Tripterine derivative and preparation method thereof

Abstract

The invention discloses a tripterine derivative and a preparation method thereof in the technical field of medicaments, and provides a method for solving the problem that side reaction is easy to occur in the preparation process of the tripterine derivative by using a heterogeneous amphoteric catalyst. The heterogeneous amphoteric catalyst is prepared from the following components in parts by weight: 6-10 parts of zinc nitrate hexahydrate, 15-25 parts of 2-methylimidazole, 4-6 parts of ferric chloride and 3-5 parts of magnesium chloride. By preparing the heterogeneous amphoteric catalyst, the reaction selectivity is improved, side reactions are reduced, and the technical effect of improving the yield of the final product tripterine derivative is achieved.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations and relates to a tripterygium wilfordii derivative and a preparation method thereof. Background Art

[0002] Tripterine is one of the main active ingredients of the Chinese herbal medicine Tripterygium wilfordii, also known as celastrol, and is the first natural active product isolated from the root bark of Tripterygium wilfordii. Studies in recent years have found that tripterine has good anti-inflammatory, antioxidant, immunosuppressive, anti-tumor, anti-obesity, anti-fertility and other pharmacological activities, and has therapeutic effects on neurodegenerative diseases and type 2 diabetes. Tripterine is a pentacyclic triterpenoid compound with a quinone methyl structure, among which the C-29 carboxylic acid, C-3 hydroxyl, and quinone methyl structure on the A / B ring are considered to be the main pharmacodynamic groups. Therefore, the structural modification of tripterine at home and abroad is mainly concentrated on these three positions. At present, most of the research focuses on the modification of C-29 carboxylic acid and C-3 hydroxyl. Although C-6 of the B ring in the quinone methyl structure of tripterygium wilfordii is a good site for Michael addition reaction, the yield of the target product is low and the molecular utilization rate is low due to the reversible reaction and the occurrence of side reactions.

[0003] The existing technologies currently have the following main problems: side reactions are prone to occur during the preparation of tripterygium wilfordii derivatives, and the product yield is low. Summary of the invention

[0004] In view of the above situation, in order to overcome the defects of the prior art, the present invention provides a tripterygium wilfordii derivative and a preparation method thereof. In order to solve the problem that side reactions are prone to occur during the preparation of tripterygium wilfordii derivatives, the present invention proposes to prepare a heterogeneous amphoteric catalyst to improve the reaction selectivity and reduce the occurrence of side reactions, thereby achieving the technical effect of increasing the yield of the final product tripterygium wilfordii derivative.

[0005] In order to achieve the above object, the technical solution adopted by the present invention is as follows: The present invention proposes a method for preparing a tripterygium wilfordii derivative, comprising the following steps:

[0006] The heterogeneous amphoteric catalyst was added to anhydrous ethanol in an amount of 0.01-0.02 g / mL, and tripterygium wilfordii and 2-mercaptoethanol were added at 60°C, the mass ratio of tripterygium wilfordii to 2-mercaptoethanol was 1:0.65, the reaction was carried out for 1.5 hours, and the tripterygium wilfordii derivative was obtained by cooling, low-temperature concentration and drying.

[0007] Preferably, the heterogeneous amphoteric catalyst is prepared from the following components in parts by weight: 6-10 parts of zinc nitrate hexahydrate, 15-25 parts of 2-methylimidazole, 4-6 parts of ferric chloride and 3-5 parts of magnesium chloride.

[0008] Preferably, the method for preparing the heterogeneous amphoteric catalyst specifically comprises the following steps:

[0009] S1. adding zinc nitrate hexahydrate to methanol to obtain a zinc nitrate solution, and adding 2-methylimidazole to methanol to obtain a 2-methylimidazole solution;

[0010] S2, dropping the 2-methylimidazole solution obtained in S1 into the zinc nitrate solution obtained in S1, stirring in a water bath for reaction, separating and drying to obtain a ZIF-8 precursor;

[0011] S3, adding the ZIF-8 precursor obtained in S2 into a ferric chloride solution, immersing for 10-12 hours, adjusting the pH to 6-7, calcining under an argon atmosphere, then heating to 1000°C and continuing calcining, cooling to room temperature, and obtaining C-Fe2O3;

[0012] S4. Add the C-Fe2O3 obtained in S3 to a magnesium chloride solution, immerse for 8-10 hours, adjust the pH to 10-11, calcine under an argon atmosphere to obtain C-Fe2O3 / MgO, cool to room temperature, wash and dry to obtain a heterogeneous amphoteric catalyst.

