Preparation method of N-(5-(N-t-butyloxycarbonyl-N-methylamino)-2-thenoyl)-L-diethyl glutamate

A technology of diethyl glutamate and thiophenoyl, which is applied in the field of medicine, can solve problems such as difficult industrial production, hidden safety hazards, and difficult purification, and achieves the effects of mild reaction conditions, simple operation, and high yield

Inactive Publication Date: 2016-08-31
HONGGUAN BIO PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The disadvantages of this route are: the need to use reagents such as sodium hydride and n-butyllithium, the reagents are expensive, the operating conditions are strict (the reaction needs to be performed at a low temperature of -78°C and under the protection of argon), and there are potential safety hazards, making it difficult to realize industrial production.
[0020] The disadvantage of this route is that the reaction conditions of methylation with methyl iodide are not easy to control, especially in the amplification reaction, the reaction system is easy to become mixed, so it is difficult to purify

Method used

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  • Preparation method of N-(5-(N-t-butyloxycarbonyl-N-methylamino)-2-thenoyl)-L-diethyl glutamate
  • Preparation method of N-(5-(N-t-butyloxycarbonyl-N-methylamino)-2-thenoyl)-L-diethyl glutamate
  • Preparation method of N-(5-(N-t-butyloxycarbonyl-N-methylamino)-2-thenoyl)-L-diethyl glutamate

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Experimental program
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Embodiment 1

[0039] A kind of preparation method of N-[5-[N-(tert-butoxycarbonyl)-N-methylamino]-2-thienoyl] L-glutamic acid diethyl ester, concrete steps are: N-[ 5-[N-(tert-butoxycarbonyl)amino]-2-thienoyl]-L-glutamic acid diethyl ester (210g, 0.5mol) was dissolved in acetonitrile (2000mL), cesium carbonate (240g, 0.74 mol), stirred for 10 minutes, then methyl iodide (178.6 g, 1.26 mol) dissolved in acetonitrile (100 mL) was added dropwise to the reaction solution, and the methylation reaction was carried out at room temperature for 30 minutes after the addition was completed. Remove inorganic salts by filtration, wash the filter cake with a small amount of ethyl acetate, concentrate the filtrate under reduced pressure to obtain a crude product, dissolve the crude product in ethyl acetate (500 mL), wash once with water (300 mL), separate the layers, and dry the organic phase with anhydrous magnesium sulfate , filtered and concentrated to dryness to obtain 190 g of the product with a puri...

Embodiment 2

[0041] A kind of preparation method of N-[5-[water (tert-butoxycarbonyl)-N-methylamino]-2-thienoyl]-L-glutamic acid diethyl ester, concrete steps are: N-[ 5-[N-(tert-butoxycarbonyl)amino]-2-thienoyl]-L-glutamic acid diethyl ester (210g, 0.5mol) was dissolved in acetonitrile (2000mL), potassium carbonate (207g, 1.5 mol), vigorously stirred for 10 minutes, and then methyl iodide (178.6 g, 1.26 mol) dissolved in acetonitrile (100 mL) was added dropwise to the reaction solution, and the methylation reaction was carried out at room temperature for 30 minutes after the addition was completed. The inorganic salt was removed by filtration, and the filter cake was washed with a small amount of ethyl acetate. The filtrate was concentrated under reduced pressure to obtain a crude product, which was then dissolved in ethyl acetate (500 mL), washed with water (300 mL), separated, and the organic phase was dried with anhydrous magnesium sulfate. After filtration and concentration to dryness...

Embodiment 3

[0043]A kind of preparation method of N-[5-[N-(tert-butoxycarbonyl)-N-methylamino]-2-thienoyl] L-glutamic acid diethyl ester, concrete steps are: N-[ 5-[N-(tert-butoxycarbonyl)amino]-2-thienoyl]L-glutamic acid diethyl ester (210g, 0.5mol) was dissolved in acetonitrile (2000mL), sodium carbonate (159g, 1.5mol) was added ), and vigorously stirred for 10 minutes, then methyl iodide (178.6 g, 1.26 mol) dissolved in acetonitrile (100 mL) was added dropwise to the reaction solution, and the methylation reaction was carried out at room temperature for 30 minutes after the addition was completed. The inorganic salt was removed by filtration, and the filter cake was washed with a small amount of ethyl acetate. The filtrate was concentrated under reduced pressure to obtain a crude product, which was then dissolved in ethyl acetate (500 mL), washed with water (300 mL), separated, and the organic phase was dried with anhydrous magnesium sulfate. After filtration and concentration to dryne...

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Abstract

The invention provides a preparation method of N-(5-(N-t-butyloxycarbonyl-N-methylamino)-2-thenoyl)-L-diethyl glutamate. The preparation method is characterized by including dissolving N-(5-(N-t-butyloxycarbonyl amino)-2-thenoyl)-L-diethyl glutamate in organic solvent, adding alkali, then adding methylation reagent for methylation, filtering, concentrating filtrate to obtain a crude product, and purifying a pure product to obtain the N-(5-(N-t-butyloxycarbonyl-N-methylamino)-2-thenoyl)-L-diethyl glutamate. The preparation method is mild in reaction condition, easy to operate, high in yield, high in purity of reaction products and suitable for industrial production.

Description

technical field [0001] The invention relates to the preparation of a raltitrexed intermediate N-[5-[N-(tert-butoxycarbonyl)-N-methylamino]-2-thiophenoyl]-L-glutamic acid diethyl ester The method belongs to the technical field of medicine. Background technique [0002] Colorectal cancer (CRC) is the second most common malignancy in the world after lung cancer. In the past 30 years, colorectal cancer has become one of the two fastest growing malignant tumors in my country. Raltitrexed is a Thymidylatesynthase (TS) inhibitor and a strong inhibitor of the activity of colorectal cancer cell lines. It has become the first-line drug for the treatment of advanced colon cancer in Western European countries such as the United Kingdom. , the drug also has a certain effect on other cancers such as head and neck tumors, prostate cancer, lung cancer, soft tissue sarcoma and leukemia. Raltitrexed has a large market demand in China, and the improvement of its synthesis technology will br...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D333/38
CPCC07D333/38
Inventor 杨继斌程宜兴朱金龙于学彬
Owner HONGGUAN BIO PHARMA CO LTD
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