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Synthesis methods of raltitrexed

A compound and aqueous solution technology, applied in the field of anti-tumor drug synthesis, can solve the problems of complex and lengthy synthesis steps, unobtainable raw materials, large environmental pollution, etc., to solve the problems of toxicity and safety, avoid post-processing difficulties, and the total yield high effect

Active Publication Date: 2015-12-02
SHANGHAI DINGYA PHARM CHEM CO LTD
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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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  • Synthesis methods of raltitrexed
  • Synthesis methods of raltitrexed
  • Synthesis methods of raltitrexed

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Experimental program
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Embodiment 1

[0053] The experimental condition screening of embodiment one 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 two adopts 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 HNMR (400MHz...

Embodiment 3

[0115] Embodiment three adopts scheme two method to prepare raltitrexed

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

[0117] .

[0118] Add 200 mL of DMF, 10.15 g of L-diethylglutamate (1 eq), 11.39 g of 5-bromothiophene-2-carboxylic acid (1.1 eq), 10.13 g of HOBT (1.5 eq), 19.35 g of N,N-diisopropyl Ethylamine (3eq), 14.40gEDCI (1.5eq), under nitrogen protection conditions, stirred at room temperature for reaction, after the reaction was complete, added 500mL ethyl acetate for extraction, the mixture was washed 5 times with saturated saline, and the organic phase was washed with anhydrous Dry over sodium sulfate, filter, evaporate the solvent, and dry to obtain 16.50 g of diethyl N-(5-bromothien-2-yl)glutamate, with a yield of 84.2%.

[0119] 1 HNMR (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,3H),1.25-1.22(...

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Abstract

The invention provides two method for preparing a compound disclosed as Formula 4. The scheme 1 comprises the following steps: reacting the raw material methyl 5-bromothienyl-2-formate with 6-((methylamino)methyl)-3,4-dihydro-2-methyl-4-oxo-6-quinazoline (compound 1) to obtain methyl 2-[N-(2-methyl-4-oxoquinazolinyl-6-methyl)-N-methyl]-aminothienyl-2-formate, hydrolyzing in an alkaline water solution, and carrying out condensation reaction with diethyl L-glutamate to obtain the compound disclosed as Formula 4. The scheme 2 comprises the following steps: carrying out condensation on the raw material 5-bromothienyl-2-formic acid and di L-glutamate to obtain diethyl N-(5-bromothienyl-2-yl)glutamate, and reacting with a compound disclosed as Formula 1 to obtain the compound disclosed as Formula 4. The invention also provides a method for preparing raltitrexed, which comprises the following steps: hydrolyzing the compound disclosed as Formula 4 in an alkaline water solution, and acidifying with hydrochloric acid to obtain the raltitrexed. The synthesis route has the advantages of fewer reaction steps, low environmental pollution and high product yield, and is simple to operate.

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, and 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,...

Claims

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Application Information

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Patent Type & Authority Applications(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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