Novel tenofovir disoproxil salt and the preparation method thereof

A technology of tenofovir and tenofovir disoproxil, which is applied in the field of new tenofovir salt and its preparation, can solve the physical and chemical properties of tenofovir disoproxil fumarate and other problems, and achieve excellent preparation processing performance , stable treatment, good photostability effect

Inactive Publication Date: 2016-03-30
DONG A ST CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] The object of the present invention is to solve the shortcoming in the production that the physicochemical property problem of tenofovir disoproxil fumarate causes, provide a kind of novel tenofovir salt with excellent physical and chemical properties convenient to produce and preparation method thereof

Method used

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  • Novel tenofovir disoproxil salt and the preparation method thereof
  • Novel tenofovir disoproxil salt and the preparation method thereof
  • Novel tenofovir disoproxil salt and the preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] preparation of tenofovir disoproxil orotate (1)

[0056] Tenofovir (25 g) was added to the reaction apparatus and dissolved with methanol (125 ml). Orotic acid (7.96 g) and purified water were added to the reaction solution, which was then suspended at room temperature for 10 minutes and heated at an internal temperature of 70° C. for 1 hour until all solids had dissolved. The reaction solution was reacted at an internal temperature of 20°C for 1-2 hours to obtain crystals. The obtained crystals were vacuum filtered, washed with methanol:water (100ml, 1:3), and dried. The dried crystals were vacuum dried at an internal temperature of 60° C. for 15 hours.

[0057] Purity (by HPLC): 99.3%; Yield: 27.69g (85%)

[0058] 1 HNMR(DMSO-d6)δppm11.29(s,1H,NH), 10.8(s,1H,NH), 8.14(s,1H,CH), 8.04(s,1H,CH), 7.36(s,2H, NH 2 ), 5.97(s,1H,CH), 5.48-5.56(m,4H,CH 2 ), 4.79-4.81 (m,2H,CH 2 ), 4.14-4.26 (ddd, 2H, CH 2 ), 3.92-4.01(m,3H,CH), 1.22(s,12H,CH 3 ), 1.04(s,3H,CH 3 ). ...

Embodiment 2

[0059] preparation of tenofovir disoproxil orotate (2)

[0060] Tenofovir (25 g) was added to the reaction apparatus and dissolved with methanol (125 ml). Orotic acid (7.96 g) and purified water were added to the reaction solution, which was then suspended at room temperature for 10 minutes and warmed at an internal temperature of 70° C. for 1 hour until all solids had dissolved. The reaction solution was reacted at an internal temperature of 20°C for 1-2 hours to obtain crystals. The obtained crystals were vacuum filtered, washed with ethanol:water (100ml, 1:3), and dried. The dried crystals were vacuum dried at an internal temperature of 60° C. for 15 hours.

[0061] Purity (by HPLC): 99.3%; Yield: 27.58g (84.7%)

[0062] 1 HNMR: same as Example 1.

Embodiment 3

[0063] preparation of tenofovir disoproxil orotate (3)

[0064] Tenofovir (25 g) was added to the reaction apparatus and suspended in purified water (750 ml). Orotic acid (7.96 g) was added to the reaction solution and warmed at an internal temperature of 70-80° C. for 1-2 hours until all solids had dissolved. The reaction solution was reacted at an internal temperature of 20°C for 1-2 hours to obtain crystals. The obtained crystals were subjected to vacuum filtration, washed with purified water (100 ml), and dried. The dried crystals were vacuum dried at an internal temperature of 60° C. for 15 hours. This example provides an environmentally friendly method for preparing crystalline tenofovir disoproxil orotate without using organic solvents.

[0065] Purity (tested by HPLC): 98%; Yield: 26g (79.8%)

[0066] 1 HNMR: same as Example 1.

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Abstract

The present invention relates to a novel tenofovir disoproxil salt and the preparation method thereof. The crystalline form of tenofovir disoproxil orotate according to the present invention is an anhydride and it has superior physicochemical properties that are useful in pharmaceutical preparation as it resolves problems caused by physicochemical properties of tenofovir disoproxil fumarate. Namely, the crystalline form of tenofovir disoproxil orotate according to the present invention has a better than equal light stability compared to tenofovir disoproxil fumarate and has a superior stability especially under extreme stress conditions. Additionally, it is neither corrosive nor harmful to human body, thus making it safe for preparation and easy to manage. All of these characteristics make this invention useful for mass production. The present invention also provides a preparation method with and without using organic solvent, thus providing an industrially applicable and environment-friendly preparation method. Furthermore, tenofovir disoproxil orotate prepared according to the present invention can be used as an antiviral treating agent and can also be made into an anti-HIV treating composition if mixed with other drugs that have anti-HIV activity. The composition can be made into mixtures with one to six of the following other anti-HIV active ingredient medications that include Emtricitabine, Efavirenz, Rilpivirenz, Cobicistat, Elvitegravir, Raltegravir, Ritonavir, Lopinavir, Darunavir, Atazanavir and salts thereof for the treatment of HIV infection.

Description

technical field [0001] The invention relates to a novel tenofovir disoproxil salt and a preparation method thereof. Background technique [0002] Hepatitis B virus (HBV, HepatitisBvirus) is considered to be an important pathogen causing liver cancer in many people. HBV infection can also trigger fulminant hepatitis, a deadly disease that destroys the liver. Chronic hepatitis infection can lead to chronic persistent infection, fatigue, cirrhosis, liver cancer, and death. Approved HBV drugs now in clinical use rapidly raise tolerability problems and limited dosing related to HBV therapy due to their toxicity. Therefore, there is a need for drugs with sustained medical effects and reduced toxicity. Drugs allowed for clinical use include alpha interferon, genetically engineered proteins and nucleotide analogs, such as lamivudin, clevudine, telbivudine and Entecavir. Other permitted anti-HBV drugs include adefovir and tenofovir, which are considered mononucleotide phosphate ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/34A61K31/52A61P31/18
CPCC07D473/34A61K31/675C07B2200/13
Inventor 朴商国林重仁金容稙金容德金后淑孙文虎金舜会金哉翰郭佑宁
Owner DONG A ST CO LTD
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