Preparation method of Telavancin

A technology of telavancin and intermediates, which is applied to the preparation of telavancin and the synthesis process of pharmaceutical intermediates, can solve the problems of high total amount of impurities and large number of telavancin impurities, and achieve high purity. , low cost, less impurities

Active Publication Date: 2018-12-07
LIVZON NEW NORTH RIVER PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0012] Although some effective methods for synthesizing telavancin or its pharmaceutically acceptable salts can be obtained, repeating the methods of the prior art, the number of impurities in telavancin obtained is relatively large, and the total amount of impurities is relatively high

Method used

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  • Preparation method of Telavancin
  • Preparation method of Telavancin
  • Preparation method of Telavancin

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preparation example Construction

[0036] A preparation method of telavancin, comprising the steps of:

[0037] 1) Protecting the carboxyl group of vancomycin to obtain intermediate 1;

[0038] 2) Dissolve intermediate 1 and base in organic solvent A, add compound N-decyl N-R 1 -Aminoacetaldehyde undergoes aldehyde-amine condensation, and reductive amination obtains intermediate 2;

[0039] 3) removing the carboxyl protecting group and the amino protecting group of intermediate 2 to obtain intermediate 3;

[0040] 4) Intermediate 3 and aminomethyl phosphoric acid are subjected to Mannich reaction to obtain telavancin;

[0041] Its synthetic route is as follows:

[0042]

[0043] In the formula, R is a carboxyl protecting group, R 1 For the amino protecting group.

[0044] Carboxyl protection can be carried out by esterification or substitution reaction with R-OH.

[0045] The carboxyl protecting group and the amine protecting group can be commonly used protecting groups in this field, and the protectin...

Embodiment 1

[0060] Synthesis of intermediate 4:

[0061]

[0062] 1) Dissolve 320mg vancomycin in 15mL CH 3 In OH solvent, add 0.02mL concentrated sulfuric acid dropwise, and heat up to 60°C for 3h;

[0063] 2) Add 50 mL of diethyl ether, filter with suction, and wash the solid with diethyl ether; 313 mg of powder is obtained, with a yield of 97%;

[0064] Synthesis of Telavancin:

[0065]

[0066] 3) Dissolve 307mg of intermediate compound 4 in a mixed solvent of 15mL DMF and 0.25mL DIPEA, add 121mg of N-decyl N-Fmoc-aminoacetaldehyde, stir at 20-30°C for 2h, add 150mL of ether to precipitate, filter with suction, and use for filter cake Wash and filter with ether;

[0067] 4) Dissolve the filter cake directly in 10mL DMF, slowly add 25mg NaBH in batches at 20-30°C 3 CN and 5mL CH 3 OH, 0.1mL TFA, react at 20-30°C for 2h, add 100mL ether and suction filter, wash the filter cake with 50mL ether and water successively, and dry to obtain 250mg of white solid;

[0068] 5) Dissolv...

Embodiment 2

[0070] Synthesis of Intermediate 6:

[0071]

[0072] 1) Dissolve 300mg vancomycin in 15mL (CH 3 ) 2 In CHOH solvent, add 0.02mL of concentrated sulfuric acid dropwise, and heat up to 60°C for 3h;

[0073] 2) Add 50 mL of diethyl ether, filter with suction, and wash the solid with diethyl ether; obtain 303 mg of powder with a yield of 98%;

[0074]

[0075] 3) Dissolve 250mg of intermediate compound 6 in a mixed solvent of 15mL DMF and 0.25mL DIPEA, add 106mg of N-decyl N-Fmoc-aminoacetaldehyde, stir at 20-30°C for 2h, add 150mL of ether to precipitate, filter with suction, and use for filter cake Wash and filter with ether;

[0076] 4) Dissolve the filter cake directly in 10mL DMF, slowly add 14mg NaBH in batches at 20-30°C 3 CN and 5mL CH 3 OH, 0.1mL TFA, react at 20-30°C for 2h, add 100mL ether and filter with suction, wash the filter cake with 50mL ether and water successively, and dry to obtain 246mg of white solid;

[0077] 5) Dissolve 148mg of aminomethylpho...

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Abstract

The invention discloses a preparation method of Telavancin. The preparation method comprises the steps of protecting carboxyl of vancomycin, carrying out aldehydic-amide condensation and reductive amination, removing protecting groups, and carrying out Mannich reaction with aminomethylphosphonic acid, so as to obtain Telavancin. The method has the beneficial effects that the reaction conditions are simple and safe, the cost is relatively low, industrialization is easily realized, and prepared Telavancin contains few impurities, is high in purity, easy to purify and particularly suitable for industrial production.

Description

technical field [0001] The invention relates to the field of pharmacy, in particular to a synthesis process of a pharmaceutical intermediate, in particular to a preparation method of telavancin. Background technique [0002] Telavancin Hydrogenchloride, trade name It has a specific three-dimensional structure, and its structural formula is as follows: [0003] [0004] Telavancin is a new type of glycopeptide antibiotic jointly developed by Theravance Company of the United States and Astellas Company of Japan. It is a semi-synthetic derivative of vancomycin. Its structure It is characterized in that the hydrophobic decylaminoethyl side chain is linked to the vancosamine, which increases the affinity to the bacterial cell membrane and improves the activity of sensitive bacteria and drug-resistant bacteria. It is introduced at the para position of the 7-amino acid aromatic ring Hydrophilic phosphonomethyloxymethyl groups increase water solubility and improve the pharmaco...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K9/00C07K1/06C07K1/02
CPCC07K9/008Y02P20/55
Inventor 黄丽霞李冰冰姜桥陈果李成波
Owner LIVZON NEW NORTH RIVER PHARMA
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