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The synthetic method of raltitrexed

A technology for raltitrexed and a compound is applied in the field of raltitrexed synthesis, and can solve the problems of unobtainable raw materials, large environmental pollution, complicated and lengthy synthesis steps and the like

Active Publication Date: 2021-05-04
SHANGHAI DINGYA PHARM CHEM CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] The technical problem to be solved by the present invention is to provide a synthetic method of anticancer drug raltitrexed, which overcomes the defects in the prior art that the raw materials are not easy to obtain, the environment is polluted, the synthetic steps are complex and lengthy, and the reaction time is long. total reaction yield

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  • The synthetic method of raltitrexed
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  • The synthetic method of raltitrexed

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Experimental program
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Effect test

Embodiment 1

[0053] Embodiment one The experimental condition screening of preparation method of the present invention

[0054] Now mainly illustrate the synthesis process research process of the intermediate compound 1 of the present invention.

[0055] (1), preparation of 6-((methylamino)methyl)-3,4-dihydro-2-methyl-4-oxo-6-quinazoline (compound 1)

[0056] .

[0057] The reaction step is an amination reaction, and the raw material 6-bromomethyl-3,4-dihydro-2-methyl-4-oxo-6-quinazoline reacts with methylamine to obtain 6-((methylamino) Methyl)-3,4-dihydro-2-methyl-4-oxo-6-quinazoline (Compound 1). In the research, the solvent was first screened. We used small molecule alcohol as the solvent. The experimental results found that in the alcohol solvent, the reaction occurred rapidly. In 10 to 20 minutes, TLC detected the raw material 6-bromomethyl-3,4-di The reaction of hydrogen-2-methyl-4-oxo-6-quinazoline is complete, but there are many impurity spots and the impurity situation is co...

Embodiment 2

[0094] Embodiment 2 Using scheme one method to prepare raltitrexed

[0095] (1) Preparation of 6-((methylamino)methyl)-3,4-dihydro-2-methyl-4-oxo-6-quinazoline (compound 1)

[0096] .

[0097] Slowly add 6-bromomethyl-3,4-dihydro-2-methyl-4-oxo-6-quinazoline (m =25.3g, n=0.1mol), the temperature is controlled at -10°C~-5°C, after the dropwise addition is completed, the temperature is gradually raised to room temperature, and the stirring is continued to confirm that the reaction is complete (TLC detection). Add sodium bicarbonate solution to the reaction solution, adjust the pH to alkaline (pH>7), extract with dichloromethane, wash the organic phase with saturated aqueous sodium chloride solution, remove the solvent by rotary evaporation of the organic phase, and then add 500 mL of water for beating , stirred for 30 minutes, filtered, the filter cake was washed with water (3×100mL), drained and dried to obtain an off-white solid (14.1g, 69.4%).

[0098] 1 H NMR (400 MHz,...

Embodiment 3

[0115] Embodiment 3 Adopt scheme two method to prepare raltitrexed

[0116] (1), the preparation of N-(5-bromothiophen-2-yl) diethyl glutamate (compound 5)

[0117] .

[0118] Add 200mL DMF, 10.15g diethyl L-glutamate (1eq), 11.39g 5-bromothiophene-2-carboxylic acid (1.1eq), 10.13g HOBT (1.5eq), 19.35g N,N - Diisopropylethylamine (3eq), 14.40g EDCI (1.5eq), under the condition of nitrogen protection, the reaction was stirred at room temperature, after the reaction was complete, 500mL ethyl acetate was added for extraction, and the mixture was washed 5 times with saturated brine , the organic phase was dried with anhydrous sodium sulfate, filtered, the solvent was evaporated, and dried to obtain 16.50 g of N-(5-bromothiophen-2-yl) diethyl glutamate, with a yield of 84.2%.

[0119] 1 H NMR (CDCl 3 ) δ7.30-7.27(m, 1H), 7.05-7.03(m, 1H), 7.01-6.98(m, 1H),4.72-4.68 (m, 1H), 4.24-4.22(m, 2H), 4.13- 4.10(m, 2H), 2.52-2.37(m, 2H), 2.31-2.25(m, 1H), 2.17-2.13(m, 1H), 1.31-1.29(m...

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Abstract

The present invention provides two methods for preparing the compound of formula 4. Scheme 1 uses methyl 5-bromothiophene-2-formate as raw material, and 6-((methylamino)methyl)-3,4-dihydro-2- Methyl-4-oxo-6-quinazoline (compound 1) reacts to prepare 2-[N-(2-methyl-4-oxyquinazoline-6-methyl)-N-methyl]- Aminothiophene-2-formic acid methyl ester is then hydrolyzed in an aqueous alkali solution, and the compound of formula 4 is obtained through condensation reaction with L-diethyl glutamate; scheme two uses 5-bromothiophene-2-formic acid as raw material and N-(5-bromothiophene-2-yl) diethyl glutamate is obtained through condensation of L-glutamic acid diester, and reacts with formula 1 compound to make formula 4 compound; The present invention also provides a kind of preparation In the method of raltitrexed, the compound of formula 4 is hydrolyzed in an aqueous alkali solution, and then acidified with hydrochloric acid to prepare raltitrexed. The synthesis route adopted by the invention has few reaction steps, simple and convenient operation, little environmental pollution and high product yield.

Description

technical field [0001] The present invention relates to the synthesis of an antineoplastic drug, in particular to a synthesis method of raltitrexed. Background technique [0002] Raltitrexed (Raltitrexed) is an antineoplastic drug developed by the British Zeneca Pharmaceutical Company in the late 1980s. Its chemical name is N-[5-[N-[(3,4-dihydro-2- Methyl-4-oxo-6-quinazolinyl)-methyl]-N-methylamino]-2-thienyl]-L-glutamic acid hydrochloride, the structural formula is as follows: [0003] . [0004] The synthetic method of raltitrexed reported in the literature mainly contains two kinds, and method one uses 5-nitro-2-thiophenecarboxylic acid (2) as starting material, after esterification and nitro reduction, there is an esterification reaction with acetic anhydride Obtain 5-(N-acetylaminothiophene-2-methyl carboxylate (5). Compound (5) undergoes methylation reaction with methyl iodide under the action of potassium carbonate, and after deprotection in hydrochloric acid, est...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D409/12
CPCC07D409/12
Inventor 阮诗文詹家明严恭超徐丽萍
Owner SHANGHAI DINGYA PHARM CHEM CO LTD
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