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New crystal form of Velpatasvir and preparation method of new crystal form

A technology of crystal form and crystallization treatment, which is applied in the field of co-crystal compound of velpatasvir and saccharin, new crystal form of velpatasvir, which can solve the problems of crystal form stability, purification effect, hygroscopicity and process stability, etc.

Active Publication Date: 2017-02-22
SHANGHAI FOREFRONT PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the stability, purification effect, hygroscopicity and process stability of these crystal forms are not perfect enough to meet the needs of practical applications.

Method used

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  • New crystal form of Velpatasvir and preparation method of new crystal form
  • New crystal form of Velpatasvir and preparation method of new crystal form
  • New crystal form of Velpatasvir and preparation method of new crystal form

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] Embodiment 1 Preparation of the amorphous substance of the compound of formula I

[0065] Weigh 84 mg of the crude compound of formula II (99% purity) into a 1.5 ml centrifuge tube, add 1 mL of ethyl acetate, sonicate until dissolved, add 40 mg of saccharin and sonicate for 5 minutes, a light yellow oily precipitate forms.

[0066] Centrifuge and remove the supernatant, and dry in an oven at 60° C. for 12 hours to obtain a yellow solid, which is determined to be an amorphous compound of formula I by a polarizing microscope.

Embodiment 2

[0067] Embodiment 2 Preparation of the crystal form A of the compound of formula I

[0068] Weigh 84mg of crude compound of formula II (99% purity) into a 1.5ml centrifuge tube, add 0.4ml of acetone, sonicate until dissolved, then add 38mg of saccharin, sonicate until dissolved. The solution was left at room temperature. After 7 days, a solid precipitate was observed, which was confirmed to be crystal by polarizing microscope.

[0069] Place the centrifuge tube in a centrifuge (Eppendorf minispin) at 12,000 rpm for 5 minutes, remove the supernatant, and dry the separated solid at room temperature for 1 hour to obtain the co-crystal form A of velpatasvir and saccharin .

[0070] result

[0071] The crystal form A obtained in Example 2 was detected by XRD, DSC, TGA and HPLC.

[0072] The XRD figure of the formula I compound crystal form A of the embodiment of the present invention 2 is as follows figure 1 , wherein the main diffraction peaks and relative intensities of Form...

Embodiment 3

[0081] Example 3 Preparation of Form A of Formula I Compound

[0082] Weigh 100 mg of the amorphous compound of Formula I (purity 99%) into a 1.5 ml centrifuge tube, add 1 ml of acetone, sonicate until dissolved, then add the seed crystal of Form A, and place the solution at room temperature. Precipitation of a solid was observed after 4 hours.

[0083] Place the centrifuge tube in a centrifuge (Eppendorf minispin) at 12,000 rpm for 5 minutes, remove the supernatant, and dry the separated solid at room temperature for 1 hour, which is confirmed by XRPD to be a co-crystal of velpatasvir and saccharin Form A.

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PUM

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Abstract

The invention discloses a new crystal form of Velpatasvir and a preparation method of the new crystal form. The structure of a compound with a formula I is shown as follows; a crystal form A of the compound with the formula I, which is prepared by the preparation method disclosed by the invention, has a good purification effect and physiochemical properties. (The formula I is shown in the description.).

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a new crystal form of velpatasvir, in particular to a co-crystal compound of velpatasvir and saccharin. Background technique [0002] Velpatasvir (VLP, formula II) is a hepatitis C treatment drug developed by Gilead, which was approved by the FDA in June 2016, and approved by the EMA in July 2016. Combined with Sofosbuvir (SOF), the combination therapy can cure all known genotypes (1-6) of HCV patients in as little as 8 weeks without the need for interferon injections or combined ribavir Lin (Ribavirin). [0003] [0004] Due to the characteristics of molecular structure, velpatasvir has poor crystallinity. Currently, Gilead's patent US20150361085A1 has applied for protection of the channel solvate, hydrochloride, phosphate, hydrobromide, and tartrate of velpatasvir. However, the stability, purification effect, hygroscopicity and process stability of these crystal forms a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/052
CPCC07B2200/13C07D491/052
Inventor 李巍任毅傅绍军
Owner SHANGHAI FOREFRONT PHARMA CO LTD
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