Synthesis method of pemetrexed disodium
By using T4P as a condensant and acetonitrile single solvent system for purification, the existing pemetrexed disodium synthesis method is solved and the problems of complexity and difficulty in removing impurities are achieved, efficient purification of intermediates and improved reaction yield, and production costs are reduced.
Patent Information
- Application Number
- CN202411956224.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-28
- Publication Date
- 2025-05-06
AI Technical Summary
The existing synthesis method of pemetrexed disodium is complex, using expensive DMTMM and generating a large number of by-products, making it difficult to effectively remove impurities of opposite configurations, resulting in the intermediate not meeting the raw material standards.
The lower-cost T4P is used as a condensing agent, and the crude product of the intermediate is refined through a single solvent system of acetonitrile to remove impurities in opposite configurations, and the disodium pemetrexed is obtained through salt-forming reaction, which avoids the introduction of new solvents and improves the removal efficiency and reaction yield.
The process route is simplified, the purity and reaction yield of the intermediates are improved, the cost is reduced, and pollution is reduced through continuous design is improved, and the production efficiency is improved.
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Figure CN119930628A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to the technical field of raw material drug synthesis and intermediate synthesis, and in particular to a method for synthesizing pemetrexed disodium. Background Art
[0002] Pemetrexed disodium is a tumor treatment drug successfully developed by Eli Lilly and Company in the United States. It is a multi-target antifolate preparation with a core pyrrolopyrimidine group in its structure. It is a dual inhibitor of nucleotide synthase / dihydrofolate reductase. It inhibits cell replication by destroying the normal metabolic process of intracellular folate dependence. It can simultaneously block three different enzyme targets that are essential for the survival of cancer cells, thereby inhibiting tumor growth. In February 2004, the U.S. Food and Drug Administration (FDA) approved the combination with cisplatin to treat a rare cancer - malignant pleural mesothelioma. Malignant pleural mesothelioma is a rare lung pleural cancer. Pemetrexed disodium can interfere with cancer cell replication and further promote tumor cell apoptosis by blocking the unique mechanism of three key enzymes in cancer cell metabolism. This treatment plan is a synergistic inhibitory effect of three targets, which is better than the single-target treatment plan using cisplatin in the past. At the same time, supplementing folic acid and vitamins can effectively control toxic and side effects and enhance patient tolerance. In August 2004, the FDA approved pemetrexed disodium as a second-line treatment for locally advanced lung cancer or metastatic non-small cell lung cancer through fast-track approval. In December 2005, pemetrexed disodium was launched in China as a patented drug of Eli Lilly and Company and was approved for the treatment of malignant pleural mesothelioma. The chemical name of pemetrexed disodium is (S)-2-(4-(2-(2-amino-4-oxo-4,7-dihydro-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl)benzoylamino)-2-methyl glutaric acid sodium.
[0003] Currently, the preparation of pemetrexed disodium is mainly prepared by the following two methods:
[0004] ① Method 1: Use expensive DMTMM to synthesize the crude intermediate 3, dry the crude 3, and then purify it with DMF / tetrahydrofuran to obtain 3. After drying again, 3 is hydrolyzed with sodium hydroxide to obtain the crude 4, and the crude 4 is further purified to obtain 4. The whole process is complicated, DMTMM is expensive, the condensation reaction system is complicated, a large number of by-products are generated, the reaction time is long, and it is not easy to remove the opposite configuration impurities (greater than the limit of 0.1%) with DMF / tetrahydrofuran during the post-treatment process, and the standard requirements for the API intermediate cannot be met. Therefore, this process is not conducive to the production of APIs.
[0005] ②Method 2: Use expensive DMTMM to synthesize the crude intermediate 3. The crude 3 needs to be dried, and then the crude 3 is refined by DMF / acetone to obtain 3. After 3 is dried again, it is hydrolyzed by sodium hydroxide to obtain the crude 4, and the crude 4 is refined to obtain 4. The whole process is complicated, DMTMM is expensive, the condensation reaction system is complicated, a large number of by-products are generated, the reaction time is long, and DMF / acetone is not easy to remove the opposite configuration impurities (greater than the limit of 0.1%) during the post-treatment process, which cannot meet the standard requirements of the API intermediate. Therefore, this process is not conducive to the production of APIs. Among them, the structural formula of the opposite configuration impurity is as follows:
[0006] Summary of the invention
[0007] The object of the present invention is to provide a method for synthesizing pemetrexed disodium in view of the above-mentioned problems.
