CN112521405A - Impurity compound of pemetrexed disodium - Google Patents
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Abstract
The invention belongs to the technical field of drug synthesis, and particularly relates to a pemetrexed disodium impurity compound; the method for synthesizing the pemetrexed disodium impurity compound comprises the following steps: adding SM-1, SM-2, a condensing agent and alkali into an organic solvent, controlling the temperature until the reaction is finished, cooling the reaction liquid to room temperature, filtering, extracting the extract, and collecting an organic phase to obtain pemetrexed disodium impurity H; the preparation method of the compound has mild reaction conditions, simple and convenient operation process, high purity and high yield; the compound can be used as an impurity reference substance for quality control of pemetrexed disodium in the production process.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a pemetrexed disodium impurity compound and a preparation method thereof.
Background
Pemetrexed is an antifolate preparation containing a pyrrole pyrimidine group as a core, and inhibits cell replication by destroying normal metabolic processes of intracellular folate dependence, thereby inhibiting tumor growth. In vitro studies have shown that pemetrexed inhibits the activity of thymidylate synthase, dihydrofolate reductase and glycinamide nucleotide formyltransferase, which are enzymes essential for the synthesis of folic acid, involved in the biological re-synthesis of thymine and purine nucleotides. The pemetrexed disodium is a multi-target antifolate, interferes folic acid necessary in the cell proliferation process to exert antiproliferative activity according to the metabolism resistant process, and has activity on various solid tumors. The chemical name of pemetrexed disodium is N- [4- [2- (2-amino-4, 7-dihydro-4-oxo-1H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethyl ] benzoyl ] -L-glutamic acid disodium salt, and the chemical formula is as follows:
the currently reported methods for synthesizing pemetrexed disodium are more, but most processes cannot achieve the effect of impurity removal. E.g., j.med.chem., 1992, 35 (23): 4450-4454, Org Process Res Dev.1999, 3: 181-188, Med.biol, 1993, 338: 387 to 408, Tetrahedron Lett.1999.40: 4023 to 4026; US patent applications US5028608, US5416211, US6013828, chinese patent applications CN200610024564.4, CN200710024889.7, CN 200710015438.7, CN200710166742.1 and the like. The crystallization method of the product is a method of dissolving in water and adding ethanol, isopropanol and the like for direct crystallization, and because impurities obtained in the synthesis process of pemetrexed disodium are dissolved in water under an alkaline condition like the product, and then anti-solvents such as ethanol, isopropanol and the like are added, the impurities are separated out together, and the effect of removing the impurities is basically not achieved. The pemetrexed disodium drug substance is already on the market, and known related substances of the drug, which are mentioned by the U.S. drug approval (USP) and European Union drug Standard (EP) and the like, include five related substances A, B, C, D, E and the like, namely process impurities (A and D), alkaline degradation impurities (B and C) and an optical isomer impurity E.
In addition, patent CN 106220634a reports that pemetrexed disodium is used as a raw material, and related substance F and related substance G are obtained by oxidation reaction with hydrogen peroxide.
In the process of research and development of new drugs, the quality of the drugs is an important standard for measuring the quality of the drugs, and the quality of the drugs is determined by the curative effect and the toxic and side effects of the drugs, namely the effectiveness and the safety of the drugs. The content of the effective components of the medicine is an important mark for reflecting the purity of the medicine, and impurities in the medicine directly influence the curative effect of the medicine and can cause toxic and side effects. The impurities of the medicine are other chemical substances except the introduced or generated medicine in the processes of production, storage and transportation, and the existence of the impurities not only affects the purity of the medicine, but also brings non-therapeutic active toxic and side effects and must be controlled. For safe and effective use of drugs, the quality standards of drugs have strict requirements on the purity of active ingredients of drugs and the limits of impurities, and generally, more than 0.1% of drug impurities should be identified and quantified by a selective method.
For drug developers, the main work is not only how to obtain high-quality drug Substances (APIs) and develop efficient synthesis processes, but also how to study the types and sources of impurities in the drug substances and how to control the generation of process impurities. Usually, researchers can firstly orient impurities generated in a synthesis process, and secondly develop an efficient impurity synthesis route so as to obtain a large amount of impurity reference substances and ensure the development of quality detection work (such as impurity HPLC positioning, impurity content measurement and the like) of each batch of raw material medicines.
