Method for efficiently preparing teniposide precursor
By phenol protection of 4'-norphagophyllotoxin and coupling reaction using silicon-protected sugar ring blocks, the low overall yield and purity ratio in the preparation of IV in the key precursor of teniposide were solved. The problem of low results enables efficient and high yield synthesis.
Patent Information
- Application Number
- CN202411631781.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-11-15
- Publication Date
- 2025-02-25
AI Technical Summary
In the preparation of key precursor IV of teniposide, the prior art has problems with low overall yield, low purity and poor selectivity, especially in the deacetylation and coupling reaction steps.
Using 4'-norphagophyllotoxin as the initial substrate, the protection of phenol and the use of silicon-protected sugar ring blocks were carried out under the catalysis of BF3·Et2O, and finally the key preparation was prepared by hydrogenolysis. body IV.
The efficiency and total yield of the reaction are improved, the required equivalent is reduced, and the later deacetylation operation is avoided, achieving high purity and high yield synthesis.
Smart Images
Figure BDA0005136109580000011 
Figure BDA0005136109580000012 
Figure BDA0005136109580000021
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of drug synthesis, and particularly relates to the synthesis of a key precursor IV of teniposide. Background Art
[0002] The chemical formula of (5R,5aR,8aR,9S)-5-(4-hydroxy-3,5-dimethoxyphenyl)-9-(((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)-5,8,8a,9-tetrahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxolan-6(5aH)-one (i.e., the key precursor IV of teniposide) is: C 27 H 30 O 13 , the structural formula is shown below:
[0003]
[0004] Teniposide, also known as teniposide, is a semi-synthetic glycoside derivative of podophyllotoxin. Its chemical name is 4'-demethyl epipodophyllotoxin-β-D-thienylmethylpyranoglucoside, and it is an anti-tumor drug. As a classic anti-tumor drug, teniposide has a history of production and application for many years. Its therapeutic effect has been confirmed through long-term clinical use, and its long-term toxicity and other adverse reactions have also been fully demonstrated. In general, this variety has a definite therapeutic effect for its indications and prolongs survival. The market highly recognizes this variety and the market can be further expanded.
[0005]
[0006] In the early days, the complete synthesis route of teniposide was reported in the literature (US: 3524844, 1970). Among them, 4'-demethylpodophyllotoxin was used as the initial substrate, and the key precursor IV of teniposide was prepared through phenol protection, sugar ring coupling, hydrogenation and deacetylation. However, the overall yield of this process was low, and the purity of the reaction was low in the last step of deacetylation, which made the post-processing purification difficult.
[0007]
[0008] In order to solve the above problems, in the paper (Zhao Chenguang. Research on the Synthesis Process of Teniposide [D]. Shenyang Pharmaceutical University, 2009.), 4'-demethyl epipodophyllotoxin is used as the initial raw material and directly coupled with the sugar ring skeleton. Therefore, the process has obvious step economy, avoiding the protection of the phenolic group and the later hydrogenation process. However, it was found in the experimental process that if CbzCl protection is not used, the selectivity is poor and the yield is also low. At the same time, in the Zn deacetylation process, there are many intermediate states, and the actual yield of the reaction is also low.
[0009]
[0010] In summary, the following difficulties exist in the preparation of the key precursor IV of teniposide: (1) When using acetyl-protected sugar ring building blocks, there are multiple intermediate states in the later deacetylation process using Zn / Zn(OAc)2, and the purity of the reaction solution is low, and the total yield is low; (2) When using 4'-demethylepipodophyllotoxin as the initial raw material and directly coupling it with the sugar ring building block, there are selectivity problems, low reaction efficiency (a large amount of substrate residue), and the need to use a superstoichiometric amount of sugar ring building blocks. Summary of the invention
[0011] In order to solve the above technical problems, the present invention provides a method for synthesizing a key precursor IV of teniposide. Using 4'-demethyl epipodophyllotoxin as the initial substrate, after protection of phenol, it is beneficial to the later selective coupling; using a silicon-protected sugar ring building block (intermediate II), not only can the reaction efficiency be higher, but also the required equivalent is lower, and no later deacetylation operation is required, so that the total yield of the reaction is higher.
