Nitrogen mustard derivative n,n-di(2-chloroethyl)-n'-tetradecanoyl-1,4-phenylenediamine and its preparation method

A tetradecanoyl and chloroethyl technology, applied in the preparation of carboxylic acid amides, amino compounds, and organic compounds, etc., can solve problems such as blocking and killing, reducing the body's defense function, etc., to enhance the therapeutic index, reduce Risk of complications, effect of reducing toxic side effects

Inactive Publication Date: 2019-05-03
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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  • Nitrogen mustard derivative n,n-di(2-chloroethyl)-n'-tetradecanoyl-1,4-phenylenediamine and its preparation method
  • Nitrogen mustard derivative n,n-di(2-chloroethyl)-n'-tetradecanoyl-1,4-phenylenediamine and its preparation method
  • Nitrogen mustard derivative n,n-di(2-chloroethyl)-n'-tetradecanoyl-1,4-phenylenediamine and its preparation method

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preparation example Construction

[0039] The preparation method of the above-mentioned nitrogen mustard derivative N,N-bis(2-chloroethyl)-N'-tetradecanoyl-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 50°C-70°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-Hydroxyethy...

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 solution, mix well. 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 50°C, stirred vigorously, left to stand overnight, and the water layer is removed by suction filtration to obtain a crude product, which is recrystallized with absolute ethanol to obtain a yellow needle Crystalline N,N-bi...

Embodiment 2

[0060] 1.1 Synthesis of N,N-bis(2-hydroxyethyl)-4-nitroaniline

[0061]

[0062] 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 specifically discloses the structural formula of a nitrogen mustard derivative N,N-di(2-chloroethyl)-N'-tetradecanoyl-1,4-phenylenediamine; and a preparation method thereof: firstly prepare N, N-bis(2-chloroethyl)-1,4-phenylenediamine; then N,N-bis(2-chloroethyl)-1,4-phenylenediamine, dichloromethane and triethylamine into the reactor, cooled in an ice-water bath, stirred, and added dropwise a mixed solution of myristyl chloride and dichloromethane to the reactor, after the dropwise addition was completed, the ice-water bath was removed, and the room temperature was reacted for 10-14 hours. After the reaction was complete, The reaction solution is washed, dried with anhydrous copper sulfate, and distilled at normal pressure, and the distilled filter cake is purified to obtain the obtained product. Under the premise of enhancing the nitrogen mustard therapeutic index, the nitrogen mustard derivatives of the present invention can effectively reduce the toxic and side effects of the nitrogen mustard, and at the same time have the curative effects of sterilization and anti-inflammation, so as to reduce the symptoms caused by the decreased immunity of patients after chemotherapy. risk of complications.

Description

technical field [0001] The invention relates to the technical field of nitrogen mustard antitumor drugs, in particular to a nitrogen mustard derivative N,N-di(2-chloroethyl)-N'-tetradecanoyl-1,4-phenylenediamine and its Preparation. 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 of two parts in t...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C233/43C07C231/02A61P35/00A61P29/00A61P31/00
CPCC07C209/325C07C209/74C07C213/02C07C231/02C07C233/43C07C215/16C07C211/52C07C211/51
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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