Method for synthesizing bifunctional chelating agent p-SCN-NODA (1,4,7-triazacyclooctane-1,4-diacetic acid-7-p-isothiocyanobenzyl)

The technology of a bifunctional chelating agent and a synthesis method, which is applied in the field of medicinal chemistry, can solve the problems of high preparation cost and poor economy, and achieve the effects of simple operation, guaranteed quality and mild reaction

Inactive Publication Date: 2014-05-14
JIANGSU INST OF NUCLEAR MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The present invention solves the problem that the preparation cost of p-SCN-NODA is relatively high when using 1,4,7-triazacyclooctane-1,4-di-tert-butyl acetate as the starting material in the prior art, The problem of poor economy, and then provide a kind of synthesis method suitable for industrialized production, low cost, easy to operate p-SCN-NODA

Method used

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  • Method for synthesizing bifunctional chelating agent p-SCN-NODA (1,4,7-triazacyclooctane-1,4-diacetic acid-7-p-isothiocyanobenzyl)
  • Method for synthesizing bifunctional chelating agent p-SCN-NODA (1,4,7-triazacyclooctane-1,4-diacetic acid-7-p-isothiocyanobenzyl)
  • Method for synthesizing bifunctional chelating agent p-SCN-NODA (1,4,7-triazacyclooctane-1,4-diacetic acid-7-p-isothiocyanobenzyl)

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Experimental program
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Effect test

Embodiment 1

[0039] The synthetic method of bifunctional chelating agent p-SCN-NODA described in the present embodiment comprises the steps:

[0040] (1) Add 1,4,7-triazacycloctane I (3.0g, 23.23mmol) and 30ml of chloroform into a round bottom flask, then dissolve tert-butyl bromoacetate (9.97g, 51.11mmol ) of the chloroform solution 60ml was slowly added dropwise to the round bottom flask (the dropping time was 1 hour); the molar ratio of the tert-butyl bromoacetate and the 1,4,7-triazacycloctane I It is 2.2:1. After stirring overnight at room temperature, the solvent was evaporated to dryness, the remaining residue was dissolved in 15ml of water, the pH value was adjusted to 3.0 with 0.1M HCl, and the by-products were removed by extraction twice with 30ml of anhydrous ether; Add 0.1M NaOH in the remaining aqueous phase to carry out alkalization, the aqueous phase after alkalization is white milky, then extract 2 times with 50ml dichloromethane, collect organic phase, dichloromethane ext...

Embodiment 2

[0046] The synthetic method of bifunctional chelating agent p-SCN-NODA described in the present embodiment comprises the steps:

[0047] (1) Add 1,4,7-triazacycloctane I (3.14g, 24.33mmol) and 32ml of chloroform into a round bottom flask, then dissolve tert-butyl bromoacetate (9.97g, 51.11mmol ) of chloroform solution 60ml was slowly added dropwise to the round bottom flask (the dropping time was 1 hour), the molar ratio of the tert-butyl bromoacetate and the 1,4,7-triazacycloctane I is 2.1:1. After stirring overnight at room temperature, the solvent was evaporated to dryness, the remaining residue was dissolved in 15ml of water, the pH value was adjusted to 3.5 with 1M HCl, and the by-products were removed by extraction twice with 30ml of anhydrous ether; Add 1M NaOH in the remaining aqueous phase and carry out alkalization, the aqueous phase after alkalization is white milky, then extract 2 times with 50ml methylene chloride, collect organic phase, dichloromethane extract i...

Embodiment 3

[0054] The synthetic method of bifunctional chelating agent p-SCN-NODA described in the present embodiment comprises the steps:

[0055] (1) Add 1,4,7-triazacycloctane I (2.87g, 22.22mmol) and 30ml of chloroform into a round bottom flask, then dissolve tert-butyl bromoacetate (9.97g, 51.11mmol ) of chloroform solution 60ml was slowly added dropwise to the round bottom flask (the dropping time was 1 hour), the molar ratio of the tert-butyl bromoacetate and the 1,4,7-triazacycloctane I It is 2.3:1. After stirring overnight at room temperature, the solvent was evaporated to dryness, the remaining residue was dissolved in 15 ml of water, the pH value was adjusted to 3.2 with 0.5 M HCl, and the by-products were removed by extraction twice with 30 ml of anhydrous ether; Add 0.5M NaOH to the remaining aqueous phase after extraction for alkalization, the aqueous phase after alkalization is white and milky, then extract twice with 50ml dichloromethane, collect the organic phase, conce...

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Abstract

The invention discloses a method for synthesizing a bifunctional chelating agent p-SCN-NODA ((1,4,7-triazacyclooctane-1,4-diacetic acid-7-p-isothiocyanobenzyl)). The method comprises the following steps: reacting 1,4,7-triazacyclooctane I (serving as a raw material) with tert-butyl bromoacetate in an organic solution, reacting an obtained product 1,4,7-triazacyclooctane-1,4-di-tert-butyl acetate II with 4-nitro-benzyl bromide to obtain a product 1,4,7-triazacyclooctane-1,4-di-tert-butyl acetate-7-p-nitrobenzyl III, performing decarboxylation protection on the product III in trifluoroacetic acid to obtain a product 1,4,7-triazacyclooctane-1,4-diacetic acid-7-p-nitrobenzyl IV, reducing in the presence of H2 to obtain an amino product 1,4,7-triazacyclooctane-1,4-diacetic acid-7-p-aminobenzyl V, and finally reacting the product V in the presence of SCCl2 to prepare the bifunctional chelating agent p-SCN-NODA. According to the method, the operation is easy, the cost is low, and the quality is stable and controllable.

Description

technical field [0001] The invention relates to a synthesis method of a bifunctional chelating agent p-SCN-NODA, which belongs to the technical field of medicinal chemistry. technical background [0002] Bifunctional chelators are an essential bridge for the connection of radionuclides and targeting carriers, and play a vital role in molecular imaging research. The so-called bifunctional chelating agent is a type of chelating agent that contains two reactive groups at the same time. Usually, the reactive group is a carboxyl group and a coordination atom on a heterocyclic ring. Groups such as amino groups or mercapto groups react to form stable covalent bonds; in addition, the coordination atoms on the heterocycle are easy to interact with metal nuclides such as 68 Ga, 64 Cu, etc. generate stable complexes. [0003] The chemical name of p-SCN-NODA is 1,4,7-triazacyclooctane-1,4-diacetate-7-p-isothiocyanatobenzyl, and its chemical structure is as follows: [0004] [00...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D255/02
CPCY02P20/55C07D255/02
Inventor 杨敏陈飞罗世能潘栋辉徐宇平赵富宽杨润琳张波王立振
Owner JIANGSU INST OF NUCLEAR MEDICINE
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