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Synthesis of anticancer medicine Raltiprexed

A synthesis process and a drug mine technology are applied in the field of a new synthesis process of the anticancer drug raltitrexed, which can solve the problems of high price and long reaction time, and achieve the effects of simple operation, low reagent cost and high total yield.

Inactive Publication Date: 2005-08-31
CAPITAL NORMAL UNIVERSITY
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0005] In this synthetic route, the introduction of the methyl group on the N atom needs to use sodium hydride as a strong basic catalyst, and the reaction must be carried out under strict anhydrous conditions, and the reaction time is long; the introduction of the carboxyl group on the thiophene ring requires the use of expensive n-Butyllithium reagent, a low temperature of 78°C and strict anhydrous reaction conditions, the reaction time is also longer

Method used

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  • Synthesis of anticancer medicine Raltiprexed
  • Synthesis of anticancer medicine Raltiprexed
  • Synthesis of anticancer medicine Raltiprexed

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Experimental program
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Embodiment Construction

[0022] The synthetic route is as follows:

[0023]

[0024] The first step: the synthesis of N-(5-carboxy-2-thiophenoyl)-L-diethyl glutamate (I):

[0025] Suspend 2.93 g (17.2 mmol) of 2,5-thiophenedicarboxylic acid in 30 mL of dry tetrahydrofuran (THF), and add N, N'-dicyclohexylcarbodiimide (DCC) 3.55 g (17.2 mmol). After stirring for a while, 3.5 g (17.2 mmol) of L-diethyl glutamate dissolved in 20 mL of dry THF was added dropwise, and the reaction was stirred overnight at room temperature. Filter, wash the filter cake with THF, combine the filtrate and washings, and remove THF by rotary evaporation. The residue was dissolved in 15 mL of chloroform, then petroleum ether was added until cloudy, and after standing at room temperature, the precipitated solid was removed by filtration. The filtrate was rotary evaporated to remove the solvent to obtain 3.67 g of viscous liquid with a yield of 59.8%.

[0026] The second step: the synthesis of N-[5-[N-(tert-butoxycarbonyl)a...

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Abstract

The synthesis of anticancer medicine Raltitrexed with 2, 5-thienyl diformic acid and diethyl glutamate as initial material and through six reaction steps of monocondensation, rearrangement, N-methylation, e;limination of tert-butoxy carbonyl group, condensation with 6-bromomethyl-2-methyl-4-quinbolone and saponification. The present invention has total yield of 18.1%, higher than that of available synthesis line, less reaction steps, mild condition and simple operation, and is suitable for mass production.

Description

technical field [0001] The invention belongs to a process for chemically synthesizing medicines, in particular to a new process for synthesizing anticancer drug Raltitrexed. Background technique [0002] Raltitrexed is a quinazoline antifolate that produces antitumor effects by specifically inhibiting thymidylate synthase (TS), an enzyme that converts deoxyuridine monophosphate (dUMP) into It is converted into deoxythymidine monophosphate (dTMP), which is one of the key enzymes in the process of DNA biosynthesis. Raltitrexed is quickly metabolized into multiple forms of polyglutamic acid in the cell and exerts a stronger enzyme inhibitory effect than the parent drug. In the treatment of colorectal cancer, its efficacy is better than or similar to that of 5-fluorouracil Combining with folinic acid, but avoiding the toxic and side effects of 5-fluorouracil and complicated administration methods, it has become the first-line drug for the treatment of advanced colorectal cancer...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61P35/00C07D409/12
Inventor 曹胜利
Owner CAPITAL NORMAL UNIVERSITY
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