[0008] The present invention provides a method for synthesizing pemetrexed disodium, comprising the following steps:
[0009] 1) Under nitrogen protection, add acetonitrile purified water into the reaction bottle, add 1, stir, add potassium hydroxide aqueous solution using a dropping bottle, add condensation agent using a dropping bottle, then take a sample of 1 ml to prepare a control solution:
[0010] 2) Add triethylamine and dropwise add the aqueous solution of 2;
[0011] 3) After the addition is complete, the temperature of the reaction system is maintained at 20-25°C and the reaction is stirred for 2.5-4.0 hours. The reaction is terminated when the active ester intermediate state does not exceed 3%;
[0012] 4) Control the system temperature at 20-25°C, use a dropping bottle to add purified water to the system to crystallize, and control the dropping time to 0.5-1h. After the dropping is completed, cool to 5-10°C, control the temperature at 5-10°C and stir for 1-1.5h;
[0013] 5) After the insulation is completed, the system is placed in a suction filtration funnel for suction filtration until no liquid flows out, and the filter cake is rinsed three times with purified water;
[0014] 6) Put the filtered "crude product of 3" into a flat oven, control the vacuum degree ≤-0.09MPa, heat to 30-50℃ and dry, collect the material when the moisture content is ≤4.0%, weigh the collected material after it is qualified, and obtain the crude product of 3;
[0015] 7) Under nitrogen protection, acetonitrile and purified water were added to the reaction flask; the crude product of 3 was added to the reaction flask, and the heating was turned on to raise the temperature of the system to 40-45°C, and the system was stirred until it was dissolved, and then the temperature was controlled at 40-45°C, and purified water was added dropwise for crystallization. When the system became turbid or a small amount of solid precipitated, the addition was stopped, and the crystal was grown by stirring at the temperature for about 2h±30min, and then the remaining amount of purified water was added dropwise for 2-3h;
[0016] 8) Cool the system to 23-27°C and stir to crystallize for 1-2 hours;
[0017] 9) The crystallized system was placed in a suction funnel for suction filtration until no liquid flowed out, and the filter cake was rinsed with the mixed solution each time, twice in total, and centrifuged for 0.5-1.0h to dryness to obtain "wet product 3", the structural formula of 3 is as follows:
[0018] ;
[0020] 10) Under nitrogen protection, add 1N sodium hydroxide solution to the reaction bottle, start stirring, open the reaction bottle, add the whole amount of 3 in the previous step, and start stirring;
[0021] 11) Control the system temperature at 20-25°C, stir for about 30 minutes until the system is dissolved and clear, and take the reaction solution directly without dilution. Sample name: 4 crude reaction solution, until the reaction is completed;
[0022] 12) Add 2 mol / L hydrochloric acid solution dropwise to the reaction system and adjust the pH to 10.5-11.0. After the pH is adjusted, control the temperature and stir for 5-10 minutes to confirm that the pH is within the range;
[0023] 13) Filter the reaction solution, rinse once with purified water, and transfer the filtrate to a reaction bottle;
[0024] 14) Control the system temperature at 20-25°C, and slowly add saturated sodium chloride solution to the reaction system under nitrogen protection; stop adding when the system becomes turbid or a small amount of solid precipitates, stir for 30-40 minutes, and then add the remaining saturated sodium chloride solution; after the addition is completed, start cooling to 5-10°C, and keep stirring for 2-2.5 hours;
[0025] 15) After the insulation is completed, the system is filtered until no liquid flows out. A 23% sodium chloride solution is prepared in the reaction flask. After cooling to 0℃~10℃, the filter cake is washed three times and centrifuged until no liquid flows out. The reaction flask is prepared. After cooling to -5℃~5℃, the filter cake is washed three times and centrifuged until no liquid flows out. Centrifuge for 0.5~1.0h to dryness to obtain "4 crude wet products";
[0026] 16) Under nitrogen protection, add purified water to the reaction bottle, start stirring, open the reaction bottle and put all the "4 crude wet products" into the reactor, heat the system to 40-45°C to dissolve, after the system is dissolved, cool the system to 20-25°C, and control the temperature at 20-25°C to add a small amount of 1N sodium hydroxide solution, adjust the pH to 9.2-9.6, after the pH is adjusted, control the temperature at 20-25°C and stir for 5-10 minutes, re-measure the pH at 9.2-9.6, then filter the system, rinse the reaction bottle once with purified water, filter to dryness, and transfer the filtrate to the reaction bottle;
[0027] 17) Control the system temperature at 20-25°C, and use a dropping bottle to drop isopropanol for crystallization: stop dropping when the system becomes turbid or a small amount of solid precipitates, stir for 30-40 minutes, and then drop the remaining isopropanol, and control the dropping time to 60-90 minutes; after the dropping is completed, cool the system to 5-10°C, and keep it warm and stir for 2-2.5 hours;
[0028] 18) Filter the system by suction until no liquid flows out, and rinse the filter cake with isopropanol until no liquid flows out, and finally rinse the filter cake with isopropanol again and filter it by suction until dry to obtain "4 wet products";
[0029] 19) Put the filtered "4 wet products" into a tray, open the vacuum valve, control the vacuum degree ≤-0.09MPa, heat to 30-40℃ and dry, collect the material when the moisture content is 15.0-22.1%. If the moisture content is unqualified, continue to dry the material for one hour and resample the moisture content. Collect the material when it is qualified. The structural formula of 4 is as follows:
[0030]
[0031] In some embodiments, the condensing agent is one of DMTMM and T4P, and the structural formula of T4P is as follows:
[0032]
[0033] In some embodiments, it is characterized in that the purification solvent is acetonitrile / water.
