Ledipasvir intermediate monosulfate, crystalline form thereof and preparation method therefor

A kind of intermediate, sulfate technology, applied in its crystal form and amorphous and its preparation, ledipasvir intermediate monosulfate field, can solve the problems such as poor crystallinity of formula II compound, difficult to form salt and the like

Inactive Publication Date: 2015-11-04
SHANGHAI FOREFRONT PHARMA CO LTD
View PDF5 Cites 2 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the characteristics of the molecular structure, the compound of formula II itself has poor crystallinity and is difficult to form a salt. At present, there is no report on the salt-forming crystal form of the compound of formula II.

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Ledipasvir intermediate monosulfate, crystalline form thereof and preparation method therefor
  • Ledipasvir intermediate monosulfate, crystalline form thereof and preparation method therefor
  • Ledipasvir intermediate monosulfate, crystalline form thereof and preparation method therefor

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0078] The present invention provides a method for preparing the compound of formula I, comprising preparing the compound of formula I in amorphous and crystalline forms.

[0079] Since the crystal form has higher purity (eg ≥99%), it is preferred to prepare the crystal form in the present invention and use this crystal form as the raw material of ledipasvir.

[0080] One way to prepare the crystal form is to prepare the amorphous compound of formula I first, for example, those skilled in the art can prepare the amorphous compound of formula I with reference to the teachings of the present invention, and then use the amorphous compound to prepare the compound of formula I Crystalline raw materials to obtain crystalline products, such as crystal form I.

[0081] Another method for preparing crystal forms is to react the compound of formula II with an appropriate amount of sulfuric acid, and directly form the compound of formula I in crystal form during or after the reaction.

...

Embodiment 1

[0102] The preparation of embodiment 1 formula I compound (amorphous substance)

[0103] Weigh 37mg of the compound of formula II into a 1.5ml centrifuge tube, add 0.1mL of THF, sonicate until dissolved, add 0.1mL of 0.5M sulfuric acid in acetonitrile, immediately a white solid precipitates.

[0104] Part of the white solid precipitate was taken and identified by a polarizing microscope and confirmed to be an amorphous form.

Embodiment 2

[0105] Preparation of Embodiment 2 Formula I Compound (Crystal Form I)

[0106] (1) Weigh 37mg of the compound of formula II into a 1.5ml centrifuge tube, and add 0.1mL of ethanol. Sonicate until dissolved. Add 0.1 mL of 0.5M sulfuric acid in ethanol. The reaction mixture was left at room temperature for 6 hours and a solid precipitated out. Part of the solid precipitate was taken and identified as crystal by polarizing microscope.

[0107] (2) Place the centrifuge tube containing the centrifuge 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.

[0108] (3) Test the sulfate content of the dried solid by ion chromatography, and characterize the solid form by XRPD, DSC and TGA.

[0109] result

[0110] (1) The ion chromatographic analysis results show that the sulfate content in the crystal is basically consistent with the theoretical content (11.0 wt%) of the sulfate in the compound ...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

No PUM Login to view more

Abstract

The invention discloses a ledipasvir intermediate monosulfate, a crystalline form thereof and a preparation method therefor, and specifically discloses a compound (crystal-form or amorphous) shown in a formula I, a preparation method therefor and application thereof. According to the preparation method provided by the invention, the crystal form I of the prepared compound shown in the formula I is good in light stability.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry, in particular to a ledipasvir intermediate monosulfate, its crystal form and amorphous form, its preparation method and application. Background technique [0002] Ledipasvir (LDV) is a hepatitis C treatment drug developed by Gilead. The FDA has granted Breakthrough Therapy Designation to the LDV / SOF (Sofosbuvir) fixed-dose combination drug, which is expected to cure the genotype in as little as 8 weeks 1HCV patients do not need to inject interferon or combine ribavirin (Ribavirin). [0003] The synthetic route of ledipasvir is shown in the following formula, wherein the compound of formula II is the key intermediate of ledipasvir, and the quality of the compound of formula II has a profound impact on the quality of subsequent reactions and the quality of ledipasvir raw materials. [0004] [0005] Among them, different salt forms of compounds are an important means to improve the cr...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/14A61K31/4184A61P31/14
CPCC07D403/14C07B2200/13
Inventor 李巍任毅黄成军朱燕燕傅绍军富刚魏哲文
Owner SHANGHAI FOREFRONT PHARMA CO LTD
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap