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Preparation method of pemetrexed disodium

A technology of pemetrexed disodium and pemetrexed acid, applied in the direction of organic chemistry, etc., can solve the problems of inability to realize industrial production, excessive N-methylation products, and decline in total yield, and achieve the purpose of inhibiting N-methylation The effect of minimizing the generation of impurities, overcoming cost increases, and improving total yield

Inactive Publication Date: 2014-10-29
NINGBO MENOVO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] In the prior art, there are many reports on the synthesis process of pemetrexed disodium. For example, Organic Process Research & Development (2005, 9, 738-742) reports a synthesis process in which excessive 2-chloro- 4,6-dimethoxy-1,3,5-triazine and N-methylmorpholine are prepared by a one-pot method, which will inevitably lead to the content of impurity N-methylated products being greater than 0.1%. To obtain The product needs to be salted out with p-toluenesulfonic acid, and then purified by recrystallization using a mixed solvent of dimethyl sulfoxide / ethanol. Realize industrial production
[0004] The Chinese invention patent application with publication number CN102344452A "New Method for Synthesizing Pemetrexed Disodium Salt" (application number: 201110204375.6) also discloses a new process, which also uses excessive 2-chloro-4,6- Dimethoxy-1,3,5-triazine and N-methylmorpholine are prepared by a one-pot cooking method. The impurity N-methylated product in the product exceeds the standard, and the product is further recrystallized and purified by ethanol. This method It will also lead to a decrease in the overall yield
[0005] The Taiwan patent application "Method for Manufacturing Pemetrexed" (Application No.: 099126443) with publication number TW201118098A1 also discloses a new process, which also uses excess 2-chloro-4,6-dimethoxy- 1,3,5-triazine and N-methylmorpholine are prepared by one-pot cooking method. The impurity N-methylation product in the product exceeds the standard, and it is further salted out with p-toluenesulfonic acid. This method will inevitably lead to The decline of the total yield cannot realize industrialized production

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  • Preparation method of pemetrexed disodium
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  • Preparation method of pemetrexed disodium

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Experimental program
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Effect test

Embodiment 1

[0032] The preparation method of the present embodiment pemetrexed disodium comprises the following steps:

[0033] (1) in N 2 Under protection, add 200mL tetrahydrofuran to a 500mL four-necked flask at 20°C, then continue to add 20g of N-methylmorpholine to the above-mentioned four-necked flask under stirring, continue to add 35g of 2-chloro-4 after stirring for 10min, 6-dimethoxy-1,3,5-triazine, reacted for 30min, filtered with suction, rinsed the obtained filter cake with 20mL tetrahydrofuran, filtered, dried the filter cake to obtain 46.38g 4-(4,6-dimethoxy- 1,3,5-triazin-2-yl)-4-methylmorpholine hydrochloride, spare;

[0034] (2) in N 2 Under protection, add 300mL of N,N-dimethylformamide to a 500mL three-necked flask, continue to add 50g of pemetic acid under stirring, then cool down to 0°C, and continue to add 46.38g of 4-(4,6-Dimethylformamide Methoxytriazin-2-yl)-4-methylmorpholine hydrochloride, reacted for 1h;

[0035] (3) Add 44g of L-diethyl glutamate hydrochl...

Embodiment 2

[0041] The preparation method of the present embodiment pemetrexed disodium comprises the following steps:

[0042] (1) in N 2 Under protection, add 200mL of dichloromethane to a 500mL four-necked flask at 22°C, then continue to add 45g of N-methylmorpholine to the above-mentioned four-necked flask under stirring, and continue to add 29.7g of 2-chloro -4,6-dimethoxy-1,3,5-triazine, reacted for 40min, filtered with suction, rinsed the resulting filter cake with 20mL of dichloromethane, dried the filter cake after filtering to obtain 39.4g4-(4,6- Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholine hydrochloride, spare;

[0043] (2) in N 2 Under protection, add 300mL N,N-dimethylacetamide to a 500mL three-necked flask, continue to add 50g of pemetic acid under stirring, then cool down to 1°C, and continue to add 39.4g of 4-(4,6-Dimethylacetamide Methoxy-1,3,5-triazin-2-yl)-4-methylmorpholine hydrochloride, reacted for 1.5h;

[0044] (3) Add 50 g of L-diethyl glutamate hydrochlor...

Embodiment 3

[0049] The preparation method of the present embodiment pemetrexed disodium comprises the following steps:

[0050] (1) in N 2 Under protection, add 200mL of ethyl acetate to a 500mL four-necked flask at 24°C, then continue to add 50g of N-methylmorpholine to the above-mentioned four-necked flask under stirring, and continue to add 37g of 2-chloro- 4,6-dimethoxy-1,3,5-triazine, reacted for 50min, filtered with suction, rinsed the obtained filter cake with 20mL ethyl acetate, dried the filter cake after filtering to obtain 49g of 4-(4,6-dimethyl Oxy-1,3,5-triazin-2-yl)-4-methylmorpholine hydrochloride, spare;

[0051] (2) in N 2 Under protection, add 300mL dimethyl sulfoxide to a 500mL three-necked flask, continue to add 50g of pemetic acid under stirring, then lower the temperature to 2°C, and continue to add 49g of 4-(4,6-dimethoxy-1 ,3,5-triazin-2-yl)-4-methylmorpholine hydrochloride, reacted for 1.2h;

[0052] (3) Add 65g of L-diethyl glutamate hydrochloride to the reac...

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Abstract

The invention discloses a preparation method of pemetrexed disodium, which can directly hydrolyzing into salt after an organic solvent is removed, rather than salifying together with p-toluenesulfonic acid and / or purifying a product by adopting a crystallization method during the preparation process, thus omitting the step of salifying together with p-toluenesulfonic acid and / or crystallization through ethanol, effectively improving the total yield of drugs to 68-75%; in the preparation process, a peptide condensing agent is firstly prepared and is fully reacted with pemedolac in the organic solvent into transient-state acid ester, so that the generation of N-methylation impurities can be effectively inhibited in the reaction together with L-glutamic acid diethyl ester hydrochloride, the defect that the content of N-methylation impurities during the one-pot preparation process in the prior art exceeds 0.1% can be avoided, the advantages for opening up Europe and America markets can be brought, the defect that the raw materials are not reacted thoroughly to cause high cost can also be overcome; the HPLC (High Performance Liquid Chromatograph) of the finished pemetrexed disodium obtained by adopting the method is more than or equal to 99.8%, and the content of single impurities is less than 0.1%.

Description

technical field [0001] The invention relates to a preparation method of pemetrexed disodium. Background technique [0002] Pemetrexed disodium is the active ingredient contained in the pharmaceutical specialty Alimta, which is a new type of folic acid anti-tumor compound widely used in the treatment of non-small cell lung cancer (NSCLC) and malignant pleural mesothelioma , and is under investigation for the treatment of other tumor pathologies. Alimta mainly acts on the DNA base synthetase system, and blocks the DNA synthesis of tumor cells by designing a variety of DNA base synthetases, so as to achieve the purpose of inhibiting and eliminating tumor cells. It effectively solves the problem of tumors in clinical treatment. The problem of drug resistance to anticancer drugs is a representative new drug in the current anticancer drug research. Pemetrexed disodium belongs to the class of multitargeted antifolates, that is, those antineoplastic active ingredients that act at ...

Claims

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Application Information

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IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 林祖峰赵成磊刘涛姚成志
Owner NINGBO MENOVO PHARMA
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