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Delafloxacin impurities I and II and product refining method

A technology of delafloxacin and a refining method, which is applied in the field of impurities I and II of delafloxacin and product refining, can solve the problems of difficulty in detecting impurities, and achieve the effects of reducing energy consumption, mild conditions and improving product quality.

Inactive Publication Date: 2020-09-29
NANJING HAIRUN PHARM CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] However, drug research is a systematic project, and all links are related to each other. By analyzing the relationship between the process and impurities, the process can be optimized, the process conditions can be controlled, and the impurities can be controlled within a safe and reasonable range; on the other hand, in a certain In some cases, impurity detection is difficult to achieve. Therefore, if we can limit the impurity content of raw materials, optimize the formulation process, ensure product quality and stability, and use quality standards to control specific impurities in them, we can jointly grasp the Product quality, it can be seen that standard control is not the only means of impurity control, the organic combination of process control and standard control is an effective measure to ensure product quality

Method used

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  • Delafloxacin impurities I and II and product refining method
  • Delafloxacin impurities I and II and product refining method
  • Delafloxacin impurities I and II and product refining method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Embodiment 1 impurity preparation

[0035]

[0036] Add compound 1 (4.050Kg), LiCl (0.8Kg) and N-methylpyrrolidone (15Kg) into a 100L vertical reactor, stir the system well, and slowly add DBU (1.5Kg) dropwise. After the dropwise addition was completed and the reaction was stirred for 2 hours, 3-hydroxyazetidine hydrochloride (1.5Kg) was added, and DBU (4.0Kg) was slowly added dropwise. After the dropwise addition was completed, the internal temperature was controlled at 80°C to continue the reaction for 1 hour. The reaction solution was lowered to 20°C, and 31.6Kg of 10% citric acid aqueous solution was added dropwise at an internal temperature of ≤20°C. During the dropwise addition, a yellow solid was precipitated, centrifuged until dry, and the solid was dried in vacuum to obtain Compound 2 (3.96kg);

[0037] Add compound 2 (3.96Kg) and isopropanol (23.5Kg) into a 100L vertical reactor, and stir to raise the temperature. Add 6% potassium hydroxide aqueous solutio...

Embodiment 2

[0072] Embodiment 2 delafloxacin meglumine salt refining

[0073] Weigh delafloxacin meglumine salt (15.0g, 0.023mol) into a 250ml three-necked flask, add 45mL of purified water and 44mL of isopropanol, keep stirring at 60°C for 1h until all solids are dissolved, filter, and cool the filtrate to 5-10°C, slowly add 89mL of isopropanol dropwise, stir and crystallize for 12h, filter with suction, rinse with a small amount of isopropanol, collect the filter cake and dry it in vacuum at 80±5°C for 10h to obtain 12.5g of the refined product with a yield of 83.3 %, detected with the HPLC method described in Example 1, HPLC main component: 99.75%; Impurity I: not detected; Impurity II: 0.14%; Impurity III: not detected; Impurity IV: 0.11%; .

Embodiment 3

[0074] Embodiment 3 delafloxacin meglumine salt refining

[0075] Weigh delafloxacin meglumine salt (15.0g, 0.023mol) into a 250ml three-necked flask, add 45mL of purified water and 44mL of isopropanol, keep stirring at 50°C for 2h, until all solids are dissolved, filter, and cool the filtrate to 5-10°C, slowly add 89mL of isopropanol dropwise, stir and crystallize for 18h, filter with suction, rinse with a small amount of isopropanol, collect the filter cake and dry it in vacuum at 80±5°C for 10h to obtain 11.5g of refined product with a yield of 76.7 %, detected with the HPLC method described in Example 1, impurity I: not detected; impurity II: 0.15%; impurity III: not detected; impurity IV: 0.12%; does not contain other substances.

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Abstract

The invention belongs to the field of medicine impurities, and particularly relates to delafloxacin impurities I and II and a product refining method. A proper analysis method is selected through optimization to detect related stubborn impurities of a product. The specific structure of related impurities is separated, detected and confirmed. Finally, synthesis and process routes are optimized, impurities are controlled within a safe range, a basis is provided for product process amplification, stability, quality, pharmacology and toxicology and clinical research, and the method has important significance in reducing the safety risk of drug impurities.

Description

technical field [0001] The invention belongs to the field of pharmaceutical impurities, in particular to impurities I and II of delafloxacin and a product refining method. Background technique [0002] Delafloxacin (Delafloxacin) is a new type of fluoroquinolone antibiotics for the treatment of acute bacterial skin and skin tissue infections caused by special G- and G+ bacteria, including MRSA and Pseudomonas aeruginosa; The chemical structure of the amine salt is shown in the following formula: [0003] [0004] Delafloxacin was first developed by Wakunaga Pharmaceuticals. In 2006, Rib-X (now Melinta) obtained the global exclusive authorization of the drug, and it was approved by the US Food and Drug Administration (FDA) on June 19, 2017. , the product name is At present, the drug has not been approved for marketing in China. [0005] Impurity control is one of the core contents of drug quality control. The adverse reactions of drugs in clinical use are often related...

Claims

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Application Information

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IPC IPC(8): C07D401/14
CPCC07D401/14
Inventor 赵俊赵骞付锐杨瑞峰李淦潘仁明
Owner NANJING HAIRUN PHARM CO LTD
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