Isavuconazole monohydrate crystal form and preparation method thereof

A technology of isavuconazole monohydrate and monohydrate, which is applied in the field of pharmacy, can solve the problems of complex process technology, complicated preparation process, and long time consumption, and achieve simple crystallization process, strong operability, and favorable industrial production Effect

Active Publication Date: 2017-05-31
YANGTZE RIVER PHARM GRP CO LTD
View PDF4 Cites 1 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Patent international application: WO2016055918A1 also mentioned a crystal form of isavuconazole hydrobromide or prepared three crystal forms of isavuconazole hydrobromide by free isavuconazole hydrobromide, but these crystal forms The preparation methods of the type all need to be prepared through isavuconazole hydrobromide, the preparation process is complicated and its crystal form does not involve hydrate
Since there is no process of crystal precipitation in the preparation process of amorphous powder, slurry or non-hydrate, there are great difficulties in the removal of impurities and solvent residues
In the actual preparation process, the amorphous powder tends to be sticky when the solid is precipitated, and there are serious wall-hanging, wall-attaching, and agglomeration phenomena. The process is complicated and time-consuming. Unbreakable technical barriers in production

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
  • Isavuconazole monohydrate crystal form and preparation method thereof
  • Isavuconazole monohydrate crystal form and preparation method thereof
  • Isavuconazole monohydrate crystal form and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] The preparation of formula 3 compound

[0055] In the 5L three-necked round bottom reaction flask, add formula 2 compound successively, i.e. diethyl dithiophosphate (804g), formula 1 compound (300g), isopropanol (1.5L) and purified water (194ml), stir and heat up To reflux reaction (oil temperature 85°C), internal temperature 78°C, keep reflux, gradually a large amount of H 2 S gas is released until the temperature stabilizes at an internal temperature of 78°C, without a large amount of gas being released, and the temperature is kept stirring. After 15 hours, sampling and monitoring were performed, and TLC showed that SM1 spots disappeared and new spots were formed.

[0056] Cool down to below 20°C, add DCM (1.5L), purified water (1.5L). Slowly add 10wt% NaOH solution (about 2.3 L) dropwise under stirring to adjust the pH value to 7-8, and the system turns yellow and gray during the addition. Separate and extract, and collect the lower DCM phase. The aqueous phase w...

Embodiment 2

[0058] The preparation of formula 5 compound

[0059] In the 5L three-necked round-bottom reaction flask, add the formula 3 compound (300g) that embodiment 1 prepares, the formula 4 compound namely 2-bromo-4 cyano-acetophenone (215g) and 95% ethanol (1.5L), stir Lower the temperature to 85°C oil temperature and 76°C internal temperature. During the heating process, the color of the system turns yellow-green, and keep stirring for 2 hours. Sampling and monitoring, TLC showed that M1 spots disappeared and new spots were generated.

[0060] Cool down to below 20°C, under stirring, dissolve saturated NaHCO 3 Slowly add the solution into the reaction solution, adjust the pH value to 4-5, white solid precipitates, continue to stir until the crystals are completely precipitated, then add water dropwise into the system, so that the total water volume reaches 1.5L. After stirring for 2 h, it was filtered, and the solid was washed with a mixed solvent of EtOH: water = 1:1. The result...

Embodiment 3

[0063] The preparation of formula 5 compound

[0064] In the 5L three-necked round-bottom reaction flask, add the formula 3 compound (300g) that embodiment 1 prepares, the formula 4 compound namely 2-bromo-4 cyano-acetophenone (215g) and 95% ethanol (1.5L), stir Lower the temperature to 85°C oil temperature and 76°C internal temperature. During the heating process, the color of the system turns yellow-green, and keep stirring for 2 hours. Sampling and monitoring, TLC showed that M1 spots disappeared and new spots were generated.

[0065] Cool down to below 20°C, under stirring, dissolve saturated NaHCO 3 Slowly add the solution into the reaction solution, adjust the pH value to 4-5, and then slowly pour the reaction solution into purified water (1.5L), a large amount of white solids are precipitated, and after suction filtration, the filter cake is naturally aired to semi-dry, and the The drying time is about 16 hours. Add DCM (1.2L) and purified water (600ml) to the semi-d...

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 an isavuconazole monohydrate crystal form and further discloses a preparation method thereof. The method comprises the following steps: by taking (2S,3R)-3-(2,5-difluoro)-3-hydroxyl-2-methyl-4-(1H-1,2,4-triazole-1-yl) butyronitrile, diethylphosphorodithioate and 2-bromo-4 cyan-acetophenone as raw materials, carrying out steps of an addition reaction and penta-heterocycle closing and a unique post-treatment and crystallization process to prepare isavuconazole monohydrate which is white crystalized solid powder. The solid powder has the crystal form when being detected by XRPD (X-ray Powder Diffraction). Compared with previous isavuconazole amorphous powder, isavuconazole monohydrate crystal powder prepared by the process has the advantages of simple crystallization process, high operability, good stability and the like, and industrialized production is easier to realize.

Description

technical field [0001] The invention belongs to the field of pharmacy, and in particular relates to a crystal form of isavuconazole monohydrate and a preparation method thereof. Background technique [0002] Isavuconazonium sulfate (Isavuconazonium sulfate) was jointly developed by Astellas (Japan) and Basilea (Switzerland), and the FDA has granted its Qualified Infectious Disease Product (QIDP). fungal drugs. On July 8, 2014, Astellas submitted a marketing application to the FDA, which was approved in March 2015. Isavuconazolium sulfate is a prodrug used in the treatment of invasive Aspergillus infections and invasive Mucoral infections. [0003] In the blood, the prodrug is rapidly hydrolyzed into the active substance isavuconazole by the action of esterase (mainly butyrylcholinesterase). The mechanism of action of isavuconazole is similar to that of other azole antifungal drugs, and its mechanism of action is mainly to reduce the synthesis of ergosterol. Ergosterol is...

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): C07D417/06
CPCC07B2200/07C07B2200/13C07D417/06
Inventor 阴启明周崴海龚仁巍韩冬许鑫王俊元倪海华郝秀斌
Owner YANGTZE RIVER PHARM GRP 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