Processes for the preparation of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-2-pyrimidinyl]amino]benzonitrile

A process for the preparation of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile of formula (I), a N-oxide, a pharmaceutically acceptable acid addition salt, a quaternary amine or a stereochemically isomeric form thereof

• which comprises reacting an intermediate of formula (IV), an appropriate acid addition salt or a N-oxide thereof
• wherein W2 represents a suitable leaving group, with acrylonitrile in the presence of a suitable palladium catalyst, a suitable base and a suitable solvent,
• optionally followed by converting the free base into an acid addition salt by treatment with an acid, or alternatively, by converting the acid addition salt form into the free base by treatment with alkali;
• and optionally followed by preparing stereochemically isomeric forms, N-oxide forms or quaternary amines thereof.

A process for the preparation of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile of formula (I), a N-oxide, a pharmaceutically acceptable acid addition salt, a quaternary amine or a stereochemically isomeric form thereof

• which comprises reacting an intermediate of formula (VI), an appropriate acid addition salt or a stereochemically isomeric form thereof
• with an intermediate of formula III, an appropriate acid addition salt or a N-oxide thereof
• wherein W1 represents a suitable leaving group, in the presence of a suitable solvent, followed by dehydration of the thus obtained intermediate of formula (VII), a pharmaceutically acceptable acid addition salt, a stereochemically isomeric form or a N-oxide thereof,
• optionally followed by converting the free base into an acid addition salt by treatment with an acid, or alternatively, by converting the acid addition salt form into the free base by treatment with alkali;
• and optionally followed by preparing stereochemically isomeric forms, N-oxide forms or quaternary amines thereof.

A process for the preparation of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile of formula (I), a N-oxide, a pharmaceutically acceptable acid addition salt, a quaternary amine or a stereochemically isomeric form thereof

• which comprises reacting an intermediate of formula (IV), an appropriate acid addition salt or N-oxide thereof
• wherein W2 represents a suitable leaving group, with acrylamide in the presence of a suitable palladium catalyst, a suitable base and a suitable solvent,
• followed by dehydration of the thus obtained intermediate of formula (VII), a pharmaceutically acceptable acid addition salt, a stereochemically isomeric form or N-oxide thereof,
• optionally followed by converting the free base into an acid addition salt by treatment with an acid, or alternatively, by converting the acid addition salt form into the free base by treatment with alkali;
• and optionally followed by preparing stereochemically isomeric forms, N-oxide forms or quaternary amines thereof.

A process for the preparation of an intermediate of formula (II), an appropriate acid addition salt, a quaternary amine or a stereochemically isomeric form thereof

• which comprises reacting an intermediate of formula (V), an appropriate acid addition salt or a quaternary amine thereof
• wherein W3 represents a suitable leaving group, with acrylamide in the presence of a suitable palladium catalyst, a suitable base and a suitable solvent, followed by dehydration of the thus obtained intermediate of formula (VI), an appropriate acid addition salt, a quaternary amine or a stereochemically isomeric form thereof,
• optionally followed by converting the free base into an acid addition salt by treatment with an acid, or alternatively, by converting the acid addition salt form into the free base by treatment with alkali;
• and optionally followed by preparing stereochemically isomeric forms, N-oxide forms or quaternary amines thereof.