[0012] The technical solution adopted by the present invention is as follows:
[0013] A method for preparing a key precursor of teniposide comprises the following steps:
[0014] 1) Using 4'-demethyl epipodophyllotoxin as the starting material, after phenol protection, intermediate I is generated;
[0015] 2) Using α-anhydroglucose ester as substrate, selectively protecting the hydroxyl group to generate intermediate II;
[0016] 3) Under the catalysis of BF3·Et2O, intermediate I and intermediate II are coupled to generate intermediate III;
[0017] 4) hydrogenolysis of intermediate III to obtain the key precursor intermediate IV of teniposide;
[0018] The reaction formula is:
[0019]
[0020] The synthesis method of the intermediate I is as follows: 4'-demethyl epipodophyllotoxin reacts with benzyl chloroformate under alkaline conditions;
[0021] 4'-demethylepipodophyllotoxin, pyridine and solvent were added to the reaction kettle, and the temperature was lowered to -10 to -15°C. Benzyl chloroformate was added dropwise and stirred for reaction. After the reaction was completed, intermediate I was obtained by post-treatment.
[0022] In the above method for preparing intermediate I, the molar ratio of 4'-demethylepipodophyllotoxin, benzyl chloroformate and pyridine is 1:1.1-1.3:1.3-1.5, and the solvent is DCE.
[0023] In the above method for preparing intermediate I, the temperature is -10 to -15°C, and the reaction time is 0.5 to 1.0 h.
[0024] In the above-mentioned method for preparing intermediate I, the post-treatment steps include adding purified water for quenching, extraction, concentration, acetone / methyl tert-butyl ether crystallization and suction filtration to obtain intermediate I after drying.
[0025] The synthesis method of intermediate II: α-anhydrous glucose ester and trimethylsilyl chloride are subjected to substitution reaction under alkaline conditions. It includes the following steps:
[0026] In a reaction kettle, α-anhydrous glucose ester, triethylamine and solvent were added, the internal temperature was maintained at 15-20°C, trimethylsilyl chloride was slowly added dropwise, and the reaction was stirred. After the reaction was completed, intermediate II was obtained by post-treatment.
[0027] In the above method for preparing intermediate II, the molar ratio of α-anhydrous glucose ester, trimethylsilyl chloride and triethylamine is 1:1.1-1.3:1.1-1.5, and more preferably the molar ratio of the three is 1:1.2:1.2; the solvent is DCE.
[0028] In the above method for preparing intermediate II, the temperature is 17-20° C. and the reaction time is 0.5-1.0 h.
[0029] In the above method for preparing intermediate II, the post-treatment steps include adding purified water for quenching, extraction, concentration, isopropyl ether crystallization and suction filtration to obtain intermediate II after drying.
[0030] The synthesis method of intermediate III: intermediate I and intermediate II are subjected to coupling reaction under the catalysis of boron trifluoride-ether. The method comprises the following steps: adding intermediate I, solvent and intermediate II to a reaction kettle respectively, cooling to -10 to -15°C, dropping boron trifluoride-ether solution, and keeping the temperature to react after the dropping is completed, and post-treating to obtain intermediate III.
[0031] In the above method for preparing intermediate III, the molar ratio of intermediate I, intermediate II and boron trifluoride is 1:1.0-1.2:1.1-1.3, and more preferably, the molar ratio of the three is 1:1.1:1.2. The solvent is DCE.
[0032] In the above method for preparing intermediate III, the temperature is -10 to -15°C, and the reaction time is 3.0 to 5.0 hours.
[0033] In the above method for preparing intermediate III, the post-treatment steps include adding purified water for quenching, extraction, concentration, 95% ethanol / water crystallization and suction filtration to obtain intermediate III after drying.
[0034] The synthesis method of intermediate IV: intermediate III is subjected to hydrogenolysis reaction under Pd / C / H2 conditions to obtain intermediate IV, comprising the following steps: intermediate III, solvent and 10% Pd / C are respectively added into an autoclave, the internal temperature is controlled at 35-40°C, the hydrogen pressure is controlled at 0.2-0.4Mpa, the reaction is carried out for 8.0-10.0h, and after the reaction is completed, intermediate IV is obtained by treatment.
