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Synthetic method for high-purity tigecycline

A technology of tigecycline and synthesis method, which is applied in chemical instruments and methods, preparation of organic compounds, organic chemistry and other directions, can solve the problems such as difficulty in controlling the quality of crude intermediates, failing to meet technical requirements, and high adverse reactions in patients.

Active Publication Date: 2014-01-08
NANJING HAIRUN PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] In addition, the three routes have a common disadvantage that the quality of intermediates or crude products is difficult to control, and the purity of the product needs to be refined many times to barely reach 99%. % below is unreachable, it is difficult to meet the quality requirements of injection raw materials, and it also cannot meet the relevant technical requirements of ICH, the European Union's quality research technical guidelines
If the raw materials with high impurities are used to make injections, it is bound to bring high adverse reactions to patients

Method used

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  • Synthetic method for high-purity tigecycline
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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Example 1 Preparation of Tigecycline

[0031] Add 4.2g (0.025mol) of N-tert-butylglycine to a 500ml three-necked flask, add 126ml of dichloromethane, and add the condensing agent HOAt (4.1g, 0.03mol) and triethylamine (7.6g, 0.075mol) under stirring After 30 minutes, 9-aminominocycline (12.7 g, 0.025 mol) was added, and the reaction was stirred at 35-40° C. for 3 h. HPLC monitors that the content of 9-aminominocycline in the reaction solution is less than 1.0% (area normalized), adjust the pH of the reaction solution to 3.0-4.5 with 1mol / L hydrochloric acid solution, separate the organic layer, adjust the pH to 7.0-7.5 with ammonia water, The aqueous phase was extracted with a mixed solvent of dichloromethane / methanol (250ml*3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 8.2 g of crude tigecycline.

[0032] The obtained crude product was dissolved in 82ml of acetone, at 38-45°C, slowly added 82ml of m...

Embodiment 2

[0036] Example 2 Preparation of Tigecycline

[0037] Add 6.3g (0.038mol) of N-tert-butylglycine into a 500ml three-necked flask, add 150ml of dichloromethane, and add the condensing agent CDI (9.2g, 0.057mol) and N,N-diisopropylethylamine under stirring (14.7g, 0.114mol), after 20 minutes, 9-aminominocycline (19.3g, 0.038mol) was added, and the reaction was stirred at 10°C for 6h. HPLC monitors that the content of 9-aminominocycline in the reaction solution is less than 1.0% (area normalized), adjust the pH of the reaction solution to 3.0-4.5 with 1mol / L hydrochloric acid solution, separate the organic layer, adjust the pH to 7.0-7.5 with ammonia water, The aqueous phase was extracted with a mixed solvent of dichloromethane / methanol (250ml*3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 10.1 g of crude tigecycline.

[0038] The obtained crude product was dissolved in 100ml of acetone, at 38-45°C, slowly added...

Embodiment 3

[0039] Example 3 Preparation of Tigecycline

[0040] Add 4.2g (0.025mol) of N-tert-butylglycine to a 500ml three-necked flask, add 63ml of N,N-dimethylformamide, add the condensing agent HATU (5.23g, 0.014mol) and triethylamine ( 2.53g, 0.025mol), after 30 minutes, 9-aminominocycline (6.4g, 0.013mol) was added, and the reaction was stirred at 25°C for 3h. HPLC monitors that the content of 9-aminominocycline in the reaction solution is less than 1.0% (area normalized), adjust the pH of the reaction solution to 3.0-4.5 with 1mol / L hydrochloric acid solution, separate the organic layer, adjust the pH to 7.0-7.5 with ammonia water, Extract the aqueous phase with dichloromethane / methanol mixed solvent (250ml*3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to obtain 4.1g of crude tigecycline.

[0041] The obtained crude product was dissolved in 40ml of acetone, at 38-45°C, slowly added 40ml of methanol solution containing 2% lactose, added...

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Abstract

The invention relates to a novel preparation method for antibioticdrug tigecycline. 9-amino minocycline and N-tert-butyl group glycine are taken as starting materials. The novel preparation method is characterized in that the N-tert-butyl group glycine is dissolved in indifferent solvent, under the existence of an acidic acceptor and an amino acid condensating agent, reaction with 9-amino minocycline is carried out along the route of amino acid condensation for 3 hours to 10 hours, and then an indifferent solvent is cooled to a room temperature. Tigecycline is obtained through acidification, neutralization, extraction, drying, concentration and refining. In the preparation method disclosed by the invention, the operation is simplified, the purity of the obtained product reaches more than 99.5 percent, individual impurities are controlled to be lower than 0.1 percent, and an epimer is controlled to be lower than 0.5 percent; and the yield is high, the stability of the product is good, and the preparation method is suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of antibiotic drug tigecycline, which belongs to the technical field of medicinal chemistry. Background technique [0002] Tigecycline (tigecycline) chemical name (4S, 4aS, 5aR, 12aS)-4,7-bis(dimethylamino)-9-[(tert-butylamino)acetamido]-3,10,12, 12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide is the first intravenous drug approved for clinical use Glycylcycline antibiotics administered internally, similar in structure to tetracyclines, were approved by the US FDA in June 2005 for complex skin and soft tissue infections in adults and complicated intra-abdominal infections in adults. The structural formula of tigecycline is: [0003] [0004] Although tigecycline and minocycline have many similarities in structure, the former is obviously superior to traditional tetracyclines in terms of antibacterial spectrum range and drug-resistant bacteria, and has broad-spectrum an...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C237/26C07C231/14
Inventor 赵俊宗在伟杨建楠
Owner NANJING HAIRUN PHARM CO LTD
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