Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic halides
Patent
1997-05-29
1999-01-05
Killos, Paul J.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic halides
C07C 6300
Patent
active
058565701
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP95/04635 filed 24 Nov. 1995.
The present invention relates to a process for the preparation of an intermediate useful in the synthesis of organic compounds and, more particularly, it relates to a process for the preparation of 5-amino-2,4,6-triiodoisophthalic acid dichloride.
5-Amino-2,4,6-triiodoisophthalic acid dichloride is a known compound useful for the preparation of iodinated contrast agents among which Iopamidol (British patent No. 1,472,050--Savac AG) and Ioversol (European patent application No. 0083964 Mallinckrodt Inc.) can be cited.
Several examples of synthesis of 5-amino-2,4,6-triiodoisophthalic acid dichloride are reported in the literature and all of them foresee the chlorination of 5-amino-2,4,6-triiodoisophthalic acid with thionyl chloride.
In particular, we can cite the syntheses described in the already mentioned British patent No. 15 1,472,050, in the Belgian patent No. 852,418 (Mallinckrodt Inc.) and in the U.S. Pat. No. 3,655,752 (Sterling Drug Inc.) which use a strong excess of thionyl chloride and which require a long and cumbersome work up, hardly suitable under an industrial viewpoint, even if in some cases they allow to afford the desired dichloride with high yields.
The synthesis described in the European patent application No. 0118347 (Guerbet S.A.) foresees the use of excess thionyl chloride too, but in the presence of catalytic amounts of N,N-dimethylformamide. The yields are high but the work up requires the removal of excess thionyl chloride by evaporation also in this case.
The use of solvents such as ethyl acetate, as described in the International patent applications No. WO 91/09007 (Mallinckrodt Inc.) and No. WO 93/10825 (Mallinckrodt Inc.) or in the already mentioned European patent application No. 0083964, does not allow to obtain the desired dichloride with satisfactory yields.
We have now found that, by carrying out the chlorination reaction of 5-amino-2,4,6-triiodoisophthalic acid with thionyl chloride in a suitable solvent in the presence of a tertiary amine salt or quaternary ammonium salt, the corresponding dichloride is obtained not only in high yields but also substantially free from impurities and in crystalline form by simple dilution of the reaction mixture with water.
Therefore, object of the present invention is a process for the preparation of 5-amino-2,4,6-triiodoisophthalic acid dichloride by chlorination of 5-amino-2,4,6-triiodoisophthalic acid with thionyl chloride in the presence of a solvent characterized in that the reaction is carried out in the presence of a tertiary amine salt or quatemary ammonium salt in a molar ratio from 1:1 to 1:2 with respect to 5-amino-2,4,6-triiodoisophthalic acid.
The 5-amino-2,4,6-triiodoisophthalic acid dichloride obtained according to the process of the present invention is useful as intermediate in the synthesis of Iodinated contrast agents.
The amount of thionyl chloride used in the process object of the present invention is generally from 2 to 8 moles with respect to 5-amino-2,4,6-triiodoisophthalic acid.
Preferably, from 4 to 6 moles of thionyl chloride by mole of 5-amino-2,4,6-triiodoisophthalic acid are used.
Tertiary amine salts which can be used in the process object of the present invention are generally hydrohalides, preferably hydrochlorides or hydrobromides.
Quaternary ammonium salts which can be used in the process object of the present invention are generally halides, preferably chlorides or bromides.
The tertiary amines are generally trialkylamines, preferably trethylamine.
Quatemary ammonium salts are generally tetraalkvlammonium salts, preferably tetraethylammonium or tetrabutylammoniuum salts.
Examples of tertiary amine salts and of quatemary ammonium salts used in the process object of the present invention are triethylamine hydrochloride, triethylamine hydrobromide, tetrabutylammonium chloride, tetrabutylammonium bromide, tetraethylammonium bromide and tetraethylammonium chloride.
Preferably triethylamine hydrochloride, which can be optionally prepared in situ
REFERENCES:
patent: 5616795 (1997-04-01), Mauro et al.
Barreca Giuseppe
Cannata Vincenzo
Velgi Corrado
Bracco International B.V.
Killos Paul J.
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