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Preparation method of sofosbuvir crystal form 6

A technology of sofosbuvir crystals and sofosbuvir, which is applied in the field of medicine, can solve problems such as infeasibility, difficult process control, and lengthy steps, and achieve simple and efficient crystallization process, good repeatability, and good stability Effect

Inactive Publication Date: 2015-08-12
CHARM PHARMATECH NANJING
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  • Abstract
  • Description
  • Claims
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AI Technical Summary

Problems solved by technology

There is a lot of waste in the process, and the efficiency is low
[0019] Secondly, the process of the preparation methods of the two Sofosbuvir crystal forms 6 is more difficult to control
The steps of method 1 are tedious, including the formation of gel, grinding and slow change for 6 to 10 weeks, so it is not feasible for actual production; method 2 involves heterogeneous state transformation in water, the process is difficult to control, and it is difficult to Difficult to reproduce under the conditions given in the literature
[0020] Third, the existing preparation methods of the two Sofosbuvir crystal forms 6 are difficult to achieve the purpose of purifying the product and removing impurities, so the chemical purity of the product needs to be strictly controlled in the raw material link
This greatly increases the process cost
[0021] Fourth, the existing water conversion process will produce a large amount of impurity-containing wastewater, which is difficult to post-treat and recycle

Method used

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

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preparation example Construction

[0042] In the preparation method of crystal form 6 of the present invention, sofosbuvir all uses the sofosbuvir product (such as J.Med.Chem.2010,53,7202-7218) prepared by the method reported in existing literature; Other All solvents and reagents were commercially available chemically pure or analytically pure products.

[0043] The X-ray powder diffractometer used in the embodiment of the present invention is an X'pert PRO X-ray powder diffractometer from PANalytical Company. Cu-Kα rays are used, the test power is 40kV×250mA, the scanning speed is 5° / min, and the scanning range is 4-80° (2θ) θ-2θ continuous scanning. In the X-ray powder diffraction diagram obtained in the embodiment of the present invention, the horizontal axis represents the 2θ position of the diffraction peak (unit: degree); the vertical axis represents the intensity of the diffraction peak.

[0044]The differential scanning calorimetry-thermogravimetric (DSC-TGA) analysis instrument used in the embodiment...

Embodiment 1

[0047] Mix 1.0 g of sofosbuvir with 10.0 ml of cyclopentyl methyl ether and 1.0 ml of anisole, heat the mixture to 75±3°C and stir at 20 rpm to completely dissolve the solids, then cool within 90 minutes to 10±3°C and stand at this temperature for 48 hours, the precipitated white powdery crystals were taken out by filtration, washed with 3 ml of isopropyl ether and dried to obtain 0.92 g of product.

[0048] Carry out powder X-ray diffraction analysis to the obtained crystal sample, its result is as follows figure 1 shown. and figure 1 Correspondingly, the powder X-ray diffraction data of Sofosbuvir Form 6 are shown in Table 1.

[0049] The pXRD characteristic peak position of table 1 embodiment 1 product

[0050]

[0051] The powder sample was subjected to differential scanning calorimetry-thermogravimetric analysis, and the results were as follows: figure 2 shown. The shown pXRD, DSC-TGA and other test results are all the same as the characteristic spectrum of sofos...

Embodiment 2

[0053] Mix 1.0 g of sofosbuvir with 10.0 ml of cyclopentyl methyl ether and 2.0 ml of dibenzyl ether, heat the mixture to 75±3°C and stir at 20 rpm to completely dissolve the solid, then cool within 90 minutes to 5±3°C and stirred at this temperature for 48 hours, the precipitated white powdery crystals were taken out by filtration, washed with 3 ml of isopropyl ether and dried to obtain 0.93 g of the product with a yield of 93%. After the product was ground, pXRD, DSC-TGA and other tests were performed, all of which were identical to the characteristic spectrum of sofosbuvir crystal form 6 reported in the literature, confirming that the product was sofosbuvir crystal form 6.

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Abstract

The invention discloses a novel crystallization method for preparing a sofosbuvir crystal form 6. Compared with an original preparation method of the crystal form 6, the novel crystallization method disclosed by the invention has the advantages that the purification effect is good, products are easy to dry, an environment-friendly effect is achieved and the like since sofosbuvir is prepared from a solution containing various organic mixed solvents through cooling crystallization.

Description

technical field [0001] The invention belongs to the technical field of medicine, and more specifically relates to a preparation method of a novel sofosbuvir crystal form 6. Background technique [0002] Sofosbuvir, chemical name isopropyl (2S)-2-[[[(2R,3R,4R,5R)-5-(2,4-dioxypyrimidin-1-yl)-4 -Fluoro-3-hydroxy-4-methyl-tetrahydrofuran-2-yl]-methoxy-phenoxy-phosphoryl]amino]propionate, CAS number is 1190307-88-0, the chemical structure is as follows: [0003] [0004] Sofosbuvir, an NS5B polymerase inhibitor developed by Glead Sciences, blocks a specific protein required for replication of hepatitis C virus when used alone or in combination with other drugs. sex protein for the treatment of hepatitis C. Sofosbuvir was approved by the U.S. Food and Drug Administration in December 2013 under the trade name Sovaldi (400 mg dosage form). Sofosbuvir is the first drug approved for the full oral treatment of hepatitis C. When used for the treatment of specific genotypes of chro...

Claims

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Application Information

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IPC IPC(8): C07H19/10C07H1/06
CPCC07H1/06C07H19/10
Inventor 胡咏波
Owner CHARM PHARMATECH NANJING
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