Process for manufacturing dihydropteridinones and intermediates thereof

A process for manufacturing a compound of formula (6)

• wherein
• R5 denotes C1-C6-alkyl, C1-C4-alkyl-C3-C10-cycloalkyl or C3-C10-cycloalkyl,
• comprising removing by acidic hydrolysis the protecting group PG in a compound of general formula (5)
• wherein
• R5 and PG are as hereinbefore defined, to produce the compound of formula (6).

A process for manufacturing a compound of formula (8)

• wherein
• R5 denotes C1-C6-alkyl, C1-C4-alkyl-C3-C10-cycloalkyl or C3-C10-cycloalkyl,
• R4 denotes hydrogen or a group selected from among —CN, hydroxy, C1-C6-alkyl, C1-C5-alkyloxy and C1-C6-alkylthio,
• comprising
• reacting a compound of general formula (7)
• wherein
• R4 is as hereinbefore defined, and wherein (7) is optionally converted into an acyl halide compound, with the amine compound of formula (6)
• wherein
• R5 is as hereinbefore defined,
• using an alkali or alkaline earth hydroxide as base, and a protic solvent.

A process for manufacturing a compound of formula (9)

• wherein
• R4 denotes hydrogen or a group selected from among —CN, hydroxy, C1-C6-alkyl, C1-C5-alkyloxy and C1-C6-alkylthio,
• and R5 denotes C1-C6-alkyl, C1-C4-alkyl-C3-C10-cycloalkyl or C3-C10-cycloalkyl,
• comprising
• 1) reacting a compound of formula (3)
• wherein PG is a protecting group
• with a compound of general formula (4)
• wherein
• R5 is as hereinbefore defined,
• via an enamine intermediate which is hydrogenated in the presence of a metal catalyst and a solvent or a mixture of solvents to produce
• 2) removing by acidic hydrolysis using p-toluenesulfonic acid (TsOH) the protecting group PG in a compound of general formula (5) to produce (6)
• 3) reacting a compound of general formula (7)
• wherein (7) is optionally converted into an acyl halide compound, with the amine compound of formula (6)
• using an alkali or alkaline earth hydroxide as base, and a protic solvent, to obtain
• and
• 4) the compound of general formula (8) is hydrogenated to obtain a compound of formula (9).

A process for manufacturing a compound of formula (11)

• comprising
• reacting a compound of formula (9)
• with a compound of formula (10)
• wherein A is a leaving group,
• to obtain a compound of formula (11),
• wherein R1 and R2 denote independently from each other a hydrogen or C1-C6-alkyl,
• R3 denotes hydrogen or a group selected from C1-C6-alkyl and C3-C8-cycloalkyl,
• R4 denotes hydrogen or a group selected from among —CN, hydroxy, C1-C6-alkyl, C1-C5-alkyloxy and C1-C6-alkylthio,
• R5 denotes C1-C6-alkyl, C1-C4-alkyl-C3-C8-cycloalkyl or C3-C8-cycloalkyl.

A process for manufacturing a compound of formula (11)

• wherein
• wherein R1 and R2 denote independently from each other a hydrogen or C1-C6-alkyl,
• R3 denotes hydrogen or a group selected from C1-C6-alkyl and C3-C8-cycloalkyl,
• R4 denotes hydrogen or a group selected from among —CN, hydroxy, C1-C6-alkyl, C1-C5-alkyloxy and C1-C6-alkylthio,
• R5 denotes C1-C6-alkyl, C1-C4-alkyl-C3-C8-cycloalkyl or C3-C8-cycloalkyl,
• comprising
• hydrogenating a compound of formula (8)
• to produce
• reacting a compound of formula (9)
• wherein
• with a compound of formula (10)
• wherein A is a leaving group,
• to obtain a compound of formula (11).

A process (step 4) for manufacturing a compound of formula (9)

• wherein
• R4 denotes hydrogen or a group selected from among —CN, hydroxy, C1-C6-alkyl, C1-C5-alkyloxy and C1-C6-alkylthio,
• R5 denotes C1-C6-alkyl, C1-C4-alkyl-C3-C8-cycloalkyl or C3-C8-cycloalkyl,
• comprising hydrogenating a compound of general formula (8)