Process for the preparation of 2-substituted and 2,3-disubstituted maleimides
AssigneeHoffmann-La Roche Inc.
InventorChristopher H. Hill
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AssigneeHoffmann-La Roche Inc.
InventorChristopher H. Hill
Estimating the term…
The invention relates to a process for the manufacture of substituted maleimides of the formula ##STR1## wherein R.sup.1 is alkyl, aryl or heteroaryl and R.sup.2 is hydrogen, alkyl, alkoxycarbonyl, aryl or heteroaryl, by reacting an activated glyoxylate of the formula ##STR2## wherein R.sup.1 has the above significance and X is a leaving atom or group, with an imidate of the formula ##STR3## wherein R.sup.2 has the above significance, R.sup.3 is alkyl, aryl or trialkylsilyl and Y is oxygen or sulfur, in the presence of a base and, after treating the resulting reaction product obtained in which R.sup.2 is hydrogen or alkyl with a strong base, hydrolyzing and dehydrating the resulting hydroxy-pyrrolinone of the formula ##STR4## wherein R.sup.1, R.sup.2, R.sup.3 and Y have the above significance. The substituted maleimides of formula I are pharmacologically active, for example as protein kinase C inhibitors and which a useful, for example, in the treatment and prophylaxis of inflammatory, immunological, bronchopulmonary and cardiovascular disorders, or as antiproliferative agents useful, for example, in the treatment of immune diseases and allergic disorders.
A process for the preparation of substituted maleimides of the formula ##STR11## wherein R.sup.1 is an optionally substituted bicyclic or tricyclic aromatic ring in which one or more carbon atoms have been replaced by one or more nitrogen atoms and R.sup.2 is hydrogen, alkyl of a maximum of 8 carbon atoms, an optionally substituted monocyclic or bicyclic aromatic ring, or an optionally substituted monocyclic, bicyclic, or tricyclic aromatic ring in which one or more carbon atoms have been replaced by one or more nitrogen and/or sulfur atoms which comprises reacting an activated glyoxylate of the formula ##STR12## wherein R.sup.1 is as described above and X is a halogen atom, alkoxycarbonyloxy of a maximum of 8 carbon atoms in the alkoxy group, or pentafluorophenoxy, with an imidate of the formula ##STR13## wherein R.sup.2 is as described above, R.sup.3 is alkyl of a maximum of 8 carbon atoms, an optionally substituted monocyclic, bicyclic or polycyclic aromatic ring, or trialkylsilyl wherein the alkyl group is of a maximum of 8 carbon atoms, and Y is oxygen or sulfur, in the presence of a base and, after treating a reaction product obtained in which R.sup.2 is hydrogen or alkyl of a maximum of 8 carbon atoms, with a strong base, treating the resulting hydroxy-pyrrolinone of the formula ##STR14## wherein R.sup.1, R.sup.2, R.sup.3 and Y are as described above, with a mineral acid or an organic acid or by treatment with acylating agent and a suitable base, and recovering the resulting of formula I.
Dependencies are inferred from the claim text.