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Synthesis method for intermediate of impurity A of pemetrexed disodium

A technology of pemetrexed disodium and synthesis method, which is applied in the synthesis field of intermediates and can solve the problems of high impurities, expensive methyl iodide and the like

Inactive Publication Date: 2015-01-21
SHANDONG BOYUAN PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] Synthesis of pemetrexed disodium impurity A prior art reported in Organic Process Research and Development, 2005, vol.9, #6 p.738–742 is N-[4-[2-(2-amino-4 , 7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid reacts with methyl iodide to produce impurities, wherein methyl iodide is too expensive and produces More impurities

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  • Synthesis method for intermediate of impurity A of pemetrexed disodium
  • Synthesis method for intermediate of impurity A of pemetrexed disodium
  • Synthesis method for intermediate of impurity A of pemetrexed disodium

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example 1

[0022] Take 50g of compound I 1-methylguanidine and add it to a 1000ml three-neck flask, add 300ml of toluene, add 77g of compound II ethyl cyanoacetate, heat and reflux for 5 hours, control the temperature at 70°C and evaporate the toluene to dryness under reduced pressure, and add iso Propanol 300ml, start stirring, add compound IV 4-(4-carbonyl-3 bromobutyl)methyl benzoate 190g, sodium methoxide 37g, control temperature at 35°C for 7 hours, cool down to 10°C, add purified water 300ml, stir After 30 minutes, an off-white solid was obtained by suction filtration, and 149.5 g was obtained after drying, with a purity of 97.8% and a yield of 65.5%.

example 2

[0024] Take 50g of compound I 1-methylguanidine and add it to a 1000ml three-necked flask, add 300ml of toluene, add 77g of compound II ethyl cyanoacetate, heat and reflux for 7 hours, control the temperature at 70°C and evaporate the toluene to dryness under reduced pressure, and add acetonitrile into the three-neck flask 300ml, start stirring, add compound IV 4-(4-carbonyl-3 bromobutyl) methyl benzoate 190g, sodium ethoxide 46g, control temperature at 40°C for 5 hours, cool down to 10°C, add purified water 300ml, stir for 30 minutes After suction filtration, an off-white solid was obtained, and after drying, 143.2 g was obtained, with a purity of 98.4% and a yield of 63.1%.

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Abstract

The invention discloses a synthesis method for an intermediate of an impurity A of pemetrexed disodium and belongs to the field of drug synthesis. (4-(2-(2-amino-1-methyl-4,7-dihydro-4-oxo-1H-pyrrolo(2,3-d)pyrimidine-5-yl)ethyl)benzoyl)-L-glutamic acid is an impurity A of pemetrexed disodium, and 4-(2-(2-amino-1-methyl-4,7-dihydro-4-oxo-1H-pyrrolo(2,3-d)pyrimidine-5-yl)ethyl)methyl benzoate is an important intermediate required for synthesis of the impurity A. The synthesis method of the intermediate comprises the following steps: carrying out a reaction on a compound I 1-methylguanidine and a compound II ethyl cyanoacetate to obtain a compound III 2,6-diamino-4-carbonyl-1-methylpyrimidine, and carrying out a reaction on a compound IV 4-(4-carbonyl-3 brombutyl)methyl benzoate and the compound III to obtain a compound V 4-(2-(2-amino-1-methyl-4,7-dihydro-4-oxo-1H-pyrrolo(2,3-d)pyrimidine-5-yl)ethyl)methyl benzoate.

Description

technical field [0001] The invention relates to a method for synthesizing the intermediate of the impurity A of pemetrexed disodium. Background technique [0002] Pemetrexed disodium, chemical name N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidine-5- Base) ethyl] benzoyl] -L-glutamic acid disodium salt is a multi-targeted antifolate agent developed by Eli Lilly Company of the United States, which is suitable for the combined treatment of inoperable malignant pleural mesothelioma with cisplatin. The chemical name of impurity A of pemetrexed disodium is [4-[2-(2-amino-1-methyl-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d ] pyrimidin-5-yl) ethyl] benzoyl] -L-glutamic acid. [0003] 4-[2-(2-Amino-1-methyl-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid methyl Esters are key intermediates in the synthesis of pemetrexed disodium impurity A. [0004] Synthesis of pemetrexed disodium impurity A prior art reported in Organic Process Research and Developmen...

Claims

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Application Information

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IPC IPC(8): C07D487/04
CPCC07D487/04C07D239/48
Inventor 赵孝杰刘远慧
Owner SHANDONG BOYUAN PHARM CO LTD
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