[0034] Compared with the prior art, the beneficial effects of the present invention are:
[0035] The invention provides a novel process route for synthesizing and purifying a pemetrexed disodium intermediate. The process comprises the following steps: firstly using relatively low-cost and stable T4P as a reaction condensation agent, then refining a crude product by using an acetonitrile single solvent system, thereby removing impurities of opposite configuration, and then obtaining the pemetrexed disodium through a salt-forming reaction. The process avoids the introduction of a new solvent, and at the same time improves the impurity removal efficiency, thereby improving the reaction yield. In addition, a continuous design is adopted in the process, thereby reducing pollution, improving the yield and reducing the cost. BRIEF DESCRIPTION OF THE DRAWINGS
[0036] Figure 1 It is the existing synthetic purification route 1 of pemetrexed disodium;
[0037] Figure 2 This is the synthesis and purification route 2 of pemetrexed disodium in the background technology of the present invention;
[0038] Figure 3 The HPLC spectrum of the pemetrexed disodium intermediate 3 in the current market background technology;
[0039] Figure 4 This is the HPLC spectrum of pemetrexed disodium intermediate 3 in one embodiment of the present invention. DETAILED DESCRIPTION
[0040] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and are not intended to limit the scope of the present invention. In addition, it should be understood that after reading the content taught by the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms fall within the scope limited by the appended claims of the application equally.
[0041] Embodiment 1, as Figure 2 As shown:
[0042] 1) Under nitrogen protection, add acetonitrile purified water into the reaction bottle, add 1, stir, add potassium hydroxide aqueous solution using a dropping bottle, add condensation agent using a dropping bottle, then take a sample of 1 ml to prepare a control solution:
[0043] 2) Add triethylamine and dropwise add the aqueous solution of 2;
[0044] 3) After the addition is completed, the reaction system temperature is maintained at 20°C, and the reaction is stirred for 4.0 hours. If the active ester intermediate state does not exceed 3%, the reaction can be terminated;
[0045] 4) Control the system temperature at 25°C, use a dropping bottle to add purified water to the system to crystallize, and control the dropping time at 0.5. After the dropping is completed, cool to 10°C and control the temperature at 5°C and stir for 1.5h.
[0046] 5) After the insulation is completed, the system is placed in a suction filtration funnel for suction filtration until no liquid flows out, and the filter cake is rinsed three times with purified water.
[0047] 6) Put the filtered "crude product of 3" into a flat oven, control the vacuum degree ≤-0.09MPa, heat to 50℃ and dry, collect the material when the moisture content is ≤4.0%, weigh the collected material after it passes the test, and obtain the crude product of 3.
[0048] 7) Under nitrogen protection, add acetonitrile and purified water into the reaction flask; put the crude product of 3 into the reaction flask, turn on the heating, raise the temperature of the system to 45°C, stir until dissolved, control the temperature at 45°C, add purified water dropwise for crystallization, stop adding when the system becomes turbid or a small amount of solid precipitates, keep warm and stir to grow the crystal for about 2hmin, then continue to add the remaining amount of purified water dropwise, and finish adding it in 2h.
[0049] 8) The system was cooled to 23°C and stirred for crystallization for 2 h.
[0050] 9) Put the crystallized system into a suction funnel for suction filtration until no liquid flows out. Rinse the filter cake with the mixed solution twice each time, centrifuge for 0 h to dryness, and obtain the "wet product 3".
[0051]
[0052] 10) Under nitrogen protection, add 1N sodium hydroxide solution to the reaction bottle, start stirring, open the reaction bottle, add the entire amount of 3 from the previous step, and start stirring.
