalyst, which is prepared by the method of any one of claims 1-6, characterized in that: The catalyst is a light yellow powder, the strong alkaline active site is supported on the surface of the SBA-15 carrier through a covalent bond; the catalyst is insoluble in a non-polar organic solvent, and the supported active component does not fall off, and can be separated and recovered by filtration.

8. The use of the supported TBD-IPTS / SBA-15 catalyst according to claim 7 in the catalytic resolution of methyl L-3-acetylmethyl-2-methylpropionate, characterized in that: The method comprises the following steps: L-3-acetylmercapto-2-methylpropionic acid methyl ester, a supported TBD-IPTS / SBA-15 catalyst, and a non-polar organic solvent are mixed, heated to reflux for racemization reaction, after the reaction is completed, the catalyst is recovered by hot filtration, and after the solvent in the filtrate is recovered by distillation, DL-3-acetylmercapto-2-methylpropionic acid methyl ester is obtained.

9. The use of the supported TBD-IPTS / SBA-15 catalyst according to claim 8 in the catalytic racemization of L-3-acetylmethylthio-2-methylpropionic acid methyl ester, characterized in that: The supported TBD-IPTS / SBA-15 catalyst recovered after the reaction can be directly reused for the racemization reaction of L-3-acetylmercapto-2-methylpropionic acid methyl ester without activation.

10. The use of the supported TBD-IPTS / SBA-15 catalyst according to claim 8 in the catalytic racemization of L-3-acetylmethylthio-2-methylpropionic acid methyl ester, characterized in that: The non-polar organic solvent is ethyl acetate or toluene; the mass ratio of the L-3-acetylmercapto-2-methylpropionic acid methyl ester to the supported TBD-IPTS / SBA-15 catalyst is 2.5:1 to 3:1; the mass-volume ratio of the L-3-acetylmercapto-2-methylpropionic acid methyl ester to the non-polar organic solvent is 0.2 g / mL to 0.3 g / mL; the time of the racemization reaction is 8-12 h; and the progress of the racemization reaction is monitored by gas chromatography. The non-polar organic solvent is ethyl acetate or toluene; the mass ratio of the L-3-acetylmercapto-2-methylpropionic acid methyl ester to the supported TBD-IPTS / SBA-15 catalyst is 2.5:1 to 3:1; the mass-volume ratio of the L-3-acetylmercapto-2-methylpropionic acid methyl ester to the non-polar organic solvent is 0.2 g / mL to 0.3 g / mL; the time of the racemization reaction is 8-12 h; and the progress of the racemization reaction is monitored by gas chromatography.

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