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Preparation method of pemetrexed disodium

A technology of pemetrexed disodium and dihydrogen, which is applied in the field of new preparation of pemetrexed disodium, can solve the problems of many steps and increased product cost, and achieve the effects of avoiding oxidation, high product purity and reducing cost

Active Publication Date: 2013-02-06
DEZHOU DEYAO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are many steps in this method, resulting in an increase in product cost

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] (1). Synthesis of 4-[2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid ( S-2)

[0038] Reaction formula:

[0039]

[0040] Feeding:

[0041] 4-[2-(2-Amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid methyl ester (S-1 ) 58.4g

[0042] 2mol / L sodium hydroxide 200ml

[0043] Ethanol 200ml

[0044]Add 58.4g of S-1 and 200ml of 2mol / l sodium hydroxide into the three-neck flask, stir and react at 45°C for 3 hours, TLC detects that the raw material point basically disappears as the end of the reaction (developing agent: ethyl acetate:cyclohexane=4:1) . Add 200ml of ethanol, adjust the pH of the reaction solution to 4 with 5mol / L hydrochloric acid under water cooling, and precipitate a yellow solid, filter it, wash it with 50% ethanol, and dry it under vacuum at 50°C for 5 hours to obtain 40.6g of a light yellow solid 4-[2- (2-Amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid (S-2), yiel...

Embodiment 2

[0068] In Example 1, except that the ratio of ethanol and dimethyl sulfoxide used in steps 4 and 5 was adjusted to 10:1.9, the rest were the same as in Example 1 to obtain 22.0 g of pemetrexed disodium two and a half The crystallization of the hydrate has a yield of 80.9%, and the HPLC purity of the product is 99.6%.

Embodiment 3

[0070] In Example 1, except that the ratio of ethanol and dimethyl sulfoxide used in steps 4 and 5 was adjusted to 10:2.5, the rest were the same as in Example 1 to obtain 22.1 g of pemetrexed disodium two and a half The crystallization of the hydrate has a yield of 81.2%, and the HPLC purity of the product is 99.4%.

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Abstract

The invention provides a preparation method of pemetrexed disodium, which comprises the steps of performing hydrolysis reaction of 4-[2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl] methyl benzoate in sodium hydroxide to generate acid, then condensing with L-glutamic acid diethyl ester to obtain N-[4-[2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid diethyl ester toluenesulfonate, obtaining the crude pemetrexed disodium through saponification under the action of sodium hydroxide, and finally crystallizing in a mixed solvent at room temperature to obtain the end product. With the adoption of the technical scheme, the purification and purification of the crude pemetrexed disodium can be directly performed, so that the cost can be effectively lowered. As the steps are carried out at room temperature, the oxidation of the pemetrexed disodium caused by high temperature can be effectively avoided. The purity of the end product is high and meets the national requirement on purity of chemicals.

Description

technical field [0001] The invention relates to a new preparation method of pemetrexed disodium. Background technique [0002] Pemetrexed disodium (Pemetrexed disodium), the chemical name is N-(4-[2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrole[2,3-d]pyrimidine) -5-yl)ethyl]benzoyl)-L-glutamic acid disodium salt two sesquihydrate. It is a novel pyrimidine analog, thymidylate synthase inhibitor. It exerts antitumor effects by interfering with folate-dependent metabolic processes during cell replication. Studies have shown that pemetrexed produces cytotoxicity through intracellular polyglutamate, which inhibits several folate-dependent enzymes including thymidylate synthase, dihydrofolate reductase, glycine ribose Nucleoside formyltransferase. [0003] Pemetrexed disodium has a certain therapeutic effect on non-small cell lung cancer, head and neck cancer, colon cancer, and breast cancer. Pemetrexed disodium is also used in combination with other anticancer drugs, especially in c...

Claims

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Application Information

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IPC IPC(8): C07D487/04
Inventor 卞建钢潘秀芝张书明李吉林宋晓丽孙中志宋桓袁霞仇淑芹
Owner DEZHOU DEYAO PHARMA
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