[0053] 11) Control the system temperature at 25°C, stir for about 30 minutes until the system is clear, and take the reaction solution directly without dilution. Sample name: 4 crude reaction solution, until the reaction is complete.
[0054] 12) Add 2 mol / L hydrochloric acid solution dropwise to the reaction system and adjust the pH to 11.0. After the pH is adjusted, control the temperature and stir for min to confirm that the pH is within the range.
[0055] 13) Filter the reaction solution, rinse once with purified water, and transfer the filtrate to a reaction bottle.
[0056] 14) Control the system temperature at 25°C, and slowly add saturated sodium chloride solution to the reaction system under nitrogen protection; stop adding when the system becomes turbid or a small amount of solid precipitates, stir for 3 minutes, and then add the remaining saturated sodium chloride solution; after the addition is completed, start cooling to 5°C, and keep stirring for 2.5 hours.
[0057] 15) After the insulation is completed, the system is filtered until no liquid flows out. A 23% sodium chloride solution is prepared in the reaction flask. After cooling to 0°C, the filter cake is washed three times and centrifuged until no liquid flows out. The reaction flask is prepared. After cooling to -5°C, the filter cake is washed three times and centrifuged until no liquid flows out. Centrifuge for 1.0h to dryness to obtain "4 crude wet products".
[0058] 16) Under nitrogen protection, add purified water to the reaction bottle, start stirring, open the reaction bottle and put all the "4 crude wet products" into the reactor, heat the system to 45°C to dissolve, after the system is dissolved, cool the system to 25°C, and control the temperature at 25°C to add a small amount of 1N sodium hydroxide solution, adjust the pH to 9.6, after the pH is adjusted, control the temperature at 25°C and stir for 5 minutes, re-measure the pH at 9.2, then filter the system, rinse the reaction bottle once with purified water, filter to dryness, and transfer the filtrate to the reaction bottle.
[0059] 17) Control the system temperature at 20°C and use a dropping bottle to add isopropanol for crystallization: stop adding when the system becomes turbid or a small amount of solid precipitates, stir for 40 minutes, and then add the remaining isopropanol, and control the addition time to 90 minutes; after the addition is completed, cool the system to 10°C and keep it warm and stirred for 2 hours.
[0060] 18) The system is filtered until no liquid flows out, and the filter cake is rinsed with isopropanol until no liquid flows out. Finally, the filter cake is rinsed with isopropanol again and filtered until dry to obtain "4 wet products".
[0061] 19) Put the filtered "4 wet products" into the tray, open the vacuum valve, control the vacuum degree ≤-0.09MPa, heat to 30℃ and dry, collect the material when the moisture content is 22.1%. If the moisture content is unqualified, continue to dry the material for one hour and resample the moisture content. Figure 4 As shown, the material will be collected after passing the test.
[0062]
[0063] The embodiment of the present invention provides a new process route for synthesizing and purifying a pemetrexed disodium intermediate, wherein relatively low-cost and stable T4P is first used as a reaction condensation agent, and then a crude product is refined by using an acetonitrile single solvent system to remove impurities of opposite configuration, and then pemetrexed disodium is obtained through a salt-forming reaction. This process avoids the introduction of new solvents, while improving the impurity removal efficiency and the reaction yield, and adopts a continuous design in the process, thereby reducing pollution, improving the yield and reducing the cost.
[0064] Finally, it should be noted that: technicians in this industry should understand that the present invention is not limited to the above-mentioned implementation cases. The above-mentioned embodiments and descriptions are only for explaining the principles of the present invention. Without departing from the spirit and scope of the present invention, the present invention may have various changes and improvements, which shall fall within the scope of the present invention to be protected. The scope of protection of the present invention is defined by the attached claims and their equivalents.
