Reductive alkylation method for glycopeptide antibiotics

A technology of glycopeptide antibiotics and alkylation, which is applied in the preparation method of peptides, chemical instruments and methods, peptides, etc., can solve the problems of low yield and many secondary substitution impurities, achieve high yield and control by-products Effect

Active Publication Date: 2017-03-01
CHIA TAI TIANQING PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method uses vancomycin as a raw material, because there is only one side reaction site in vancomycin, the amino group on leucine (N 1 bits), so theoretically only N 1 Position-replacing a by-product; The inventors test found that when using A82846B as raw material, the yield was low, N 4 ,N 6 - More secondary substitution impurities

Method used

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  • Reductive alkylation method for glycopeptide antibiotics
  • Reductive alkylation method for glycopeptide antibiotics
  • Reductive alkylation method for glycopeptide antibiotics

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Add A82846B (0.446g, 0.28mmol) to 45ml of anhydrous methanol, stir at room temperature for 0.5h, add DIEA (550ul, 3.3mmol, 11.9eq), stir at room temperature for 0.5h, add copper acetate monohydrate (56mg, 0.28mmol , 1eq) continued to stir for 2h, added 4'-chloro-4-biphenylcarbaldehyde (212.3mg, 0.98mmol, 3.5eq), and continued to stir for 24h. Under the protection of nitrogen, the system was cooled to 0-10°C, trifluoroacetic acid (278.9ul, 3.64mmol, 13eq) was added, and after the reaction was stirred for 1h under temperature control, TBAB (40mg, 0.46mmol, 1.6eq) was added to the reaction in 4 times solution (0.4eq / time / hour), add and react for 1h. The reaction solution was taken for HPLC detection. After the reaction is finished, add 1mol / L sodium hydroxide solution dropwise to adjust the pH of the system to 9.0, concentrate under reduced pressure to leave about 15ml, add 15ml of acetonitrile dropwise into the system, stir and crystallize for 1 hour, filter with suction...

Embodiment 2

[0031] Add A82846B (0.43g, 0.27mmol) to 43ml of anhydrous methanol, stir at room temperature for 0.5h, add DIEA (267ul, 1.62mmol, 6eq), stir at room temperature for 0.5h, add copper acetate monohydrate (53.9mg, 0.27mmol , 1eq) continued to stir for 2h, added 4'-chloro-4-biphenylcarbaldehyde (204.75mg, 0.945mmol, 3.5eq), and continued to stir for 24h. Under the protection of nitrogen, the system was cooled to 0-10°C, trifluoroacetic acid (206.9ul, 2.7mmol, 10eq) was added, and after stirring for 1 hour under temperature control, TBAB (37.57mg, 0.432mmol, 1.6eq) was added to the In the reaction solution (0.4eq / time / hour), the reaction was completed for 1h. The reaction solution was taken for HPLC detection. After the reaction is finished, add 1mol / L sodium hydroxide solution dropwise to adjust the pH of the system to 9.0, concentrate under reduced pressure to leave about 15ml, add 15ml of acetonitrile dropwise into the system, stir and crystallize for 1 hour, filter with suctio...

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Abstract

The invention relates to a reductive alkylation method for glycopeptide antibiotics and particularly relates to the reductive alkylation method for the glycopeptide antibiotics, of which N<4> bits have amino sugar. The method comprises the step of carrying out a reaction in a solution containing the glycopeptide antibiotics and a soluble copper compound in the presence of aldehyde and tert-butyl amine borane, wherein the reductive alkylation reaction is carried out firstly at the N<4> bits of the glycopeptide antibiotics. According to the method disclosed by the invention, the reaction yield is high, the production of byproducts is effectively controlled, the amount of N<4>,N<6>-disubstituted impurities is small, and the consumption of sodium cyanoborohydride is avoided, so that the method reaches environmental protection standards and is particularly applicable to industrial production.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular, the invention relates to a reductive alkylation method of glycopeptide antibiotics. Background technique [0002] Glycopeptide antibiotics are antibiotics with complex polycyclic peptide structures produced by various microorganisms and provide antibacterial drugs effective against most Gram-positive bacteria. In recent years, a number of glycopeptide antibiotics have appeared on the market, such as vancomycin, teicoplanin, oritavancin, etc. [0003] Many modifications have been made to naturally occurring glycopeptide antibiotics, an important modification is the reductive alkylation of reactive amino groups in glycopeptides. For example, oritavancin is the N of A82846B (also known as chloroorienticin A, ChloroorienticinA). 4 The amino group is obtained by reductive alkylation of 4-(4-chlorophenyl)benzaldehyde. [0004] Oritavancin is a glycopeptide antibiotic originally deve...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K9/00C07K1/113
Inventor 桑光明李雨张爱明张喜全夏春光冯军于敏
Owner CHIA TAI TIANQING PHARMA GRP CO LTD
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