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Synthesis of two types of abiraterone derivatives

A technology of abiraterone and abiraterone ester, which is applied in the field of preparation of organic compounds, can solve the problems of enhanced toxicity and side effects, poor water solubility, insoluble, etc., and achieves the effect of low cost, easy operation and high-efficiency preparation

Inactive Publication Date: 2017-07-25
HUNAN NORMAL UNIVERSITY
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  • Abstract
  • Description
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Problems solved by technology

The reason why abiraterone acetate is used as the prodrug of abiraterone is that abiraterone has extremely poor water solubility. After being transformed into abiraterone acetate, the water solubility has improved, but it is still insoluble (<1 mg / mL)
Because abiraterone acetate has poor water solubility, the market is only sold in tablets, and other dosage forms are still blank
This requires increasing the dose to improve the curative effect, leading to a sharp increase in the cost of medication and increased toxicity and side effects

Method used

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  • Synthesis of two types of abiraterone derivatives

Examples

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Effect test

Embodiment 1

[0022] Example 1. β- N -methyl- N 1 , N 1 -Di-n-heptylcarbamate-Py- N - Preparation of Methyl-Abiraterone Ester Nanoparticles:

[0023]Add ethylenediamine (1.9 g, 33.3 mmol) into a 100.0 mL eggplant-shaped flask, dissolve it with methanol (50.0 mL), add triethylamine (10.1 g, 100.0 mmol) under stirring, and di-tert-butyl dicarbonate Esters (7.3 g, 33.3 mmol) were dissolved in methanol (60.0 mL), then added dropwise, after the addition was completed, the reaction was carried out at room temperature, TLC (V 乙酸乙酯 : V 甲醇 = 5:1) Monitor the reaction until no significant change. After concentration, a white solid precipitated, washed with water three times, filtered with suction, and concentrated the filtrate to obtain a yellow liquid compound (2-aminoethyl) tert-butyl carbamate (3.0 g, 56.6%). 1 H NMR (500 MHz, CDCl 3 ):δ (ppm) 5.01 (s, 1 H, CH 2 N H CO), 3.12-3.11 (d, 2 H, NHC H 2 CH 2 NH 2 ), 2.75-2.73 (m,2 H, NHCH 2 C H 2 NH 2 ), 1.39 (s, 9 H, (C H 3 ) 3 ...

Embodiment 2

[0029] Example 2. β- N -methyl- N 1 , N 1 -Dioctylcarbamate-Py- N - Preparation of Methyl-Abiraterone Ester Nanoparticles:

[0030] Add the compound (2-aminoethyl) tert-butyl carbamate (4.0 g, 25.0 mmol) into a 100.0 mL round bottom flask, dissolve it in ethyl acetate, add anhydrous K under stirring 2 CO 3 (13.8 g, 100.0 mmol), 1-bromooctane (19.3 g, 100.0 mmol ). The reaction mixture was at 70 o C under reflux reaction 48 h, TLC (V 石油醚 : V 乙酸乙酯 = 5 : 1) Monitor the reaction until the basic reaction of the starting material is complete. Filter and concentrate. by column chromatography (eluent: V 石油醚 : V 乙酸乙酯 = 5 : 1) separated and purified to obtain a white solid (2-( N 1 , N 1 -Dioctyl)ethyl)carbamate (6.1 g, 58.9%). 1 H NMR (500 MHz, CDCl 3 ): δ (ppm) 5.0 (s, 1 H, N H CH 2 CH 2 ), 3.13-3.12 (d, 2 H, NHC H 2 CH 2 ),2.48-2.46 (m, 2 H, NHCH 2 C H 2 ), 2.38-2.35 (m, 4 H, N(C H 2 CH 2 ) 2 ), 1.43 (s, 9 H, (C H 3 ) 3 C), 1.39-1.37 (m, 4 H, N(CH...