From the above 7 related substances and the analysis of their production mechanism, the research did not involve the alkaline hydrolysis of amidation reaction product of pemetrexed intermediate and activated pemetrexed acid to obtain impurity H. The content of related impurities is high, the drug effect and the quality of the product are directly reduced, the generated impurities are not easy to remove, multiple refining is needed to ensure that the product quality meets the requirement, so that the yield is reduced, the production cost is improved, the industrial production is not facilitated, and the finally obtained pemetrexed disodium product is difficult to meet the standard of pharmacopeia. The research result of the impurity H has practical significance for improving the product quality and safety of the anti-tumor drug pemetrexed disodium, and the economic and social benefits of the drug can be better realized.
Therefore, the research and the provision of a synthesis method of the pemetrexed disodium impurity H are of great significance.
Disclosure of Invention
The invention aims to provide a pemetrexed disodium impurity compound H and a preparation method thereof on the basis of the existing quality standard of pemetrexed disodium.
The specific technical scheme of the invention is as follows:
an impurity compound H of pemetrexed disodium has a structural formula shown as follows:
a preparation method of pemetrexed disodium impurity H shown as a formula comprises the following steps:
adding SM-1, SM-2, a condensing agent and alkali into an organic solvent, controlling the temperature until the reaction is finished, adding an extraction liquid for extraction, collecting an organic phase, washing with purified water, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain pemetrexed disodium impurity H.
The reaction route is as follows:
preferably, the organic solvent in step (A) is one or a combination of dimethyl sulfoxide, tetrahydrofuran, N-dimethylformamide, N-methylpyrrolidone and toluene, wherein N, N-dimethylformamide is particularly preferred, and the added organic solvent is a reaction complete amount.
Preferably, the base in step (a) is one or a combination of Triethylamine (TEA), N-Diisopropylethylamine (DIPEA), pyridine, N-methylmorpholine, and particularly preferably Triethylamine (TEA).
Preferably, the condensing agent in the step (A) is one of N-hydroxyphthalimide, N '-carbonyldiimidazole, dicyclohexylcarbodiimide and 4-dimethylaminopyridine or a combination thereof, and N, N' -carbonyldiimidazole is particularly preferred.
Preferably, the feeding molar ratio of SM-1 to SM-2 in the step is 1: 1.1 to 1.5, wherein 1: 1.2.
preferably, the feeding molar ratio of the SM-1 to the alkali and the condensing agent in the step is 1: 1.5-2.0: 0.8 to 1.2, wherein a ratio of 1: 1.7: 1.
preferably, the extraction solvent in the step is one of dichloromethane/purified water, ethyl acetate/purified water, and chloroform/purified water, wherein dichloromethane/purified water is particularly preferred, and the added amount of the solvent is the extraction complete amount.
Preferably, the reaction temperature in the step is 0-50 ℃, wherein the reaction temperature is preferably 25-30 ℃.
The compound of formula H may be converted into pharmaceutically acceptable salts, solvates.
The compound shown in the formula H, and the salt or solvate thereof can be applied to detection of pemetrexed disodium intermediates, raw material medicines and/or preparations.
The structure of the compound of formula H obtained in the present invention was confirmed:
TABLE 11H-NMR spectrum data (detailed in FIG. 1) and assignment
Note: the type of the measuring instrument: bruker Avance 500MH nmr; solvent: DMSO-d6. Mass spectrometry data: ESI-MS (m/z): 765.40[ M + H]+. (see FIG. 2 for details)
Compared with the prior art, the invention has the following technical effects:
1. the method for synthesizing the impurity H of pemetrexed disodium is provided, the whole synthesis method is short in route, simple in operation steps, high in reaction yield and high in product purity;
2. a high purity pemetrexed disodium related impurity is provided, which can be used as an impurity reference substance for quality control of pemetrexed disodium in the production process.
Drawings
FIG. 1 shows the impurity H of pemetrexed disodium1H-NMR spectrum.
Fig. 2 is a mass spectrum of pemetrexed disodium impurity H.
Detailed Description
The invention is further illustrated by the following examples, which should be properly understood: the examples of the present invention are merely illustrative and not restrictive, and therefore, the present invention may be modified in a simple manner without departing from the scope of the invention as claimed. The starting materials for the reactions referred to in the examples are obtained commercially or by simple substitution of groups by known synthetic methods.
The following are examples of the preparation of the impurity compounds:
example 1
Adding SM-1(50.0g,0.168mol), N-carbonyl diimidazole (27.2g,0.168mol), triethylamine (28.90g,0.286mol) and SM-2(97.4g,0.202mol) into N, N-dimethylformamide (520mL), controlling the temperature at 25-30 ℃, stirring for reaction for 2h, and adding dichloromethane/purified water (V) after the reaction is finishedMethylene dichloride：VPurified water1: 1, 1000mL), collecting an organic phase, washing the organic phase twice with purified water, drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain pemetrexed disodium impurity H with the yield of 92.6 percent and the purity of 99.85 percent.
