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Method for preparing tigecycline intermediate

A Chinese compound technology, applied in the preparation of tigecycline intermediates and 9-nitrominocycline, can solve the problems of low purity, achieve simple operation, reduce the requirements of reaction equipment, and avoid corrosion

Active Publication Date: 2017-06-13
JIANGSU HANSOH PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The use of non-solvent precipitation to separate the compound 9-nitrominocycline of formula II has the problem of co-precipitation of oxidation by-products and metal salts with the product, resulting in very low purity.

Method used

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  • Method for preparing tigecycline intermediate
  • Method for preparing tigecycline intermediate
  • Method for preparing tigecycline intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Add concentrated sulfuric acid (180ml) into the reaction bottle, add minocycline hydrochloride (100g) at temperature control -20°C, and stir until it dissolves. Potassium nitrate (24.3 g) was added slowly and uniformly at a temperature of -20°C for 2.5 hours. After adding and keeping warm for 1 h, HPLC detection showed that the purity was 89.8%, and the C4-epimer was 0.2%. Control the temperature at -5°C and slowly add 10% ammonia methanol solution dropwise until no precipitation occurs, filter, and the filtrate is 9-nitrominocycline methanol solution. HPLC detection shows that the purity is 93.2%. 9-Nitrocycline C4-epimer of Kiminocycline 0.2%. The filtrate was concentrated to dryness under reduced pressure to obtain a solid, which was detected by HPLC, showing that the purity was 93.2%, and the C4-epimer of 9-nitrominocycline was 0.2%, which had no significant difference from that in the solution. The resulting solid residue on ignition was 0.05%.

[0036] It can b...

Embodiment 2

[0038] Add concentrated sulfuric acid (180ml) into the reaction bottle, add minocycline hydrochloride (90g) at temperature control -5°C, and stir until it dissolves. Potassium nitrate (25 g) was added slowly and uniformly at a temperature of -5°C for 2.5 hours. After adding and keeping warm for 1 hour, HPLC detection showed that the purity was 88.5%, and the C4-epimer of 9-nitrominocycline was 0.2%. Control the temperature at 0°C and slowly add 10% methanol solution of ammonia gas dropwise until no more precipitation occurs, filter, and the filtrate is 9-nitrominocycline methanol solution. HPLC detection shows that the purity is 92.1%, 9-nitrominocycline C4-epimer of minocycline 0.2%. The filtrate was concentrated to dryness under reduced pressure to obtain a solid, which was detected by HPLC, showing a purity of 92.0%, and a C4-epimer of 9-nitrominocycline of 0.2%. The resulting solid residue on ignition was 0.06%.

Embodiment 3

[0040] Add concentrated sulfuric acid (180ml) into the reaction bottle, add minocycline hydrochloride (60g) at -20°C under temperature control, and stir until it dissolves. Potassium nitrate (17 g) was added slowly and uniformly at a temperature of -15°C for 2.2 hours. After adding and keeping warm for 1 hour, HPLC detection showed that the purity was 89.1%, and the C4-epimer of 9-nitrominocycline was 0.2%. Control the temperature at -5°C and slowly add 10% ammonia methanol solution dropwise until no precipitation occurs, filter, and the filtrate is 9-nitrominocycline methanol solution. HPLC detection shows that the purity is 92.3%. 9-Nitrocycline C4-epimer of Kiminocycline 0.2%. The filtrate was concentrated to dryness under reduced pressure to obtain a solid, which was detected by HPLC, showing a purity of 92.4%, and a C4-epimer of 9-nitrominocycline of 0.2%. The resulting solid residue on ignition was 0.04%.

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Abstract

The invention relates to a method for preparing a tigecycline intermediate. The tigecycline intermediate can be obtained at a high yield and high purity. The method has the advantages of convenience in operation, safety and environment protection. The obtained product has the characteristics of high purity and low epimer contents and is favorable for industrial amplification.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a method for preparing a tigecycline intermediate, more precisely a method for preparing 9-nitrominocycline. Background technique [0002] Tigecycline (Tigecycline), developed by the Wyeth Pharmaceutical Company of the United States, is a new type of broad-spectrum active intravenous antibiotics. It is also active against drug-resistant methicillin-resistant Staphylococcus aureus. It is a glycylcycline class The first drug in , has the following chemical structure: [0003] [0004] Tigecycline is unstable and can be degraded by epimerization. Epimerization is generally a known degradation pathway for tetracyclines, although the rate of degradation can vary from tetracycline to tetracycline. In contrast, the epimerization of tigecycline may be rapid, even eg under slightly acidic conditions and / or slightly elevated temperatures. [0005] Tigecycline differs fr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C231/12C07C237/26
CPCC07C231/12C07C237/26
Inventor 徐士伟陈刚胜孙长安
Owner JIANGSU HANSOH PHARMA CO LTD
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