Method for preparing triptolide by highly stereoselective reduction of triptolide ketone
By optimizing the reduction conditions of triptolide and using specific reducing agents and solvents, the problem of insufficient reduction selectivity of triptolide was solved, achieving highly selective preparation of triptolide A with fewer isomers, making it suitable for industrial production.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- CINKATE PHARMA INTERMEDIATES
- Filing Date
- 2024-11-28
- Publication Date
- 2026-06-05
Smart Images
Figure CN122145544A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the fields of organic chemistry, medicinal chemistry and natural product chemistry, and specifically relates to a method for preparing triptolide by highly stereoselective reduction of triptolide lactone. Background Technology
[0002] Tripterygium wilfordii is a traditional Chinese herbal medicine with anti-inflammatory, antirheumatic, and analgesic properties.
[0003] Among the many natural products of Tripterygium wilfordii, triptolide is recognized as the main active ingredient. Tripterygium wilfordii, also known as triptolide lactone, is mainly extracted from the leaves and roots of Tripterygium wilfordii. It possesses significant anti-tumor, immunosuppressive, and anti-inflammatory biological activities, attracting widespread attention from medicinal chemistry and pharmacology researchers. Unfortunately, the content of triptolide in the plant Tripterygium wilfordii is extremely low; approximately 7-8g of triptolide can be extracted from about 1000kg of Tripterygium wilfordii root bark. Relying solely on extraction from natural Tripterygium wilfordii is far from meeting the current clinical research needs for Tripterygium wilfordii drugs and future market demands.
[0004] Multiple research groups and institutions both domestically and internationally have studied the total synthesis of triptolide. These synthetic routes typically involve the reduction of triptolide (compound I) to triptolide (compound II).
[0005]
[0006] The reported reduction methods for triptolide (compound of formula II) currently exhibit poor selectivity, generating a large number of isomers (compound of formula III) during the reaction. According to existing literature or patents, the highest ratio of triptolide to its isomer (compound of formula III) in the reduction products is approximately 1:1, as shown below.
[0007] In 1980, Berchtold et al. reduced triptolide (II) in ethanol with sodium borohydride at 25 degrees Celsius, with a ratio of triptolide (I) to isomer (III) of 21:68 (J. Am. Chem. Soc., 1980, 102, 1200.).
[0008] In 1998, Yang Dan et al. reduced triptolide (II) in methanol at -40 degrees Celsius using sodium borohydride and Eu(fod)3, achieving a ratio of triptolide (I) to its isomer (III) of 47:47 (J.Org.Chem.1998,63,6446.).
[0009] During the reduction of triptolide, the formation of isomers should be suppressed as much as possible, and there have been no reports of highly selective formation of triptolide. Summary of the Invention
[0010] The purpose of this invention is to provide a method for preparing triptolide by highly stereoselective reduction of triptolide ketone.
[0011] The stereoselective synthesis method of triptolide of Formula I provided by this invention includes the following steps:
[0012]
[0013] When triptolide ketone of Formula II is mixed with a reducing agent, it reacts to obtain triptolide A of Formula I.
[0014] Wherein, the reducing agent is MR x BH y Or MAlHR' m (R”O) n ,
[0015] Where M is Li, Na, or K,
[0016] R is a C1-C6 alkyl group.
[0017] R' is a C1-C6 alkyl group or hydrogen.
[0018] R”O is a C1-C6 alkoxy group.
[0019] x+y=4, x=0~3, y=1~4;
[0020] m+n=3, m=0~3, n=0~3.
[0021] In another preferred embodiment, x is 0, 1, 2 or 3, and y is 1, 2, 3 or 4.
[0022] In another preferred embodiment, m is 0, 1, 2 or 3, and n is 0, 1, 2 or 3.
[0023] In another preferred embodiment, the triptolide ketone of Formula II reacts with a reducing agent in a solvent, wherein the solvent is one or a mixture of two or more of the following: tetrahydrofuran, 2-methyltetrahydrofuran, toluene, dichloromethane, methyl tert-butyl ether, 1,4-dioxane, acetonitrile, methanol, ethanol, isopropanol, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone.
