Preparation method of novel triazole antifungal drug

A compound, posaconazole technology, applied in the field of preparation of novel triazole antifungal drugs, can solve problems such as difficulty in ensuring product quality standards, increased difficulty in process control, high requirements for reaction equipment, etc. The effect of increased impurities, low equipment requirements and high product purity

Active Publication Date: 2016-06-01
BRIGHTGENE BIO MEDICAL TECH (SUZHOU) CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

When using this method to prepare posaconazole, due to the need to catalyze the hydrogenation reaction under high pressure, the requirements for the reaction equipment are very high, the operation is complicated and complicated, and the safety hazard is very large, and the material cost of the catalyst is also very high. Inconvenient monitoring, not conducive to industrial production
Moreover, the content of heavy metals, especially palladium (Pd) content in products prepared by palladium (Pd) catalysis is difficult to control, especially for posaconazole injection formulations, the content of palladium (Pd) needs to be controlled within 1ppm
Using the above method, in order to control the content of heavy metals, the difficulty of process control is increased, and it is also difficult to ensure that the product can meet the quality standards of various dosage forms of raw materials, which is not conducive to the wide application of raw materials to different dosage forms of preparation products

Method used

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  • Preparation method of novel triazole antifungal drug
  • Preparation method of novel triazole antifungal drug
  • Preparation method of novel triazole antifungal drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Example 1 Preparation of posaconazole (compound I)

[0038]

[0039] Add concentrated hydrochloric acid (40ml) into a 100ml three-neck flask, then add compound II (8.0g, 10.1mmol), stir to dissolve and react at 60~65°C for 2~4h. After the reaction, cool to room temperature, add water (40ml) to dilute, and wash twice with dichloromethane (50ml×2) to remove impurities. Dichloromethane (50ml) was added to the remaining aqueous phase, and then 20% sodium hydroxide solution was added to adjust the pH to 6~7, and the organic phase was collected by liquid separation. The organic phase was washed with 20% sodium chloride solution and concentrated. Dissolve the concentrate in ethanol (50ml), add medicinal activated carbon (0.15g), reflux and stir for 2~3h, then filter while it is hot, add water (7ml) to the filtrate, reflux and stir, cool and crystallize, then filter. The filter cake was crystallized with ethanol / water=9:1 (70ml). After filtration, the filter cake was vacu...

Embodiment 2

[0040] Example 2 Preparation of posaconazole (compound I)

[0041]Add concentrated hydrochloric acid (40ml) into a 100ml three-neck flask, then add compound II (8.0g, 10.1mmol), stir to dissolve and react at 60~65°C for 2~4h. After the reaction, cool to room temperature, add water to dilute to pH about 3, and wash twice with toluene (50ml×2) to remove impurities. Add toluene (50ml) to the remaining aqueous phase, then add 5% potassium carbonate solution to adjust the pH to about 6, and collect the organic phase by liquid separation. The organic phase is washed with sodium chloride solution and concentrated. Dissolve the concentrate in ethanol (56ml), add medicinal activated carbon (0.15g), reflux and stir for 2-3 hours, then filter while it is hot, add water (9ml) to the filtrate, reflux and stir, cool and crystallize and then filter. The filter cake was crystallized with ethanol / water=6:1 (7ml / g). After filtration, the filter cake was vacuum-dried (55~60°C) to obtain 5.78...

Embodiment 3

[0042] Example 3 Preparation of posaconazole (compound I)

[0043] Add concentrated hydrochloric acid (40ml) into a 100ml three-neck flask, then add compound II (8.0g, 10.1mmol), stir to dissolve and react at 60~65°C for 2~4h. After the reaction, cool to room temperature, add water (120ml) to dilute, and wash twice with ethyl acetate (50ml×2) to remove impurities. Ethyl acetate (50ml) was added to the remaining aqueous phase, and then 20% ammonia water was added to adjust the pH to 5, and the organic phase was collected by liquid separation. The organic phase is washed with sodium chloride solution and concentrated. Dissolve the concentrate in ethanol (240ml), add medicinal activated carbon (0.15g), reflux and stir for 2~3h, then filter while it is hot, add water (16ml) to the filtrate, reflux and stir, cool and crystallize and then filter. The filter cake was crystallized with ethanol / water=15:1 (116ml) (15ml / g). After filtration, the filter cake was vacuum-dried (55~60°C...

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PUM

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Abstract

The invention relates to a preparation method of a novel triazole antifungal drug and concretely relates to a posaconazole preparation method. The preparation method comprises that a compound II undergoes a debenzylation reaction without a Pd catalyst under normal pressure to produce posaconazole, and after the reaction, posaconazole is extracted through a water-insoluble organic solvent under acidic conditions so that genotoxic impurity benzyl chloride is substantially removed. The preparation method has the advantages of operation simpleness and convenience, high safety, controllable final product quality and high purity and yield.

Description

technical field [0001] The invention relates to the technical field of pharmacy, in particular to a preparation method of a novel triazole antifungal drug. Background technique [0002] Posaconazole (posaconazole) CAS: 171228-49-2, chemical name 4-[4-[4-[4-[[(3R,5R)-5-(2,4-difluorophenyl)- 5-(1,2,4-Triazol-1-ylmethyl)oxolan-3-yl]methoxy]phenyl]piperazin-1-yl]phenyl-2-[(2S, 3S)-2-hydroxypent-3-yl]-1,2,4-triazol-3-one; the structural formula is as shown in formula I below: [0003] [0004] Posaconazole is a derivative of itraconazole. It is a second-generation triazole antifungal drug developed by Schering-Plough. Approved for oral suspension, extended-release tablets on November 25, 2013, and injections have also received FDA priority review, and their development and application are increasingly popular for the treatment of adult patients with invasive fungal infections, especially for those It is especially useful in patients who are refractory and cannot tolerate ot...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/14
Inventor 袁建栋徐安佗王圣奔
Owner BRIGHTGENE BIO MEDICAL TECH (SUZHOU) CO LTD
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