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New crystal form of benzyl ether posaconazole, and preparation method and use thereof

A technology of posaconazole and benzyl ether, which is applied to the new crystal form of benzyl ether posaconazole and the fields of its preparation and use, can solve the problems of poor quality stability, difficult to achieve purity, poor crystallinity, etc. Low cost, easy operation, and the effect of improving stability

Inactive Publication Date: 2017-05-24
CHENGDU ZIHAO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the diffraction peaks of this crystal form A are in a disordered state, indicating that its crystallinity is poor, it is easy to absorb moisture, its quality stability is poor, and its purity is difficult to reach more than 95%.

Method used

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  • New crystal form of benzyl ether posaconazole, and preparation method and use thereof
  • New crystal form of benzyl ether posaconazole, and preparation method and use thereof
  • New crystal form of benzyl ether posaconazole, and preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Embodiment 1 prepares the new crystal form of benzyl ether posaconazole

[0034] With 50g (97mmol) posaconazole side chain (2-[(1S,2S)-1-ethyl-2-benzyloxypropyl]-2,4-dihydro-4-[4[4-( 4-Hydroxyphenyl-1-piperazinyl)]phenyl]-3H-1,2,4-triazol-3-one) was dissolved in 450ml DMSO, and added dropwise at 0-10°C under nitrogen protection 20% solution prepared by 4.8g NaOH (120mmol), stirred for 30min after addition; then added 46g (102mmol) posaconazole main ring ((5R-cis)-toluene-4-sulfonic acid-5-(2,4 -difluoro-phenyl)-5-[1,2,4]triazolyl-1-methyl-tetrahydrofuran-3-methyl ester), after removing the ice bath, raise the temperature to 55°C and continue stirring for 20-24 hours The reaction solution was slowly poured into 2L of ice water, a large amount of off-white solid was precipitated, filtered, the solid was washed with 1L of water, and the solid was dried to obtain 81 g of crude product (the yield of crude product was greater than 100%).

[0035] Add 1.3L isopropanol to 81g...

Embodiment 2

[0039] Embodiment 2 prepares the new crystal form of benzyl ether posaconazole

[0040]With 60g (117mmol) posaconazole side chain (2-[(1S,2S)-1-ethyl-2-benzyloxypropyl]-2,4-dihydro-4-[4[4-( 4-Hydroxyphenyl-1-piperazinyl)]phenyl-]-3H-1,2,4-triazol-3-one) was dissolved in 750ml DMF, under nitrogen protection, at 0-10°C Add 4.92g of NaH (123mmol) with a content of 60% in batches, and stir for 30min after the addition; then add 53.6g (118mmol) of posaconazole main ring ((5R-cis)-toluene-4-sulfonic acid- 5-(2,4-difluoro-phenyl)-5-[1,2,4]triazolyl-1-methyl-tetrahydrofuran-3-methyl ester), remove the ice bath and raise the temperature to 52°C to continue stirring React for 20-24 hours; the reaction solution was slowly poured into 3L of ice water, and a large amount of off-white solid was precipitated, filtered, washed with 1L of water, and dried to obtain 96g of crude product (the crude product yield was greater than 100%).

[0041] Add 96g of the crude product to 1.5L of isopropan...

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Abstract

The invention discloses a crystal form of benzyl ether posaconazole; an X-ray powder diffraction pattern of the crystal form has characteristic peaks at diffraction angles 2 theta: 11.82+ / -0.2, 13.38+ / -0.2, 15.50+ / -0.2, 16.25+ / -0.2, 16.94+ / -0.2, 17.84+ / -0.2, 18.30+ / -0.2, 18.90+ / -0.2, 20.07+ / -0.2, 21.48+ / -0.2, 22.86+ / -0.2, 24.95+ / -0.2, 26.01+ / -0.2, 27.54+ / -0.2, and 28.77+ / -0.2 DEG. According to the new crystal form of benzyl ether posaconazole, the diffraction peaks of the crystal form are regular, the crystalline particles are good, the hygroscopicity of products can be significantly reduced, deliquescence or degradation of the products is effectively avoided, the stability of the products is improved, and storage and transportation of the products are facilitated.

Description

technical field [0001] The invention relates to a new crystal form of benzyl ether posaconazole, a preparation method and application thereof. Background technique [0002] Posaconazole is a new triazole derivative with broad-spectrum and potent antifungal activity. It has strong in vivo and in vitro activity against various pathogenic fungi, and has oral activity. Posaconazole was first developed by Schering-Plough, and was approved by the FDA in the United States in September 2006 for the treatment of fungal infections. Currently, the dosage forms of posaconazole marketed abroad include oral suspension 40mg / ml, sustained-release tablet 100mg and injection 18mg / ml, and domestic oral suspension has been imported and marketed. Posaconazole, a new type of broad-spectrum and potent antifungal drug, has attracted great attention from domestic and foreign pharmaceutical companies and is actively conducting research and development. [0003] Benzyl ether posaconazole, the chemic...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/14
Inventor 周武春李春中刘爱吴思思
Owner CHENGDU ZIHAO PHARMA