[0024] In another preferred embodiment, the method includes the following steps: adding a reducing agent or a solution thereof to a solution of triptolide.
[0025] In another preferred embodiment, triptolide is dissolved in a solvent and then a reducing agent is added to react.
[0026] In another preferred embodiment, triptolide and a reducing agent are dissolved in a solvent, and the reducing agent solution is added to the triptolide solution for reaction.
[0027] In another preferred embodiment, the method includes the following steps: adding triptolide or a solution thereof to a solution of a reducing agent.
[0028] In another preferred embodiment, the reducing agent is dissolved in a solvent, and then tripterygium lactone is added to react.
[0029] In another preferred embodiment, triptolide and a reducing agent are dissolved in a solvent, and the triptolide solution is added dropwise to the reducing agent solution to react.
[0030] In another preferred embodiment, each of the solvents is independently one or a mixture of two or more of the following: tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, methyl tert-butyl ether, 1,4-dioxane, ethanol, isopropanol, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone.
[0031] In another preferred embodiment, each of the solvents is independently one or a mixture of two or more of the following: tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, methyl tert-butyl ether, 1,4-dioxane, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone.
[0032] In another preferred embodiment, the solvents are each independently one or a mixture of two or more of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, and 1,4-dioxane.
[0033] In another preferred embodiment, the solvent is tetrahydrofuran.
[0034] In another preferred embodiment, the reducing agent is MR. x BH y Or MAlHR' m (R”O) n ,
[0035] Where M is Li, Na, or K,
[0036] R is a C1-C5 alkyl group.
[0037] R' is a C1-C4 alkyl group or hydrogen.
[0038] R”O is a C1-C4 alkoxy group.
[0039] x+y=4, x=0~3, y=1~4;
[0040] m+n=3, m=0~3, n=0~3.
[0041] In another preferred embodiment, R is methyl, ethyl, propyl, butyl, or pentyl.
[0042] In another preferred embodiment, R' is H, methyl, ethyl, propyl, or butyl.
[0043] In another preferred embodiment, R”O is methoxy, ethoxy, propoxy, or butoxy.
[0044] In another preferred embodiment, the reducing agent is one or a combination of two or more of lithium triethylborohydride, lithium trisec-butylborohydride, lithium tripentylborohydride, potassium trisec-butylborohydride, and lithium tritert-butoxyaluminum hydride.
[0045] In another preferred embodiment, the reducing agent is one or a combination of two or more of lithium triethylborohydride, lithium trisec-butylborohydride, and lithium tripentylborohydride.
[0046] In another preferred embodiment, the equivalent ratio of the reducing agent to tripterygium lactone is 0.5 to 10:1.
[0047] In another preferred embodiment, the equivalent ratio of the reducing agent to tripterygium lactone is 1 to 5:1.
[0048] In another preferred embodiment, the temperature of the reaction is -70 to 80 degrees Celsius.
[0049] In another preferred embodiment, the temperature of the reaction is between -70 and 50 degrees Celsius.
[0050] In another preferred embodiment, the reaction produces the isomer shown in Formula III:
[0051]
[0052] The ratio of triptolide (as shown in Formula I) to the isomer shown in Formula III is greater than 1.5:1.
[0053] The method of the present invention has high stereoselectivity, and while generating triptolide as shown in Formula I, it reduces the generation of the isomer shown in Formula III.
[0054] In another preferred embodiment, the ratio of triptolide of Formula I to the isomer of Formula III is higher than 2:1, 5:1, 10:1, 20:1, 50:1, 75:1, 90:1, 95:1, 100:1, 150:1, 200:1, and even 250:1.
[0055] The method for reducing tripterygium lactone of the present invention has a high raw material conversion rate and generates fewer isomers during the reaction, and has good prospects for development and application.
[0056] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Attached Figure Description
[0057] Figure 1 HPLC chromatograms of triptolide (II), triptolide (I), and its isomer (III).
