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Pemetrexed-N,N-dibenzylethylenediamine salt and preparation method thereof

A technology of dibenzylethylenediamine salt and pemetrexed diacid is applied in the field of pemetrexed-N,N-dibenzylethylenediamine salt and preparation thereof, and can solve the problems of poor drug stability and preparation process. Complex problems, to achieve good stability, simple and reasonable steps

Active Publication Date: 2015-08-05
NINGBO MENOVO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Although many studies have been done on pemetrexed and its compounds in the prior art, and some salts of pemetrexed have been provided as clinical drugs, but the previous drugs often have problems such as poor stability and complicated preparation process.

Method used

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  • Pemetrexed-N,N-dibenzylethylenediamine salt and preparation method thereof
  • Pemetrexed-N,N-dibenzylethylenediamine salt and preparation method thereof
  • Pemetrexed-N,N-dibenzylethylenediamine salt and preparation method thereof

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Embodiment 1

[0031] In this embodiment, the preparation method of pemetrexed-N,N-dibenzylethylenediamine salt comprises the following steps:

[0032] (1)N 2 Under protection, put 5.0g of pemetrexed disodium heptahydrate into a 250mL four-neck flask filled with 100mL of purified water, and stir at 20°C until completely dissolved;

[0033] (2) in N 2 Under protection, add 26mL of acetic acid aqueous solution with a volume concentration of 23% to the system of step (1), and the aqueous acetic acid solution will be dripped within 30 minutes; the temperature of the control system is 20 ° C, and the reaction is stirred for 1 hour; Wash the filter cake with purified water and drain it twice, each time using 25 mL of purified water, then rinse the filter cake with absolute ethanol and drain it twice, each time using 10 mL of absolute ethanol; The filter cake was vacuum-dried at 40°C for 12 hours to obtain pemetrexed diacid;

[0034] (3) in N 2 Under protection, get the pemetrexed diacid that 3...

Embodiment 2

[0038] In this embodiment, the preparation method of pemetrexed-N,N-dibenzylethylenediamine salt comprises the following steps:

[0039] (1)N 2 Under protection, put 5.0g of pemetrexed disodium heptahydrate into a 250mL four-neck flask filled with 100mL of absolute ethanol, and stir at 35°C until completely dissolved;

[0040] (2) in N 2 Under protection, add 52mL of ethanol acetate solution with a volume concentration of 23% to the system of step (1), and the ethanol acetate solution will be dripped within 30min; the temperature of the control system is 35°C, and the reaction is stirred for 1.5h; Filter, rinse the filter cake with purified water and drain it twice, each time the amount of purified water is 25mL, then use absolute ethanol to rinse the filter cake and drain it twice, each time the amount of absolute ethanol is 10mL ; The obtained filter cake was vacuum-dried at 45° C. for 16 hours to obtain pemetrexed diacid;

[0041] (3) in N 2 Under protection, get the pe...

Embodiment 3

[0044]In this embodiment, the preparation method of pemetrexed-N,N-dibenzylethylenediamine salt comprises the following steps:

[0045] (1)N 2 Under protection, put 5.0 g of pemetrexed disodium heptahydrate into a four-necked flask filled with 100 mL of 50% ethanol aqueous solution, and stir at 25°C until completely dissolved;

[0046] (2) in N 2 Under protection, add 78mL of acetic acid aqueous solution with a volume concentration of 23% to the system of step (1), and the aqueous acetic acid solution will be dripped within 30min; the temperature of the control system is 25°C, and the reaction is stirred for 1.2h; after the reaction is completed, suction filtration, Rinse the filter cake with purified water and drain it twice, each time using 25 mL of purified water, then rinse the filter cake with absolute ethanol and drain it twice, each time using 10 mL of absolute ethanol; The resulting filter cake was vacuum-dried at 42°C for 14 hours to obtain pemetrexed diacid;

[00...

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Abstract

The invention relates to a pemetrexed-N,N-dibenzylethylenediamine salt and a preparation method thereof. The chemical name of the pemetrexed-N,N-dibenzylethylenediamine salt is N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]-pyrimidyl-5-yl)ethyl]benzoyl]-L-glutamic acid-N,N-dibenzylethylenediamine salt. The pemetrexed-N,N-dibenzylethylenediamine salt has favorable stability, can exist in the form of an anhydrous substance or hydrate. The pemetrexed-N,N-dibenzylethylenediamine salt is not reported in the prior art, thereby providing new options for research of pemetrexed preparation formulations. The preparation method has the advantage of simple and reasonable steps. The HPLC (high performance liquid chromatography) of the obtained product is greater than or equal to 99.70%, the single impurity content is less than 0.1%, and the total mol yield is up to 75-80%.

Description

technical field [0001] The invention relates to a pemetrexed-N,N-dibenzylethylenediamine salt and a preparation method thereof. Background technique [0002] Pemetrexed, a folic acid antagonist, is the world's first and currently only drug for the treatment of malignant pleural mesothelioma. At present, some progress has been made in the research on pemetrexed in the treatment of non-small cell lung cancer. The research structure shows that pemetrexed is very likely to become the first-line drug for the treatment of NSCLC. [0003] At present, the main dosage form of pemetrexed is disodium salt. U.S. Patent No. 5,344,932 discloses the compound patent of pemetrexed and its medicinal salt. The preparation method of pemetrexed disodium salt is also disclosed in U.S. Patent No. 6,013,828 . At home, the Chinese patent "Pemetrexed Salt and Its Preparation Method" (Application No.: CN03138056.5) with publication number CN1552713A discloses a method using pemetrexed divalent metal...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61P35/00
CPCC07D487/04
Inventor 林祖峰刘涛施良群姚成志
Owner NINGBO MENOVO PHARMA
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