Preparation methods of tenofovir disoproxil and fumarate thereof

A technology of tenofovir and dipivoxil, which is applied in the field of compound preparation, can solve problems such as high solubility, low yield of salt-forming reaction, and excessive monoester content, and achieve simple post-processing, low impurity content, and high yield. high rate effect

Active Publication Date: 2016-10-12
NORTHEAST PHARMA GRP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The obtained oil is produced directly into salt without purification. Such a production process often leads to excessive monoester content of the final product, and tenofovir disoproxil oil contains incompletely distilled high-boiling solvents and chloroform base isopropyl carbonate, which leads to low yield of salt-forming reaction, and the residual solvent is easy to exceed the standard
Wherein the publication number is WO2014141092 and the patent of publication number is CN101870713A carries out crystallization of oily tenofovir disoproxil with ethyl acetate, although this method can obtain solid, but because ethyl acetate has greater solubility to tenofovir disoproxil, Lead to a substantial reduction in yield and high costs

Method used

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  • Preparation methods of tenofovir disoproxil and fumarate thereof
  • Preparation methods of tenofovir disoproxil and fumarate thereof
  • Preparation methods of tenofovir disoproxil and fumarate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] The impact of using different phase transfer catalysts on the reaction yield of tenofovir disoproxil:

[0020] In the reaction flask, add tenofovir monohydrate 10g (0.0328mol), phase transfer catalyst 0.025mol (see Table 1 for the selection of the phase transfer catalyst), 20mlN-methylpyrrolidone and 8.86g (0.0876mol) Triethylamine, warmed up to 50°C, stirred at this temperature for 0.5h. 21.4 g (0.14 mol) of chloromethyl isopropyl carbonate was slowly added dropwise to the reaction solution. After the dropwise addition was completed, the temperature was raised to 60° C. and stirred at this temperature for 4 h. After the reaction was completed, the reaction solution was poured into a cooled supersaturated aqueous sodium chloride solution, and stirred at -10°C for 24 hours. Suction filtration, washing with cold water, and the obtained solid was dried at 25°C in a blast drying oven. The yield and yield of the crude product are shown in Table 1. The crude product was adde...

Embodiment 2

[0025] The impact of adopting different highly polar organic solvents on the reaction yield of tenofovir disoproxil:

[0026]Add tenofovir monohydrate 10g (0.0328mol), tetrabutylammonium bromide 8g (0.0248mol), 20ml highly polar organic solvent (see the table for the selection of the highly polar organic solvent) in the reaction flask successively 2) and 8.86g (0.0876mol) of triethylamine, heated up to 50°C, and stirred at this temperature for 0.5h. 21.4 g (0.14 mol) of chloromethyl isopropyl carbonate was slowly added dropwise to the reaction solution. After the dropwise addition was completed, the temperature was raised to 60° C. and stirred at this temperature for 4 h. After the reaction was completed, the reaction solution was poured into a cooled supersaturated aqueous sodium chloride solution, and stirred at -10°C for 24 hours. Suction filtration, washing with cold water, the obtained solid was dried at 25°C in a blast drying oven, the yield and yield of the crude produ...

Embodiment 3

[0030] The impact of adopting different acid-binding agents on the reaction yield of tenofovir disoproxil:

[0031] Add tenofovir monohydrate 10g (0.0328mol), tetrabutylammonium bromide 8g (0.0248mol), 20mlN-methylpyrrolidone and 0.088mol acid-binding agent successively in reaction flask (the selection of described acid-binding agent The situation is shown in Table 3), the temperature was raised to 50°C, and stirred at this temperature for 0.5h. 21.4 g (0.14 mol) of chloromethyl isopropyl carbonate was slowly added dropwise to the reaction solution. After the dropwise addition was completed, the temperature was raised to 60° C. and stirred at this temperature for 4 h. After the reaction was completed, the reaction solution was poured into a cooled supersaturated aqueous sodium chloride solution, and stirred at -10°C for 24 hours. Suction filtration, washing with cold water, and the obtained solid was dried at 25°C in a blast drying oven. See Table 1 for the yield and yield of...

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Abstract

The invention discloses preparation methods of tenofovir disoproxil and fumarate thereof, and belongs to the field of preparation of compounds. The methods comprise the following steps: carrying out a condensation reaction of a tenofovir anhydrous substance or tenofovir hydrate with chloromethyl isopropyl carbonate to obtain a reaction liquid, pouring the reaction liquid obtained from the condensation reaction into supersaturated salt water, stirring, filtering, washing, and drying to obtain a tenofovir disoproxil crude product; adding the tenofovir disoproxil crude product into a certain amount of a nonpolar organic solvent with low boiling point, heating up to a reflux temperature, carrying out beating reflux, then carrying out gradient cooling and stirring, filtering, washing the obtained product with a certain amount of the nonpolar organic solvent with low boiling point, and drying, to obtain powdered tenofovir disoproxil; and in the presence of isopropyl alcohol, carrying out a reaction of the powdered tenofovir disoproxil with fumaric acid to obtain the tenofovir disoproxil fumarate. The method has the advantages of simple post treatment and high yield, and the obtained product has the characteristics of high purity, low impurity content and the like.

Description

technical field [0001] The invention belongs to the field of compound preparation, in particular to a preparation method of tenofovir disoproxil and fumarate thereof. Background technique [0002] Tenofovir disoproxil (abbreviated as tenofovir disoproxil, English name Tenofovir disoproxil) is a nucleotide antiviral drug developed by Gilead in the United States. It was approved by the FDA in 2001 for the treatment of human immunodeficiency Virus infection, its marketed product form is the fumarate of tenofovir disoproxil (ie tenofovir disoproxil fumarate). Due to its definite therapeutic effect, good applicability and appropriate dosage, tenofovir disoproxil has become the first-line HIV drug recommended by multiple treatment guidelines. It is the first-line anti-retroviral drug recommended by the World Health Organization (WHO) AIDS treatment guidelines, and is listed as the second-line anti-retroviral drug for national free AIDS anti-retroviral treatment in China. [0003...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6561C07C51/41C07C57/15
CPCC07C51/412C07F9/65616C07C57/15
Inventor 刘丹祝春艳白跃飞韩晓丹皮昌桥刘九知杨渐飞胡铁军
Owner NORTHEAST PHARMA GRP
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