Example 2
Weighing SM-1(50.0g,0.168mol), N-carbonyldiimidazole (27.2g,0.168mol), triethylamine (28.0g,0.277mol) and SM-2(121.5g,0.252mol), adding into N, N-dimethylformamide (600mL), controlling the temperature at 25-30 ℃, stirring for reaction for 2h, and adding dichloromethane/purified water (V) after the reaction is finishedMethylene dichloride：VPurified water1: 1, 1000mL), collecting an organic phase, washing the organic phase twice with purified water, drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain pemetrexed disodium impurity H with the yield of 90.5 percent and the purity of 99.75 percent.
Example 3
Weighing SM-1(50.0g,0.168mol), N-carbonyldiimidazole (27.2g,0.168mol), triethylamine (28.0g,0.277mol) and SM-2(89.1g,0.185mol), adding into N, N-dimethylformamide (450mL), controlling the temperature at 25-30 ℃, stirring for reaction for 2h, and adding dichloromethane/purified water (V) after the reaction is finishedMethylene dichloride：VPurified water1: 1, 1000mL), collecting an organic phase, washing the organic phase twice with purified water, drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain pemetrexed disodium impurity H with the yield of 89.2 percent and the purity of 99.77 percent.
Example 4
Weighing SM-1(50.0g,0.168mol), N-carbonyldiimidazole (27.2g,0.168mol), triethylamine (28.0g,0.277mol) and SM-2(137.7g,0.288mol), adding into N, N-dimethylformamide (640mL), controlling the temperature at 25-30 ℃, stirring for reaction for 2h, and adding dichloromethane/purified water (V) after the reaction is finishedMethylene dichloride：VPurified water1: 1, 1000mL), collecting an organic phase, washing the organic phase twice with purified water, drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain pemetrexed disodium impurity H with the yield of 88.7 percent and the purity of 99.65 percent.
Example 5
Weighing SM-1(50.0g,0.168mol), N-carbonyldiimidazole (27.2g,0.168mol), triethylamine (28.0g,0.277mol) and SM-2(81.0g,0.168mol), adding into N, N-dimethylformamide (400mL), controlling the temperature at 25-30 ℃, stirring for reaction for 2h, and adding dichloromethane/purified water (V) after the reaction is finishedMethylene dichloride：VPurified water1: 1, 1000mL), collecting an organic phase, washing the organic phase twice with purified water, drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain pemetrexed disodium impurity H with the yield of 88.3 percent and the purity of 99.64 percent.
Example 6
Weighing SM-1(50.0g,0.168mol), N-carbonyldiimidazole (32.6g,0.202mol), triethylamine (34.0g,0.336mol) and SM-2(121.5g,0.252mol), adding into N, N-dimethylformamide (520mL), controlling the temperature at 25-30 ℃, stirring for reaction for 2h, and adding dichloromethane/purified water (V) after the reaction is finishedMethylene dichloride：VPurified water1: 1, 1000mL), collecting an organic phase, washing the organic phase twice with purified water, drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain pemetrexed disodium impurity H with the yield of 87.4 percent and the purity of 99.64 percent.
Example 7
Weighing SM-1(50.0g,0.168mol), N-carbonyldiimidazole (40.8g,0.252mol), triethylamine (28.90g,0.286mol) and SM-2(89.1g,0.185mol), adding into N, N-dimethylformamide (600mL), controlling the temperature at 25-30 ℃, stirring for reaction for 2h, and adding dichloromethane/purified water (V) after the reaction is finishedMethylene dichloride：VPurified water＝1：1，1000mL) And (3) extracting, collecting an organic phase, washing the organic phase twice with purified water, drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain pemetrexed disodium impurity H with the yield of 87.0% and the purity of 99.61%.
Example 8
Weighing SM-1(50.0g,0.168mol), N-hydroxyphthalimide (27.4g,0.168mol), N-diisopropylethylamine (37.0g,0.286mol) and SM-2(97.4g,0.202mol), adding tetrahydrofuran (450mL), controlling the temperature to be between 50 and 55 ℃, stirring for reaction for 1h, and adding ethyl acetate/purified water (V) after the reaction is finishedEthyl acetate：VPurified water2: 1, 1000mL), collecting an organic phase, washing the organic phase twice with purified water, drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain pemetrexed disodium impurity H with the yield of 84.2 percent and the purity of 99.55 percent.
