Method for preparing 6-aminohexyl lactoside-NOTA conjugate

Patent metadata

Field	Value
Publication number	US-10081653-B2
Application number	US-201615214675-A
Country	US
Kind code	B2
Filing date	Jul 20, 2016
Priority date	Dec 25, 2015
Publication date	Sep 25, 2018
Grant date	Sep 25, 2018

Abstract

The present invention provides a method for preparing a 6-aminohexyl lactoside-NOTA conjugate. The preparation method comprises brominating perbenzoylated lactose with hydrobromic acid; glycosylating 6-azidohexanol to obtain 6-azidohexyl perbenzoyl lactoside; and deprotecting this precursor in two steps to obtain 6-aminohexyl lactoside and conjugating 6-aminohexyl lactoside to NCS-benzyl-NODA GA (i.e. 2,2′-(7-(1-carboxy-4-((4-isothiocyanate benzyl) amino)-4-oxobutyl)-1,4,7-triazonane-1,4-diyl) diacetic acid) in triethyl amine as an alkaline solvent, to obtain a 6-aminohexyl lactoside-NCS-benzyl-NODA GA conjugate. In this novel preparation method, no deglycosylated side product is produced, such that the yield is considerably increased to 46%. Therefore, the method is suitable for future massive production since the requirement for repeated preparations for massive production is reduced, and the impurities produced in the previously scaled-up preparation process are not present.

First claim

What is claimed is:

1. A method for preparing a 6-aminohexyl lactoside-NOTA conjugate, comprising:
brominating perbenzoylated lactose with hydrobromic acid;
glycosylating 6-azidohexanol to obtain a precursor; and
deprotecting the precursor in two steps to obtain 6-aminohexyl lactoside, and conjugating 6-aminohexyl lactoside to p-NCS-benzyl-NODA-GA in triethyl amine as an alkaline solvent, to obtain a 6-aminohexyl lactoside-p-NCS-benzyl-NODA GA conjugate.

2. The preparation method according to claim 1 , wherein the hydrobromic acid is a 33% solution of hydrobromic acid in acetic acid.

3. The preparation method according to claim 1 , wherein the perbenzoylated lactose is prepared with benzoyl chloride in the presence of pyridine while in an ice bath.

4. The preparation method according to claim 1 , wherein the brominating comprises
dissolving perbenzoylated lactose in absolute dichloromethane; and
adding hydrobromic acid slowly while in an ice bath.

5. The preparation method according to claim 1 , wherein the 6-azidohexanol is prepared by reacting 6-bromo-1-hexanol dissolved in DMF with a NaN 3 solution at 80° C.

6. The preparation method according to claim 1 , wherein the deprotecting comprises
dissolving the precursor in methanol; and
adding a catalytic amount of sodium methoxide, and removing the benzoyl group through reaction at 60° C.

7. The preparation method according to claim 1 , wherein the deprotecting comprises
dissolving the precursor in a co-solvent of methanol/water 1:1; and
adding palladium on carbon, and removing the azido group through hydrogenation.

8. The preparation method according to claim 1 , wherein the NOTA is p-NCS-benzyl-NODA-GA.

9. The preparation method according to claim 1 , wherein the conjugating comprises reacting p-NCS-benzyl-NODA-GA with 6-aminohexyl lactoside for 6 hrs in triethyl amine as an alkaline solvent.

Assignees

• Iner Aec Executive Yuan
• Iner Aec Executive Yuan

Inventors

• Chen rui-yu
• Jiang yan-feng
• Wang Mei-Hui
• Wang Jen-Tsung
• Lin Wuu-Jyh

Classifications

• C07H15/26 Primary

  Acyclic or carbocyclic radicals, substituted by hetero rings · CPC title

• C07H1/00

  Processes for the preparation of sugar derivatives · CPC title

• A61K49/0002

  General or multifunctional contrast agents, e.g. chelated agents · CPC title