[0035] In the above method for preparing intermediate IV, the weight ratio of intermediate III to 10% Pd / C is 29.3:0.8-1.2, preferably 29.3:1; and the solvent is acetone / water.
[0036] In the above method for preparing intermediate IV, the temperature is 37-39°C, the reaction time is 8.0-10.0h, and the hydrogen pressure is 0.2-0.4Mpa. More preferably, the temperature is 37°C, the reaction time is 8.0h, and the hydrogen pressure is 0.3Mpa.
[0037] In the above-mentioned method for preparing intermediate IV, the post-treatment steps are filtering, concentrating, methanol crystallizing and suction filtration, and intermediate IV is obtained after drying.
[0038] Beneficial effects:
[0039] Compared with the prior art, the present invention has the following advantages: (1) Using 4'-demethyl epipodophyllotoxin as the initial substrate, after the protection of phenol, it is beneficial to the later selective coupling. Although this step increases the later hydrogenation process, the volume yield of these two steps is above 95%, so this patent still adopts the selective reaction after protection;
[0040] (2) The use of silicon-protected sugar ring building blocks not only makes the reaction more efficient, but also requires a lower equivalent amount, and does not require a subsequent deacetylation operation, thereby increasing the overall yield of the reaction;
[0041] (3) The route of the present invention has a short reaction step (only 4 steps are required) and a high yield, which solves the problem of late deacetylation of the sugar ring building block after coupling. The overall yield of the reaction is relatively high, with an overall yield of 53%. At the same time, if the synthesis step of the cheap sugar ring building block (the average yield is about 60%) is removed, the total yield of the three key steps involving the modification of the podophyllotoxin skeleton is as high as 88%. DETAILED DESCRIPTION
[0042] The present invention will be further described below in conjunction with specific embodiments so that those skilled in the art can better understand the present invention, but the invention is not limited thereby.
[0043] A method for preparing a key precursor of teniposide, firstly, using 4'-demethyl epipodophyllotoxin as a starting material, after phenol protection, to generate intermediate I; secondly, using α-anhydroglucose ester as a substrate, selectively protecting the hydroxyl group to generate intermediate II; then, under the catalysis of BF3·Et2O, intermediate I and intermediate II are coupled to generate intermediate III; finally, by hydrogenolysis, intermediate IV can be prepared, which is used as a key precursor for synthesizing teniposide. The synthetic route is shown in the following formula:
[0044]
[0045] Example 1 (Preparation of Intermediate I)
[0046]
[0047] In a 20L reactor, add 4'-demethyl epipodophyllotoxin (2.00kg, 5.0mol), dichloroethane (10kg) and pyridine (0.55kg, 7.0mol), and cool to -12°C. After cooling, begin to drop a mixture of benzyl chloroformate (1.02kg, 6.0mol) and dichloroethane (2kg). After dropping, keep the internal temperature at -12°C and stir for 0.5h, take a sample for HPLC detection (the residual rate of 4'-demethyl epipodophyllotoxin is 0.3%). After the reaction, add 2.00kg of purified water to quench. Let stand for stratification, retain the organic phase, and add 2.0kg of purified water to the organic phase for two extractions. Combine the organic phases and distill under reduced pressure at 45°C. Add 1.0kg of acetone to dissolve the material, and drop 5.0kg of methyl tert-butyl ether. After dropping, the internal temperature is reduced to -2°C and filtered. After forced air drying at 45°C for 10 h, 2.57 kg of white powder was obtained with a yield of 96%.
[0048] Example 2 (Preparation of Intermediate I)
[0049] In a 20L reactor, add 4'-demethyl epipodophyllotoxin (2.00kg, 5.0mol), dichloroethane (10kg) and pyridine (0.55kg, 7.0mol), and cool to -15°C. After cooling, start to drop a mixture of benzyl chloroformate (1.02kg, 6.0mol) and dichloroethane (2kg). After dropping, keep the internal temperature at -13°C and stir for 1.0h, take a sample for HPLC detection (the residual rate of 4'-demethyl epipodophyllotoxin is 0.1%). After the reaction, add 2.00kg of purified water to quench. Let stand for stratification, retain the organic phase, and add 2.0kg of purified water to the organic phase for two extractions. Combine the organic phases and distill under reduced pressure at 45°C. Add 1.0kg of acetone to dissolve the material, and add 5.0kg of methyl tert-butyl ether. After dropping, the internal temperature is reduced to -3°C and filtered. After drying at 45°C for 10 h, 2.60 kg of white powder was obtained with a yield of 97%.
