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New velpatasvir intermediate crystal form

A technology of crystal forms and polymorphs, which is applied in the field of new crystal forms of velpatasvir intermediates, can solve the problems of difficult formula I compounds and poor crystallinity of formula I compounds

Inactive Publication Date: 2016-12-14
SHANGHAI FOREFRONT PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the characteristics of the molecular structure, the crystallinity of the formula I compound itself is very poor, and it is difficult to obtain a highly pure formula I compound

Method used

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  • New velpatasvir intermediate crystal form
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  • New velpatasvir intermediate crystal form

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0060] The polymorphic form of the present invention can be prepared by the following preparation method, which includes the steps of: mixing the compound of formula I and an inert solvent, and placing it, so as to obtain the polymorphic form of the present invention; wherein, The inert solvent is selected from the following group: toluene, isopropyl ether or a mixed solvent of the two.

[0061] The compound of formula I may be other polymorphs or amorphous form of the compound of formula I.

[0062] In another preferred example, the purity of the compound of formula I is ≤92%.

[0063] In another preferred example, the weight and volume ratio (g / mL) of the compound of formula I to the inert solvent is 1:0.5-1:100; preferably, 1:1-1:20.

[0064] In another preferred embodiment, after the mixing, the resulting mixture is a solution or a suspension.

[0065] In another preferred example, the standing is for 8-72 hours; preferably, for 12-48 hours; more preferably, for 12-24 hour...

Embodiment 1

[0086] The preparation of embodiment 1 crystal form I

[0087] (1) Weigh 74 mg of the compound of formula I (HPLC purity: 91.6%) into a 1.5 ml centrifuge tube, and add 0.1 mL of toluene. Sonicate until dissolved. After standing at room temperature for 16 hours, a solid precipitated out. Part of the solid precipitate was taken and identified as crystal by polarizing microscope.

[0088] (2) Place the centrifuge tube in a centrifuge, centrifuge at 12,000 rpm for 5 minutes, remove the supernatant, and dry the separated solid at room temperature for 1 hour.

[0089] (3) Characterize the solid form of the dried solid by XRPD, DSC and TGA.

[0090] result

[0091] (1) XRPD pattern

[0092] The crystal of the compound of formula I is named as crystal form I, and its XRPD pattern is as follows: figure 1 shown. The main diffraction peaks and their relative intensities are shown in Table 1.

[0093] Table 1 XRPD data of the crystal

[0094] 2θ(°)

Relative Strength(...

Embodiment 2

[0102] (1) Weigh 74 mg of the compound of formula I (HPLC purity: 91.6%) into a 1.5 ml centrifuge tube, and add 0.1 mL of isopropyl ether. Sonication forms a suspension. After standing at room temperature for 16 hours, a part of the solid precipitate was taken and identified by a polarizing microscope, which was confirmed to be a crystal.

[0103] (2) Place the centrifuge tube in a centrifuge, centrifuge at 12,000 rpm for 5 minutes, remove the supernatant, and dry the separated solid at room temperature for 1 hour.

[0104] (3) Characterize the solid form of the dried solid by XRPD.

[0105] result

[0106] (1) XRPD pattern

[0107] The XRPD spectrum of the crystal obtained in Comparative Example 2 is consistent with the crystal form I XRPD spectrum, and it is confirmed to be crystal form I.

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Abstract

The invention relates to a new velpatasvir intermediate crystal form. Specifically, the invention discloses a polymorphic substance of the formula I compound and a preparation method thereof. The polymorphic substance has good purifying effect.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a new crystal form of a velpatasvir intermediate. Background technique [0002] Velpatasvir (VLP), a hepatitis C drug developed by Gilead, and Sofosbuvir fixed-dose combination drug are expected to cure all genotypes of HCV patients in as little as 8 weeks, while requiring no injections Interferon or combined with ribavirin (Ribavirin). [0003] The synthesis route of velpatasvir is shown below, wherein the compound of formula I is the key intermediate of velpatasvir, and the quality of the compound of formula I has a profound impact on the subsequent reaction and the quality of velpatasvir raw material. [0004] [0005] Synthetic route of velpatasvir [0006] [0007] Formula I [0008] Crystallization is an important means to remove impurities and improve product quality. However, due to the characteristics of the molecular structure, the crystallinity of the compo...

Claims

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Application Information

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IPC IPC(8): C07D491/052
CPCC07D491/052C07B2200/13
Inventor 李巍任毅朱燕燕
Owner SHANGHAI FOREFRONT PHARMA CO LTD
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