[0013] Preferably, in S1, the amount of zinc nitrate hexahydrate added to methanol is 0.028-0.032 g / mL.

[0014] Preferably, in S1, the amount of 2-methylimidazole added to methanol is 0.06-0.07 g / mL.

[0015] Preferably, in S2, the reaction is stirred in a water bath at a temperature of 30-40°C, a speed of 60-80 rpm, and a time of 10-12 h.

[0016] Preferably, in S3, the calcination is carried out under an argon atmosphere at a temperature of 450-550° C. and a time of 50-60 min.

[0017] Preferably, in S3, the temperature is raised to 1000°C and calcination is continued, the heating rate is 30-50°C / min, and the calcination time is 15-20min.

[0018] Preferably, in S4, the calcination is carried out under an argon atmosphere at a temperature of 400-450° C. for 30-40 min.

[0019] The beneficial effects achieved by the present invention are as follows: the preparation of the tripterygium wilfordii derivative of the present invention is based on the Michael addition reaction, 2-mercaptoethanol is combined with tripterygium wilfordii to enhance its water solubility and stability; the present invention proposes to use ZIF-8 as a precursor, adjust the pH to deposit Fe on the precursor, calcine and decompose at low temperature to form iron oxide with Lewis acidity, and then calcine at high temperature to completely form a C skeleton of the organic framework, and evaporate and remove Zn to obtain C-Fe2O3, and then load magnesium oxide with Lewis basicity to obtain a heterogeneous amphoteric catalyst C-Fe2O3 / MgO, the acid and base centers are evenly distributed on the surface of the carrier and in the pore structure, thereby achieving an improvement in the reaction selectivity in the reaction, reducing the occurrence of side reactions, and improving the yield of the tripterygium wilfordii derivative, thereby achieving an improvement in the yield of the final product tripterygium wilfordii derivative. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 The result diagram of the yield of tripterygium wilfordii derivatives of Example 1-3 and Comparative Example 1-2;

[0021] Figure 2 This is a result diagram of the yield of tripterygium wilfordii derivatives when Example 1-3 and Comparative Example 1-2 were used for the 30th time;

[0022] Figure 3 This is an electron micrograph of the heterogeneous amphoteric catalyst obtained in Example 1 after being recycled 30 times;

[0023] Figure 4 The synthetic flow chart of the tripterygium wilfordii derivative prepared in Example 1 of the present invention.

[0024] The accompanying drawings are used to provide further understanding of the present invention and constitute a part of the specification. They are used to explain the present invention together with the embodiments of the present invention and do not constitute a limitation of the present invention. DETAILED DESCRIPTION

[0025] The technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the drawings in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments; based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0026] Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein may be applied to the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only and are not intended to limit the content of this application.

[0027] The experimental methods in the following examples are conventional methods unless otherwise specified; the experimental materials used in the following examples are purchased from commercial channels unless otherwise specified.

[0028] Example 1

[0029] A method for preparing a tripterygium wilfordii derivative comprises the following steps:

[0030] The heterogeneous amphoteric catalyst was added to anhydrous ethanol in an amount of 0.01 g / mL, and tripterygium wilfordii and 2-mercaptoethanol were added at 60°C, the mass ratio of tripterygium wilfordii to 2-mercaptoethanol was 1:0.65, the reaction was carried out for 1.5 hours, and the mixture was cooled, concentrated at low temperature, and dried to obtain a tripterygium wilfordii derivative.

[0031] The heterogeneous amphoteric catalyst is prepared from the following components in parts by weight: 6 parts of zinc nitrate hexahydrate, 15 parts of 2-methylimidazole, 4 parts of ferric chloride and 3 parts of magnesium chloride.