Example 9
Weighing SM-1(50.0g,0.168mol), dicyclohexylcarbodiimide (34.7g,0.168mol), N-methylmorpholine (28.90g,0.286mol) and SM-2(97.4g,0.202mol), adding N-methylpyrrolidone (500mL), controlling the temperature at 10-15 ℃, stirring for reacting for 4h, and adding trichloromethane/purified water (V) after the reaction is finishedTrichloromethane：VPurified water3: 1, 1000mL), collecting an organic phase, washing the organic phase twice with purified water, drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain pemetrexed disodium impurity H with the yield of 84.5 percent and the purity of 99.57 percent.
Example 10
Weighing SM-1(50.0g,0.168mol), 4-dimethylaminopyridine (27.2g,0.168mol), pyridine (28.90g,0.286mol) and SM-2(97.4g,0.202mol), adding into dimethyl sulfoxide (550mL), controlling the temperature at 60-65 ℃, stirring for reacting for 2h, and adding ethyl acetate/purified water (V) after the reaction is finishedEthyl acetate：VPurified water2: 1, 1000mL), collecting an organic phase, washing the organic phase twice with purified water, drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain pemetrexed disodium impurity H with the yield of 84.7% and the purity of 99.56%.
Example 11
Weighing SM-1(50.0g,0.168mol) and N-hydroxyphthalimide (27.4g,0.168mol)Adding 28.90g of N-methylmorpholine (0.286 mol), 97.4g of SM-2 (0.202 mol) into toluene (600mL), controlling the temperature to be between 50 and 55 ℃, stirring and reacting for 2 hours, and adding trichloromethane/purified water (V) after the reaction is finishedTrichloromethane：VPurified water3: 1, 1000mL), collecting an organic phase, washing the organic phase twice with purified water, drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain pemetrexed disodium impurity H with the yield of 84.1 percent and the purity of 99.49 percent.
Example 12
Weighing SM-1(50.0g,0.168mol), N-carbonyldiimidazole (27.2g,0.168mol), triethylamine (28.90g,0.286mol) and SM-2(97.4g,0.202mol), adding into N, N-dimethylformamide (600mL), controlling the temperature at 45-50 ℃, stirring for reaction for 2h, and adding ethyl acetate/purified water (V) after the reaction is finishedEthyl acetate：VPurified water2: 1, 1000mL), collecting an organic phase, washing the organic phase twice with purified water, drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain pemetrexed disodium impurity H with the yield of 84.2 percent and the purity of 99.50 percent.
Claims (10)
1. An impurity compound of pemetrexed disodium is shown as a formula H, and the structural formula is as follows:
2. a process for the preparation of a compound according to claim 1, comprising the steps of:
adding SM-1, SM-2, a condensing agent and alkali into an organic solvent, controlling the temperature until the reaction is finished, adding an extraction liquid for extraction, collecting an organic phase, washing with purified water, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain pemetrexed disodium impurity H; the reaction route is as follows:
3. the method according to claim 2, wherein the organic solvent in step (a) is one or a combination of dimethyl sulfoxide, tetrahydrofuran, N-dimethylformamide, N-methylpyrrolidone and toluene.
4. The method according to claim 2, wherein the base in step (a) is one of triethylamine, N-diisopropylethylamine, pyridine, N-methylmorpholine, or a combination thereof.
5. The method according to claim 2, wherein the condensing agent in step (a) is one of N-hydroxyphthalimide, N-carbonyldiimidazole, dicyclohexylcarbodiimide, 4-dimethylaminopyridine, or a combination thereof.
6. The method according to claim 2, wherein the molar ratio of SM-1 to SM-2 fed in step (A) is 1: 1.1 to 1.5.
7. The method according to claim 2, wherein the molar ratio of SM-1 to the base and the condensing agent in step (A) is 1: 1.5-2.0: 0.8 to 1.2.
8. The method according to claim 2, wherein the extraction solvent in the step (A) is one of dichloromethane/purified water, ethyl acetate/purified water, and chloroform/purified water.
9. The compound of formula H according to claim 1, convertible into a pharmaceutically acceptable salt, solvate.
10. The use of a compound of formula H as defined in claim 1 and salts or solvates thereof for the detection of pemetrexed disodium intermediates, drug substances and/or formulations.
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