Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Patent
1989-10-10
1991-11-19
Robinson, Allen J.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
560 9, 560 16, 560 25, 560 26, 560 27, 560 30, 560 37, 560 43, 560 44, 560 45, 560 47, 562430, 562432, 562443, 562444, 562451, 562457, 562621, 564153, 564154, 564156, 564158, C07C31504
Patent
active
050668234
DESCRIPTION:
BRIEF SUMMARY
The invention relates to a new synthetic process, particularly suited for the preparation of 5-acylamino-2,4,6-triiodo or tribromo-benzoic acid derivatives of formula I ##STR1## wherein: X is I or Br, alkoxy-hydroxyalkanoyl group or a C.sub.2 -C.sub.4 unsubstituted alkanoyl group, alkoxy-hydroxyalkyl group, or a H(OCH.sub.2 CH.sub.2).sub.2-5 --, Me(OCH.sub.2 CH.sub.2).sub.2-4 -- or Et(OCH.sub.2 CH.sub.2).sub.2-4 -- group, or a group of formula ##STR2## wherein X, Y, Z and Acyl have the same meanings as in formula I and alkylene- is a straight or branched C.sub.2 -C.sub.8 alkylene group, which in turn may be substituted by hydroxy groups and/or interrupted by O, S, SO or SO.sub.2, hydroxyalkylamino group of formula ##STR3## wherein R" is H or a C.sub.1 -C.sub.5 alkyl, hydroxyalkyl, alkoxyalkyl or alkoxy-hydroxyalkyl group, 3, hydroxyalkylaminocarbonyl group of formula ##STR4## wherein R", Alkyl and n are as above defined or Z may also be a C.sub.2 -C.sub.5 acylamino, hydroxyacylamino, N-alkyl-acylamino, N-hydroxyalkylacylamino or acylaminomethyl group, substituted, said process being characterized in that corresponding 5-(alkylaminocarbonyl-alkoxy)-2,4,6-triiodo or tribromobenzoic acid derivatives of formula II, or 5-(acylamino-alkoxy)-2,4,6-triiodo or tribromo-benzoic acid derivatives of formula III, ##STR5## wherein: X and Y have the same meanings as in formula I, ##STR6## wherein R', R.sub.1 and Acyl are as hereinbelow defined, R' is H or a C.sub.1 -C.sub.6 alkyl, hydroxyalkyl, alkoxyalkyl or alkoxy-hydroxyalkyl group or a H(OCH.sub.2 CH.sub.2).sub.2-5 --, Me(OCH.sub.2 CH.sub.2).sub.2-4 -- or Et(OCH.sub.2 CH.sub.2).sub.2-4 -- group, or a group of formula ##STR7## wherein X, Y, Z' are as above defined, R.sub.1 is as hereinbelow defined, Alkylene- is a straight or branched C.sub.2 -C.sub.8 alkylene group, which in turn may be substituted by hydroxy groups and/or interrupted by O, S, SO or SO.sub.2, group, alkoxy-hydroxyalkanoyl group or an unsubstituted C.sub.2 -C.sub.4 alkanoyl group, the desired compounds of formula I.
The present invention also relates to 5-acylamino-2,4,6-triiodo or tribromo-benzoic acid derivatives which, having never being disclosed so far, were for the first time obtained by the process described in the present invention.
Rearrangment reaction of II and/or respectively III into I is only formally analogous to Smiles rearrangement reaction (Smiles Rearrangement; The MERCK Index, Tenth Edition, Organic Name Reactions, pag. ONR-84) and may be represented as follows: ##STR8## wherein: R', R.sub.1 and Acyl are as above defined and
Rearrangement takes place in presence of bases and, generally but not exclusively, at a temperature equal to or higher than room temperature, in order to increase the reaction rate. The equilibrium which takes place between compound II or III and compound I is often so shifted towards I that, by means of the process described in the present invention, yields even higher than 90% may be obtained.
Said process is of the greatest interest from the technical point of view since it makes it possible to obtain compounds of formula I, starting from easily available compounds such as the ether derivatives of 5-hydroxy-2,4,6-triiodo or tribromo-benzoic acid, said compounds of formula I being very interesting but generally more difficult to obtain in high yields, according to the known methods.
Compounds of formula I are valuable components of contrast agents in radiology.
Among these, particularly, useful are some 5-(N-acyl-amino)-2,4,6-triiodo or tribromo-bis-(hydroxyalkyl)isophthalamide derivatives, since they are non-ionic contrast agents endowed with good tolerability and high water-solubility. Ionic contrast agents used hitherto, are being replaced to a higher and higher extent by this new class of products, since it has a lot of outstanding advantages in particular as far as tolerability is concerned.
As in no way limitative examples of non-ionic contrast agents used in radiology, which may be prepared according to the process described in the present invention, t
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Felder Ernest
Fumagalli Luciano
Musu Carlo
Uggeri Fulvio
Bracco Industria Chemica S.p.A.
Robinson Allen J.
Treanor Susan P.
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