Method for producing folic acid antagonist and its intermediate

A Chinese-style, metal catalyst technology, applied in organic chemistry and other fields, can solve problems affecting the purity of finished products

Active Publication Date: 2006-12-20
JIANGSU HANSOH PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] 4,996,206, US 5,028,608, and US 5,034,493, and its preparation methods have also been reported in many patents, such as CN 1055182, CN 1271338, CN 1087910, US 5,254,687, and US 6,013,828. Among the methods for preparing the compound of fo

Method used

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  • Method for producing folic acid antagonist and its intermediate
  • Method for producing folic acid antagonist and its intermediate
  • Method for producing folic acid antagonist and its intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] N-(4-[2-(2-Amino-4(3H)-oxy-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl-L-glutamic acid di Benzyl ester

[0029] 10 grams (33.6 mmol) of 4-[2-(2-amino-4(3H)-oxygen-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid and 100ml dimethyl Put methyl formamide into a 250ml three-necked flask, stir, cool to 5°C, add 10ml (91mmol) of N-methylmorpholine, 7.5g (42.7mmol) of 2-chloro-4,6-dimethoxytriazine, Stir at 5-10°C for 1 hour, add 20 g (40.2 mmol) of L-dibenzyl glutamate p-toluenesulfonate, stir at 25°C for 2 hours, pour into a 500 ml separating funnel, add 100 ml of dichloromethane 100ml of water, shake well, separate the organic layer, extract the aqueous layer with dichloromethane, combine the organic layers, evaporate the organic solvent under reduced pressure to the utmost, add 50ml of ethyl acetate and stir, filter, wash with ethyl acetate successively, After drying, 15 g of off-white solid was obtained, with a yield of 73.5%.

[0030] 1 HNMR (400MHz DMSO d 6 )δ ...

Embodiment 2

[0036] N-(4-[2-(2-Amino-4(3H)-oxy-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl-L-glutamic acid di Benzyl ester

[0037] 10 grams (15.2 mmol), 50ml (100mmol) of 2N sodium hydroxide were put into a 100ml reaction bottle, stirred at room temperature for 2 hours, and the reaction solution was added dropwise to 100ml of 4N sulfuric acid at 0°C. 60ml×2 extraction, combined, washed with 60ml of water, dried over anhydrous magnesium sulfate, filtered, the filtrate was evaporated to dryness under reduced pressure, added 30ml of ethyl acetate, stirred, filtered, washed with ethyl acetate, dried to obtain 7 grams of white solid, yield 75.9 %.

Embodiment 3

[0039] N-(4-[2-(2-amino-4(3H)-oxy-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl-L-glutamic acid

[0040] Put N-(4-[2-(2-amino-4(3H)-oxygen-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl- 5 g (8.2 mmol) of L-dibenzyl glutamate, 100 ml of methanol, 200 ml of tetrahydrofuran, stir to dissolve, add 1 g of 10% Pd / C, hydrogenate at room temperature and normal pressure for 3 hours, filter, wash with 50 ml of tetrahydrofuran, and depressurize The solvent was evaporated to give the title compound.

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Abstract

This invention relates to a method for producing antifolic N-(4-[2-(2-amidol(3H)-oxy--7H-pyrrolo-[2,3-d]pyrimidine-5-radical)ethyl]benzoyl-L-glutamic acid, the intermediate thereof N-(4-[2-(2-amidol(3H)-oxy--7H-pyrrolo-[2,3-d]pyrimidine-5-radical)ethyl]benzoyl-L-dibenzyl glutamate and the pharmaceutical salt thereof.

Description

technical field [0001] The present invention relates to synthetic organic chemistry, in particular the present invention relates to the preparation of folic acid antagonists and their intermediates useful in the synthesis of valuable. Background technique [0002] The compound of the following formula I has been used in the United States Patent US as a folic acid antagonist for the treatment of cancer [0003] [0004] 4,996,206, US 5,028,608, and US 5,034,493, and its preparation methods have also been reported in many patents, such as CN 1055182, CN 1271338, CN 1087910, US 5,254,687, and US 6,013,828. Among the methods for preparing the compound of formula I, the last one is The diethyl ester of the compound of formula I is prepared by hydrolysis with sodium hydroxide, because sodium hydroxide may hydrolyze the amide in the compound of formula I and affect the purity of the finished product. Contents of the invention [0005] Point out in order to overcome the defici...

Claims

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Application Information

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IPC IPC(8): C07D487/04C07D239/00C07D209/00
Inventor 岑均达吕爱峰
Owner JIANGSU HANSOH PHARMA CO LTD
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