[0032] The preparation method of the heterogeneous amphoteric catalyst specifically comprises the following steps:

[0033] S1. Adding zinc nitrate hexahydrate in an amount of 0.028 g / mL to methanol to obtain a zinc nitrate solution, and adding 2-methylimidazole in an amount of 0.06 g / mL to methanol to obtain a 2-methylimidazole solution;

[0034] S2, drop the 2-methylimidazole solution obtained in S1 into the zinc nitrate solution obtained in S1, stir in a 30°C water bath at 60 rpm for 10 h, separate and dry to obtain a ZIF-8 precursor;

[0035] S3, adding the ZIF-8 precursor obtained in S2 into a ferric chloride solution, immersing for 10 h, adjusting the pH to 6, calcining at 450 ° C for 50 min under an argon atmosphere, then heating to 1000 ° C at 30 ° C / min and continuing to calcine for 15 min, cooling to room temperature, and obtaining C-Fe2O3;

[0036] S4. Add the C-Fe2O3 obtained in S3 into a magnesium chloride solution, immerse for 8 hours, adjust the pH to 10, calcine at 400°C for 30 minutes under an argon atmosphere to obtain C-Fe2O3 / MgO, cool to room temperature, wash and dry to obtain a heterogeneous amphoteric catalyst.

[0037] Example 2

[0038] A method for preparing a tripterygium wilfordii derivative comprises the following steps:

[0039] The heterogeneous amphoteric catalyst was added to anhydrous ethanol in an amount of 0.02 g / mL, and tripterygium wilfordii and 2-mercaptoethanol were added at 60°C, the mass ratio of tripterygium wilfordii to 2-mercaptoethanol was 1:0.65, the reaction was carried out for 1.5 hours, and the mixture was cooled, concentrated at low temperature, and dried to obtain a tripterygium wilfordii derivative.

[0040] The heterogeneous amphoteric catalyst is prepared from the following components in parts by weight: 10 parts of zinc nitrate hexahydrate, 25 parts of 2-methylimidazole, 6 parts of ferric chloride and 5 parts of magnesium chloride.

[0041] The preparation method of the heterogeneous amphoteric catalyst specifically comprises the following steps:

[0042] S1. Adding zinc nitrate hexahydrate in an amount of 0.032 g / mL to methanol to obtain a zinc nitrate solution, and adding 2-methylimidazole in an amount of 0.07 g / mL to methanol to obtain a 2-methylimidazole solution;

[0043] S2, dripping the 2-methylimidazole solution obtained in S1 into the zinc nitrate solution obtained in S1, stirring in a water bath at 30°C and 80 rpm for 12 h, separating and drying to obtain a ZIF-8 precursor;

[0044] S3, adding the ZIF-8 precursor obtained in S2 into a ferric chloride solution, immersing for 12 hours, adjusting the pH to 7, calcining at 550°C for 60 minutes under an argon atmosphere, then heating to 1000°C at a rate of 50°C / min and continuing to calcine for 20 minutes, and cooling to room temperature to obtain C-Fe2O3;

[0045] S4. Add the C-Fe2O3 obtained in S3 into a magnesium chloride solution, immerse for 10 hours, adjust the pH to 11, calcine at 450°C for 40 minutes under an argon atmosphere to obtain C-Fe2O3 / MgO, cool to room temperature, wash and dry to obtain a heterogeneous amphoteric catalyst.

[0046] Experimental Example 3

[0047] A method for preparing a tripterygium wilfordii derivative comprises the following steps:

[0048] The heterogeneous amphoteric catalyst was added to anhydrous ethanol in an amount of 0.015 g / mL, and tripterygium wilfordii and 2-mercaptoethanol were added at 60°C, the mass ratio of tripterygium wilfordii to 2-mercaptoethanol was 1:0.65, the reaction was carried out for 1.5 hours, and the mixture was cooled, concentrated at low temperature, and dried to obtain a tripterygium wilfordii derivative.

[0049] The heterogeneous amphoteric catalyst is prepared from the following components in parts by weight: 8 parts of zinc nitrate hexahydrate, 20 parts of 2-methylimidazole, 5 parts of ferric chloride and 4 parts of magnesium chloride.

