Process for preparing aminocrotonylamino-substituted quinazoline derivatives

A process for preparing a compound of general formula

• Ra denotes a benzyl, 1-phenylethyl or 3-chloro-4-fluorophenyl group,
• Rb denotes a methyl, ethyl, isopropyl, cyclopropyl, 2-methoxyethyl, tetrahydrofuran-3-yl, tetrahydrofuran-2-yl-methyl, tetrahydrofuran-3-yl-methyl, tetrahydropyran-4-yl or tetrahydropyran-4-yl-methyl group,
• Rc denotes a methyl, ethyl or 2-methoxyethyl group or
• Rb and Rc together with the nitrogen atom to which these groups are bound denotes a morpholino or homomorpholino group optionally substituted by one or two C1-3-alkyl groups,
• Rd denotes a cyclopropylmethyl, cyclobutyl, cyclopentyl, tetrahydrofuran-3-yl, tetrahydrofuran-2-yl-methyl, tetrahydrofuran-3-yl-methyl, tetrahydropyran-4-yl or tetrahydropyran-4-yl-methyl group, and
• R1 and R2 each independently of one another denote a C1-4-alkyl group,
• comprising the following process steps:
• a) reacting 7-chloro-6-nitro-3H-quinazolin-4-one
• with a primary amine of formula Ra—NH2 (XV), wherein Ra denotes a benzyl, 1-phenylethyl or 3-chloro-4-fluorophenyl group, in the presence of POCl3,
• b) converting the resulting compound of general formula
• into the sulphonyl derivative of formula
• wherein
• R3 denotes a C1-4-alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, or
• a phenyl group optionally substituted by one to three substituents selected from C1-3-alkyl groups, halogen atoms, particularly fluorine, chlorine or bromine atoms, cyano or nitro groups, while the substituents may be identical or different, and wherein Ra in the two formulae (X) and (XIII) has the meanings given under a),
• c) converting the sulphonyl derivative of formula (XIII) into a compound of formula
• by reacting with an alcohol of formula Rd—OH (XVI) in the presence of a base,
• wherein Ra has the meanings given under a) and Rd denotes a cyclopropylmethyl, cyclobutyl, cyclopentyl, tetrahydrofuran-3-yl, tetrahydrofuran-2-yl-methyl, tetrahydrofuran-3-yl-methyl, tetrahydropyran-4-yl or tetrahydropyran-4-yl-methyl group,
• d) reducing the compound of formulae (XI) thus obtained to the amino derivative of formula
• wherein Ra has the meanings given under a) and Rd has the meanings given under c),
• e) converting the amino derivatives of formula (XII) into the phosphonic ester of formula
• wherein Ra has the meanings given under a) and Rd has the meanings given under c), R1 and R2 each independently of one another denote a C1-4-alkyl group,
• f) reacting the resulting phosphonic ester of formula (III) with a hydrogen sulphite adduct of formula
• wherein
• M+ denotes a cation, and
• Rb denotes a methyl, ethyl, isopropyl, cyclopropyl, 2-methoxyethyl, tetrahydrofuran-3-yl, tetrahydrofuran-2-yl-methyl, tetrahydrofuran-3-yl-methyl, tetrahydropyran-4-yl or tetrahydropyran-4-yl-methyl group,
• Rc denotes a methyl, ethyl or 2-methoxyethyl group or
• Rb and Rc together with the nitrogen atom to which these groups are bound denote a morpholino or homomorpholino group optionally substituted by one or two C1-3-alkyl groups.