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Improved process of preparing Raltitrexed

A technology of raltitrexed and a process method, which is applied in the field of medicine, can solve the problems of restricting industrialization, high toxicity of bromine, and low process yield, and achieve the effects of reducing solvent consumption and solving toxicity and safety problems

Inactive Publication Date: 2007-12-19
魏秀华
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The yield of this process is low, and the yield in terms of thiophene-2-formaldehyde is 7%, and the use of column chromatography purification limits the amplification of this product, and the use of bromine is more toxic, which limits the industry of this variety change

Method used

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  • Improved process of preparing Raltitrexed

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0013] Example 1: Preparation of N-(5-methylaminothiophene-2-formyl)-L-glutamic acid diethyl ester

[0014] (N-(5-aminothiophene-2-formyl)-L-glutamic acid diethyl ester) (60g,), 2,6-lutidine (29.35g, 19.5ml,), DMF ( 150ml), the temperature was raised and protected by nitrogen gas. Iodomethane (25.98g, 11.43ml) was added dropwise at a temperature of about 50°C and protected from light. After the dropwise addition was completed, the reaction was maintained at 100° C. for 24 hours. After the heat preservation is completed, lower the temperature, add 500ml of water, and extract with ethyl acetate (3×500ml); combine the organic layers, wash with saturated brine (2×500ml), dry over anhydrous magnesium sulfate, and evaporate the organic solvent under reduced pressure to obtain a brown color 57.1 g of oily product, yield: 91.2%.

Embodiment 2

[0015] Example 2: Preparation of (N-(5-aminothiophene-2-formyl)-L-diethyl glutamate)

[0016] Put (N-(5-nitrothiophene-2-formyl)-L-glutamic acid diethyl ester) (180g), methanol (500ml) and water (500ml) in sequence in a 2000ml three-necked bottle, sodium sulfide (195g) was slowly heated up to 70°C, and kept for 5 hours for reaction. TLC (developing agent: ethyl acetate: n-hexane = 2: 1) detects the end point of the reaction. After the reaction solution has no raw material spots, stop the reaction, add diatomaceous earth, filter with suction, concentrate the filtrate to dryness, and then add 500 ml of dichloromethane. Wash twice with water, dry over anhydrous magnesium sulfate, filter with suction, and concentrate the filtrate under reduced pressure to obtain 135 g of brown oil, yield: 82.1%.

Embodiment 3

[0017] Example 3: N-[5-[N-methyl-N-(2-methyl-4-oxo-3,4-dihydroquinoline-6-methyl)amino]-2-thiophenoyl Preparation of ]-L-diethyl glutamate

[0018] Diethyl N-(5-methylaminothiophene-2-formyl)-L-glutamate (25g), 2,6-lutidine (7.82g,), DMF (430ml) and 2- Methyl-6-bromomethyl-4-oxo-3,4-dihydroquinazoline (21.44g) was added into a 1000ml reaction flask, the temperature was raised and protected by nitrogen, and the reaction was kept at 80°C-85°C for 18 hours. After the heat preservation was completed, DMF was evaporated under reduced pressure. Cool down, add 500ml of water, and extract with ethyl acetate (3×600ml); combine the organic layers, wash with saturated brine (2×500ml), dry over anhydrous magnesium sulfate, and distill off the organic solvent under reduced pressure, the residue in Add 60ml of methanol, move it to a reaction bottle, slowly add 300ml of ether dropwise under stirring, crystallize, and filter with suction to obtain 35.8g of the product, yield: 95.1%.

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Abstract

The improvement in the process of preparing Raltitrexed as antitumor medicine includes the reaction between N-(5-aminothienyl-2-formoxyl)-L-diethyl glutarate and methyl iodide at temperature raised to 100 deg.c in lucifugous condition with yield raised to 91 %; the replacement of sodium sulfide for iron powder as reductant to facilitate post-treatment and raise yield; the replacement of re-crystallization in mixed solvent of methanol and ether for column separation to expand the production capacity; and oxidizing 5-nitrothienyl-2-formaldehyde with chromic acid, rather than bromine, to eliminate toxicity and raise safety. The improved preparation process of Raltitrexed has high yield, great production capacity, low solvent consumption and high safety.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to an improvement of a process method of an antineoplastic drug raltitrexed. Background technique [0002] Raltitrexed is an antineoplastic drug for the treatment of advanced colon cancer, head and neck tumors, and hormone-resistant prostate cancer. It is the first new first-line cytotoxic agent for the treatment of colorectal cancer registered in the UK in 30 years. There has been no new drug in the field of colon cancer treatment for 40 years, and its effect in the treatment of colon and rectal cancer has been hailed as a major advancement in the past 35 years. Raltitrexed is a quinazoline folate analog whose anticancer effects are produced through the specific inhibition of thymidine synthase. Its characteristics: (1) curative effect is similar to that of fluorouracil; (2) less toxic and side effects; (3) can replace fluorouracil. [0003] [0004] Raltitrexed preparation pat...

Claims

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Application Information

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IPC IPC(8): C07D409/12A61K31/517A61P35/00
Inventor 魏秀华
Owner 魏秀华
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