[0050] The preparation method of the heterogeneous amphoteric catalyst specifically comprises the following steps:

[0051] S1. Adding zinc nitrate hexahydrate in an amount of 0.03 g / mL to methanol to obtain a zinc nitrate solution, and adding 2-methylimidazole in an amount of 0.065 g / mL to methanol to obtain a 2-methylimidazole solution;

[0052] S2, drop the 2-methylimidazole solution obtained in S1 into the zinc nitrate solution obtained in S1, stir in a water bath at 35°C and 70 rpm for 11 h, separate and dry to obtain a ZIF-8 precursor;

[0053] S3, adding the ZIF-8 precursor obtained in S2 into a ferric chloride solution, immersing for 11 hours, adjusting the pH to 6.5, calcining at 500°C for 55 minutes under an argon atmosphere, then heating to 1000°C at a rate of 40°C / min and continuing to calcine for 18 minutes, and cooling to room temperature to obtain C-Fe2O3;

[0054] S4. Add the C-Fe2O3 obtained in S3 to a magnesium chloride solution, immerse for 9 hours, adjust the pH to 10.5, calcine at 425°C for 35 minutes under an argon atmosphere to obtain C-Fe2O3 / MgO, cool to room temperature, wash and dry to obtain a heterogeneous amphoteric catalyst.

[0055] Comparative Example 1

[0056] This comparative example provides a method for preparing a tripterygium wilfordii derivative, which differs from Example 1 only in that the catalyst used in the reaction is different, and the remaining components and component contents are the same as those in Example 1;

[0057] The catalyst is prepared by a deposition precipitation method: ferric nitrate is dissolved in distilled water, and then magnesium oxide is added, the pH is raised to 10, stirred at 150 rpm for 24 hours, filtered, washed, dried in an oven at 100°C for 7 hours, and then calcined at 600°C to obtain Fe2O3-MgO.

[0058] Comparative Example 2

[0059] This comparative example provides a method for preparing a tripterygium wilfordii derivative, which differs from Example 1 only in that the catalyst used in the reaction is different, and the remaining components and component contents are the same as those in Example 1;

[0060] The catalyst is a mixed powder of nano-Fe2O3 and MgO.

[0061] Experimental example

[0062] Take the tripterygium wilfordii derivatives obtained in Example 1-3 and Comparative Example 1-2, add internal standards, perform gas chromatography analysis, and calculate the yield of the tripterygium wilfordii derivatives using the following formula:

[0063] The yield of tripterygium wilfordii derivatives = the amount of tripterygium wilfordii derivatives produced / theoretical amount of tripterygium wilfordii derivatives produced × 100%;

[0064] After the first preparation, the catalyst was recovered, and the corresponding preparation was continued, and the yield of the tripterygium wilfordii derivative at the 30th time was recorded.

[0065] Figure 1 The result graph of the yield of tripterygium wilfordii derivatives of Examples 1-3 and Comparative Examples 1-2; as shown in the figure, the yields of Examples 1-3 and Comparative Examples 1-2 are 89.6%, 90.2%, 88.5% and 66.9%, 23.8%, respectively; the yield of Example 1-3 is significantly higher than that of Comparative Examples 1-2, indicating that the use of amphoteric catalysts and the loading of carbon skeletons effectively improve the yield of the reaction, which is beneficial to the improvement of the yield of tripterygium wilfordii derivatives; the metal oxide particles are loaded on the carbon skeleton so that the catalyst has a larger specific surface area, providing more reaction sites, which is conducive to the reaction, and the Lewis-acidic iron oxide and the Lewis-basic magnesium oxide are simultaneously immobilized on the surface of the carbon skeleton to form an amphoteric catalytic material, the acid-base centers are located at similar sites, the activity is higher than that of the isolated acid-base centers, and the activity and selectivity of the catalyst after immobilization are improved.

[0066] Figure 2 The result graph of the yield of celastrol derivatives when Example 1-3 and Comparative Example 1-2 were used for the 30th time; as shown in the figure, after 30 times of use, the yields of Example 1-3 and Comparative Example 1-2 were 86.3%, 88.9%, 86.6% and 39.2%, 13.3%, respectively; the presence of the carbon skeleton of Example 1-2 significantly slowed down the passivation of the catalyst and facilitated recovery, so that the obtained catalyst could be reused many times.

[0067] Figure 3 This is an electron microscope image of the heterogeneous amphoteric catalyst obtained in Example 1 after being recycled 30 times; as shown in the figure, the morphology of the heterogeneous amphoteric catalyst is intact after being used 30 times.

