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Reductive alkylation process on glycopeptides

A technology of alkylation and alkylation, applied in chemical instruments and methods, peptide preparation methods, organic chemistry, etc.

Inactive Publication Date: 2003-07-23
CUMBERLAND PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

One difficulty encountered in the preparation of such alkylated derivatives is the non-selective alkylation of multiple amine sites within the glycopeptide compound

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0198] According to the reductive alkylation of vancomycin according to the method of the invention (synthesis of the compound of formula II, wherein R 3 is -OH; R 5 is H; R 19 is H; R 20 is CH 3 (CH 2 ) 9 SCH 2 CH 2 -)

[0199] At 25°C, the ACN / H of vancomycin hydrochloride (3.0g, 2.1mmol) 2 The O (1:1, 30 mL) solution was treated with diisopropylethylamine (0.54 g, 0.72 mL, 4.2 mmol) followed by decylethional (0.91 g, 4.2 mmol). After 30 minutes, the reaction solution was treated with trifluoroacetic acid (1.92 g, 1.29 mL, 16.8 mmol), followed by sodium cyanoborohydride (NaCNBH 3 , 0.132g, 2.1mmol) treatment. After 5-10 minutes, acetonitrile (300 mL) was added to give the title compound as a white precipitate.

Embodiment 2

[0201] According to the reductive alkylation of vancomycin according to the method of the invention (synthesis of the compound of formula II, wherein R 3 is -OH; R 5 is H; R 19 is H; R 20 is CH 3 (CH 2 ) 9 SCH 2 CH 2 -)

[0202]To a solution of S-decylmercaptoaldehyde (crude, 48 g, 220 mmol) in N,N-dimethylformamide (1.4 L) was added solid vancomycin hydrochloride hydrate (173 g, 100 mmol) under nitrogen, then N,N-Diisopropylethylamine (58 mL, 330 mmol) was added. The suspension was stirred vigorously at room temperature for 2 hours to dissolve all the vancomycin. Then trifluoroacetic acid (53 mL, 690 mmol) was added. The solution was stirred for another 90 minutes, then solid sodium cyanoborohydride (10.5 g, 170 mmol) was added, followed by methanol (800 mL). After three hours, the reaction was analyzed by reverse phase HPLC. The product distribution based on UV absorption at 280 nm is as follows.

[0203] Elution time (min) area%

[0204] 2.0 15 Vancomycin

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Abstract

The invention provides a novel reductive alkylation method useful for selectively alkylating saccharide-amines of glycopeptide antibiotics.

Description

[0001] This application claims the benefit of U.S. Provisional Application No. 60 / 201,178, filed May 2, 2000, and U.S. Provisional Application No. 60 / 213,148, filed June 22, 2000, which are incorporated herein by reference in their entirety . Background of the invention [0002] field of invention [0003] The present invention relates to improved methods for the reductive alkylation of sugar-amines of glycopeptide antibiotics. In particular, the methods of the invention can selectively alkylate sugar-amines in glycopeptides but not other amine sites (eg, leucyl nitrogen). [0004] background [0005] Glycopeptides are a well-known class of antibiotics produced by various microorganisms (see Glycopeptide Antibiotics, Ed. R. Nagarajan, Marcel Dekker, Inc. New York (1994)). These complex polycyclic peptide compounds are effective antibacterial agents against most Gram-positive bacteria. Despite being effective antimicrobials, glycopeptide antibiotics are not used as often...

Claims

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Application Information

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IPC IPC(8): A61K9/00A61K38/00A61K47/40C07K1/113C07K9/00
CPCA61K9/0019C07K9/008A61K47/40A61K38/00A61K9/0014B82Y5/00C07K9/00
Inventor M·S·林赛尔
Owner CUMBERLAND PHARM INC
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