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Diethyl 4(4-oxobutyl) benzoyl-L-glutamate and its preparation and use

A technology of diethyl glutamate and oxobutyl, applied in the field of the new compound 4-benzoyl-L-diethyl glutamate, can solve the problem of low total yield and unsuitability for large-scale industrial production , long steps, etc.

Inactive Publication Date: 2008-03-26
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-oxobutyl) benzoyl-L-glutamate and its preparation and use
  • Diethyl 4(4-oxobutyl) benzoyl-L-glutamate and its preparation and use
  • Diethyl 4(4-oxobutyl) benzoyl-L-glutamate and its preparation and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Example 1 Synthesis of 4-(4-oxobutyl)benzoyl-L-glutamic acid diethyl ester (III)

[0034] The amount ratio of feeding material is 4-bromobenzoyl-L-glutamic acid diethyl ester (II): lithium acetate: tetrabutylammonium bromide: lithium chloride: 3-butene-1-alcohol: palladium acetate =1:2:1.5:2.5:1.05:0.08.

[0035]In a 500ml three-necked reaction flask equipped with mechanical stirring, nitrogen inlet and outlet and a thermometer, add 4-bromobenzoyl-L-glutamic acid diethyl ester (II) (38.6g, 0.1mol), lithium acetate (13.2g , 0.2mol), tetrabutylammonium bromide (48.4g, 0.15mol), lithium chloride (10.6g, 0.25mol), N, N-dimethylformamide 300ml, stirred for 10 minutes, added palladium acetate (1.8 g), 3-buten-1-ol (7.6 g, 0.105 mol), heated up to 68-70° C. to react, followed the reaction by TLC. After the reaction was completed and cooled properly, it was filtered through a layer of diatomaceous earth, and the filter cake was washed three times with 50 mL of N, N-dimethylfo...

Embodiment 2

[0037] Example 2 Synthesis of 4-(4-oxobutyl)benzoyl-L-glutamic acid diethyl ester (III)

[0038] The amount ratio of feeding material is 4-bromobenzoyl-L-glutamic acid diethyl ester (II): triethylamine: tetrabutylammonium bromide: lithium chloride: 3-butene-1-alcohol: acetic acid Palladium = 1:2:1.5:2.5:1.05:0.08.

[0039] The feeding amount of triethylamine is 20.2g, and the feeding amount and operation process of all the other raw materials are the same as in Example 1. 19.2 g of 4-(4-oxobutyl)benzoyl-L-glutamic acid diethyl ester (III) was obtained, the yield was 51%, the melting point was 86-88.2°C, and the physical and chemical data were the same as in Example 1.

Embodiment 3

[0040] Example 3 Synthesis of 4-(4-oxobutyl)benzoyl-L-glutamic acid diethyl ester (III)

[0041] The amount ratio of feeding material is 4-bromobenzoyl-L-glutamic acid diethyl ester (II): lithium acetate: tetrabutylammonium chloride: lithium chloride: 3-butene-1-alcohol: palladium acetate =1:2:1.5:2.5:1.05:0.08.

[0042] Tetrabutylammonium chloride charging amount is 41.9g, and all the other raw material charging amounts and operating process are with embodiment 1. 23.8 g of 4-(4-oxobutyl)benzoyl-L-glutamic acid diethyl ester (III) was obtained, the yield was 63.2%, the melting point was 86-87.9° C., and the physical and chemical data were the same as those in Example 1.

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Abstract

The present invention relates to new compound diethyl 4-(4-oxobutyl) benzoyl-L-glutamate and its preparation process and application. The compound diethyl 4-(4-oxobutyl) benzoyl-L-glutamate in the chemical expression as shown is prepared through the reaction of compound diethyl 4-bromo benzoyl-L-glutamate and 3-butene-1-alcohol inside N,N-dimethyl formamide solvent under the action of palladium acetate catalyst, weak alkali reagent, lithium halide and phase transfer catalyst in the protection of inert gas at 50-70 deg.c. The compound diethyl 4-(4-oxobutyl) benzoyl-L-glutamate is used in synthesizing diethyl 4-[(4-oxo-3-bromo) butyl] benzoyl-L-glutamate as the intermediate of Pemetrexed disodium. The present invention 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-oxobutyl)benzoyl-L-glutamic acid diethyl ester, its preparation method and application. (2) Background technology [0002] Pemetrexed (also known as LY231514, trade name Alimta) is a new type of anti-folate anti-metabolite drug, the target of action includes a variety of enzymes in the synthesis of pyrimidine and purine, so it is also known as multi-targeted antifolate (multi2targeted antifolate) , MTA). It has shown a wide range of anti-tumor activities in vitro and clinical trials, and is a very potential anti-tumor drug. [0003] Pemetrexed was successfully developed by Dr. Shi Quan, a Chinese scientist from Eli Lilly and the Department of Chemistry, Princeton University, after ten years of research. Since the 1990s, many patents and documents have introduced the chemical synthesis method of pemetrexed and its disodium salt, such as Taylor, E.C.; Kuhnt.D.; Shih, C.; etc.J. Med. Chem. 1992, 35, 4450...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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