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Synthesis method of tenofovir disoproxil fumarate dimer impurity

A technology of ester fumarate dimer and tenofovir, which is applied in the field of synthesis of impurities of tenofovir disoproxil fumarate dimer, can solve the limitation of tenofovir disoproxil fumarate dimer problems such as the research process of polymer impurities, to achieve the effect of short route and simple operation steps

Inactive Publication Date: 2017-05-31
NINGBO MENOVO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In the prior art, there is no introduction about the synthetic method of this impurity, which severely limits people's research process on the tenofovir disoproxil fumarate dimer impurity, therefore, a reasonable tenofovir disoproxil fumarate is provided The synthetic method of fumarate dimer impurity appears particularly necessary

Method used

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  • Synthesis method of tenofovir disoproxil fumarate dimer impurity
  • Synthesis method of tenofovir disoproxil fumarate dimer impurity
  • Synthesis method of tenofovir disoproxil fumarate dimer impurity

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Embodiment 1

[0030] The synthetic method of tenofovir disoproxil fumarate dimer impurity in the present embodiment comprises the following steps:

[0031] (1) Add 5g of paraformaldehyde and 150mL of hydrochloric acid with a volume concentration of 15% to a 250mL four-neck flask at room temperature. After the addition is completed, heat up to 35-40°C and stir for 1 hour. After completely dissolving, cool down to 10-15°C. And at this temperature, add 10 g of the compound of formula II below, and keep it warm for 48 hours at the same temperature;

[0032]

[0033] (2) step (1) completes the reaction, decompresses and evaporates hydrochloric acid to the utmost, obtains the compound of formula III; figure 1 It can be seen that the molecular weight of the product obtained in this step is consistent with the target product formula III compound; as figure 2 As shown, the purity HPLC=57.56% of the obtained formula III compound;

[0034]

[0035] (3) Add the compound of formula III obtained...

Embodiment 2

[0044] The synthetic method of tenofovir disoproxil fumarate dimer impurity in the present embodiment comprises the following steps:

[0045] (1) Add 5g of paraformaldehyde and 150mL of hydrobromic acid with a volume concentration of 15% to a 250mL four-necked flask at room temperature. 15°C and add 15g of the following compound of formula II at this temperature, and keep the reaction at the same temperature for 48h;

[0046] (2) Step (1) completes the reaction, and decompression steams and removes hydrobromic acid to the utmost, and obtains the compound of formula III;

[0047] (3) Add the compound of formula III obtained in step (2) into a 250 mL four-necked flask, and add 27 g of chloromethyl isopropyl carbonate, 30 mL of DMSO, 20 mL of triethylamine, and 5.3 g of TBAB in sequence, and stir to raise the temperature to 50-60 °C and stirred at this temperature for 4 hours, then cooled to 30-35 °C and filtered, and the obtained filtrate A was collected;

[0048] Rinse the fi...

Embodiment 3

[0050] The synthetic method of tenofovir disoproxil fumarate dimer impurity in the present embodiment comprises the following steps:

[0051] (1) Add 5g of paraformaldehyde and 150mL of hydrochloric acid with a volume concentration of 15% to a 250mL four-neck flask at room temperature. After the addition is completed, heat up to 35-40°C and stir for 1 hour. After completely dissolving, cool down to 10-15°C. And at this temperature, add 10 g of the compound of formula II below, and keep it warm for 48 hours at the same temperature;

[0052] (2) step (1) completes the reaction, decompresses and evaporates hydrochloric acid to the utmost, obtains the compound of formula III; figure 1 It can be seen that the molecular weight of the product obtained in this step is consistent with the target product formula III compound;

[0053] (3) Add the compound of formula III obtained in step (2) into a 250 mL four-neck flask, and add 27 g of chloromethyl isopropyl carbonate, 30 mL of DMF, 2...

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Abstract

The invention relates to a synthesis method of a tenofovir disoproxil fumarate dimer impurity. The synthesis method comprises the following steps: in the presence of an acid reagent and paraformaldehyde, preparing a compound shown as a formula III by using tenofovir or tenofovir monohydrate as a reactive raw material first, and then in the presence of chloromethyl isopropyl carbonate and a catalyst TBAB, performing a reaction on the compound shown as the formula III to obtain a target compound shown as a formula I. The whole synthesis method is short in route and simple in operating steps; the purity of the obtained product is above 90%; by the synthesis method, a foundation is laid for qualitative and quantitative impurity analysis on tenofovir disoproxil fumarate.

Description

technical field [0001] The invention relates to a method for synthesizing dimer impurities of tenofovir disoproxil fumarate. Background technique [0002] Tenofovir disoproxil fumarate was developed by Gilead, and its trade name is Viread. It was approved for marketing in the United States in October 2001. It is used to treat HIV and HBV infections and is used together with other reverse transcriptase preparations. The drug was approved for marketing in China in August 2013. GlaxoSmithKline retains the exclusive right to market tenofovir (trade name: Viread) in China and is responsible for the registration of the drug for the treatment of patients with HBV infection. Due to their strong antiviral activity, Viread and Entecavir have become the first-line anti-HBV drugs recommended by the Chinese liver disease prevention and treatment guidelines. In addition, due to its definite therapeutic effect, good applicability, and appropriate dosage, tenofovir disoproxil is also a fir...

Claims

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Application Information

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IPC IPC(8): C07F9/6561
CPCC07F9/65616
Inventor 林祖峰贾江南刘涛黄勤黄想亮陈为人姚成志
Owner NINGBO MENOVO PHARMA
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