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Method for preparing dalbavancin

A technology of dalbavancin and intermediates, which is applied in the field of antibiotic preparation, can solve the problems of difficulty in obtaining dalbavancin, high purification cost and the like, and achieves the effects of reduced preparation cost, easy removal and high yield

Active Publication Date: 2019-03-15
LIVZON NEW NORTH RIVER PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

CN87106876A, CN101851277A, CN103060405A disclose the preparation method of antibiotic A40926 complex, but the reaction sites on the antibiotic A40926 complex are numerous and have relatively similar reactivity, and the existing method for preparing dalbavancin using antibiotic A40926 complex as raw material It is generally difficult to obtain higher purity dalbavancin, and because the structure of the impurities in the reaction product is close to that of the target product, the purification cost is also high
Therefore, the preparation and purification methods of dalbavancin are seldom reported.

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  • Method for preparing dalbavancin
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  • Method for preparing dalbavancin

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preparation example Construction

[0029] A preparation method of dalbavancin, the synthetic route is as follows:

[0030]

[0031] In the formula, R 1 It is a C4-C30 hydrocarbon group;

[0032] Including the following steps:

[0033] 1) Protecting the carboxyl group of the A40926 complex to obtain intermediate I;

[0034] 2) Amidation reaction of intermediate I with 3,3-dimethylamino-1-propylamine to obtain intermediate II;

[0035] 3) The intermediate II is hydrolyzed in alkaline solution, acidified and purified to obtain dalbavancin.

[0036] As a further improvement of the above preparation method, using R 1 The carboxyl group of the A40926 complex was protected by the esterification reaction between -OH and the A40926 complex.

[0037] As a further improvement of the above preparation method, R 1 It is a C4-C30 chain alkyl group. Considering the cost of raw materials, reaction conditions, etc., C4-C20 alkanyl is preferred. Further, R 1 -OH is a hydroxyl-terminated alcohol.

[0038] As a furthe...

Embodiment 1

[0049] 1) Add 100ml of n-butanol to a three-necked flask, cool to 5°C, add concentrated hydrochloric acid dropwise, adjust the pH value to 1.0-1.5, add A40926 complex (10.00g, 5.77mmol), and stir the reaction at 3-5°C After 8 hours, triethylamine was slowly added dropwise to adjust the pH to 5.5 when precipitation appeared, filtered, and dried in vacuum below 35°C to obtain 9.60 g of intermediate I with a yield of 92%;

[0050] 2) Dissolve Intermediate I (9.50g, 5.28mmol) in 150ml DMSO at 25-30°C, add 3,3-dimethylamino-1-propanamine (0.65g, 6.36mmol) and DCC (1.30g , 6.35mmol), stirred and reacted at 20°C for 8 hours, added 170ml of methyl tert-butyl ether to precipitate, filtered, and vacuum-dried below 35°C to obtain 8.80g of intermediate II, with a yield of 84%;

[0051] 3) Dissolve intermediate II (8.70g, 4.83mmol) in a mixed solution of 10ml of acetonitrile and water, slowly add 1mol / L LiOH solution dropwise at 5°C to pH 10, and continue to stir and react at this temperat...

Embodiment 2

[0054] 1) Add 100ml of phenylethanol to a three-necked flask, cool to 5°C and add concentrated sulfuric acid dropwise to adjust the pH to 1.0-1.5. Add A40926 complex (10.00g, 5.77mmol), stir and react at 5-8°C for 10 hours, slowly add triethylamine dropwise to adjust the pH to 5.5 when precipitation occurs, filter, and vacuum dry below 35°C to obtain intermediate I9. 89g, the yield is 94%;

[0055] 2) 20~25°C, dissolve intermediate I (9.50g, 5.13mmol) in 170ml DMF, add 3,3-dimethylamino-1-propanamine (0.65g, 6.36mmol) and benzotrifluorophosphate Azol-1-yl-oxytripyrrolidinylphosphonium (3.40 g, 6.35 mmol). Stir the reaction at 30°C for 12 hours, add 170ml of methyl tert-butyl ether to precipitate, filter, and dry under vacuum below 35°C to obtain 8.28g of intermediate II with a yield of 83%;

[0056] 3) Take intermediate II (8.00g, 4.14mmol) and dissolve it in a mixed solution of 10ml tetrahydrofuran and water, slowly add 1mol / L NaOH solution dropwise at 5°C to pH 9, and cont...

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Abstract

The invention discloses a method for preparing dalbavancin. The method comprises the following steps: protecting carboxyl of a complex A40926, carrying out an amidation reaction with 3,3-dimethylamino-1-propylamine, hydrolyzing in an alkaline solution, acidifying and purifying, so as to obtain the dalbavancin. According to the preparation method disclosed by the invention, the reaction conditionsare mild, the yield is high, the impurities are easily removed, and the preparation cost of the dalbavancin can be effectively reduced.

Description

technical field [0001] The invention relates to a preparation method of antibiotics, in particular to a preparation method of dalbavancin. Background technique [0002] Dalbavancin (Dalbavancin), also known as Daucomycin, is a second-generation glycopeptide antibiotic with the following structural formula: [0003] [0004] Dalbavancin has the strongest activity among the second-generation glycopeptide antibiotics. Dalbavancin is one of the few drugs that can treat multidrug-resistant Staphylococcus aureus and Enterococcus infectious diseases, and has the properties of vancomycin and Teraconin has no anti-neisseria gonorrhoeae effect. It can be used to treat complicated skin and soft tissue infections and blood infections caused by urinary catheters, and is well tolerated. Indications for the treatment of skin and skin structure infection SSSI, approved for marketing in the United States (2014). Indications ABSSSI, acute bacterial skin and skin structure infection, was...

Claims

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Application Information

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IPC IPC(8): C07K9/00C07K1/06C07K1/02
CPCC07K9/00
Inventor 王龙书卢增杰姜桥谢伟健陈月嫦
Owner LIVZON NEW NORTH RIVER PHARMA
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