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Method for preparing crystalline form 6 of Sofosbuvir

A technology of febuvir crystal form and crystal form, which is applied in the field of medicinal chemistry, can solve the problems that crystal form 6 cannot be stably obtained, the process conditions are difficult to control, and the crystallization process takes a long time to achieve easy implementation and good reproducibility , the effect of simple operation

Active Publication Date: 2016-07-27
SHANGHAI ARYL PHARMTECH CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Patent US8618076 also discloses a method for preparing Sofosbuvir crystal form 6, but this method crystallizes Sofosbuvir in water, the crystallization process takes a long time, the process conditions are difficult to control, and the reproducibility is poor, so the crystal form 6 cannot be stably obtained , and a large amount of viscous jelly is formed in the middle process, which is easy to block the discharge port and is not suitable for large-scale production

Method used

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  • Method for preparing crystalline form 6 of Sofosbuvir
  • Method for preparing crystalline form 6 of Sofosbuvir

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Dissolve 10 grams of sofosbuvir in 100 ml of methanol, add the solution to 300 ml of pure water preheated to 45°C, drop the temperature to -15°C and stir for 2 to 3 hours after the addition is complete, filter, and filter cake Vacuum drying at 60° C. to constant weight yielded 9.1 g of a white solid with a yield of 91% and a purity of 99.7%. The 2θ angles of the X-ray powder diffraction pattern of the prepared product are at 6.1°, 8.2°, 10.4°, 12.7°, 17.1°, 17.6°, 18.0°, 18.8°, 19.4°, 19.8°, 20.1°, 20.8°, There are characteristic peaks at 21.8° and 23.3°, which are confirmed to be Sofosbuvir Form 6.

Embodiment 2

[0025] Dissolve 10 grams of sofosbuvir in 80 milliliters of ethanol, slowly drop the solution into 480 milliliters of pure water preheated to 60° C., and add 0.05 grams of sofosbuvir crystal form 6 as a seed crystal. After the dropwise addition was completed, heat and stir for about 3 to 4 hours to crystallize, then lower the temperature to 0°C and stir for 2 to 3 hours, filter, and vacuum-dry the filter cake at 60°C to constant weight to obtain 9.6 grams of white solid with a yield of 96%. The purity is 99.6%. The X-ray powder diffraction pattern of the prepared product is consistent with the sofosbuvir crystal form 6.

Embodiment 3

[0027] Dissolve 10 grams of sofosbuvir in 60 milliliters of acetone, slowly add the solution dropwise to 480 milliliters of pure water preheated to 60° C., and add 0.2 grams of sofosbuvir crystal form 6 as a seed crystal. After the dropwise addition was completed, heat and stir for about 3 to 4 hours to crystallize, then lower the temperature to 0°C and stir for 2 to 3 hours, filter, and vacuum-dry the filter cake at 60°C to constant weight to obtain 9.4 grams of white solid with a yield of 94%. The purity is 99.5%. The X-ray powder diffraction pattern of the prepared product is consistent with the sofosbuvir crystal form 6.

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Abstract

The invention relates to a method for preparing crystalline form 6 of Sofosbuvir. The method has the advantages of simple operation, stable process conditions, good reproducibility, high yield, and good purity; viscous jelly does not generate in the middle process, and the blocking problem of a discharge port is solved; the method is suitable for industrial production with higher economic value.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a method for preparing Sofosbuvir crystal form 6. Background technique [0002] Sofosbuvir (Sofosbuvir) is a new generation of anti-HCV drug developed by Gilead Sciences of the United States. It was approved by the US FDA for marketing in December 2013 under the trade name Sovaldi. Sofosbuvir has a CAS registration number: 1190307-88-0, and its chemical name is: (S)-2-(((S)-(((2R,3R,4R,5R)-5-(2,4 -dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorus Acyl) amino) propionate isopropyl ester, the molecular formula is: C 22 h 29 FN 3 o 9 P, has the following structure: [0003] [0004] U.S. Patent US8618076 discloses at least six crystal forms of sofosbuvir: sofosbuvir crystal form 1-6, and using X-ray powder diffraction (XRPD), single crystal X-ray diffraction, differential scanning calorimetry (DSC ...

Claims

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Application Information

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IPC IPC(8): C07H19/10C07H1/06A61K31/7072A61P31/14
CPCC07H1/06C07H19/06C07H19/10A61P31/14C07B2200/13
Inventor 郭阳辉赵世国张玥张亮杨志清柴健
Owner SHANGHAI ARYL PHARMTECH CO LTD
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