Vancomycin derivatives and preparation and application thereof

A technology of vancomycin and derivatives, applied in the field of vancomycin derivatives, can solve the problems of increasing the water solubility of compounds, reducing the fat solubility, and a single optical isomer.

Inactive Publication Date: 2016-10-05
ACESYS PHARMATECH LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The present invention provides a vancomycin derivative on the basis of PCT / CN2014 / 075905, which can easily obtain a single optical isomer, and effectively increase the water solubility and reduce the fat solubility of the compound, thereby solving the problem of lipid high solubility problem

Method used

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  • Vancomycin derivatives and preparation and application thereof
  • Vancomycin derivatives and preparation and application thereof
  • Vancomycin derivatives and preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0189]

[0190] 21.6 g of methallyl alcohol, 357 ml of N'N-dimethylformamide and 17 g of imidazole were added to a 1 L single-necked bottle, and after nitrogen replacement, 68.5 g of tert-butyldiphenylchlorosilane was added dropwise. After the dropwise addition was complete, stir overnight. After the reaction was detected by TLC, water and ethyl acetate were added for extraction, the organic phase was dried after liquid separation, and 56.8 g of the product was obtained after being spin-dried and passed through the column, with a yield of 60%.

[0191]

[0192] Into a 250ml three-necked flask, add 7.75g of the product from the previous step, 37g of AD-Mix-α, 25ml of tert-butanol, and 25ml of water, and stir overnight. After the reaction was detected by TLC, water and ethyl acetate were added, the organic phase was dried after liquid separation, and 7.88 g of the product was obtained after being spin-dried and passed through the column, with a yield of 90%.

[0193]

...

Embodiment 2

[0212] Compounds V101, V102, V103, V104, V121, V123, V161, V162, V163, V164, V165, V166 and other compounds can be prepared according to the method in Example 1.

Embodiment 3

[0214]

[0215] Add 1.48g of norvancomycin hydrochloride to a 250ml single-mouth bottle, dissolve it with 80ml of N'N-dimethylformamide, add 332mg of aldehyde, heat and stir at 80 degrees, add 16ml of acetic acid and 126mg of sodium cyanoborohydride, and react After the solution was stirred and reacted for 2 hours, it was cooled to room temperature, 500 ml of diethyl ether was added, filtered, and the filter cake was purified by HPLC to obtain 60.8 g of product V12, with a yield of 48%, MS m / e 1749.5, 1750.5 (M+1).

[0216]

[0217] Add 0.1g of the product from the previous step into a 50ml single-necked bottle, add 1.5ml of tetrahydrofuran, 1.5ml of water, add 24mg of lithium hydroxide monohydrate in batches, add acetic acid to quench after the reaction is completed, spin to dry the solvent, and purify by HPLC to obtain the product V12849mg , 50% yield, MS m / e 1735.5, 1736.5 (M+1).

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PUM

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Abstract

The invention discloses a series of vancomycin derivatives as shown in a formula (I). The series of compounds can be used for treating infection of gram-positive bacteria or vancomycin-resistant bacteria and can be prepared from vancomycin through a chemical synthesis method. (Please see the description for the formula (I).).

Description

technical field [0001] The invention relates to a class of vancomycin derivatives, a preparation method and an application thereof. Background technique [0002] Since the clinical use of penicillin in 1940, there have been thousands of antibiotics, and hundreds of them are commonly used clinically. In 2006, the number of anti-infective drugs among the top 500 best-selling drugs in the world has reached 77, which ranks first among the 19 categories of drugs. Due to the large-scale clinical use of antibiotics, bacteria have gradually evolved drug resistance, making more and more antibiotics gradually ineffective. [0003] Vancomycin is a glycopeptide antibiotic produced by a strain of Streptomyces orientalis. It was approved by the US FDA for clinical use in 1958. It is mainly effective against Gram-positive bacteria and has a strong bactericidal ability. It was once known as the last line of defense for humans against bacterial infections. It was not until the 1990s, afte...

Claims

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Application Information

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IPC IPC(8): C07K9/00C07K1/107A61K38/14A61P31/04
CPCA61K38/14C07K9/00
Inventor 葛敏
Owner ACESYS PHARMATECH LTD
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