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Diethyl 4[(4-oxo-3-bromo) butyl] benzoyl-L-glutamate and preparation and use

A technology of diethyl glutamate and benzoyl, applied in the field of 4-[(4-oxo-3-bromo)butyl]benzoyl-L-diethyl glutamate and its preparation and application , can solve the problems of low total yield, long steps, unsuitable for large-scale industrial production, etc.

Inactive Publication Date: 2006-08-23
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Although compared with the previous route, the yield has increased, but the starting material aldehyde is unstable and still needs to be synthesized by itself, so the steps are still relatively long and the total yield is still relatively low; secondly, this method is a laboratory process, and the synthesis process To use toxic nitromethane, it is not suitable for large-scale industrial production

Method used

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  • Diethyl 4[(4-oxo-3-bromo) butyl] benzoyl-L-glutamate and preparation and use
  • Diethyl 4[(4-oxo-3-bromo) butyl] benzoyl-L-glutamate and preparation and use
  • Diethyl 4[(4-oxo-3-bromo) butyl] benzoyl-L-glutamate and preparation and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Example 1 Preparation of 4-[(4-oxo-3-bromo)butyl]benzoyl-L-glutamic acid diethyl ester (IV)

[0031] The quantity ratio of the feed substances is 4-(4-oxobutyl)benzoyl-L-glutamate diethyl (III): 5,5-dibromo-2,2-dimethyl-4, 6-Dicarbonyl-1,3-dioxane=1:1.5;

[0032] Add 37.7g (0.1mol) of 4-(4-oxobutyl)benzoyl-L-glutamic acid diethyl (III) into a 1500ml three-necked reaction flask equipped with mechanical stirring, nitrogen inlet and outlet and thermometer, Dichloromethane 1000ml, under the protection of nitrogen, add 45.0g (0.15mol) 5,5-dibromo-2,2-dimethyl-4,6-dicarbonyl-1,3-dioxane, add Then react at 20-25°C and follow the reaction by TLC. After the reaction, filter, wash the organic layer twice with 1N sodium thiosulfate solution 100mL each time, then wash with 200ml 5% sodium bicarbonate solution, and finally wash twice with saturated saline water 100mL each time, add anhydrous magnesium sulfate After drying, the solvent was evaporated to obtain 48.2 g of viscous solid 4-[...

Embodiment 2

[0033] Example 2 Preparation of 4-[(4-oxo-3-bromo)butyl]benzoyl-L-glutamic acid diethyl ester (IV)

[0034] The quantity ratio of the feed substances is 4-(4-oxobutyl)benzoyl-L-glutamate diethyl (III): 5,5-dibromo-2,2-dimethyl-4, 6-Dicarbonyl-1,3-dioxane=1:1.5, the organic solvent is changed to chloroform, and the amount is 1000ml.

[0035]The feeding amount and operation process of other materials are the same as in Example 1. 48.0 g of 4-[(4-oxo-3-bromo)butyl]benzoyl-L-glutamic acid diethyl ester (IV) was obtained as a viscous solid.

Embodiment 3

[0036] Example 3 Preparation of 4-[(4-oxo-3-bromo)butyl]benzoyl-L-glutamic acid diethyl ester (IV)

[0037] The quantity ratio of the feed substances is 4-(4-oxobutyl)benzoyl-L-glutamate diethyl (III): bromobarbituric acid=1:1.5;

[0038] Add 37.7g (0.1mol) of 4-(4-oxobutyl)benzoyl-L-glutamic acid diethyl (III) into a 1500ml three-necked reaction flask equipped with mechanical stirring, nitrogen inlet and outlet and thermometer, Dichloromethane 1000ml, under the protection of inert gas, add 42.9g (0.15mol) bromobarbituric acid, and react at 20-25°C after the addition. TLC follows the reaction situation. After the reaction, filter, wash the organic layer twice with 1N sodium thiosulfate solution 100mL each time, then wash with 200ml 5% sodium bicarbonate solution, and finally wash twice with saturated saline water 100mL each time, add anhydrous magnesium sulfate After drying, the solvent was evaporated to obtain 48.5 g of viscous solid 4-[(4-oxo-3-bromo)butyl]benzoyl-L-glutamic aci...

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Abstract

The present invention relates to new compound diethyl 4-[(4-oxo-3-bromo) butyl] benzoyl-L-glutamate and its preparation process and application. The compound diethyl 4-[(4-oxo-3-bromo) butyl] benzoyl-L-glutamate in the chemical expression as shown is prepared through the reaction of material diethyl 4-(4-oxo-butyl) benzoyl-L-glutamate and bromo reagent inside C1-C4 halohydrocarbon solvent at 20-30 deg.c. The compound diethyl 4-[(4-oxo-3-bromo) butyl] benzoyl-L-glutamate is used as the important intermediate of antitumor medicine Pemetrexed disodium. The present invention provides new path of synthesizing Pemetrexed disodium, and results in shortened Pemetrexed disodium synthesizing path and lowered production cost.

Description

(1) Technical field [0001] The invention relates to a new compound 4-[(4-oxo-3-bromo)butyl] benzoyl-L-glutamic acid diethyl ester, and a preparation method and application thereof. (2) Background technology [0002] Pemetrexed (also known as LY231514, trade name Alimta) is a new type of antifolate antimetabolites. Its targets include multiple enzymes in the synthesis of pyrimidine and purine, so it is also known as multi-targeted antifolate (multi2targeted antifolate). , MTA). It has shown extensive anti-tumor activity in in vitro and clinical trials and is a promising anti-tumor drug. [0003] Pemetrexed was successfully developed by Dr. Shi Quan, a Chinese scientist from Eli Lilly and Company, after a decade of research and development in the Department of Chemistry, Princeton University. Since the 1990s, there have been many patents and documents describing the chemical synthesis methods of pemetrexed and its disodium salt, such as Taylor, EC; Kuhnt.D.; Shih, C.; etc.J. Med. C...

Claims

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Application Information

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IPC IPC(8): C07C235/84C07C231/12
Inventor 苏为科李振华王平蔡继平
Owner ZHEJIANG UNIV OF TECH
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