[0058] Figure 2 The image shows the HPLC chromatogram obtained in Example 2 during the reaction control phase. Detailed Implementation
[0059] Through extensive and in-depth research, the inventors have developed a method for the highly stereoselective synthesis of triptolide represented by Formula I. This method features high raw material conversion and generates very few, or even almost none, isomers represented by Formula III during the reaction. The ratio of triptolide represented by Formula I to the isomer represented by Formula III is higher than 2:1, and even as high as 250:1. Based on this, the present invention was completed.
[0060] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and parts by weight.
[0061] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.
[0062] General Method
[0063] The proportions of triptolide (II), triptolide (I), and its isomer (III) were determined.
[0064] Liquid phase conditions:
[0065] Using octadecylsilane-bonded silica gel as the packing material, purified water as mobile phase A, and methanol as mobile phase B, gradient elution was performed according to the table below, with a flow rate of 1 mL / min.
[0066] Time (min) Mobile phase A (%) Mobile phase B (%) 0 90 10 50 10 90 55 10 90 55.1 90 10 60 90 10
[0067] HPLC chromatograms of triptolide (II), triptolide (I), and its isomer (III) are attached. Figure 1 .
[0068] The ratio between compounds was calculated using the area normalization method.
[0069] Example 1
[0070]
[0071] 20 mg (0.056 mmol) of triptolide (II) and 1 mL of tetrahydrofuran were added to the reaction flask. After dissolution, the mixture was cooled to approximately -70°C, and then 0.11 mL (0.11 mmol) of 1 M trisec-butylborohydride tetrahydrofuran solution was added. After the addition was complete, the mixture was stirred at approximately -70°C for about 1 hour. The conversion rate of triptolide (II) was 100%, and the ratio of triptolide (I) to its isomer (III) was approximately 24:1.
[0072] Example 2
[0073] Add 0.22 mL (0.22 mmol) of 1M lithium triethylborohydride tetrahydrofuran solution and 1 mL of tetrahydrofuran to the reaction flask, cool to approximately -70°C, and then add dropwise a solution of 20 mg (0.056 mmol) of triptolide (II) and 1 mL of tetrahydrofuran. After the addition is complete, stir at approximately -70°C for about 1 hour. The conversion rate of triptolide (II) was 100%, and the ratio of triptolide (I) to its isomer (III) was approximately 250:1. See the HPLC chromatogram in the central control unit. Figure 2 .
[0074] Example 3
[0075] 20 mg (0.056 mmol) of triptolide (II) and 1 mL of tetrahydrofuran were added to the reaction flask. After dissolution, the mixture was cooled to approximately -70°C, and then 0.11 mL (0.11 mmol) of 1 M triethyl borohydride tetrahydrofuran solution was added. After the addition was complete, the mixture was stirred at approximately -70°C for about 1 hour. The conversion rate of triptolide (II) was 100%, and the ratio of triptolide (I) to its isomer (III) was approximately 24:1.
[0076] Example 4
[0077] Add 0.22 mL (0.22 mmol) of 1M lithium triethylborohydride tetrahydrofuran solution and 1 mL of tetrahydrofuran to the reaction flask, cool to approximately 0–5°C, and then add dropwise a solution of 20 mg (0.056 mmol) of triptolide (II) and 1 mL of tetrahydrofuran. After the addition is complete, stir at approximately 0–5°C for 1 hour. The conversion rate of triptolide (II) is approximately 100%, and the ratio of triptolide (I) to its isomer (III) is approximately 53:1.
[0078] Example 5
[0079] 20 mg (0.056 mmol) of triptolide (II) and 1 mL of tetrahydrofuran were added to the reaction flask. After dissolution, the mixture was cooled to approximately 0–5°C. Then, 0.11 mL (0.11 mmol) of 1 M triethyl borohydride tetrahydrofuran solution was added. After the addition was complete, the mixture was stirred at approximately 0–5°C for about 1 hour. The conversion rate of triptolide (II) was 100%, and the ratio of triptolide (I) to its isomer (III) was approximately 19:1.