[0068] Figure 4 The synthetic flow chart of the tripterygium wilfordii derivative prepared by the present invention; as shown in the figure, the derivative is obtained by reacting tripterygium wilfordii with 2-mercaptoethanol, and the catalyst is C-Fe2O3 / MgO.

[0069] While the embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that many changes, modifications, substitutions and variations can be made to the embodiments without departing from the principles and spirit of the invention.

[0070] The present invention and its implementation methods are described above, which is not restrictive. The drawings are only one of the implementation methods of the present invention, and the actual application is not limited thereto. In short, if ordinary technicians in the field are inspired by it and design methods and embodiments similar to the technical solution without creativity without departing from the purpose of the invention, they should all fall within the protection scope of the present invention.

Claims

1. A tripterygium wilfordii derivative, characterized in that: The structure of the tripterygium wilfordii derivative is: 。 2. A method for preparing a tripterygium wilfordii derivative according to claim 1, characterized in that: The method comprises the following steps: adding a heterogeneous amphoteric catalyst in an amount of 0.01-0.02 g / mL into anhydrous ethanol, adding tripterygium wilfordii and 2-mercaptoethanol at 60°C, wherein the mass ratio of tripterygium wilfordii to 2-mercaptoethanol is 1:0.65, reacting for 1.5 hours, cooling, low-temperature concentrating and drying to obtain a tripterygium wilfordii derivative.

3. The method for preparing a tripterygium wilfordii derivative according to claim 2, characterized in that: The heterogeneous amphoteric catalyst is prepared from the following components in parts by weight: 6-10 parts of zinc nitrate hexahydrate, 15-25 parts of 2-methylimidazole, 4-6 parts of ferric chloride and 3-5 parts of magnesium chloride.

4. The method for preparing a tripterygium wilfordii derivative according to claim 3, characterized in that: The preparation method of the heterogeneous amphoteric catalyst specifically comprises the following steps: S1. adding zinc nitrate hexahydrate to methanol to obtain a zinc nitrate solution, and adding 2-methylimidazole to methanol to obtain a 2-methylimidazole solution; S2, dropping the 2-methylimidazole solution obtained in S1 into the zinc nitrate solution obtained in S1, stirring in a water bath for reaction, separating and drying to obtain a ZIF-8 precursor; S3, adding the ZIF-8 precursor obtained in S2 into a ferric chloride solution, immersing for 10-12 hours, adjusting the pH to 6-7, calcining under an argon atmosphere, then heating to 1000°C and continuing calcining, cooling to room temperature, and obtaining C-Fe2O3; S4. Add the C-Fe2O3 obtained in S3 to a magnesium chloride solution, immerse for 8-10 hours, adjust the pH to 10-11, calcine under an argon atmosphere to obtain C-Fe2O3 / MgO, cool to room temperature, wash and dry to obtain a heterogeneous amphoteric catalyst.

5. The method for preparing a tripterygium wilfordii derivative according to claim 4, characterized in that: In S1, the zinc nitrate hexahydrate is added in an amount of 0.028-0.032 g / mL in methanol.

6. The method for preparing a tripterygium wilfordii derivative according to claim 5, characterized in that: In S1, the amount of 2-methylimidazole added to methanol is 0.06-0.07 g / mL.

7. The method for preparing a tripterygium wilfordii derivative according to claim 6, characterized in that: In S2, the reaction is stirred in a water bath at a temperature of 30-40°C, a speed of 60-80 rpm, and a time of 10-12 h.

8. The method for preparing a tripterygium wilfordii derivative according to claim 7, characterized in that: In S3, calcination is performed under an argon atmosphere at a temperature of 450-550° C. for 50-60 min.

9. The method for preparing a tripterygium wilfordii derivative according to claim 8, characterized in that: In S3, the temperature is raised to 1000°C and calcination is continued, the heating rate is 30-50°C / min, and the calcination time is 15-20min.

10. The method for preparing a tripterygium wilfordii derivative according to claim 9, characterized in that: In S4, the calcination is carried out under an argon atmosphere at a temperature of 400-450° C. for 30-40 minutes.

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