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N-[4-(1-(2-propinyl)-3, 4-dioxo-n-butyl) benzoyl]-L-glutamic dialkyl ester and preparation method thereof

A technology of dialkyl glutamate and dioxo-n-butyl, which is applied to the preparation of carboxylic acid amides, chemical instruments and methods, and the preparation of organic compounds, and can solve problems such as hindering industrial production, rare raw materials, and difficult separation , to achieve the effect of low cost, easy access to raw materials, and simple process

Active Publication Date: 2015-05-20
迁安华韵知识产权服务中心
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although this method can prepare the target compound pralatrexate, due to factors such as rare raw materials, many steps, and difficult separation, the industrial production of this product has been hindered.

Method used

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  • N-[4-(1-(2-propinyl)-3, 4-dioxo-n-butyl) benzoyl]-L-glutamic dialkyl ester and preparation method thereof
  • N-[4-(1-(2-propinyl)-3, 4-dioxo-n-butyl) benzoyl]-L-glutamic dialkyl ester and preparation method thereof
  • N-[4-(1-(2-propinyl)-3, 4-dioxo-n-butyl) benzoyl]-L-glutamic dialkyl ester and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Under dryness and nitrogen atmosphere, N-methylmorpholine (2.0g, 20mmol) and 4-chloro-2,6-dimethyltriazine (3.5g, 20mmol) and 4-(1- Hydroxy-3-butyne)benzoic acid (II) (1.9 g, 10 mmol) and 50 mL of N,N-dimethylformamide were stirred at room temperature for 1 hour. Add L-glutamic acid dimethyl ester hydrochloride (III) (2.75 g, 13 mmol) and N-methylmorpholine (1.5 g, 15 mmol), and continue to stir for 3 hours, and TLC detects that the reaction is complete. The reaction solution was poured into water, and dichloromethane was added for extraction. The organic phase was washed with water and dried over anhydrous sodium sulfate. The solvent was recovered under reduced pressure, and the resulting residue was recrystallized with ethyl acetate and n-hexane (1:1) to obtain off-white solid N-[4-(1-hydroxy-3-butyne)benzoyl]-L-glutamine Acid dimethyl ester (IV) 2.90g, yield 83.6%.

Embodiment 2

[0023] Under dryness and nitrogen atmosphere, N-methylmorpholine (2.0g, 20mmol) and 4-chloro-2,6-dimethyltriazine (3.5g, 20mmol) and 4-(1- Hydroxy-3-butyne)benzoic acid (II) (1.9 g, 10 mmol) and 50 mL of N,N-dimethylformamide were stirred at room temperature for 1 hour. Add L-glutamic acid diethyl ester hydrochloride (III) (3.1 g, 13 mmol) and N-methylmorpholine (1.5 g, 15 mmol), and continue stirring for 3 hours, and TLC detects that the reaction is complete. The reaction solution was poured into water, and dichloromethane was added for extraction. The organic phase was washed with water and dried over anhydrous sodium sulfate. The solvent was recovered under reduced pressure, and the resulting residue was recrystallized with ethyl acetate and n-hexane (1:1) to obtain off-white solid N-[4-(1-hydroxy-3-butyne)benzoyl]-L-glutamine Acid diethyl ester (IV) 3.15g, yield 84.0%.

Embodiment 3

[0025] Under nitrogen protection, methylglyoxal dimethyl acetal (4.72 g, 40 mmol), triethylamine (5.5 g, 54 mmol) and 50 mL of tetrahydrofuran were added into a three-necked flask. The temperature was lowered to 0°C, and under stirring, trisilyl trifluoromethanesulfonate (10 mL, 50 mmol) was added dropwise. After the drop was completed, the mixture was reacted at room temperature for 4 hours, and the reaction was detected by TLC. After adding n-hexane and stirring for 15 minutes, the solid was removed by filtration. The mother liquor was washed with water, water and brine in sequence, dried over anhydrous magnesium sulfate, and the solvent was recovered by distillation under reduced pressure. The obtained pale yellow oil was dissolved in 100mL of dichloromethane and placed in a dry three-necked flask, and N-[4-(1-hydroxy-3-butyne)benzoyl]-L-glutamic acid dimethyl Ester (IV) (3.47 g, 10 mmol). The temperature was lowered to -60°C, under the protection of nitrogen, 7 mL of 1 M...

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Abstract

The invention discloses a medical intermediate N-[4-(1-(2-propinyl)-3, 4-dioxo-n-butyl) benzoyl]-L-glutamic dialkyl ester (I) and a preparation method thereof. The preparation method comprises the following steps of carrying out a condensation reaction on 4-(1-hydroxyl-3-butyne) benzoic acid (II) and L-glutamic dialkyl ester (III) to generate N-[4-(1-hydroxyl-3-butyne) benzoyl]-L-glutamic dialkyl ester (IV); and carrying out a coupled reaction on the intermediate (IV) and methylglyoxal dimethylacetal subjected to enolization to generate the N-[4-(1-(2-propinyl)-3, 4-dioxo-n-butyl) benzoyl]-L-glutamic dialkyl ester (I). According to the intermediate (I) and the preparation method thereof, a novel preparation way for the antineoplastic pralatrexate is provided and the economic and technological development of the pralatrexate is promoted.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis route design and preparation of raw materials and intermediates, and particularly relates to a new compound N-[4-(1-(2-propynyl)-3,4-dioxo-n-butyl Base) benzoyl]-L-glutamic acid dialkyl ester and preparation method thereof. Background technique [0002] Pralatrexate is a drug developed by Allos Therapeutics Inc in the United States for the treatment of relapsed and refractory peripheral T-cell lymphoma. Pralatrexate injection was approved by the US FDA on September 24, 2009 in the United States, with a trade name of Folotvn. The chemical name of pralatrexate is N-[4-(1-(2,4-diamino-6-pteridine)methyl-3-butynyl)benzoyl]-L-glutamic acid. [0003] [0004] U.S. Patent No. US6028071, No. US2010248249, No. US2011111436 and World Patent No. WO2012061469 originally developed by Aros Therapeutics reported the preparation method and pharmaceutical use of pralatrexate. The method is to use m...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C235/84C07C231/12
Inventor 许学农
Owner 迁安华韵知识产权服务中心
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