EP0888287A1

EP0888287A1 - A process for the purification of an intermediate useful in the synthesis of iodinated contrast media

Info

Publication number: EP0888287A1
Application number: EP97953838A
Authority: EP
Inventors: Marco Villa; Maurizio Paiocchi; Fabio Benedetti
Original assignee: Bracco International BV
Current assignee: Bracco International BV
Priority date: 1996-12-24
Filing date: 1997-12-17
Publication date: 1999-01-07
Also published as: NO983872D0; ITMI962737A1; AU5759098A; IT1289521B1; NO983872L; IN184019B; WO1998028261A1; NO308698B1; ZA9711505B

Abstract

A process for the purification of the compound L-5-(2-acetoxypropionylamino)-2,4,6-triiodoisophthaloyl dichloride by treatment with a water-soluble C3-C5 alcohol solvent and water.

Description

A PROCESS FOR THE PURIFICATION OF AN INTERMEDIATE USEFUL IN THE SYNTHESIS OF lODINATED CONTRAST MEDIA

The present invention relates to a process for the purification of an intermediate useful in the synthesis of iodinated contrast media, more particularly to a process for the purification of the compound -5-(2- acetoxy-propionylamino)-2,4,6-triiodo-isophthaloyl di- chloride (hereinafter referred to as compound A).

Compound A, disclosed in British Patent n° 1,472,050 (Savac AG), is an intermediate for the synthesis of ( S )-N,N ' -bis[2-hydroxy-( 1-hydroxymethyl )- ethyl]-5-( 2-hydroxypropionylamino )-2 ,4 , 6-triiodo-iso- phthalamide, an X-ray non-ionic contrast medium, also known under the non-proprietary name iopamidol. As far as we know, the industrial synthesis of compound A still follows the synthetic scheme disclosed in British Patent n° 1,472,050, consisting in the following steps:

1. preparation of 5-amino-2 , 4, 6-triiodo-isophthalic acid by iodination of 5-amino-isophthalic acid;

2. preparation of 5-amino-2 , 4 , 6-triiodo-isophthaloyl dichloride; 3. reaction of 5-amino-2 , 4 , 6-triiodo-isophthaloyl dichloride with L-2-acetoxy-propionyl chloride to obtain L-5-( 2-acetoxy-pro ionylamino )-2 , 4 , 6-triio- doisophthaloyl dichloride (compound A). The reaction of step 3 has been described in example lb of the above cited British Patent. Such reaction is performed adding L-2-acetoxy-propionyl chloride to a solution of 5-amino-2 , 4 , 6-triiodo- isophthaloyl dichloride in N, N-dimethylacetamide at 3- 5°C. Improvements of the process described above have recently been reported in literature, which comprise the addition of catalytic amounts of acids to the reaction mixture. In particular, the addition of catalytic amounts of Lewis acids has been described in British

Patent application n° 2,271,990 in the Applicant's name, while the addition of catalytic amounts of halo acids has been described in International Patent application n. WO 96/37460 in the name of Fructamine S.p.a. The recovery of crude compound A according to what described in British Patent n. 1,472,050 is effected by partial evaporation of the solvent, treatment with water and ice and filtration of the crystalline precipitate which has however to be further purified by suspension in warm chloroform. The warm treatment with a chlorinated, highly toxic solvent is clearly industrially unsuitable from the economic and environmental point of views. In British Patent application n° 2,271,990 and in International Patent application n° WO 96/37460, the recovery and purification of compound A are carried out by dilution of the reaction mixture with an organic solvent and water, separation of the phases and evaporation of the solvent or precipitation of compound A with water. Now it has been found that the separation of the phases in the purification of compound A can be avoided by diluting with a water-soluble alcoholic C3-C5 solvent the reaction mixture containing crude compound A in N,N- dimethylaceta ide, then pouring the resulting solution into water. Pure compound A precipitates directly and can be separated by a simple filtration. Therefore it is an object of the present invention a process for the purification of compound L-5-(2- acetoxypropionylamino ) -2 , 4 , 6-triiodo-isophthaloyl dichloride obtained by reaction between L-2- acetoxypropionyl chloride and 5-amino-2 ,4 , 6- triiodoisophthaloyl dichloride in N,N-dimethylacetamide , which process comprises diluting the reaction mixture with a water-soluble C3-C5 alcohol solvent, adding the resulting solution to a suitable amount of water and recovering compound L-5-( 2-acetoxypropionylamino )-2 , 4 , 6- triiodoisophthaloyl dichloride by filtration. The resulting compound A is particularly pure, having a high enantiomeric purity, i.e. an e. e. higher than 92%. The water-soluble ^C2~^C5 alcohol solvent is selected from propanol, isopropanol, n-butanol, sec-butanol, isobutanol, tert-butanol , 2-ethoxyethanol ( cellosolve ) , 2-methoxyethanol ( ethylcellosolve ) . 2-Ethoxyethanol (cellosolve) is preferably used. The amount of water- soluble C,-Cr alcohol solvent generally ranges from 20% to 80% on the basis of the reaction mixture volume, preferably from 40% to 60%. The dilution of the reaction mixture with a water-soluble C₃-C₅ alcohol solvent is carried out at low temperatures, generally from 0°C to 20°C, preferably from 5°C to 10°C. After dilution with the water-soluble C3-C5 alcohol solvent, the resulting solution is added to a water amount 2-5 times the volume of the solution itself. The addition to water is carried out at a temperature from 10°C to 20°C, preferably from 15°C to 20°C. The resulting suspension is filtered to obtain pure compound A. The whole purification process is extremely simple and involves no separation of the phases, i.e. it makes use of water-soluble organic solvents. This is surprising and advantageous compared with the known technique and it is per se surprising in that the solvent used in the purification process of the present invention is an alcohol solvent which could react directly with compound A thus yielding side- products. On the contrary, with the process of the invention, compound A is obtained in a pure form. Moreover, this process allows to obtain compound A with a high enantio eric purity, i.e. an enantiomeric purity degree suitable for the subsequent use in the synthesis of iopamidol, to obtain iopamidol with a rotatory power fulfilling the requirements of Pharmacopoeia. The process of the invention is also suitable for the purification and the recovery of compound A from reaction mixtures containing halo acids.