Embodiment 3

[0034] Example 3. β- N -methyl- N 1 , N 1 -Didecylcarbamate-Py- N - Preparation of Methyl-Abiraterone Ester Nanoparticles:

[0035] Add the compound imidazole carbamate abiraterone (4.0 g, 25.0 mmol) into a 100.0 mL round bottom flask, dissolve it in ethyl acetate, add anhydrous K under stirring 2 CO 3 (13.8 g, 100.0 mmol), 1-bromodecane (22.1 g, 100.0 mmol ). The reaction mixture was at 70 o C under reflux for 48 h, with TLC (V 石油醚 : V 乙酸乙酯 = 5 : 1) Monitor until the raw material no longer changes. Filter and concentrate. by column chromatography (eluent: V 石油醚 : V 乙酸乙酯 = 5 : 1) Separated and purified to obtain a white solid (2-( N 1 , N 1 -didecyl)ethyl)carbamate (1.0 g, 61.8%). 1 H NMR (500 MHz, CDCl 3 ): δ (ppm) 5.0 (s, 1 H N H CH 2 CH 2 ), 3.14-3.13 (d, 2 H NHC H 2 CH 2 ), 2.49-2.47(m, 2 H, NHCH 2 C H 2 ), 2.39-2.36 (m, 4 H, N(C H2 CH 2 ) 2 ), 1.44 (s, 9 H, (C H 3 ) 3 C),1.40-1.38 (m, 4 H, N(CH 2 C H 2 ) 2 ), 1.30-1.26 (d, 36 H, 2 C...

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Abstract

The invention discloses preparation methods of two types of abiraterone derivatives. The preparation method of a first type of abiraterone derivatives comprises the following steps: by taking ethanediamine as a raw material, carrying out monoprotection on amino by using (Boc)2O, carrying out tertiary amination, and carrying out deprotection of trifluoroacetic acid to obtain N1,N1-di-n-alkyl-1,2-diamine; reacting abiraterone with CDI, then carrying out condensation reaction with the N1,N1-di-n-alkyl-1,2-diamine, and finally carrying out quaternary ammonium salinization reaction to prepare beta-N-methyl-N1,N1-di-n-alkyl carbamic acid-Py-N-methyl -abiraterone ester with different alkane chains. The preparation method of a second type of abiraterone derivatives comprises the following steps: by taking ethanediamine as a raw material, carrying out monoprotection on amino by using (Boc)2O, carrying out tertiary amination, carrying out quaternary ammonium salinization and carrying out deprotection of trifluoroacetic acid to obtain N-methyl-N1,N1-dialkyl ethanediamine; reacting abiraterone with nitrophenyl chloroformate, then carrying out condensation reaction with N-methyl-N1,N1-dialkyl ethanediamine to prepare beta-N-methyl-N1,N1-di-n-alkyl carbamic acid abiraterone ester with different alkane chains. The prepared abiraterone derivatives contain hydrophilic quaternary ammonium salt groups; compared with the abiraterone, the home-made two types of abiraterone derivatives are expected to have high water solubility.

Description

technical field [0001] The present invention relates to the synthesis method of two kinds of abiraterone derivatives. The invention belongs to the technical field of preparation of organic compounds. Background technique [0002] Cancer has been a troublesome disease since its inception in Egyptian textbooks. Today, despite tremendous advances in biology and medicine, the incidence of cancer continues to increase, reaching epidemic proportions. It is expected to increase from 14 million cases recorded in 2012 to 22 million over the next two decades. Before the advent of modern medicine, cancer was treated by cutting tumors with a knife, cauterizing them with red-hot irons, fumigation, etc. Today, surgery, radiation therapy, chemotherapy, immunotherapy, targeted therapy, hormone therapy, and stem cell transplant are used to successfully treat cancer. In January 2016, CA announced the latest cancer statistics in China and the United States. These data show that cancer is ...

Claims

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Application Information

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IPC IPC(8): C07J43/00
CPCC07J43/003
Inventor 曾佑林张翻刘美艳
Owner HUNAN NORMAL UNIVERSITY
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