CS272584B1 - Method of diethylenetriaminopentaacetic acid's and ethylenediaminotetraacetic acid's bicyclic anhydrides preparation - Google Patents

Abstract

A method of preparing bicyclic anhydrides of diethylene triaminopentaacetic acid and ethylene diaminotetraacetic acid. The invention concerns a method of preparing bicyclic anhydrides of aminopolycarboxylic acids, namely diethylene triaminopentaacetic acid and ethylene diaminotetraacetic acid. The principle is that acetanhydride acts on the given acids, which have had all metal cations removed, in an environment of a mixture of dioxane and pyridine with the catalytic action of N-dimethyl-4-aminopyridine at 70 degrees C for 8 hours.

Description

The invention relates to a process for the preparation of cyclic aminopolycarboxylic anhydrides, in particular cyclic anhydrides of strong chelatones. For the preparation of cyclic anhydrides, all chelatones containing one or more iminodiacetic groups in their molecule are suitable. -N (CH ₂ CO ₃ H) ₂ . These groups form the cyclic anhydrides of the type -N (CH ₂ CO ₂ ) ₂ Q as described below. The cyclic anhydrides thus prepared can be used for conjugation reactions and proteins, in particular with monoclonal and polyclonal antibodies. The strong chelatone-conjugated antibodies can then be labeled with metal radionuclides of advantageous physical characteristics (e.g., ¹¹¹ In, ⁹⁰ Y, ^9m Tc and the like) and used for therapy and diagnosis of in vivo severe diseases.

Hitherto, a process for the preparation of bicyclic diethylenetriaminopentaacetic anhydride by treatment with acetic anhydride in piridine or only with acetic anhydride under pyridine catalysis has been described. The reactions are run at 65 ° C for 24 hours.

The drawbacks of this process are eliminated by a process for the preparation of cyclic aminopolycarboxylic anhydrides by treatment with acetic anhydride on a starting aminopolycarboxylic acid free of all metal cations in dioxane and pyridine under the catalytic action of N-dimethyl-4-aminopyridine at 70 ° C. Thus, the reaction time is reduced to 8 h in 100% yield. Depending on the method of further use, the preparation is either isolated by filtration or left in suspension in dioxane.

Example 1

The following reactants are charged to a stirred reaction vessel at 70 ° C:

diethylenetriaminopentaacetic acid (DTPA) 39 , 3 g dioxane p.a. anhydrous 85 ml pyridine p.a. anhydrous 20 May ml acetic anhydride p.a. 25 ml N-dimethyl-4-aminopyridine 1 and

The reaction mixture is stirred vigorously for 8 h at 70 ° C, then cooled to room temperature and the resulting bicyclic diethylenetriaminopentaacetic anhydride (cDTPAAj, which is insoluble in the environment) is decanted three times with 40 ml of anhydrous dioxane. The solution was diluted with dioxane to 1000 ml and the resulting suspension had a cDTPAA concentration of 0.1 mol / l unless there was a loss of decantation by identification and concentration determination using infrared spectra and the titration method described below. groups at wavenumbers 1695 and 1732 cm \ whereas cDTPAA at 1819 and 1774 cm ^-1 .. cDTPAA also has a strong absorption band COC stretching vibration at 1108 cm ^-1.

Titration method: Measure 0.1 mmol of cDTPAA suspended in dioxane and dissolve the suspension at boiling in 15 ml of anhydrous methanol. After boiling for 5 min, the solution is cooled and diluted with 15 ml of water. Titrate with a standard NaOH solution in the presence of 0.2 mmol CA using a glass electrode. For cDTPAA under these conditions, the titration equivalent is 3, while for DTPA it is 5.

Example 2

The following reactants are charged to a stirred reaction vessel at 70 ° C:

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ethylenediaminotetraacetic acid (EDTA) 29,4 g dioxane p.a. anhydrous 85 ml pyridine p.a. anhydrous 20 ml acetic anhydride p.a. 25 ml N-dimethyl-4-aminopyridine 1 9

The preparation procedure is exactly the same as in Example 1, but bicyclic ethylenediaminotetraacetic anhydride (cEDTAA) is formed. In IR spectrometry, the initial EDTA absorption band of the valence vibrations of the carbonyl group appears at 1,695 cm @ ¹ , while the cEDTAA appears at 1,808 and 1,761 cm @ ¹ . The absorption band of COC valence vibrations is at 1,071 cm ^-1 . When performing the titration, the titration equivalent is 2 resp. 4.

Claims (1)

SUBJECT OF THE INVENTION A process for the preparation of bicyclic anhydrides of diethylenetriaminopentaootic acid and ethylenediaminotetraacetic acid by treatment with acetic anhydride of said acid-free metal cations, characterized in that the reaction is carried out in dioxane and pyridine under catalytic N-dimethyl-4-aminopyridine at 70 ° C for 8 hours .