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Raltitrexed-related substance F and preparation and applications thereof

A technology of raltitrexed, related substances, applied in the field of medicinal chemistry

Inactive Publication Date: 2019-01-29
NANJING CHIA TAI TIANQING PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] No matter which method is used above, it all needs to be docked with the key intermediate 6-bromomethyl-3,4-dihydro-2-methyl-quinazolin-4-one during the reaction process. A brand-new impurity will be formed in raltitrexed, and there is no relevant literature to report it, so confirming the structure of the impurity and reasonably controlling its content in the finished product are particularly important for improving the quality of raltitrexed.

Method used

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  • Raltitrexed-related substance F and preparation and applications thereof
  • Raltitrexed-related substance F and preparation and applications thereof
  • Raltitrexed-related substance F and preparation and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Example 1: Preparation of N-(5-methylamino-2-thenoyl)-L-glutamic acid diethyl ester

[0047] Add 10g of 5-nitro-2-thiophenecarboxylic acid and 20ml of thionyl chloride into the reaction flask, heat and reflux for 3 hours, transfer the reaction solution to a single-necked flask, concentrate until no liquid flows out, and dissolve it with 30ml of dichloromethane. . Add 13.8g of L-glutamic acid diethyl ester, 20.6g of triethylamine, and 50ml of dichloromethane into a 150ml three-necked flask, stir and cool to 0-5°C, slowly add the dichloromethane solution of the concentrate dropwise. After dripping, the reaction is kept for 1 hour. After the reaction is over, wash with 100ml of 2mol / L hydrochloric acid and 100ml of saturated sodium bicarbonate solution in sequence. The organic phase was separated, dried over anhydrous sodium sulfate, and after concentration was completed, 16.53 g of N-(5-nitro-2-thenoyl)-L-glutamic acid diethyl ester was obtained, with a yield of 79.9%.

[0...

Embodiment 2

[0050] Example 2 Preparation of related substance F

[0051] Take 3.42g of N-(5-methylamino-2-thenoyl)-L-glutamic acid diethyl ester and dissolve it with 52ml of N,N-dimethylformamide, and prepare the solution for later use. Add 7.6g of 6-bromomethyl-3,4-dihydro-2-methyl-quinazolin-4-one and 38ml of N,N-dimethylformamide into a 250ml three-necked flask, stir and heat to 85 After reaching temperature, 4.88g cesium carbonate was added. After stirring for 10 minutes, the solution of N-(5-methylamino-2-thenoyl)-L-glutamic acid diethyl ester was added dropwise. React at 85±5℃ for 6 hours. After the reaction is over, the temperature is lowered to 10-30°C, suction filtered until no liquid flows out, and the filtrate is washed twice with 300 ml of 15% sodium chloride aqueous solution. Separate the water phase and extract twice with 150 ml of dichloromethane. Combine the organic phases, add anhydrous magnesium sulfate, stir and dehydrate for 2 hours, and filter with suction until no l...

Embodiment 3

[0053] Example 3 Preparation of related substance F

[0054] Take 3.42g of N-(5-methylamino-2-thenoyl)-L-glutamic acid diethyl ester and dissolve it with 52ml of N,N-dimethylacetamide, and prepare the solution for later use. Add 7.6g of 6-bromomethyl-3,4-dihydro-2-methyl-quinazolin-4-one and 38ml of N,N-dimethylacetamide into a 250ml three-necked flask, stir and heat to 85 After reaching temperature, 4.88g cesium carbonate was added. After stirring for 10 minutes, the solution of N-(5-methylamino-2-thenoyl)-L-glutamic acid diethyl ester was added dropwise. The temperature is controlled at 55±5°C for 6 hours. After the reaction is over, the temperature is lowered to 10-30°C, suction filtered until no liquid flows out, and the filtrate is washed twice with 300 ml of 15% sodium chloride aqueous solution. Separate the water phase and extract twice with 150 ml of dichloromethane. Combine the organic phases, add anhydrous magnesium sulfate, stir and dehydrate for 2 hours, and filte...

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Abstract

The invention discloses a Raltitrexed-related substance F with raltitrexed with dihydrofolate reductase and methionine synthetase inhibitory activity, a preparation method thereof, and an applicationof the Raltitrexed-related substance F as an impurity reference substance.

Description

Technical field [0001] The invention belongs to the field of medicinal chemistry, and particularly relates to the preparation and application of a new impurity of raltitrexed. Background technique [0002] Raltitrexed (Raltitrexed) is a new generation of water-soluble quinazoline folate analog thymidylate synthase inhibitor developed by the British company Zeneca. It is suitable for advanced colorectal cancer. It is specific to thymidylate synthase. Inhibit and produce anti-tumor effects. Its chemical name is N-[[5-[[(1,4-Dihydro-2-methyl-4-oxo-6-quinazolinyl)methyl]methylamino]-2-thienyl]carbonyl] -L-glutamic acid. The structural formula is as follows: [0003] [0004] It is mainly composed of quinazolinone, thiophene and L-glutamic acid. The literature (Quinazoline AntifolateThymidylate Synthase Inhibitors: Heterocyclic Benzoyl Ring Modifications, J. Med. Chem. 1991, 34, 1594-1605) and U.S. Patent (US4992550) , 1991) gave two main methods in the synthesis of raltitrexed. One...

Claims

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Application Information

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IPC IPC(8): C07D409/14A61P35/00G01N30/02
CPCC07D409/14G01N30/02
Inventor 徐丹杨寿海汪传军吴晶柴雨柱王华萍朱春霞田舟山
Owner NANJING CHIA TAI TIANQING PHARMA
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