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Method for preparing improved intermediate for producing high-purity pemetrexed and method for producing high-purity pemetrexed using intermediate

A technology of pemetrexed diacid and pemetrexed diethyl ester, which is applied to pemetrexed diethyl ester or prepared high-purity, ground, used in the field of preparation, can solve the problem of low-purity by-products of products and cannot improve the level And other issues

Inactive Publication Date: 2016-04-27
SAMYANG BIOPHARMLS CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0017] In a word, for the preparation method of the pemetrexed disodium salt of the reaction formula 1, there are serious problems in the low purity of the obtained product and the generation of by-products during the preparation of the intermediate, and these problems are even by reducing The reaction temperature, and the deformation of further purification, etc. can not be improved to the allowable level

Method used

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  • Method for preparing improved intermediate for producing high-purity pemetrexed and method for producing high-purity pemetrexed using intermediate
  • Method for preparing improved intermediate for producing high-purity pemetrexed and method for producing high-purity pemetrexed using intermediate
  • Method for preparing improved intermediate for producing high-purity pemetrexed and method for producing high-purity pemetrexed using intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0095] Embodiment 1: the preparation of pemetrexed diethyl ester p-toluenesulfonate (chemical formula 3)

[0096] Add 1 L of saturated NaHCO to the reactor 3 Aqueous solution and 88 g of L-glutamic acid diethyl ester hydrochloride (LGA), and after stirring at room temperature for 30 minutes, 1 L of DCM was thrown in, and the organic layer was extracted. After adding 0.5 L of DMF to the separated organic layer, it was concentrated at 20 to 30° C. to remove more than 80% of DCM. Put 93g of 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzene into the concentrate Formic acid (chemical formula 6, HPLC purity is 98.3%), and after cooling to 0 ~ 10 ° C, 93g of N-methylmorpholine (NMM) and 65g of 2-chloro-4,6-dimethoxy- 1,3,5-Triazine. After stirring the reaction solution at 5-15° C. for 1 hour, 1 L of DCM and 1 L of purified water were added, and the organic layer was extracted (HPLC purity: 97.9%). 0.3 L of DMF, 3.3 L of EtOH, and 148 g of p-toluenesulf...

Embodiment 2

[0099] Embodiment 2: the preparation of pemetrexed diacid (chemical formula 2)

[0100] 1 L of 1N NaOH aqueous solution was added to the reactor, and 143 g of the compound represented by Chemical Formula 3 prepared in Example 1 was added at 5-15°C. After stirring at 5-15° C. for 2 hours, it was filtered (HPLC purity: 99.8%). 2 L of EtOH was added to the filtrate, and a 2N HCl aqueous solution was slowly added dropwise at 5 to 15° C. to adjust the pH to 3.0. After stirring the resulting crystalline mixture at 40-50°C for 1 hour, it was filtered at 40°C. The filtrate was washed with 2 L of purified water, and further washed with 1 L of EtOH. The obtained filtrate was put into 4 L of EtOH / purified water (1:1, v / v), and the mixture was stirred at 40-50° C. for 1 hour, cooled, and filtered at normal temperature. The filtrate was washed with 2 L of purified water, and further washed with 1 L of EtOH. Vacuum drying was performed at 40-50° C. for 16 hours to obtain 88 g of pemetre...

Embodiment 3

[0101] Embodiment 3: the preparation of pemetrexed disodium salt (chemical formula 1)

[0102] 1 L of 1N NaOH aqueous solution was added to the reactor, and 87 g of the compound represented by Chemical Formula 2 prepared in Example 2 was added at 5-15°C. After stirring for 30 minutes, it was filtered, and a 0.5N HCl aqueous solution was slowly added dropwise to the filtrate to adjust the pH to 7.5-8.5. The solution was heated to 50-60° C., and 7 L of EtOH was slowly added dropwise to form crystals. The resulting white solid was cooled slowly to room temperature and filtered. Wash with 1L of EtOH / purified water mixture (4:1, v / v), and carry out vacuum drying at 40° C. for 21 hours, thereby obtaining 91 g of white solid pemetrexed disodium salt (yield: 87%, HPLC purity: >99.9%, various impurities: <0.05%). The water content measured by the Karl Fischer method was 9.05% by weight, so it was confirmed that the disodium salt of pemetrexed was 2.5 hydrate (required standard: 8.5 ...

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Abstract

The present invention relates to a method for preparing an improved intermediate for producing high-purity pemetrexed and a method for producing high-purity pemetrexed using the intermediate, and more specifically, to a novel method for preparing pemetrexed diethyl ester, which is an intermediate for producing pemetrexed, or a salt thereof with high purity, and to a method for producing pemetrexed disodium salt with high purity using the intermediate.

Description

technical field [0001] The present invention relates to a method for preparing an improved intermediate for preparing high-purity pemetrexed, and a method for using it to prepare high-purity pemetrexed, and in more detail, relates to a method for preparing high-purity, A novel process for the preparation of an intermediate of pemetrexed, pemetrexed diethyl ester or a salt thereof, and a method of using the intermediate to prepare a high-purity pemetrexed disodium salt. Background technique [0002] Pemetrexed is N-(4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl) Ethyl]benzoyl)-L-glutamic acid {N-(4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5 -yl)ethyl]benzoyl)-L-glutamicacid}, its disodium salt has the structure shown in the following chemical formula 1: [0003] [chemical formula 1] [0004] [0005] Pemetrexed, which shows antifolate activity, is marketed by Eli Lilly and Company, Alimta TM The product name (active ingredient: pemetre...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/519A61P35/00
CPCA61P35/00C07D487/04A61K31/519
Inventor 金荣敏金文宿金圣镐赵镇淑
Owner SAMYANG BIOPHARMLS CORP
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