[0080] Example 6
[0081] 20 mg (0.056 mmol) of triptolide (II) and 1 mL of tetrahydrofuran were added to the reaction flask. After dissolution, the mixture was cooled to approximately -70°C, and then 0.11 mL (0.11 mmol) of 1 M tripentyl borohydride tetrahydrofuran solution was added. After the addition was complete, the mixture was stirred at approximately -70°C for about 1 hour. The conversion rate of triptolide (II) was 100%, and the ratio of triptolide (I) to its isomer (III) was approximately 6:1.
[0082] Example 7
[0083] 20 mg (0.056 mmol) of triptolide (II) and 1 mL of tetrahydrofuran were added to the reaction flask. After dissolution, the mixture was cooled to approximately -50 to -60°C. Then, 0.33 mL (0.33 mmol) of 1 M trisec-butylborohydride tetrahydrofuran solution was added. After the addition was complete, the mixture was stirred at approximately -50 to -60°C for about 2 hours. The conversion rate of triptolide (II) was approximately 94%, and the ratio of triptolide (I) to its isomer (III) was approximately 2.1:1.
[0084] Example 8
[0085] 10 mg (0.028 mmol) of triptolide (II) and 1 mL of tetrahydrofuran were added to the reaction flask and dissolved. A solution of 28 mg (0.11 mmol) of lithium tri-tert-butoxyaluminum hydride and 1 mL of tetrahydrofuran was then added dropwise at room temperature, followed by stirring at room temperature for approximately 2 hours. The conversion rate of triptolide (II) was 100%, and the ratio of triptolide (I) to its isomer (III) was approximately 1.7:1.
[0086] Example 9
[0087] Add 0.11 mL (0.11 mmol) of 1M lithium triethylborohydride tetrahydrofuran solution and 1 mL of dichloromethane to the reaction flask, cool to approximately -70°C, and then add dropwise a solution of 10 mg (0.028 mmol) of triptolide (II) and 1 mL of dichloromethane. After the addition is complete, stir at approximately -70°C for about 1 hour. The conversion rate of triptolide (II) is approximately 100%, and the ratio of triptolide (I) to its isomer (III) is approximately 99:1.
[0088] Example 10
[0089] Add 0.11 mL (0.11 mmol) of 1M lithium triethylborohydride tetrahydrofuran solution and 1 mL of 1,4-dioxane to the reaction flask. Then, add 10 mg (0.028 mmol) of triptolide (II) and 1 mL of 1,4-dioxane solution dropwise at room temperature. After the addition is complete, stir at room temperature for about 2 hours. The conversion rate of triptolide (II) is approximately 100%, and the ratio of triptolide (I) to its isomer (III) is approximately 9:1.
[0090] Example 11
[0091] Add 0.22 mL (0.22 mmol) of 1M lithium trisec-butylborohydride tetrahydrofuran solution and 1 mL of tetrahydrofuran to the reaction flask, cool to approximately -70°C, and then add dropwise a solution of 20 mg (0.056 mmol) of triptolide (II) and 1 mL of tetrahydrofuran. After the addition is complete, stir at approximately -70°C for about 1 hour. The conversion rate of triptolide (II) is 100%, and the ratio of triptolide (I) to its isomer (III) is approximately 99:1.
[0092] Example 12
[0093] Add 0.22 mL (0.22 mmol) of 1M tripentyl borohydride lithium tetrahydrofuran solution and 1 mL of tetrahydrofuran to the reaction flask, cool to approximately -70°C, and then add dropwise a solution of 20 mg (0.056 mmol) of triptolide (II) and 1 mL of tetrahydrofuran. After the addition is complete, stir at approximately -70°C for about 1 hour. The conversion rate of triptolide (II) is 100%, and the ratio of triptolide (I) to its isomer (III) is approximately 71:1.
[0094] Example 13
[0095] 20 mg (0.056 mmol) of triptolide (II) and 1 mL of tetrahydrofuran were added to the reaction flask and dissolved at room temperature. Then, 0.11 mL (0.11 mmol) of 1 M triethylborohydride tetrahydrofuran solution was added, and the mixture was stirred at approximately 35°C for about 0.5 hours. The conversion rate of triptolide (II) was 99.9%, and the ratio of triptolide (I) to its isomer (III) was approximately 32:1.