A further object of the invention is a process for the preparation of iopamidol, which process comprises the preparation of compound L-5-( 2-acetoxypropio- nylamino)-2,4, 6-triiodoisophthaloyl dichloride by reaction between L-2-acetoxypropionyl chloride and 5- amino-2,4,6-triiodo-isophthaloyl dichloride in N,N- dimethylaceta ide and the purification thereof diluting the reaction mixture with a water-soluble ₃~C₅ alcohol solvent, adding the resulting solution to a suitable amount of water and filtering.

The present invention is further illustrated by the following example.

Example L-2-acetoxypropionyl chloride (2 g; 166 mmoles) is added in 15 minutes to N,N-dimethylacetamide (23 ml), keeping the temperature at 10 - 15°C. The solution is heated to 23°C and, keeping this temperature, a solution of 5-ammmino-2 , 4 , 6-triiodoisophthaloyl dichloride (50 g; 84 mmoles) in N,N-dimethylacetamide (75 ml) is added in 6 hours. When the addition is completed, the mixture is kept under stirring for 15 hours. After this time, the starting product is lower than 1%. The mixture is accurately cooled to 5°C and added with cellosolve (50 ml) in 30 minutes, keeping the temperature below 20°C. The solution is dropped into water (400 ml) under stirring, keeping temperature at 15 - 20°C, then it is stirred for 1 hour and the precipitate is filtered, washed with water (100 ml) and dried at 60°C under vacuum until constant weight, thereby obtaining 57 g of compound A. 93% HPLC titre, 89% yield, 93.6% e. e..

Claims

1. A process for the purification of compound L-5-(2- acetoxypropionylamino ) -2 , 4 , 6-triiodo-isophthaloyl dichloride by reaction between L-2-acetoxypropionyl chloride and 5-amino-2 ,4, 6-triiodoisophthaloyl dichloride in N,N-dimethylacetamide , which process comprises diluting the reaction mixture with a water-soluble ₃~C₅ alcohol solvent, adding the resulting solution to a suitable amount of water and recovering compound L-5-(2- acetoxypropionylamino ) -2 , 4 , 6-triiodoisophthaloyl dichloride by filtration.

2. A process according to claim 1 wherein the water- soluble C -C alcohol solvent is selected from propanol, isopropanol, n-butanol, sec-butanol, isobutanol, tert- butanol, 2-ethoxyethanol , 2-methoxyethanol .

3. A process according to claim 2 in which the water- soluble C -Cc alcohol solvent is 2-ethoxyethanol .

4. A process according to claim 1 wherein the amount of water-soluble C₃-C₅ alcohol solvent ranges from 20% to 80% on the basis of the reaction mixture volume.

5. A process according to claim 1 wherein the amount of water-soluble C3-C5 alcohol solvent ranges from 40% to 60% on the basis of the reaction mixture volume.

6. A process for the preparation of iopamidol, which process comprises the preparation of compound L-5-(2- acetoxypropionylamino)-2 , 4, 6-triiodoisophthaloyl dichloride by reaction between L-2-acetoxypropionyl chloride and 5-amino-2 , 4 , 6-triiodo-isophthaloyl dichloride in N,N-dimethylacetamide and the purification thereof diluting the reaction mixture with a water-soluble C -Cr alcohol solvent, adding the resulting solution to a suitable amount of water and filtering,