[0050] Example 3 (Preparation of Intermediate II)
[0051]
[0052] In a 20L reactor, add α-anhydrous glucose ester (1.80kg, 10.0mol), DCE (5.00kg) and triethylamine (1.21kg, 12.0mol), maintain the internal temperature at 17°C, and slowly add trimethylsilyl chloride (1.30kg, 12.0mol). After the dropwise addition, stir for 30min and perform TLC detection. After the reaction, add 2.00kg of purified water to quench. Let stand for stratification, retain the organic phase, and add 2.00kg of purified water to the organic phase for two extractions. Combine the organic phases and distill under reduced pressure at 45°C. Add 2.00kg of isopropyl ether and stir at room temperature for 2h, cool to -13°C, and filter. Dry at 45°C with forced air for 10h to obtain 1.51kg of light yellow solid with a yield of 60%.
[0053] Example 4 (Preparation of Intermediate II)
[0054] In a 20L reactor, add α-anhydrous glucose ester (1.80kg, 10.0mol), DCE (5.00kg) and triethylamine (1.21kg, 12.0mol), maintain the internal temperature at 19°C, and slowly add trimethylsilyl chloride (1.30kg, 12.0mol). After the dropwise addition, stir for 30min and perform TLC detection. After the reaction, add 2.00kg of purified water to quench. Let stand for stratification, retain the organic phase, and add 2.00kg of purified water to the organic phase for two extractions. Combine the organic phases and distill under reduced pressure at 45°C. Add 2.00kg of isopropyl ether and stir at room temperature for 2h, cool to -11°C, and filter. Dry at 45°C with forced air for 10h to obtain 1.43kg of light yellow solid with a yield of 57%.
[0055] Example 5 (Preparation of Intermediate III)
[0056]
[0057] Add intermediate I (2.41kg, 4.5mol), DCE (10kg) and intermediate II (1.26kg, 5.0mol) to a 20L reactor and cool to -13°C. Add boron trifluoride-ether solution (1.53kg, 5.4mol) dropwise. After the addition, keep the reaction at -13°C for 3h, take a sample for HPLC detection (the residual rate of intermediate I is 0.2%). After the reaction, add 2.00kg of purified water to quench. Let stand for stratification, retain the organic phase, and add 2.0kg of purified water to the organic phase for two extractions. Combine the organic phases and distill under reduced pressure at 45°C. After concentration, add 3.00kg of 95% ethanol to dissolve it and add it dropwise to 10.00kg of ice water. After the addition, cool to 5°C and filter. Dry with air at 45°C for 10h to obtain 2.95kg of white powder with a yield of 94%.
[0058] Example 6 (Preparation of Intermediate III)
[0059] Add intermediate I (2.41kg, 4.5mol), DCE (10kg) and intermediate II (1.26kg, 5.0mol) to a 20L reactor and cool to -15°C. Add 50% boron trifluoride-ether solution (1.53kg, 5.4mol) dropwise. After the addition, keep the reaction at -2°C for 5h, take a sample for HPLC detection (the residual rate of intermediate I is 0.1%). After the reaction, add 2.00kg of purified water to quench. Let stand for stratification, retain the organic phase, and add 2.0kg of purified water to the organic phase for two extractions. Combine the organic phases and distill under reduced pressure at 45°C. After concentration, add 3.00kg of 95% ethanol to dissolve it and add it dropwise to 10.00kg of ice water. After the addition, cool to 2°C and filter. Dry with air at 45°C for 10h to obtain 3.11kg of white powder with a yield of 95%.
