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Posaconazole succinyl adduct impurity and preparation method and application thereof

A technology of posaconazole succinyl and posaconazole, which is applied in the field of drug synthesis, can solve the problems of no synthetic method, etc., and achieve the effects of short reaction time, simple purification and high yield

Inactive Publication Date: 2018-12-11
CHENGDU ZIHAO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Posaconazole succinyl adduct is an impurity produced during the preparation of posaconazole enteric-coated tablets. At present, posaconazole succinyl adduct has not been provided in the market, and no literature has reported its specific structure. And there is no related synthetic method

Method used

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  • Posaconazole succinyl adduct impurity and preparation method and application thereof
  • Posaconazole succinyl adduct impurity and preparation method and application thereof
  • Posaconazole succinyl adduct impurity and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Embodiment 1, the preparation of posaconazole preparation impurity

[0021]

[0022] Add 20mL of dichloromethane, 2.5g (3.56mmol) of posaconazole, 0.42g (3.56mmol) of succinic acid, 0.475g (3.56mmol) of bromotrimethylsilane into a 100mL single-necked bottle, and react at 25±5°C Stir overnight, TLC monitors that the reaction is complete, add dropwise 3.56mL of 1M sodium bicarbonate solution to quench, concentrate to dryness, add 30mL of dichloromethane to dissolve, filter, wash the filtrate with 3x30mL of water, collect the dichloromethane phase, dry and concentrate over anhydrous sodium sulfate 2.6 g of white solid was obtained with a yield of 91% and a purity of 96.1%.

[0023] 1 HNMR (400MHz, DMSO-d6) δ8.59(1H, s) δ8.39(2H, d), 7δ.81(1H, s), δ7.54-7.38(6H, m), δ7.33(2H , m), δ7.17(2H, d), δ7.02-6.95(3H, m), δ5.07(1H, q), 4.63(2H, q), ,4.10-4.01(2H, m) δ3 .84-3.71 (3H, m), δ3.5-3.3 (7H, m), δ2.60 (1H, m) δ2.43-2.39 (5H, m) 2.18 (1H, dd), 1.83-1.69 ( 1H, m) 1.32-...

Embodiment 2

[0024] Embodiment 2, the preparation of posaconazole preparation impurity

[0025] Add 20 mL of ethylene glycol dimethyl ether, 2.5 g (3.56 mmol) of posaconazole, 0.42 g (3.56 mmol) of succinic acid, and 0.71 g (5.34 mmol) of bromotrimethylsilane into a 100 mL single-port bottle, and the reaction is carried out at 25 ± Stir overnight at 5°C, TLC monitors that the reaction is complete, quench the reaction by adding 5.34 mL of 1M aqueous sodium bicarbonate solution dropwise, concentrate to dryness, add 30 mL of dichloromethane to dissolve, filter, wash the filtrate with 3x30 mL of water, collect the dichloromethane phase, anhydrous It was dried over sodium sulfate, filtered and concentrated to obtain 2.4 g of white solid with a yield of 84.2% and a purity of 97.3%.

Embodiment 3

[0026] Embodiment 3, the preparation of posaconazole preparation impurity

[0027] Add 20 mL of 1,4-dioxane, 2.5 g (3.56 mmol) of posaconazole, 0.42 g (3.56 mmol) of succinic acid, and 0.747 g (7.12 mmol) of bromotrimethylsilane into a 100 mL one-port bottle, and react in Stir overnight at 25±5°C, TLC monitors that the reaction is complete, quench the reaction by adding 7.12 mL of 1M aqueous sodium bicarbonate dropwise, concentrate to dryness, add 30 mL of dichloromethane to dissolve, filter, wash the filtrate with 3x30 mL of water, collect the dichloromethane phase, Dry over anhydrous sodium sulfate, filter and concentrate to obtain 2.3 g of white solid with a yield of 80.7% and a purity of 97.4%.

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Abstract

The invention provides a posaconazole succinyl adduct impurity and a preparation method and application thereof. Proofed by experiment results, a synthesizing method has the advantages that the thorough reaction can be performed at room temperature, the special reactor is not required, the operation is simple, the purification is simple and convenient, and the high-purity posaconazole succinyl adduct with high purity can be obtained without complicated column chromatography; the reaction time is short, and the yield rate is high; after accidental finding, the usage amount of sodium bicarbonatewater solution for reaction quenching can be controlled, the purity of the product can be effectively improved, and the unexpected technical effect can be obtained. The prepared posaconazole succinyladduct impurity can be used as the standard contrast product for the quality control on posaconazole.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to posaconazole succinyl adduct impurities and a preparation method and application thereof. Background technique [0002] Posaconazole is a derivative of itraconazole, a second-generation triazole antifungal drug listed on the FDA in 2006. Posaconazole has a broad antibacterial spectrum against Candida, Histoplasma capsulata, Seidosporum, Bipolar zygomycetes, Fusarium, yeast, including fluconazole-resistant non-albicans strains, new crypto Both cocci and aspergillus have strong inhibitory activity; especially against relatively rare, life-threatening fungal diseases (zygomycosis, fusarium and coccidioidomycosis, etc.) are also effective. [0003] Posaconazole is soluble at low pH, but posaconazole dissolved in gastric juice will precipitate when it reaches the intestinal environment, thereby hindering the absorption of posaconazole. Enteric-coated posaconazole tablets us...

Claims

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Application Information

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IPC IPC(8): C07D405/14G01N30/02
CPCC07D405/14G01N30/02
Inventor 傅辉李春中周武春陈柳钦
Owner CHENGDU ZIHAO PHARMA
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