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Preparation method of sofosbuvir crystal 6

A technology of febuvir crystal form and sofosbuvir, which is applied in the preparation of sugar derivatives, organic chemical methods, chemical instruments and methods, etc., can solve the problem that it is not easy to meet the standards of raw materials, unsuitable for industrial production, and cumbersome steps, etc. problem, to achieve simple and efficient crystallization process, short steps and good repeatability

Inactive Publication Date: 2017-03-15
FUJIAN COSUNTER PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] The technical problem to be solved by the present invention is to overcome the preparation of sofosbuvir crystal form 6 in the prior art, which needs to be converted from crystal form 2, 3, 4, 5 or amorphous form to crystal form 1, and then converted from crystal form 1 It is crystal form 6, the steps are cumbersome, the cost is high, it is not easy to meet the standards of raw materials, and it is not suitable for defects such as industrial production; and a preparation method of sofosbuvir crystal form 6 is provided

Method used

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  • Preparation method of sofosbuvir crystal 6
  • Preparation method of sofosbuvir crystal 6
  • Preparation method of sofosbuvir crystal 6

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] 10°C to 15°C, completely dissolve Sofosbuvir (amorphous, 5.0g) in ethanol (25mL) in a single-necked flask to obtain an ethanol solution of Sofosbuvir, and then transfer the ethanol solution of Sofosbuvir to Put it into the constant pressure dropping funnel and set aside.

[0039] Add water (100mL) to a three-necked flask equipped with mechanical stirring, turn on the mechanical stirring, and the stirring speed is 260 rpm. Slowly drop the funnel into the aqueous solution, which takes about 15 minutes, and a milky white suspension can be obtained after the drop is completed. Continue to stir at room temperature (10°C-35°C) for 12 hours to crystallize, filter with medium-speed filter paper, rinse the filter cake with water (15mL) once, and dry it in vacuum at 45°C-50°C for 16 hours (vacuum degree -0.008MPa), to obtain Febuvir product 4.8g, yield 96.0%, HPLC purity 99.75%, maximum single impurity 0.03%.

[0040] The crystal product obtained by drying is carried out to pow...

Embodiment 2

[0046] 5 ℃ ~ 10 ℃, sofosbuvir (crystalline form 1, 1.0kg) was completely dissolved in isopropanol (3L) in a single-necked flask to obtain the isopropanol solution of sofosbuvir, and then the sofosbuvir Transfer Wei's isopropanol solution to a constant pressure dropping funnel for later use.

[0047] Add water (22L) to the reactor equipped with mechanical stirring, turn on the mechanical stirring at a speed of 230 rpm, and at room temperature (10°C to 35°C), put the sofosbuvir isopropanol solution through constant pressure drop The funnel is slowly dropped into the aqueous solution, which takes about 60 minutes, and a milky white suspension can be obtained after the drop is completed. Continue to stir at room temperature (10°C-35°C) for 24 hours to crystallize, filter with 200-300-mesh filter cloth, rinse the filter cake with water (3L) once, and vacuum-dry at 45°C-50°C for 20 hours (vacuum degree -0.008MPa ), sofosbuvir product 967g, yield 96.7%, HPLC purity 99.97%, maximum s...

Embodiment 3

[0050] At 40°C to 45°C, completely dissolve Sofosbuvir (crystalline form 2, 100g) in isobutanol (1L) in a single-necked flask to obtain an isobutanol solution of Sofosbuvir, and then the Sofosbuvir Wei's isobutanol solution was transferred to a constant pressure dropping funnel for later use.

[0051] Add water (4L) to the reactor equipped with mechanical stirring, turn on the mechanical stirring, the rotating speed is 260 rpm, at room temperature (10 ° C ~ 35 ° C), the sofosbuvir isobutanol solution is passed through the constant pressure drop Slowly drop the funnel into the aqueous solution, which takes about 30 minutes, and a milky white suspension can be obtained after the drop is complete. Continue to stir at room temperature (10°C-35°C) for 24 hours to crystallize, filter with 200-300-mesh filter cloth, rinse the filter cake with water (100mL) once, and vacuum-dry at 45°C-50°C for 20 hours, vacuum degree -0.008MPa 95.1 g of the sofosbuvir product was obtained, the yield...

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Abstract

The invention provides a preparation method of sofosbuvir crystal 6. The preparation method includes the steps: mixing a solution formed by sofosbuvir and an alcohol solvent, with water; crystallizing to obtain the sofosbuvir crystal 6. The preparation method is simple and efficient in crystallization process, high in yield and good in repeatability, the obtained crystal is good in stability and purity and meets requirement of oral solid preparations, the requirements of bulk pharmaceutical chemicals are met, and the preparation method is green and suitable for industrial production.

Description

technical field [0001] The present invention relates to a preparation method of sofosbuvir crystal form 6. Background technique [0002] Sofosbuvir (trade name: Sovaldi, generic name: Sofosbuvir, formerly known as GS-7977, PSI-7977), chemical name: (S)-2-{[(2R,3R,4R,5R)-5- (2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxyl-4-methyl-tetrahydrofuran-2-ylmethoxy]-phosphono Amino}-propionic acid isopropyl ester. The CAS registration number is: 1190307-88-0, and the chemical structure is as follows: [0003] [0004] Sofosbuvir is a hepatitis C virus (HCV) nucleotide analog NS5B polymerase inhibitor developed by Glead Sciences in the United States. It is suitable for use as a combined component in a combined antiviral therapy or alone It is mainly used for the treatment of adult patients with genotype 1, type 2, type 3 and type 4 chronic hepatitis C (Hepatitis C) in order to block the consistent specific protein required for the replication of hepatitis C virus t...

Claims

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Application Information

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IPC IPC(8): C07H19/10C07H1/06
CPCC07H19/10C07B2200/13C07H1/06
Inventor 应述欢皮红军周军全汪仙阳王亮公绪栋
Owner FUJIAN COSUNTER PHARMA
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