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Raltitrexed related substance C as well as preparation and application thereof

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

Inactive Publication Date: 2018-02-23
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 C as well as preparation and application thereof
  • Raltitrexed related substance C as well as preparation and application thereof
  • Raltitrexed related substance C as well as preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Example 1 Preparation of N-(5-methylamino-2-thiophenoyl)-L-glutamic acid diethyl ester

[0039] Add 10g of 5-nitro-2-thiophenecarboxylic acid and 20ml of thionyl chloride into the reaction flask, raise the temperature and reflux for 3 hours, transfer the reaction solution to a single-necked flask, concentrate until no liquid flows out, and dissolve it in 30ml of dichloromethane for later use . Add 13.8g of diethyl L-glutamate, 20.6g of triethylamine, and 50ml of dichloromethane into a 150ml three-neck flask, stir and cool down to 0-5°C, and slowly add the dichloromethane solution of the concentrate dropwise. After dropping, keep warm for 1 hour. After the reaction, wash with 100 ml of 2 mol / L hydrochloric acid and 100 ml of saturated sodium bicarbonate solution successively. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated to obtain 16.53 g of N-(5-nitro-2-thiophenoyl)-L-glutamic acid diethyl ester with a yield of 79.9%.

[0040]...

Embodiment 2

[0042] Example 2 Preparation of Intermediate 2

[0043] Add 8.02g of N-(5-methylamino-2-thiophenoyl)-L-glutamic acid diethyl ester, 8g of Boc anhydride, and 100ml of absolute ethanol into the reaction flask, stir and heat up to reflux, and continue the reaction for 2 hours. TLC monitored the reaction to the end point, distilled off ethanol, added 100ml of ethyl acetate, extracted 150ml of purified water in two equal parts, removed the water phase, added 20g of anhydrous magnesium sulfate to the organic phase, stirred and dried for 1 hour, and suction filtered to obtain the filtrate. The solvent was distilled off to obtain 10.29 g of an oily yellow liquid (Intermediate 2), with a yield of 96%.

Embodiment 3

[0044] Example 3 Preparation of Intermediate 3

[0045] 10.29g intermediate 2, 3.26g AlCl 3, 15.62g of 6-bromomethyl-3,4-dihydro-2-methyl-quinazolin-4-one and 90ml of DMF were added to the reaction flask, replaced with nitrogen three times, slowly heated to 100°C, and kept for 12 hours. Cool to room temperature, add 100ml of purification and stir, wash with 150ml of ethyl acetate three times evenly, discard the lower aqueous phase, add 30g of anhydrous magnesium sulfate to the organic phase, stir and dehydrate for 1 hour, filter with suction to obtain the filtrate, distill the filtrate to obtain an oil things.

[0046] Add 200ml of ethyl acetate to the obtained oil, mix the sample with 1.2 times the mass of silica gel, spin dry to make a sandy shape, dry the sample, add 5 times the mass of silica gel and two layers of filter paper to the upper layer of the sample layer, and use the eluent ethyl acetate Esters were eluted and TLC monitored the start and end of eluate collecti...

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Abstract

The invention discloses a raltitrexed related substance C with inhibition activity on dihydrofolate reductase and methionine synthetase, a preparation method and application thereof as an impurity control group.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular 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 folic acid analogue thymidylate synthase inhibitor developed by Zeneca, UK, and is suitable for advanced colorectal cancer. Inhibition produces anti-tumor effect. 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 the US patent (US4992550 , 1991) provided two main methods in the synthesis of raltitrexed, one method is to use 2-thiophenecarboxyl...

Claims

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Application Information

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IPC IPC(8): C07D409/06G01N30/02A61P35/00
CPCC07D409/06G01N30/02
Inventor 田舟山童耀单海霞吴舰柴雨柱王华萍徐丹朱春霞
Owner NANJING CHIA TAI TIANQING PHARMA
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