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Aryl nitrogen mustard derivative N,N-di(2-chloroethyl)-N'-propionyl-1,4-phenylenediamine and preparation method thereof

A technology of arylamine nitrogen mustard and chloroethyl, which is applied in the preparation of carboxylic acid amide, amino compound, organic compound, etc., can solve the problems of reducing the body's defense function, blocking and killing, and achieve the goal of reducing complications risk, enhanced therapeutic index, and reduced toxicity

Inactive Publication Date: 2017-05-10
CHANGAN UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0002] Nitrogen mustards are commonly used anti-tumor drugs with particularly good anti-tumor activity. However, as traditional cytotoxic drugs, they still have the unique disadvantages of bioalkylating agents. At the same time, it also has an inhibitory effect on other normal cells that proliferate rapidly, for example, it also has the effect of blocking and killing some bone marrow cells, intestinal epithelial cells, and some hair cells, which will cause nausea, vomiting, Hair loss and other serious adverse reactions; in addition, nitrogen mustard drugs also have immunosuppressive effects, which will reduce the body's defense function, allowing bacteria and viruses to enter and cause various infections

Method used

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  • Aryl nitrogen mustard derivative N,N-di(2-chloroethyl)-N'-propionyl-1,4-phenylenediamine and preparation method thereof
  • Aryl nitrogen mustard derivative N,N-di(2-chloroethyl)-N'-propionyl-1,4-phenylenediamine and preparation method thereof
  • Aryl nitrogen mustard derivative N,N-di(2-chloroethyl)-N'-propionyl-1,4-phenylenediamine and preparation method thereof

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preparation example Construction

[0039] The preparation method of the above-mentioned arylamine nitrogen mustard derivative N,N-bis(2-chloroethyl)-N'-propionyl-1,4-phenylenediamine comprises the following steps:

[0040] Step 1, preparing N,N-bis(2-chloroethyl)-1,4-phenylenediamine;

[0041] Substep 1a, first prepare N,N-di(2-hydroxyethyl)-4-nitroaniline according to the following steps: 4-chloronitrobenzene, diethanolamine, potassium carbonate and 1% CuSO 4Add the solution into the reactor one by one, stir evenly, when the temperature rises to 82°C, add toluene into the reactor, continue to heat up to 115-120°C, keep stirring at a constant temperature for 6-9 hours, after the reaction is complete, remove the toluene by distillation, distill The final mother liquor was poured into hot water at 40°C-60°C, stirred, and after standing overnight, the water layer was suction filtered to obtain the crude product, which was recrystallized with absolute ethanol to obtain yellow needle-shaped crystals N,N-di( 2-Hydro...

Embodiment 1

[0046] 1.1 Synthesis of N,N-bis(2-hydroxyethyl)-4-nitroaniline

[0047]

[0048] Add 12.64g (0.080mol) of 4-chloronitrobenzene, 10.99g (0.104mol) of diethanolamine and 7.18g (0.052mol) of potassium carbonate in a 250mL three-necked flask, and finally add 1.2mL of CuSO with a mass percentage concentration of 1%. 4 well mixed. Heat to raise the temperature. When the temperature reaches 82°C, add 5.0mL of toluene to the reaction liquid, continue to raise the temperature to control the reaction temperature to 117°C, use thin-layer chromatography to track the reaction progress, and stir at constant temperature for 6h. After the reaction is complete, toluene is removed by distillation, and the mother liquor after distillation is poured into hot water at 60°C, stirred vigorously, left to stand overnight, and then filtered to remove the water layer to obtain the crude product, which is recrystallized with absolute ethanol to obtain yellow needle-shaped crystals N,N-bis(2-hydroxyet...

Embodiment 2

[0059] 1.1 Synthesis of N,N-bis(2-hydroxyethyl)-4-nitroaniline

[0060]

[0061] Add 4-chloronitrobenzene, diethanolamine and potassium carbonate at a molar ratio of 1:1.2:0.6 to a 250mL three-necked flask, and finally add CuSO with a mass concentration of 1%. 4 solution, and the mass concentration is 1% CuSO 4 The dosage ratio of the solution to 4-chloronitrobenzene is 0.5mL:3g, mix well; heat up the temperature, when the temperature reaches 82°C, add toluene to the reaction solution, and the dosage of toluene and 4-chloronitrobenzene The ratio was 1mL:2g; continue to increase the temperature to control the reaction temperature to 120°C, use thin-layer chromatography to track the reaction progress, and stir the reaction at constant temperature for 9h. After the reaction is complete, toluene is removed by distillation, and the mother liquor after distillation is poured into hot water at 60°C, stirred vigorously, left to stand overnight, and the water layer is removed by su...

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Abstract

The invention particularly discloses a structural formula and preparation method of an aryl nitrogen mustard derivative N,N-di(2-chloroethyl)-N'-propionyl-1,4-phenylenediamine. The method comprises the following steps: preparing N,N-di(2-chloroethyl)-1,4-phenylenediamine; adding the N,N-di(2-chloroethyl)-1,4-phenylenediamine, dichloromethane and triethylamine into a reactor, cooling in an ice water bath, stirring, and dropwisely adding a propionyl chloride-dichloromethane mixed solution into the reactor; after finishing the dropwise addition, removing the ice water bath, and reacting at room temperature for 4-14 hours; and after the reaction finishes, washing the reaction solution, drying with anhydrous cupric sulfate, carrying out atmospheric distillation, and purifying the filter cake. The aryl nitrogen mustard derivative can effectively lower the toxic and side effects of nitrogen mustards on the premise of enhancing the therapeutic index of the nitrogen mustards, and has the curative effects of killing germs and diminishing inflammation, thereby lowering the risk of complications caused by decrease in immunity of the patient after chemotherapy.

Description

technical field [0001] The invention relates to the technical field of nitrogen mustard antitumor drugs, in particular to N,N-di(2-chloroethyl)-N'-propionyl-1,4-phenylenediamine, an arylamine nitrogen mustard derivative, and its preparation method. Background technique [0002] Nitrogen mustards are commonly used anti-tumor drugs with particularly good anti-tumor activity. However, as traditional cytotoxic drugs, they still have the unique disadvantages of bioalkylating agents. At the same time, it also has an inhibitory effect on other fast-proliferating normal cells, such as some bone marrow cells, intestinal epithelial cells, and some hair cells, which can cause nausea, vomiting, Hair loss and other serious adverse reactions; in addition, nitrogen mustard drugs also have an immunosuppressive effect, which will reduce the body's defense function, allowing bacteria and viruses to enter and cause various infections. [0003] Nitrogen mustard anti-tumor drugs are composed o...

Claims

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Application Information

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IPC IPC(8): C07C231/02C07C233/80A61P35/00A61P31/00A61P29/00
CPCC07C209/325C07C209/74C07C213/00C07C231/02C07C233/80
Inventor 李春荣李发明邓红章郭靖茹王广华姬雨
Owner CHANGAN UNIV
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