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Solid of tenofovir disoproxil, and preparation method and application thereof

A technology of tenofovir and dipivoxil, applied in the field of pharmaceutical compositions containing these solids, can solve problems such as unstable quality and drug efficacy

Active Publication Date: 2014-03-12
SICHUAN HAISCO PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although tenofovir disoproxil fumarate has been greatly improved compared with tenofovir disoproxil fumarate in terms of water solubility and physical properties, tenofovir disoproxil fumarate has complex Polymorphism of tenofovir disoproxil fumarate (including amorphous) disclosed in patent documents CN101066980A, CN101781335A, CN101948485A, WO2007013086, WO2008140302, WO2009064174, etc., such as shown in CN101778855A , analyzed several commercially available tenofovir disoproxil fumarate, and found that these products were all mixtures of different crystal forms, which may lead to tenofovir disoproxil fumarate in the preparation, Crystal form conversion occurs during storage, which leads to unstable quality and efficacy

Method used

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  • Solid of tenofovir disoproxil, and preparation method and application thereof
  • Solid of tenofovir disoproxil, and preparation method and application thereof
  • Solid of tenofovir disoproxil, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0272] Preparation of Tenofovir Disoproxil

[0273] Add 41.4g of tenofovir monohydrate (commercially available or prepared according to the method disclosed in CN1264387A) at 20~25℃ into 164g of N-methylpyrrolidone, and then add 40g of triethylamine under stirring. After stirring for 0.5 hour at 20-25°C, add 100g of chloromethyl isopropyl carbonate, increase the temperature to 55-65°C and keep the reaction for 5 hours; stop heating, lower the temperature to 20-30°C, add 320g ethyl acetate and purified water 180g, stirred at 0~5℃ and separated, the lower layer was extracted with 110g ethyl acetate at 0~5℃, combined the ethyl acetate layers, washed twice with purified water at 0~5℃, 320g each time, 30~35 Concentrate ethyl acetate at ℃; add 150 mL of cyclohexane to the concentrate, stir at 20-25 ℃ for 10 hours, filter, and rinse with 20 mL of cyclohexane to obtain tenofovir disoproxil as a white solid.

[0274] 1 H NMR(300MHz, DMSO-d 6 )δ: 8.14 (s, 1H), 8.03 (s, 1H), 7.21 (s, 2H), 5....

Embodiment 2

[0277] Preparation of DL-tenofovir disoproxil tartrate and its crystal form A

[0278] At 40~45℃, dissolve 50.0g (96.3mmol) of Tenofovir disoproxil and 14.4g (95.9mmol) of DL-tartaric acid in 4.5L of isopropanol. After the dissolution is complete, stir and cool to 15~20. ℃, continue to stir and crystallize; filter with suction; the filter cake is dried under reduced pressure at 30-35 ℃ to obtain 57.0 g of DL-tenofovir disoproxil tartrate with a yield of 88.5%.

[0279] Tested 1 The H NMR results are: 1 H NMR(300MHz, DMSO-d 6 )δ: 8.13 (s, 1H), 8.03 (s, 1H), 7.30 (s, 2H), 5.57-5.53 (m, 4H), 4.83-4.79 (m, 2H), 4.33-4.32 (d, 2H) , 4.24-4.19 (m, 2H), 4.01-3.96 (m, 3H), 1.24-1.22 (d, 12H), 1.07-1.05 (d, 3H).

[0280] Above 1 In the H NMR results, the signal peaks with chemical shifts at δ8.13 (s, 1H) and 8.03 (s, 1H) were assigned to the two H on the adenine of tenofovir disoproxil, δ4.33- The signal peak at 4.32 (d, 2H) is attributed to the H of the 2 methine groups on DL-tartaric acid....

Embodiment 3

[0290] Preparation of DL-tenofovir disoproxil tartrate and its crystal form A

[0291] Dissolve 50.0 g (96.3 mmol) of tenofovir disoproxil and 15.9 g (105.9 mmol) of DL-tartaric acid in a mixed solvent of methanol / ethanol (volume ratio 1 / 1) at 45-50°C, After the dissolution is complete, add 500 mL of isopropyl ether dropwise under the control of the internal temperature of 45~50℃. After the addition is complete, stir and cool to 15~20℃, continue to stir and crystallize; filter with suction; the filter cake is dried under reduced pressure at 35~40℃ DL-Tenofovir disoproxil tartrate crystal form A53.0g was obtained, and the yield was 82.3%. X-ray powder diffraction pattern and figure 1 similar.

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Abstract

The invention relates to a solid of tenofovir disoproxil. The solid is (1) a tenofovir disoproxil compound represented by a formula IV or (2) a tenofovir disoproxil cocrystal or salt represented by a formula V. The invention further relates to a preparation method for the solid of tenofovir disoproxil, a pharmaceutical composition containing the solid and application of the solid in preparation of drugs used for preventing and / or treating virus infection, especially hepatitis b virus (HBV) and / or human immunodeficiency virus (HIV) infection.

Description

Technical field [0001] The present invention relates to solids of tenofovir disoproxil for the prevention or / and treatment of viral infections and preparation methods thereof, and the preparation of these solids for the prevention and / or treatment of viral infections, especially hepatitis B virus (HBV) and / or humans Use in drugs for immunodeficiency virus (HIV) infection, and pharmaceutical compositions containing these solids. Background technique [0002] Tenofovir disoproxil (Tenofovir disoproxil), chemical name: 9-[2-(R)-[[bis[[(isopropoxycarbonyl)oxy]methoxy]phosphono]methoxy Yl]propyl]adenine, its molecular structure is shown in formula I: [0003] [0004] Tenofovir disoproxil is the ester prodrug of tenofovir, an acyclic nucleotide reverse transcriptase inhibitor, has a broad-spectrum antiviral effect, and can inhibit HIV-1 and HIV- 2 reverse transcriptase and HBV polymerase, thereby inhibiting virus replication. Tenofovir disoproxil is hydrolyzed into tenofovir after or...

Claims

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Application Information

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IPC IPC(8): C07F9/6561A61K31/675A61P31/12A61P31/18A61P31/20
Inventor 潘旭松肖宁王勇向志祥陆崇玉贾晓曼罗杰郑伟
Owner SICHUAN HAISCO PHARMA CO LTD
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