[0060] Example 7 (Preparation of Intermediate IV)
[0061]
[0062] Add intermediate III (2.93kg, 4.2mol), acetone (8.00kg), water (2.00kg) and 10% Pd / C (0.10kg) into a 50L autoclave. Replace with N2 3 times and H2 3 times. Control the internal temperature at 37°C, the hydrogen pressure at 0.3Mpa, and react for 8h. Take a sample for HPLC detection (the residual rate of intermediate III is 0.3%). After the reaction, filter and reduce the pressure of the filtrate at 45°C. After concentration, add 4.00kg of methanol to dissolve it completely, cool to -6°C, and filter. Dry at 45°C with forced air for 20h to obtain 2.23kg of white powder with a yield of 95%.
[0063] Example 8 (Preparation of Intermediate IV)
[0064] Add intermediate III (2.93kg, 4.2mol), acetone (8.00kg), water (2.00kg) and 10% Pd / C (0.10kg) into a 50L autoclave. Replace with N2 3 times and H2 3 times. Control the internal temperature at 39°C, the hydrogen pressure at 0.4Mpa, and react for 8h. Take a sample for HPLC detection (the residual rate of intermediate III is 0.1%). After the reaction, filter and reduce the pressure of the filtrate at 45°C. After concentration, add 4.00kg of methanol to dissolve it completely, cool to -8°C, and filter. Dry with air at 45°C for 20h to obtain 2.26kg of white powder with a yield of 96%.
[0065] The characterization data of the synthetic intermediate IV and the comparison with the reference substance are shown in Table 1.
[0066] Table 1
[0067] Reference Intermediate IV Optical rotation -84.7° -88.6° Melting point 219.1～220.3℃ 219.8-221.2℃ Appearance Off-white powder White powder Related substances Maximum single impurity 0.3%, total impurity 0.3% Maximum single impurity 0.2%, total impurity 0.2% content 93.8％ 94.1％
Claims
1. A method for preparing a key precursor of teniposide, characterized in that: The steps include: 1) using 4'-demethyl epipodophyllotoxin as the starting material, and carrying out a substitution reaction with benzyl chloroformate under alkaline conditions to generate intermediate I; 2) Using α-anhydroglucose ester as substrate, selectively protecting the hydroxyl group to generate intermediate II; 3) Under the catalysis of BF3·Et2O, intermediate I and intermediate II are coupled to generate intermediate III; 4) hydrogenolysis of intermediate III to obtain the key precursor intermediate IV of teniposide; Among them, the structural formulas of intermediate I, intermediate II, intermediate III and intermediate IV are shown below:
2. The method for preparing the key precursor of teniposide according to claim 1, characterized in that: In step 1), the molar ratio of 4'-demethylepipodophyllotoxin to benzyl chloroformate is 1:1.1-1.
3.
3. The method for preparing the key precursor of teniposide according to claim 1, characterized in that: The reaction temperature of step 1) is -10 to -15°C, and the reaction time is 0.5 to 1.0 h.
4. The method for preparing the key precursor of teniposide according to claim 1, characterized in that: The selective protection of the hydroxyl group in step 2) is carried out by subjecting α-anhydrous glucose ester and trimethylsilyl chloride to a substitution reaction under alkaline conditions.
5. The method for preparing the key precursor of teniposide according to claim 4, characterized in that: The molar ratio of the α-anhydrous glucose ester, trimethylsilyl chloride and the base is 1:1.1-1.3:1.1-1.
5.
6. The method for preparing the key precursor of teniposide according to claim 4, characterized in that: The reaction temperature is 17-20° C., and the reaction time is 0.5-1.0 h.
7. The method for preparing the key precursor of teniposide according to claim 1, characterized in that: In step 3), the molar ratio of intermediate I, intermediate II and boron trifluoride is 1:1.0-1.2:1.1-1.
3.
8. The method for preparing the key precursor of teniposide according to claim 1, characterized in that: The reaction temperature of step 3) is -10 to -15°C, and the reaction time is 3.0 to 5.0 hours.
9. The method for preparing the key precursor of teniposide according to claim 1, characterized in that: In step 4), intermediate III is subjected to hydrogenolysis reaction under Pd / C / H2 conditions, the hydrogen pressure is 0.2-0.4 MPa, and the reaction time is 8.0-10.0 h.
10. The method for preparing the key precursor of teniposide according to claim 9, characterized in that: In step 4), the weight ratio of intermediate III to Pd / C is 29.3:0.8-1.2.