[0096] Example 14
[0097] Add 20 mg (0.056 mmol) of triptolide (II) and 1 mL of tetrahydrofuran to the reaction flask. After dissolving at room temperature, add 0.11 mL (0.11 mmol) of 1 M triethylborohydride tetrahydrofuran solution. After the addition is complete, stir at approximately 45–50°C for about 10 minutes. The conversion rate of triptolide (II) is >99%, and the ratio of triptolide (I) to its isomer (III) is approximately 28:1.
[0098] Compared with existing literature reports, this invention uses triptolide as a raw material, and the reducing agent and reduction method used are more selective, which can obtain triptolide with high selectivity and inhibit the formation of isomers.
[0099] Using reducing agents such as lithium triethylborohydride, lithium trisec-butylborohydride, lithium tripentylborohydride, potassium trisec-butylborohydride, and lithium tritert-butoxyaluminum hydride, the ratio of triptolide (I) to isomer (III) can reach 1.5:1 or higher, which is superior to existing literature reports. In particular, lithium triethylborohydride, lithium trisec-butylborohydride, and lithium tripentylborohydride yielded a ratio of triptolide (I) to isomer (III) higher than 6:1. In Example 2, using lithium triethylborohydride as a reducing agent, the conversion rate of triptolide (II) reached 100%, exhibiting excellent stereoselectivity, and the ratio of triptolide (I) to isomer (III) reached approximately 250:1.
[0100] The reducing agent used in this invention is commercially available, and the reduction process is easy to industrialize.
[0101] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.
Claims
1. A method for the stereoselective synthesis of triptolide as shown in Formula I, characterized in that, Includes the following steps: When triptolide ketone of Formula II is mixed with a reducing agent, it reacts to obtain triptolide A of Formula I. The reducing agent is MR. x BH y Or MAlHR' m (R”O) n , Where M is Li, Na, or K, R is a C1-C6 alkyl group. R' is a C1-C6 alkyl group or hydrogen. R”O is a C1-C6 alkoxy group. x+y=4, x=0~3, y=1~4; m+n=3, m=0~3, n=0~3.
2. The synthesis method according to claim 1, characterized in that, The method includes the following steps: Add a reducing agent or its solution to a solution of triptolide.
3. The synthesis method as described in claim 1, characterized in that, The method includes the following steps: Add triptolide or its solution to the reducing agent solution.
4. The synthesis method according to claim 1, characterized in that, The reducing agent is MR. x BH y Or MAlHR' m (R”O) n , Where M is Li, Na, or K, R is a C1-C5 alkyl group. R' is a C1-C4 alkyl group or hydrogen. R”O is a C1-C4 alkoxy group. x+y=4, x=0~3, y=1~4; m+n=3, m=0~3, n=0~3.
5. The synthesis method according to claim 1, characterized in that, The reducing agent is one or a combination of two or more of lithium triethylborohydride, lithium trisec-butylborohydride, lithium tripentylborohydride, potassium trisec-butylborohydride, and lithium tritert-butoxyaluminum hydride.
6. The synthesis method according to claim 1, characterized in that, When the reaction produces the isomer shown in Formula III The ratio of triptolide (as shown in Formula I) to the isomer shown in Formula III is greater than 1.5:
1.
7. The synthesis method according to claim 1, characterized in that, The reducing agent is one or a combination of two or more of lithium triethylborohydride, lithium trisec-butylborohydride, and lithium tripentylborohydride.
8. The synthesis method according to claim 1, characterized in that, The equivalent ratio of the reducing agent to tripterygium lactone is 0.5 to 10:
1.
9. The synthesis method according to claim 1, characterized in that, In a solvent, triptolide of Formula II reacts with a reducing agent, wherein the solvent is one or a mixture of two or more of the following: tetrahydrofuran, 2-methyltetrahydrofuran, toluene, dichloromethane, methyl tert-butyl ether, 1,4-dioxane, acetonitrile, methanol, ethanol, isopropanol, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone.
10. The synthesis method according to claim 1, characterized in that, The reaction temperature is between -70 and 80 degrees Celsius.