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

A technology of chloroethyl and derivatives, which is applied in the preparation of carboxylic acid amides, amino compounds, organic compounds, etc., can solve the problems of blocking and killing, reducing the body's defense function, etc., to enhance the therapeutic index and reduce concurrent The risk of disease and the effect of reducing toxic side effects

Inactive Publication Date: 2019-05-03
CHANGAN UNIV
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  • Summary
  • 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-bis(2-chloroethyl)-n'-hexadecanoyl-1,4-phenylenediamine and its preparation method
  • Nitrogen mustard derivative n,n-bis(2-chloroethyl)-n'-hexadecanoyl-1,4-phenylenediamine and its preparation method
  • Nitrogen mustard derivative n,n-bis(2-chloroethyl)-n'-hexadecanoyl-1,4-phenylenediamine and its preparation method

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preparation example Construction

[0038] The preparation method of the above-mentioned nitrogen mustard derivative N,N-bis(2-chloroethyl)-N'-hexadecanoyl-1,4-phenylenediamine comprises the following steps:

[0039] Step 1, preparing N,N-bis(2-chloroethyl)-1,4-phenylenediamine;

[0040] Substep 1a, first prepare N,N-di(2-hydroxyethyl)-4-nitroaniline according to the following steps: 4-chloronitrobenzene, diethanolamine, potassium carbonate and 1% CuSO 4 The solution is added to the reactor in turn, and stirred evenly, the CuSO 4For the solution, when the temperature is raised to 82°C, add toluene into the reactor, continue to heat up to 115-120°C, and stir at a constant temperature for 6-9 hours. Use thin-layer chromatography to track the reaction process. After the reaction is complete, distill to remove the toluene. Pour the remaining liquid after distillation into hot water at 50°C-70°C, stir, and after standing overnight, filter the water layer to obtain the crude product. Use absolute ethanol to recrystal...

Embodiment 1

[0045] 1.1 Synthesis of N,N-bis(2-hydroxyethyl)-4-nitroaniline

[0046]

[0047] Add 12.64g (0.080mol) of 4-chloronitrobenzene, 10.99g (0.104mol) and 7.18g (0.052mol) of potassium carbonate to a 250mL three-necked flask respectively, and finally add 1.2mL of CuSO with a mass 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 remaining liquid 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 11.39 g of N,N-bis(2-hydroxyeth...

Embodiment 2

[0058] 1.1 Synthesis of N,N-bis(2-hydroxyethyl)-4-nitroaniline

[0059]

[0060] 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 discloses a structural formula of a nitrogen mustard derivative N,N-bis(2-chloroethyl)-N'-hexadecanoyl-1,4-phenylenediamine; and a preparation method thereof: first preparing N,N ‑bis(2‑chloroethyl)‑1,4‑phenylenediamine; then the reaction starting materials N,N‑bis(2‑chloroethyl)‑1,4‑phenylenediamine, dichloromethane and triethylamine Put it into the reactor, cool it in an ice-water bath, stir, and add dropwise the mixed solution of hexadecanoyl chloride and dichloromethane into the reactor. After the dropwise addition is completed, remove the ice-water bath and react at room temperature for 12-14 hours. , wash the reaction solution, dry, and distill at atmospheric pressure, and purify the distilled filter cake to obtain. The arylamine nitrogen mustard derivative of the present invention can effectively reduce the toxic and side effects of the nitrogen mustard under the premise of enhancing the therapeutic index of the nitrogen mustard, and at the same time have the effects of sterilization and anti-inflammation, so as to reduce the symptoms of the patient due to decreased immunity 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-bis(2-chloroethyl)-N'-hexadecanoyl-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): C07C233/43C07C231/02A61P35/00A61P37/06A61P31/00A61P29/00
CPCC07C209/36C07C231/02C07C233/43C07C211/51
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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