Claims
1. A method for synthesizing pemetrexed disodium, characterized in that: The following steps are involved: 1) Under nitrogen protection, add acetonitrile purified water into the reaction bottle, add 1, stir, add potassium hydroxide aqueous solution using a dropping bottle, add condensation agent using a dropping bottle, then take a sample of 1 ml to prepare a control solution: 2) Add triethylamine and dropwise add the aqueous solution of 2; 3) After the addition is complete, the temperature of the reaction system is maintained at 20-25°C and the reaction is stirred for 2.5-4.0 hours. The reaction is terminated when the active ester intermediate state does not exceed 3%; 4) Control the system temperature at 20-25°C, use a dropping bottle to add purified water to the system to crystallize, and control the dropping time to 0.5-1h. After the dropping is completed, cool to 5-10°C, control the temperature at 5-10°C and stir for 1-1.5h; 5) After the insulation is completed, the system is placed in a suction filtration funnel for suction filtration until no liquid flows out, and the filter cake is rinsed three times with purified water; 6) Put the filtered "3 crude product" wet product into a flat oven, control the vacuum degree ≤-0.09MPa, heat to 30-50℃ and dry, collect the material when the moisture content is ≤4.0%, weigh the collected material after it is qualified, and obtain the 3 crude product; 7) Under nitrogen protection, acetonitrile and purified water were added to the reaction flask; the crude product of 3 was added to the reaction flask, and the heating was turned on to raise the temperature of the system to 40-45°C, and the system was stirred until it was dissolved, and then the temperature was controlled at 40-45°C, and purified water was added dropwise for crystallization. When the system became turbid or a small amount of solid precipitated, the addition was stopped, and the crystal was grown by stirring at the temperature for about 2h±30min, and then the remaining amount of purified water was added dropwise for 2-3h; 8) Cool the system to 23-27°C and stir to crystallize for 1-2 hours; 9) The crystallized system was placed in a suction funnel for suction filtration until no liquid flowed out, and the filter cake was rinsed with the mixed solution each time, for a total of two rinses, and centrifuged for 0.5-1.0h to dryness to obtain "wet product 3", the structural formula of 3 is as follows: 10) Under nitrogen protection, add 1N sodium hydroxide solution to the reaction bottle, start stirring, open the reaction bottle, add the whole amount of 3 in the previous step, and start stirring; 11) Control the system temperature at 20-25°C, stir for about 30 minutes until the system is dissolved and clear, and take the reaction solution directly without dilution. Sample name: 4 crude reaction solution, until the reaction is completed; 12) Add 2 mol / L hydrochloric acid solution dropwise to the reaction system and adjust the pH to 10.5-11.
0. After the pH is adjusted, control the temperature and stir for 5-10 minutes to confirm that the pH is within the range; 13) Filter the reaction solution, rinse once with purified water, and transfer the filtrate to a reaction bottle; 14) Control the system temperature at 20-25°C, and slowly add saturated sodium chloride solution to the reaction system under nitrogen protection; stop adding when the system becomes turbid or a small amount of solid precipitates, stir for 30-40 minutes, and then add the remaining saturated sodium chloride solution; after the addition is completed, start cooling to 5-10°C, and keep stirring for 2-2.5 hours; 15) After the insulation is completed, the system is filtered until no liquid flows out. A 23% sodium chloride solution is prepared in the reaction flask. After cooling to 0℃~10℃, the filter cake is washed three times and centrifuged until no liquid flows out. The reaction flask is prepared. After cooling to -5℃~5℃, the filter cake is washed three times and centrifuged until no liquid flows out. Centrifuge for 0.5~1.0h to dryness to obtain "4 crude wet product"; 16) Under nitrogen protection, add purified water to the reaction flask, start stirring, open the reaction flask and put all the "4 crude wet products" into the reactor, heat the system to 40-45°C to dissolve, after the system is dissolved, cool the system to 20-25°C, and control the temperature at 20-25°C to add a small amount of 1N sodium hydroxide solution, adjust the pH to 9.2-9.6, after the pH is adjusted, control the temperature at 20-25°C and stir for 5-10 minutes, re-measure the pH at 9.2-9.6, then filter the system, rinse the reaction flask once with purified water, filter to dryness, and transfer the filtrate to the reaction flask; 17) Control the system temperature at 20-25°C, and use a dropping bottle to drop isopropanol for crystallization: stop dropping when the system becomes turbid or a small amount of solid precipitates, stir for 30-40 minutes, and then drop the remaining isopropanol, and control the dropping time to 60-90 minutes; after the dropping is completed, cool the system to 5-10°C, and keep it warm and stir for 2-2.5 hours; 18) Filter the system by suction until no liquid flows out, and rinse the filter cake with isopropanol until no liquid flows out, and finally rinse the filter cake with isopropanol again and filter it by suction until dry to obtain "4 wet products"; 19) Put the filtered "4 wet products" into a tray, open the vacuum valve, control the vacuum degree ≤-0.09MPa, heat to 30-40℃ and dry, collect the material when the moisture content is 15.0-22.1%. If the moisture content is unqualified, continue to dry the material for one hour and resample the moisture content. Collect the material when it is qualified. The structural formula of 4 is as follows:
2. The synthesis method according to claim 1, characterized in that The condensing agent is one of DMTMM and T4P, and the structural formula of T4P is as follows:
3. The synthesis method according to claim 1, characterized in that The purification solvent is acetonitrile / water.