Adefovir dipivoxil CHARIOTEER crystallographic form and preparation method thereof

A technology of adefovir dipivoxil and its crystal form, which is applied in chemical instruments and methods, organic chemistry, and compounds of elements of Group 5/15 of the periodic table, etc., can solve the problem of high cost and unsatisfactory preparation of adefovir dipivoxil crystal form. Suitable for large-scale industrial production, unfavorable environmental protection and other issues, to achieve good crystal form stability, no reduction in content, and low production costs

Active Publication Date: 2007-07-11
ZHEJIANG CHARIOTEER PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] Most of the adefovir dipivoxil crystal forms reported in the above literatures have high preparation costs, some solvents are highly toxic, and some methods are not suitable for large-scale industrial production and are not conducive to environmental protection.

Method used

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  • Adefovir dipivoxil CHARIOTEER crystallographic form and preparation method thereof
  • Adefovir dipivoxil CHARIOTEER crystallographic form and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Dissolve 45g of crude adefovir dipivoxil in 150ml of dimethyl carbonate solvent, heat to 40°C, stir to clear, filter, cool the filtrate to 10-11°C, crystallize for 5 hours, and filter. The obtained solid is at 50°C, 5Kpa After vacuum drying for 20 hours, 43.8 g of adefovir dipivoxil crystals were obtained, and the content was 99.6% determined by HPLC. Cu-Kα radiation, X-ray powder diffraction expressed by 2θ angle and interplanar distance (d value) is about 8.4 (10.8), about 9.8 (9.0), about 14.2 (6.2), about 14.8 (6.0), and about 16.2 (5.5), about 17.0 (5.2), about 19.7 (4.5), about 21.1 (4.2), about 22.0 (4.1), about 23.1 (3.9), about 23.8 (3.7), about 25.1 (3.6), about 25.6 (3.5) ), about 28.8 (3.1), about 29.8 (2.9), about 33.3 (2.6), about 34.6 (2.6), and about 38.9 (2.3) have obvious characteristic absorption peaks, see Figure 1 for details. The differential thermal analysis (DSC) spectrum has an endothermic peak at 94°C, see Figure 2 for details. Infrared absorption ...

Embodiment 2

[0040] Dissolve 45g of crude adefovir dipivoxil in 150ml of diethyl carbonate solvent, heat to 40°C, stir to clear, filter, cool the filtrate to 14-15°C, crystallize for 5 hours, and filter. The obtained solid is at 50°C, 5Kpa After 25 hours of vacuum drying, 42.5 g of adefovir dipivoxil crystals were obtained, which was determined by HPLC and the content was 99.7%. Cu-Kα radiation, X-ray powder diffraction expressed by 2θ angle and interplanar distance (d value) is at 8.4 (10.9), about 9.8 (9.0), about 14.2 (6.2), about 14.8 (6.0), and about 16.2 ( 5.6), about 17.0 (5.2), about 19.7 (4.5), about 21.1 (4.2), about 22.0 (4.1), about 23.1 (3.9), about 23.8 (3.7), about 25.1 (3.6), about 25.6 (3.5) , About 28.8 (3.1), about 29.8 (2.9), about 33.4 (2.6), about 34.6 (2.6), and about 38.9 (2.3) have obvious characteristic absorption peaks. The differential thermal analysis (DSC) spectrum has an endothermic peak at 94°C. Infrared absorption spectrum (KBr tablet) at 3191cm -1 , 3122cm -1 ...

Embodiment 3

[0042] Dissolve 45g of crude adefovir dipivoxil in 150ml of ethyl methyl carbonate solvent, heat to 40°C, stir to clear, filter, cool the filtrate to 12-13°C, crystallize for 5 hours, and filter. The obtained solid is at 50°C, 5Kpa After vacuum drying for 25 hours, 43.2 g of adefovir dipivoxil crystals were obtained, which was determined by HPLC and the content was 99.7%. Cu-Kα radiation, X-ray powder diffraction expressed by 2θ angle and interplanar distance (d value) is about 8.4 (10.8), about 9.8 (9.0), about 14.2 (6.3), about 14.8 (6.0), and about 16.2 (5.5), about 17.0 (5.2), about 19.7 (4.5), about 21.1 (4.2), about 22.0 (4.1), about 23.1 (3.9), about 23.8 (3.7), about 25.1 (3.6), about 25.6 (3.5) ), about 28.8 (3.1), about 29.8 (2.9), about 33.3 (2.7), about 34.6 (2.6), and about 38.9 (2.3) have obvious characteristic absorption peaks. The differential thermal analysis (DSC) spectrum has an endothermic peak at 94°C. Infrared absorption spectrum (KBr tablet) at 3189cm -1 , 3...

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Abstract

The invention discloses an adefovir dipivoxil (AD) as medical nucleoside compound and making method, whose chemical name is 9-[2-[[di (neopentyl acyloxy group) methoxy] oxyphosphino] methoxy] ethyl) adenine], wherein the CHARIOTEER crystal system uses Cu-K alpha irradiation, which displays characteristic adsorbing peak under X-ray powder diffraction with 2thita angle and crystal face distance (d) at 8. 2(10.9), 9. 8(9. 0), 14. 2(6. 3), 16. 5(5. 5), 17. 0(5. 2), 19. 8(4. 5), 21. 1(4. 2), 21. 5(4. 2), 22. 5(3. 9), 23. 8(3. 7), 28. 8(3. 1) and 33. 3(2. 6).

Description

(1) Technical field [0001] The present invention relates to a new crystal form of adefovir dipivoxil—CHARIOTEER crystal form, and a method for preparing the new crystal form. (2) Background technology [0002] Adefovir dipivoxil is a nucleoside analogue, a new type of HBV-DNA polymerase inhibitor, which can inhibit the activity of hepatitis B virus DNA polymerase and is a new type of anti-hepatitis B virus drug. It has antiviral activity on animals and humans. Therefore, the replication and proliferation of hepatitis B virus can be inhibited. Adefovir dipivoxil has been approved abroad for two indications: chronic hepatitis B patients and chronic hepatitis B with YMDD mutation resistance after lamivudine treatment. [0003] Adefovir dipivoxil was invented in 1991 by Gillead Sciences, Inc., applied for a European patent in 1992, and was authorized in 1998. The company did not apply for a patent for the compound in China, but applied for the patent CN1251592A (application number 98...

Claims

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Application Information

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IPC IPC(8): C07F9/6561
Inventor 蒲通雷鸣万定建李东兴王乃星李丰庭范一陈恬
Owner ZHEJIANG CHARIOTEER PHARMA
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